Costas Et Al. 2010 Basal Ganglia Pathology in Schizophrenia - Dopamine Connections and Anomalies

NIH Public Access
Author Manuscript
J Neurochem. Author manuscript; available in PMC 2011 April 1.
Published in final edited form as:
NIH-PA Author Manuscript
J Neurochem. 2010 April ; 113(2): 287302. doi:10.1111/j.1471-4159.2010.06604.x.
BASAL GANGLIA PATHOLOGY IN SCHIZOPHRENIA: DOPAMINE

CONNECTIONS and ANOMALIES
Emma Perez-Costas, Miguel Melendez-Ferro, and Rosalinda C. Roberts*
Department of Psychiatry and Behavioral Neurobiology University of Alabama at Birmingham
Sparks Center (SC 865) 1720 7th Avenue South Birmingham, AL 35294
Abstract
Schizophrenia is a severe mental illness that affects 1% of the world population. The disease
usually manifests itself in early adulthood with hallucinations, delusions, cognitive and emotional
disturbances and disorganized thought and behavior. Dopamine was the first neurotransmitter to
be implicated in the disease, and though no longer the only suspect in schizophrenia
pathophysiology, it obviously plays an important role. The basal ganglia are the site of most of the
dopamine neurons in the brain and the target of antipsychotic drugs. In this review we will start
with an overview of basal ganglia anatomy emphasizing dopamine circuitry. Then, we will review
the major deficits in dopamine function in schizophrenia, emphasizing the role of excessive
dopamine in the basal ganglia and the link to psychosis.
Introduction
Schizophrenia is a devastating mental illness that affects 1% of the world population (APA,
1994). The disease usually manifests itself in early adulthood with hallucinations, delusions
and disorganized thought and behavior. In addition, most patients suffer from cognitive
impairments and a subset of patients with schizophrenia also present enduring negative
symptoms (for example poverty of thought and speech, loss of motivation and affect)
(Andreasen and Olsen, 1982; Liddle, 1987; Carpenter et al., 1988; Goldman-Rakic, 1999;
Kirkpatrick et al., 2001; Arango et al., 2004). There is evidence that negative symptoms
develop prior to positive symptoms, thus children who eventually develop schizophrenia
show disturbances in attention and social behavior before overt psychosis (Carpenter et al.,
1988; Davies et al., 1998; Walker et al., 1999). Several risk factors including genetic
vulnerability (Pulver, 2000; Pulver et al., 2000; DeLisi et al., 2002), environmental
influences and developmental issues (Fatemi and Folsom, 2009) have been identified for this
heterogeneous disease. Population studies, including twin and family studies indicate that
schizophrenia is highly heritable and probably due to a synergistic interaction of multiple
genes and environmental factors (Harrison and Weinberger, 2005). Neuropathological
studies have shown anomalies (often subtle) in many different brain areas including cerebral
cortex, thalamus, basal ganglia, limbic regions and the cerebellum (Harrison, 1999; Powers,
1999; Selemon and Goldman-Rakic, 1999; Lewis, 2000; Harrison and Weinberger, 2005;
Lewis and Sweet, 2009). Finally, several neurotransmitter systems are likely to be affected
in schizophrenia including dopamine (Carlsson and Lindqvist, 1963; Carlsson, 1988; Howes
and Kapur, 2009), glutamate (Kim et al., 1980; Coyle, 2006), GABA (Lewis, 2000; Lewis et
al., 2008) and serotonin (Meltzer, 1989; Remington, 2008).
Corresponding author: Rosalinda C. Roberts, PhD University of Alabama at Birmingham Sparks Center (SC 865) 1720 7th Avenue
*
South Birmingham, AL 35294 Phone: 2059969373 Fax: 2059969377 rcusidor@uab.edu.

Perez-Costas et al. Page 2
The dopamine hypothesis of schizophrenia was put forth in the mid 20th century following
the discovery of antipsychotic drugs (Delay et al., 1952), the observation that antipsychotic
drugs affected dopamine metabolism (Carlsson and Lindqvist, 1963), and that the efficacy
of antipsychotic drugs was directly linked to their ability to block the dopamine D2 receptor
(Creese et al., 1976; Seeman et al., 1976). Since then, the dopamine hypothesis has
continued to evolve from unidirectional-- too much dopamine in the basal ganglia linked to
psychosis (Seeman and Kapur, 2000)-- to now include too little dopamine in the prefrontal
cortex that is linked to cognitive deficits (Carlsson, 1988; Davis et al., 1991; Howes and
Kapur, 2009). The dopaminergic system of the basal ganglia manifests several anomalies in
schizophrenia and is also the primary site of action of typical antipsychotic drugs (Creese et
al., 1976; Seeman et al., 1976; Holcomb et al., 1996). In spite of the important role of
dopamine in this disease and that the majority of dopaminergic neurons and terminals are
housed in the basal ganglia, there are relatively few neuropathological studies published
concerning the basal ganglia (and especially the substantia nigra) and its involvement in the
neuropathology of schizophrenia. In the present review we will focus on neuroanatomical
evidence for anomalies in the basal ganglia dopamine system, and its implications for the
functioning of other brain regions. An overview of the basal ganglia anatomy and
connectivity with special emphasis in the dopaminergic system is provided for a better
conceptualization of the different anomalies observed.
Basal ganglia anatomy

The basal ganglia consist of several functionally related nuclei involved in cortical-
subcortical circuits that modulate motor, cognitive and emotional behavior. The organization
of connections to, from, and within the basal ganglia, is topographically and functionally
organized (Alexander et al., 1986, 1990; Haber et al., 2000; Haber, 2003). The basal ganglia
include the following nuclei: caudate nucleus, putamen, nucleus accumbens, globus pallidus
(GP), subthalamic nucleus (STN), and the mesencephalic nuclei of the substantia nigra (SN)
and ventral tegmental area (VTA). While there are many neuroanatomical similarities
among species, the primate basal ganglia have specific features and therefore will be the
focus of this review.
The striatum
The mammalian striatum processes functionally different circuitry in specific regions (Smith
and Parent, 1986; Alexander et al., 1990; Parent and Hazrati, 1995; Haber et al., 2000;
McFarland and Haber, 2002; Tepper et al., 2007). The dorsal striatum includes most of the
caudate and putamen, while the ventral striatum includes the most ventral part of the caudate
and putamen, the nucleus accumbens and parts of the olfactory tubercle (Haber and
McFarland, 1999). The striatum is a major gate for the entrance of glutamatergic cortical
and thalamic inputs to the basal ganglia (Alexander et al., 1986, 1990) as well as
dopaminergic inputs from the SN and VTA (Bjorklund and Dunnett, 2007) and serotonin
innervation (Lavoie and Parent, 1990). The striatum contains various neurochemically
distinct cell types, the most prevalent being the medium spiny projection neurons. In
humans, medium spiny neurons account for 75% of striatal cells, while in rodents the
percentage is higher (95%) (Graveland and DiFiglia, 1985). These neurons contain GABA
and either substance P or enkephalin in relatively equal proportions, and project largely and
almost exclusively to the SNr/GPi and GPe, respectively (Parent and Hazrati, 1995; Haber,
2003; Wilson, 2004). The remaining neurons are several types of aspiny interneurons,
including populations that are cholinergic, GABAergic, or contain NADPH diaphorase and
neuropeptide Y (Tepper and Bolam, 2004).
The caudate nucleus and putamen present a further level of heterogeneity: a

compartmentalization that has been demonstrated by the use of immunohistochemical

markers (Graybiel and Ragsdale, 1978). Graybiel and Ragsdale (1978) defined these
anatomically distinct compartments as striosomes (patches) and extrastriosomal matrix
(matrix), though the presence of these compartments is less clear in ventral striatal areas in
primates (Holt et al., 1997; Prensa et al., 1999a,b). These compartments differ from each
other in several ways including the content of neurotransmitters, peptides and receptors
(Graybiel and Ragsdale, 1978; Holt et al., 1997; Joel and Weiner, 2000), neuronal
organization (Penny et al., 1988; Walker et al., 1993), connectivity (Gerfen 1984, 1989),
developmental schedule (Graybiel and Hickey, 1982; van der Kooy and Fishell, 1987), and
behavioral function (White and Hiroi, 1998). Moreover, the patches and matrix themselves
are each inhomogeneous, with the patches having a belt and core (Holt et al., 1997; Prensa et
al., 1999a), and the matrix containing matrisomes, which are areas of focal afferents and
efferents (Graybiel et al., 1991). Most medium spiny neurons have their local axon
arborizations and dendritic trees located in the matrix or the striosomes, following strictly
compartmental boundaries (Penny et al., 1988). However, at least in primates, there are also
medium spiny neurons that do not respect these boundaries and have dendrites crossing from
one compartment to the other (Walker et al., 1993; Yung et al., 1996), allowing cross-talk
between compartments. Finally, ultrastructural analysis has shown that in the human
striatum the matrix and striosomes have marked differences in the frequency of various
types of synapses (Roberts and Knickman, 2002).
The nucleus accumbens and ventral striatum

The ventral striatum includes the nucleus accumbens, the ventral parts of the caudate
nucleus and putamen, and parts of the olfactory tubercle (Heimer, 1978; Haber and
McFarland, 1999). The nucleus accumbens is divided into a peripherally located shell
surrounding a central core, each having different cell types, connections, synaptic
organization and receptor distribution (Groenewegen et al., 1999; Brauer et al., 2000). The
core of the nucleus accumbens is similar to the caudate nucleus and putamen, while the shell
displays a more diverse neurochemical content as well as a wider variety of connections
(Brauer et al., 2000; Meredith et al., 2008). In primates and rodents, the shell and core can
be distinguished by several markers (Haber and McFarland, 1999; Brauer et al., 2000). For
example, calbindin and dopamine localization are dense in the core and sparse in the shell,
while calretinin localization is the opposite (Haber and McFarland, 1999; Brauer et al.,
2000). Cytologically, the core and the lateral shell contain medium sized spiny neurons,
which are smaller and somewhat less spiny than those found in the dorsal striatum, while the
medial shell contains small sparsely spiny neurons (Meredith et al., 2008). Like the dorsal
striatum, the nucleus accumbens receives the vast majority of synapses from the cortex
(Haber and McFarland, 1999; Groenewegen et al., 1999). Dopaminergic innervation to the
nucleus accumbens terminates heterogeneously with the densest representation in the medial
shell (Meredith et al., 2008).
The globus pallidus

The globus pallidus (GP) is composed of the external (GPe) and internal (GPi) segments as
well as a somewhat less defined rostral territory known as the ventral pallidum that lays
below the anterior commissure (Haber and McFarland, 1999). The GPe is involved in
internal communication among nuclei of the basal ganglia (Sato et al., 2000a; Kita, 2007),
while the GPi is one of the major inhibitory output areas of the basal ganglia (Nambu,
2007). The projection neurons in both segments of the GP are GABAergic, aspiny, and
comprise about 99% of pallidal neurons. In primates GPe projection neurons colocalize with
enkephalin (and project back to the striatum), or parvalbumin (and project to the GPi, SNr
and STN) (Kita, 2007). GABAergic neurons in the GPi project to several thalamic nuclei,
brainstem and spinal cord (Nambu, 2007).

The subthalamic nucleus

The human subthalamic nucleus (STN) is a topographically organized (Benarroch, 2008),
homogeneous nucleus composed of glutamatergic projection neurons (Parent and Parent,
2007) and a small percentage (7%) of GABAergic interneurons (Levesque and Parent,
2005). This nucleus is directly interconnected with most of all the other components of the
basal ganglia except the striatum (Haber and McFarland, 1999; Benarroch, 2008). It receives
excitatory inputs from the thalamus, pedunculopontine nucleus (PPN) and in primates, as
opposed to other species, only a sparse cortical connection (Frankle et al., 2006). The STN
also receives cholinergic and GABAergic projections from the PPN (Charara et al., 1996;
Benarroch, 2008) and dopamine inputs (Marani et al., 2008). In primates, the STN projects
to the SN compacta, SN reticulata, PPN, and both segments of the GP (Parent and Smith,
1987; Shink et al., 1996; Sato et al., 2000b; Benarroch, 2008).
The substantia nigra (compacta and reticulata) and ventral tegmental area
The substantia nigra can be divided into the pars compacta (SNc) and pars reticulata (SNr)
(Bjorklund and Dunnett, 2007). The SNc and the VTA contain predominantly, if not
exclusively, dopamine neurons. The SNc can be subdivided into a dorsal tier and a ventral
tier following cytoarchitectonic and chemoarchitectonic criteria (Halliday, 2004). The dorsal
tier includes the sparsely distributed cells of the most dorsal part of the SNc, the nucleus
parabrachialis pigmentosus and the VTA. The aspiny neurons are oriented with the long axis
of the cell and dendrites extending parallel to the nucleus. The ventral tier contains neurons
that have one or more dendrites extending into the SNr along with columns of dopaminergic
cells that extend in a finger-like fashion into the SNr (Carpenter and Peter, 1972; Halliday,
2004; Nieuwenhuys et al., 2008). The dopamine cells of the dorsal tier contain calbindin,
while those of the ventral tier are devoid of calbindin (Cote et al., 1991; Parent et al., 1996).
Other classical nomenclature (Dahlstrom and Fuxe, 1964) following chemoarchitectonic
criteria divides the mesencephalic dopaminergic populations in three groups (A8, A9 and
A10) which roughly corresponds to the nucleus parabrachialis pigmentosus, the SNc, and
the VTA, respectively (Bjorklund and Dunnett, 2007; Nieuwenhuys et al., 2008).
The activity of dopaminergic cells has a complex modulation. The majority of the synapses
on dopamine neurons are GABAergic (inhibitory), and originate from neurons in the
striatum and GP (Tepper and Lee, 2007). Excitatory glutamatergic and/or cholinergic
afferents originate from neurons in the PPN, STN, bed nucleus of the stria terminalis and
sparsely from prefrontal cortex (in primates) (Lavoie and Parent, 1990, 1994; Charara et al.,
1996; Frankle et al., 2006). Various experimental manipulations have shown a role of the
GP and STN in regulating somatodendritic dopamine release in the SN under normal and
experimental conditions (Cobb and Abercrombie, 2003).
The SNr is the other major inhibitory output area of the basal ganglia (Deniau et al., 2007;
Marani et al., 2008) and is comprised of aspiny GABAergic projection neurons, many of
which are colocalized with parvalbumin (Cote et al., 1991). The structure of the SNr is
perforated by dopamine cell columns and descending dendrites from neurons of the ventral
tier of the SNc. Axon collaterals from SNr neurons synapse with dopaminergic neurons in
the SNr (Tepper and Lee, 2007). The SNr is the source of the so-called ultra-short
pathway, in which dopamine released from dendrites in the SNr enhances the firing rate of
GABAergic projection neurons (Zhou et al., 2009). The excitatory action of dopamine on
the GABAergic neurons is mediated by a D1,5 receptor mechanism (Zhou et al., 2009).
Basal ganglia pathways

In the striatum, two main types of medium spiny neurons have been identified that
participate in two classically described pathways in the basal ganglia, the direct pathway

and the indirect pathway (Alexander et al., 1986, 1990; Hedreen and DeLong, 1991;
Smith et al., 1998; Tepper et al., 2007). It is important to note that they are not completely
independent and are interconnected at several levels (Yung et al., 1996; Parent et al., 2000;
Sato et al, 2000a,b).
The direct pathway involves the GABAergic medium spiny neurons that express
substance P and dopamine D1 receptors (Gerfen, 1992; Parent and Hazrati, 1995). These
neurons send projections to the GPi and the SNr and synapse on GABAergic projection
neurons in both output nuclei. Thus, in a rather simplistic scheme they inhibit the
GABAergic output of the basal ganglia and as a consequence of this, disinhibit the activity
of the thalamus (Deniau and Chevalier, 1985; Smith et al., 1998; Wilson, 2004).
The indirect pathway involves GABAergic medium spiny neurons that express enkephalin
and have dopamine D2 receptors (Gerfen, 1992; Parent and Hazrati, 1995). These neurons
contact GABAergic cells of the GPe, which project to the STN (Carpenter et al., 1981).
Glutamatergic neurons in the STN project to the GPi and the SN (Nauta and Cole, 1978;
Carpenter et al., 1981; Smith et al., 1990; Shink et al., 1996). When the medium spiny
striatal neurons are activated by glutamatergic inputs they inhibit the GPe, thus disinhibiting
the glutamatergic neurons of the STN. The enhanced excitatory signal to the GABAergic
neurons in the GPi and SNr produces inhibition of the thalamus (Alexander et al., 1986,
1990; Smith et al., 1998).
More recently a third basal ganglia pathway has been described called the hyperdirect
pathway (Nambu et al., 2002; Nambu, 2004). This pathway avoids the striatum altogether
and consists of a series of connections between motor cortex, STN, and the GPi (Aron and
Poldrack, 2006). The purpose of this pathway is to inhibit actions that have already been
initiated (Aron and Poldrack, 2006). Lesion studies in animals and imaging studies in people
suggest that disturbance of this pathway plays a role in impulsive behaviors (Aron and
Poldrack, 2006).
Dopamine in the basal ganglia

Dopamine neurons have been studied for over fifty years (Iversen and Iversen, 2007) and the
dopamine cell groups are organized by name (nigrostriatal, mesolimbic, and mesocortical)
or number (A8 to A16) (Dahlstrom and Fuxe, 1964; Bjorklund and Dunnett, 2007; Smith
and Kieval, 2000). The SNc and the VTA constitute the two major sources of dopamine
neurons in the basal ganglia. They are involved in the modulation of the neurotransmission
within the basal ganglia through their projection to the striatum (nigro-striatal pathway) and
to a lesser extent to the GP and the STN (Prensa et al., 2000). These dopaminergic cell
masses are also a main output of the basal ganglia reaching different brain areas, including
several cortical areas, the thalamus and the amygdala (Bjorklund and Dunnett, 2007). In
addition, dopamine modulation is not limited to the synapse but can diffuse to bind to
different dopaminergic receptors outside the synaptic cleft, thus modifying the activity of the
cells that possess these receptors (Garris et al., 1994; Yung et al., 1995). As well, dendritic
dopamine release occurs from dendrites that are interdigitated within the SNr and provide
excitation to the nearby GABAergic neurons (Zhou et al., 2009).
Although most of the dopaminergic neurons in the basal ganglia are located in the SN and
VTA, another source of dopamine has been identified in the striatum where dopaminergic
neurons are present in non human primates (Betarbet et al., 1997; Huot and Parent, 2007)
and human (Prensa et al., 2000; Cossette et al., 2005). These dopaminergic striatal neurons
express the dopamine transporter and most colocalize markers of GABA (Huot and Parent,
2007). The number of dopamine neurons increases upon experimental manipulation (Bedard
et al., 2006). There is evidence that these neurons can be generated de novo in the adult

brain (Bedard et al., 2006) or the dopamine phenotype may be expressed in existing neurons
(Huot and Parent, 2007). Either way, the increase in number of neurons expressing
dopamine may act as a compensatory source of dopamine when the nigrostriatal
dopaminergic system is compromised in illnesses such as Parkinson's disease (Porritt et al.,

2000).
There is a topographical organization for dopaminergic connections in which projections

from the most dorsal areas of the caudate nucleus and putamen contact the ventral cell
elements of the mesencephalic dopaminergic groups and vice versa, while the medial lateral
topography is not reversed (Lynd-Balta and Haber, 1994; Parent and Hazrati, 1995; Haber et
al., 2000). Neurons in the different tiers of the SNc have particular targets. The dorsal tier
and the medial part of the ventral tier project to the ventromedial striatum, which includes
the nucleus accumbens, parts of the olfactory tubercle and the ventral parts of the caudate
nucleus and putamen (Haber et al., 2000). The remainder of the ventral tier projects to
central associative areas of the striatum, while the dopaminergic cell columns that extend
into the SNr project to the dorsolateral sensorimotor striatal zone (Lynd-Balta and Haber,
1994; Haber et al., 2000). Even with this topographical organization, there is no complete
segregation of these fibers, and in fact, Francois et al. (1999) have shown that each
mesencephalic dopaminergic cell group contributes to the innervation of all parts of the
striatum.
Dopaminergic innervation to the striatum is heterogeneous with different cell groups

projecting to either the patches or the matrix (Gerfen et al., 1987; Langer and Graybiel,
1989). Ventral tier neurons and dopamine cell columns that invade the SNr reach
preferentially the striosomal compartments of the dorsal striatum (Gerfen et al., 1987, Lynd-
Balta and Haber, 1994; Prensa and Parent, 2001; Bentivoglio and Morelli, 2005). The dorsal
tier innervates the matrix compartment of the dorsal striatum (Gerfen et al., 1987; Lynd-
Balta and Haber, 1994; Prensa and Parent, 2001; Bentivoglio and Morelli, 2005), but in
primates does not innervate the post-commissural putamen (Haber et al., 2000). Dopamine
neurons in the VTA mainly target the ventromedial region of the nucleus accumbens shell
and core with the densest dopaminergic innervation being in the medial shell (Meredith et
al., 2008). Dopamine neurons in the dorsal tier and in the retrorubral fields project to the
patches in the nucleus accumbens (Gerfen et al. 1987). Interestingly, the pattern of
dopamine innervation to the patches and matrix varies during development (Graybiel, 1984)
with evidence for lower levels in the striosomes compared to the matrix in the adult
(Graybiel et al., 1987).
Mesencephalic dopamine neurons send projections to other areas of the basal ganglia
including the GP, particularly the GPi, and the STN (Parent and Smith, 1987; Hedreen,
1999) where synaptic contacts are made (Smith and Kieval, 2000). Two types of projections
exist, dopamine neurons that project mainly to the GP and STN with few collaterals to the
striatum, and the opposite pattern (Hedreen, 1999). Dopaminergic terminals in both the GP
and STN form symmetric axodendritic synapses (Smith and Kieval, 2000). Recently,
dopamine pathways to the thalamus have been demonstrated in human and non human
primates (Sanchez-Gonzalez et al., 2005; Melchitzky et al., 2006; Garcia-Cabezas et al.,
2007). Using immunohistochemistry, Garcia-Cabeza et al. (2007) reported dopaminergic
axons in almost all human thalamic nuclei, but the densest distribution was observed in the
midline, medial dorsal, lateral posterior, ventral anterior and ventral lateral nuclei. Using
tract tracing in monkeys, the dopamine innervation was shown to arise from several sources,
namely the hypothalamus, mesencephalon, lateral parabrachial nucleus and A11 region
(Sanchez-Gonzalez et al., 2005).

Dopaminergic synapses
Dopaminergic axons form predominantly symmetric synapses (Smith and Kieval, 2000). In
the striatum, dopamine inputs target mainly medium spiny projection neurons, but also form
synapses with various aspiny interneuron populations (Smith et al., 1994, 2004). In human
striatum, as in other species, symmetric axospinous and axodendritic synapses are made by
boutons labeled with tyrosine hydroxylase (TH), the rate limiting enzyme for the synthesis
of dopamine (Kung et al., 1998) (Figure 1). Inputs from the SN and glutamatergic afferents
from either cortex or thalamus converge on the same spines of medium spiny neurons
(Smith et al., 1994). Most thalamic inputs also end on dendritic spines and therefore could
also be modulated by dopaminergic afferents (Sadikot et al., 1992; Smith et al., 2004; Raju
et al., 2006). This suggests that a major function of dopaminergic inputs to the striatum is
the regulation of the glutamatergic pathways. However, the relationship among striatal
dopaminergic terminals, transporters and receptors suggests additional anatomical substrates
for the control of glutamate release by dopamine, or the reciprocal (Descarries et al., 1996).
For example, many direct, non-synaptic appositions occur between TH-labeled and non-
labeled boutons forming asymmetric synapses (Figure 1). The dopamine transporter is found
at both synaptic and non-synaptic sites, consistent with the possibility of dopamine release
from sites other than typical synapses (Descarries et al., 1996; Nirenberg et al., 1996). In the
other basal ganglia regions where dopaminergic axons terminate (the GP and STN),
synapses are symmetric and end on dendrites (Smith and Kieval, 2000).
Dopamine receptors
Two major types of dopamine receptors have been identified: D1-like receptors which
include D1 and D5, and D2-like receptors which include D2 [with further subtypes D2
short, D2 long and D2 longer], D3 and D4 receptors (Iversen and Iversen, 2007).
Dopaminergic receptors are present in several brain areas coinciding with the projection
areas for dopaminergic inputs. The distribution of these dopaminergic receptors is
heterogeneous in the density and type of receptor expressed (Palacios et al., 1988; Civelli et
al., 1991; Lahti et al., 1995) which is important for the modulatory action of dopamine in the
cells that possess those receptors. There is also heterogeneity in the location of these
receptors; D2 and D3 dopamine receptors are located not only postsynaptically but also
presynaptically acting as autoreceptors, while D1, D4 and D5 are only present
postsynaptically (Sesack et al., 1994). In the striatum all types of dopaminergic receptors
have been identified but a certain regionalization of the expression of some of these
receptors has been found [i.e., D2 and D4 are predominantly present in the caudate nucleus
and putamen, while D3 is present exclusively in the ventral striatum (Lahti et al., 1995)]. In
addition, the dopaminergic cells in the SN express D2 receptors that act as autoreceptors.
Other brain areas with a major presence of dopaminergic receptors include the cerebral
cortex, thalamus, hypothalamus and cerebellum (Lahti et al., 1995; De Keyser et al., 1998).
In the cerebral cortex all types of dopamine receptors have been identified, with D1-like
receptors being more abundant in the prefrontal cortex, however D2-like receptors are also
present (de Almeida et al., 2008).
Dopamine activity
Dopamine affects its targets in a very heterogeneous manner depending on the receptor
subtype activated (Smith and Villalba, 2008). Activation of the D1 receptor facilitates
depolarization and enhances the activity of striatal neurons in the direct pathway, while
activation of the D2 receptor inhibits the activity of indirect pathway neurons (Gerfen et al.,
1991; Gerfen, 2000). Dopamine inhibits striatal GABAergic interneurons, but has mixed
actions on cholinergic interneurons. Activation of the D2 receptor decreases acetylcholine
release while activation of the D1 receptor has the opposite action (Abercrombie and
DeBoer, 1997). Dopamine depolarizes STN neurons, increases their activity and modulates

the effect of GABAergic afferents (Cragg et al., 2004). In the GPe, dopamine is also
stimulatory (Smith and Villalba, 2008).
Reward and the dopamine system

The dopaminergic system in the basal ganglia plays a key role in arousal, emotion-driven
behavior and motivation (Dreher et al., 2009). In addition, the dopamine system plays a
major role in the recognition and prediction of reward, in selecting guiding behaviors to
obtain rewards (planning), as well as in reward-base reinforcement learning (Wichmann and
DeLong, 1996; Wilson, 2004; Hong and Hikosaka, 2008). Tract tracing in non-human
primates has revealed that a large region of the striatum receives inputs from reward related
cortical regions (Haber et al., 2006). Electrophysiological recordings of the activity of
midbrain dopamine neurons in non-human primates have shown that presentation of a
reward elicits a phasic increase in dopamine cell activity (Schultz, 1998, 2002). With
learning, the midbrain dopamine system becomes active in anticipation of a forthcoming
reward, rather than upon delivery of the reward itself, and becomes quiescent upon the
failure to receive an expected reward. Thus, there is a relationship between the firing
characteristics of midbrain dopamine neurons and the ability to predict rewards in advance
and whether predictions are verified or not. Functional MRI studies in humans also
implicate the dopamine system in reward (Knutson and Cooper, 2005; Rolls et al., 2009).
For example, using a probabilistic decision task, Rolls et al. (2009) found that prediction
error activated the ventral striatum and midbrain. Moreover, different processes involved in
reward activate specific basal ganglia components (Knutson et al., 2001). Specifically,
activation of the VTA reflects a positive reward prediction error, whereas the ventral
striatum encodes both positive and negative reward prediction errors (D'Ardenne et al.,
2008).
Basal ganglia pathology in schizophrenia

Schizophrenia pathology is not restricted to a specific brain region and in fact anomalies
have been reported across the rostro-caudal extent of the brain (Harrison, 1999; Powers,
1999; Selemon and Goldman-Rakic, 1999; Lewis, 2000; Harrison and Weinberger, 2005;
Lewis and Sweet, 2009). However, the study of anomalies in the basal ganglia is especially
important due to the fact that these brain nuclei are one of the major targets for the
antipsychotic drugs currently available and routinely administered to schizophrenia patients.
Unfortunately, there are many confounds which plague schizophrenia research including
heterogeneity of symptoms, side effects of medications, substance abuse, response to
treatment, suicide and the fact that there are no complete animal models for the disease.
Unlike many neurodegenerative diseases, there is no diagnostic pathology for schizophrenia
or other neuropsychiatric disorders. Finally, similar abnormal findings to the ones present in
schizophrenia are often found in a number of other diseases as well, especially bipolar
disorder.
Striatal pathology
Different pathological anomalies have been identified in the striatum in schizophrenia both
in patients treated with antipsychotic drugs and in drug-nave individuals. Grossly, the
striatum of neuroleptic nave schizophrenia subjects is smaller than normal, but upon
antipsychotic treatment with several but not all drugs, the striatum enlarges (Brandt and
Bonelli, 2008). Surface deformation mapping results have shown localized volume
decreases in both the caudate nucleus and putamen in neuroleptic free patients; such changes
were most pronounced in the associative striatum and affective flattening was correlated
with abnormalities in the anterior putamen (Mamah et al., 2007; Ballmaier et al., 2008).
Interestingly, such alterations in shape have also been found in bipolar disorder (Hwang et

al., 2006). Moreover, the siblings of schizophrenia patients showed intermediate changes
between that of controls and their ill siblings (Mamah et al., 2008). Offspring of
schizophrenia patients also have smaller caudate nuclei (Rajarethinam, et al., 2007). Taken
together, these data suggest that gross morphological changes in the caudate nucleus and/or
putamen may be a core feature of the illness or confer a risk factor.
At the cellular level, deficits in number of cells and anomalies in the expression of different
cellular markers have also been identified. For example, recent stereological analysis has
shown approximately a 10% decrease in cell number in the caudate nucleus and putamen
(Kreczmanski et al., 2007). Also the expression of many different receptors,
neurotransmitters and transporters seems to be altered (Kleinman et al., 1985; Korpi et al.,
1986; Simpson et al., 1992; Lahti et al., 1998; Holt et al., 1999; Nudmamud-Thanoi et al.,
2007). Cellular metabolism is compromised in schizophrenia including antipsychotic nave
patients, and metabolic rate, as measured by regional cerebral blood flow (rCBF), improves
in patients who respond to treatment (Buchsbaum et al., 1992; Buchsbaum and Hazlett,
1998). Consistent with metabolic abnormalities are studies showing mitochondrial defects in
subjects with schizophrenia (Kung and Roberts, 1999; Prince et al., 1999; Ben-Shachar,
2002; Ben-Shachar and Laifenfeld, 2004), including genetic, metabolic, structural, and
enzymatic alterations, many of which occur in the basal ganglia (Ben-Shachar, 2002).
However, the implications of mitochondrial pathology are broad and have been noted in a
number of diseases including neurodegenerative diseases and other psychiatric disorders
(Fattal et al., 2006; Pieczenik and Neustadt, 2007).
At the ultrastructural level most of the studies performed by our group and others have
concentrated on anomalies found at the synaptic level, with some studies also reporting
abnormalities in glial cells (Roberts et al., 1996, 2005a,b, 2008; Uranova et al.,1996, 2001,
2007). Our work has concentrated on synaptic organization, and anatomical indicators of
synaptic function. In summary, initially we found that the size of striatal dendritic spines
was smaller in schizophrenia (Roberts et al., 1996), a change that appeared to be unrelated to
medication (Kelley et al., 1997), and one that could impact on synaptic efficacy. Later we
found more synapses in the caudate nucleus in a mixed cohort of schizophrenia patients
(Roberts et al., 2005a). When examining the patch and matrix compartments, these synaptic
changes were specific to the caudate matrix and revealed in the putamen patches (Roberts et
al., 2005b). Specifically, the types of synapses that were increased in density were
morphologically similar to glutamatergic inputs from the cortex or the thalamus (Smith et
al., 1994). Our subsequent study investigated whether these changes were present in two
different subgroups of patients based on DSM-IV subtypes (Roberts et al., 2008). The
synaptic density of synapses characteristic of glutamatergic inputs was elevated equivalently
in striatal patches in chronic paranoid and chronic undifferentiated subjects versus controls.
The chronic undifferentiated subjects also had an increased density of glutamatergic-type

synapses in the striatal matrix compared to controls (Roberts et al., 2008). Moreover,
synapses characteristic of intrinsic inhibitory inputs and dopaminergic afferents, showed
differences in synaptic density between the two subgroups in the caudate matrix. These data
show discrete differences in synaptic organization between subtypes of schizophrenia, and
support an anatomical distinction between these subtypes of schizophrenia, perhaps based
on differing symptoms. The results suggest that abnormal corticostriatal and/or
corticothalamic inputs to striatal patches may be related to limbic dysfunction, which is
perturbed in both subtypes of schizophrenia subjects. The selective increase in
glutamatergic-type synapses in the matrix of the chronic undifferentiated subgroup
compared to that of the paranoid group may be related to the more severe cognitive
problems that undifferentiated patients typically suffer compared to paranoid patients. A
recent imaging study has revealed increased glutamate levels in the caudate nucleus of drug-
free and treated schizophrenia subjects, which supports our findings of increased

glutamatergic synapses in various subtypes of subjects with schizophrenia (de la Fuente-

Sandoval et al., 2009).
Substantia nigra pathology

Postmortem and imaging studies of the human SN in schizophrenia subjects indicate the
existence of pathology in the dopaminergic system (Averback, 1981; Bogerts et al., 1983;
Owen et al., 1984; Toru et al., 1988; Kolomeets and Uranova, 1999; Mueller et al., 2004;
Kessler et al., 2009). The few neuropathological studies of the SN in schizophrenia
performed to date have been in small sample sets, and anomalies were regionally specific.
Some studies have reported that neurons in the SN have a pale appearance (Nagaska, 1925),
show signs of degeneration (Averback, 1981), have reduced volume (Bogerts et al., 1983),
and show altered patterns of neurophysin labeling (Mai et al., 1993). At the electron
microscopic level, smaller axon terminals, hyperplasia of mitochondria, and abnormal
lamellar structures have been reported (Uranova and Levite, 1987; Kolomeets and Uranova,
1997, 1999) which could indicate possible anomalies in neurotransmission and metabolism
in the SN.
Dopamine anomalies in the basal ganglia and connected structures in

schizophrenia
Dysregulation of the dopamine system plays a critical role in psychosis, diminished

cognition, abnormal reward function, and movement disorders, all of which are manifested
in schizophrenia. However, defects in dopamine transmission are also implicated in other
psychiatric illnesses including major depression (Dunop and Nemeroff, 2007), bipolar
disorder (Cousins et al., 2009), and addiction (Wanat et al., 2009).
In the striatum, anomalies of dopamine synthesis, storage and release have been reported in
antipsychotic nave patients with most of these studies pointing towards an overactive
striatal dopaminergic system. The striatum of schizophrenia patients displays augmentation
of presynaptic dopamine function, indicating an increase in dopamine synthesis capacity
and/or an increase in presynaptic dopamine stores (Hietala et al., 1995, 1999; Breier et al.,
1997; Abi-Dargham et al., 1998). Neuroleptic nave schizophrenia subjects show increases
in striatal presynaptic dopamine synthesis (Hietala et al., 1995, 1999), and elevations in
striatal D2 receptors (Wong et al., 1986, 1990). Enhanced striatal dopamine levels, synthesis
and release are also present in drug nave or drug free schizophrenia subjects (Abi-Dargham
et al., 2009; Lyon et al., 2009; Nozaki et al., 2009). In first degree relatives of schizophrenia
subjects, striatal dopamine synthesis is higher (Huttunen et al., 2007) and abnormalities in
D2 receptors are present (Lee et al., 2008). Moreover, elevated striatal dopamine function is
correlated with prodromal psychotic symptoms in schizophrenia (Howes et al., 2009). Taken
together, increases in striatal dopamine appear to be a core feature of the illness, predate the
psychotic break, and may be a risk factor for the disease.
In the substantia nigra high variability of tyrosine hydroxylase (TH) levels, as well as
increases on homovanillic acid, and glutamate receptor subunits have been reported (Owen
et al., 1984; Toru et al., 1988; Mueller et al., 2004). Toru et al (1988) have reported overall
increases in TH in the striatum and in the substantia nigra in schizophrenia compared to
controls, with some subjects showing normal levels while a small subset showed much
higher levels (shown only for the striatum in this report). Other recent reports also have
shown a higher variability of TH protein expression in the substantia nigra of schizophrenia
compared to controls (Perez-Costas et al, 2007; Perez-Costas et al, 2009). The dysregulation
in TH synthesis and dopamine release, as well as increased D2 receptors in the substantia
nigra, which are mainly inhibitory autoreceptors, point to anomalies in the dopaminergic

neurotransmission in schizophrenia (Kessler et al., 2009) and also correlate with the
presence of anomalies of dopaminergic transmission in the striatum that were previously
addressed in this review.
Other areas of the brain that receive dopamine innervation are also affected in schizophrenia
including the thalamus and the cortex (Joyce and Meador-Woodruff, 1997; Cohen et al.,
1998; Winterer and Weinberger, 2004; Takahashi et al., 2006).
In the thalamus the reported anomalies include a full array of pathologies affecting the
availability of dopamine, recycling of dopamine through the dopamine transporter and levels
of dopamine receptors (Clinton and Meador-Woodruff, 2004; Byne et al., 2009). Subjects
with schizophrenia present increased dopamine concentrations (Oke and Adams, 1987) as
well as increases in binding of the dopamine transporter (Arakawa et al., 2009). The D2 and
D2/3 receptor levels and availability are decreased in drug nave patients (Buchsbaum et al.,
2006; Takahashi et al., 2006; Kessler et al., 2009), indicating that these changes are not
related to medication. Dopamine abnormalities are also present at the level of intracellular
integration of dopamine signaling with other neurotransmitter systems (Clinton et al., 2005).
In the cortex postmortem studies have shown that the proportion of the different subtypes of
D2 receptors is similar between patients and controls but the expression is altered in several
regions (Wong et al., 1986; Seeman and Kapur, 2000; Abi-Dargham et al., 2000; Tallerico et
al., 2001; Roberts et al., 1994). There are reports of decreased D2 receptor levels in the
anterior cingulate and temporal cortex of drug-nave patients (Suhara et al., 2002;
Tuppurainen et al., 2003), increased levels in the orbital and temporal gyri and in the
prefrontal cortex (Roberts et al., 1994; Tallerico et al., 2001), and alterations in the laminar
distribution (Goldsmith et al., 1997). Quantitative analysis of TH labeling in postmortem
schizophrenia brain has revealed anomalies that are also cortical region and layer specific
(Akil et al., 1999, 2000). These anatomical changes include decreases in the density of TH
and in the length of dopaminergic axons, observations that appear to be disease specific and
independent of medication (Akil et al., 1999, 2000). PET studies comparing healthy pairs of
twins (mono and dizygotic) with pairs of twins discordant for schizophrenia have shown that
in all cases both the twins suffering from schizophrenia and their healthy co-twins presented
higher levels of D1 receptors in the prefrontal cortex (Hirvonen et al., 2006). This points out
that the anomaly observed is not an exclusive feature of the disease but it is related with a
higher risk of suffering schizophrenia. In their PET study, Hirvonen et al. (2006) also
showed that chronic treatment with antipsychotics produces a widespread downregulation of
D1 receptor expression not only in the cortex. Decreased dopamine function in prefrontal
cortex has been hypothesized to be related to the cognitive dysfunctions observed in
schizophrenia (Goldman-Rakic, 1999).
Dopamine levels and treatment response/resistance

Not all patients respond to treatment and in those who do, only psychotic symptoms are
usually improved (Kane et al., 1988). Treatment response is defined along a gradient with
only 5%-10% of patients experiencing a full recovery. Approximately 60% of patients
experience a partial response to treatment but the remainder patients are treatment resistant,
despite several antipsychotic trials of adequate dose and length (Laruelle et al., 1999; Conley
and Kelly, 2000, 2001; Kane et al., 1988).
Numerous neuroimaging studies have shown a relationship between pathophysiology and

the degree of treatment response in schizophrenia (Stern et al., 1993; Bilder et al., 1994;
Beerpoot et al., 1996; Sheitman and Lieberman, 1998; Staal et al., 2001; Arango et al., 2003;
Altamura et al., 2005; Mitelman et al., 2005). Lower pretreatment metabolic rate in the
striatum is predictive of good treatment outcome, and good responders showed greater

striatal response compared to poor responders (Buchsbaum et al., 1992). Enhanced

dopamine release upon amphetamine stimulation has been reported in treatment responsive
subjects versus controls and treatment resistant subjects (Abi-Dargham et al., 2000). In other
words, schizophrenia subjects with high striatal dopamine release are far more responsive to
antipsychotic drugs than those patients who have dopamine levels lower than or comparable
to that of normal controls (Abi-Dargham et al., 2000). There could be several explanations
for these data, including but not limited to: differential affinity for dopamine receptors,
different postsynaptic mechanisms, and/or different amounts of dopamine. Differential
blockade of D2 receptors does not appear to be responsible since treatment resistant patients
have 95% D2 receptor occupancy (Coppens et al., 1991). We examined dopamine
innervation in the caudate nucleus in an ultrastructural study of schizophrenia subjects
divided by treatment response (Roberts et al., 2009). The density of all dopaminergic
synapses in treatment responders was significantly greater than in controls and in treatment
resistant cases. The larger number of dopaminergic synapses in treatment responsive
subjects (Roberts et al., 2009) is consistent with in vivo studies that have measured
dopamine content in live patients and suggest that one anatomical underpinning of good
treatment response may be more striatal terminals synthesizing dopamine.
Dopamine and reward

Abnormal activation of the reward system may play a role in various psychiatric disorders
including schizophrenia. Allelic variation in dopamine genes is linked to response in reward
tasks (Dreher et al., 2009). Murray et al. (2008) showed that psychotic patients have
abnormal responses associated with reward prediction errors in the midbrain, striatum and
limbic system. Unmedicated patients show reduced ventral striatal activation during the
presentation of reward-predicting cues and treatment with atypical antipsychotics tends to
normalize this response (Juckel et al., 2006). Compared to controls, patients fail to recruit
parts of the reward-related circuit (Paradiso et al., 2003; Taylor et al., 2002, 2005) and show
inappropriately strong activation in the ventral striatum in response to a neutral stimulus
(Jensen et al., 2008). In contrast to controls, medicated subjects show attenuated neuronal
responses to positive prediction errors, while responses to negative prediction errors are
largely intact (Waltz et al., 2009). In response to the omission of expected reward, patients
show exaggerated medial prefrontal cortex response and reduced ventral striatum activation
in response to the successful avoidance of monetary loss (Schlagenhauf et al., 2009).
Summary comments
Despite the obvious importance of dopamine in schizophrenia and that the majority of
dopaminergic neurons are housed in the basal ganglia, pathology studies in these nuclei in
schizophrenia have been infrequent and several findings anecdotal. Nevertheless, the
cumulative evidence suggests multiple problems in the basal ganglia in schizophrenia,

including anomalies at several anatomical levels including synaptic changes implicating an
excess amount of inputs from cortex and thalamus. Dopamine has differential effects on
various neuronal populations depending on which receptor subtype is activated and can also
act via extra synaptic mechanisms. Dopamine is involved in many of the functions that are
abnormal in schizophrenia, including psychosis, cognitive decline, and reward mechanisms.
Most recent studies indicate that dopamine dysregulation in the basal ganglia: 1) is intrinsic
to the pathology of schizophrenia rather than being a medication side effect, 2) predates
psychosis, and 3) is a risk factor for the illness. Future studies should attempt to parse out
the pathologies that are specific to schizophrenia, as well as investigating the link between
dopamine pathology, symptoms, genetics and other features which may be a continuum with
other neuropsychiatric disorders that share some features with schizophrenia such as bipolar
disorder and/or major depression.

Acknowledgments
Supported by NIMH grants RO1 MH66123 and RO1 MH60744 to RCR.
The authors declare not having conflicts of interest.
References
Abercrombie ED, DeBoer P. Substantia nigra D1 receptors and stimulation of striatal cholinergic
interneurons by dopamine: a proposed circuit mechanism. J. Neurosci. 1997; 17:84988505.
[PubMed: 9334422]
Abi-Dargham A, Gil R, Krystal J, Baldwin R, Seibyl J, Bowers M, van Dyck CH, Charney DS, Innis
RB, Laruelle M. Increased striatal dopamine transmission in schizophrenia: Confirmation in a
second cohort. Am. J. Psychiatry. 1998; 155:761767. [PubMed: 9619147]
Abi-Dargham A, Rodenhiser J, Printz D, et al. Increased baseline occupancy of D2 receptors by
dopamine in schizophrenia. Proc. Natl. Acad. Sci. U.SA. 2000; 97:81048109.
Abi-Dargham A, van de Giessen E, Slifstein M, Kegeles LS, Laruelle M. Baseline and amphetamine-
stimulated dopamine activity are related in drug-nave schizophrenic subjects. Biol. Psychiatry.
2009; 65:10911093. [PubMed: 19167701]
Akil M, Edgar CL, Pierri JN, Casali S, Lewis DA. Decreased density of tyrosine hydroxylase
immunoreactive axons in the entorhinal cortex of schizophrenic subjects. Biol. Psychiatry. 2000;
47:361370. [PubMed: 10704948]
Akil M, Pierri JN, Whitehead RE, Edgar CL, Mohila C, Sampson AR, Lewis DA. Lamina-specific
alterations in the dopamine innervations of the prefrontal cortex in schizophrenic subjects. Am. J.
Psychiatry. 1999; 156:15801589. [PubMed: 10518170]
Alexander GE, Crutcher MD, DeLong MR. Basal ganglia-thalamocortical circuits: parallel substrates
for motor, oculomotor, prefrontal and limbic functions. Prog. Brain Res. 1990; 85:119146.
[PubMed: 2094891]
Alexander GE, DeLong MR, Strick PL. Parallel organization of functionally segregated circuits
linking basal ganglia and cortex. Ann. Rev. Neurosci. 1986; 9:357381. [PubMed: 3085570]
Altamura AC, Bassetti R, Cattaneo E, Vismara S. Some biological correlates of drug resistance in
schizophrenia: a multidimensional approach. World J. Biol. Psychiatry. 2005; 6(Suppl 2):2330.
[PubMed: 16166020]
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed..
American Psychiatric Association; Washington, DC: 1994.
Andreasen NC, Olsen S. Negative vs. positive schizophrenia. Definition and validation. Arch. Gen.
Arakawa R, Ichimiya T, Ito H, et al. Increase in thalamic binding of [(11)C]PE2l in patients with
schizophrenia: A positron emission tomography study of dopamine transporter. J. Psychiatry. Res.
2009; 43:12191223.
Arango C, Breier A, McMahon R, Carpenter WT Jr. Buchanan RW. The relationship of clozapine and
haloperidol treatment response to prefrontal, hippocampal, and caudate brain volumes. Am. J.
Arango C, Buchanan RW, Kirkpatrick B, Carpenter WT. The deficit syndrome in schizophrenia:
implications for the treatment of negative symptoms. Eur. Psychiatry. 2004; 19:2126. [PubMed:
14969777]
Aron AR, Poldrack RA. Cortical and subcortical contributions to Stop signal response inhibition: a
role of the subthalamic nucleus. J. Neurosci. 2006; 26:24242433. [PubMed: 16510720]
Averback P. Lesions of the nucleus ansae peduncularis in neuropsychiatric disease. Arch. Neurol.
1981; 38:230235. [PubMed: 6452111]
Ballmaier M, Schlagenhauf F, Toga AW, Gallinat J, Koslowski M, Zoli M, Hojatkashani C, Narr KL,
Heinz A. Regional patterns and clinical correlates of basal ganglia morphology in non-medicated
schizophrenia. Schizophr. Res. 2008; 106:140147. [PubMed: 18818054]

Bedard A, Gravel C, Parent A. Chemical characterization of newly generated neurons in the striatum
of adult primates. Exp. Brain Res. 2006; 170:501512. [PubMed: 16328260]
Beerpoot LJ, Lipska BK, Weinberger DR. Neurobiology of treatment-resistant schizophrenia: new
insights and new models. Eur. Neuropsychopharmacol. 1996; 6(Suppl. 2):S2734. [PubMed:
8792118]
Benarroch EE. Subthalamic nucleus and its connections: Anatomic substrate for the network effects of
deep brain stimulation. Neurolog. 2008; 70:19911995.
Ben-Shachar D. Mitochondrial dysfunction in schizophrenia: a possible linkage to dopamine. J.
Neurochem. 2002; 83:124151. [PubMed: 12472879]
Ben-Shachar, D.; Laifenfeld, D. International Review of Neurobiology. Academic Press; 2004.
Mitochondria, synaptic plasticity, and schizophrenia.; p. 273-296.
Bentivoglio, M.; Morelli, M. The organization and circuits of mesencephalic dopaminergic neurons
and the distribution of dopamine receptors in the brain.. In: Dunnett, SB.; Bentivoglio, M.;
Bjorklund, A.; Hokfelt, T., editors. Handbook of Chemical Neuronatomy. Elsevier; 2005. p. 1-107.
Betarbet R, Turner R, Chockkan V, DeLong MR, Allers KA, Walters J, Levey AI, Greenamyre JT.
Dopaminergic neurons intrinsic to the primate striatum. J. Neurosci. 1997; 17:67616768.
[PubMed: 9254687]
Bilder RM, Wu H, Chakos MH, Bogerts B, Pollack S, Aronowitz J, Ashtari M, Degreef G, Kane JM,
Lieberman JA. Cerebral morphometry and clozapine treatment in schizophrenia. J. Clin.
Bjorklund A, Dunnett SB. Dopamine neuron systems in the brain: an update. Trends Neurosci. 2007;
30:194202. [PubMed: 17408759]

Bogerts B, Hantsch J, Herzer M. A morphometric study of the dopamine-containing cell groups in the
mesencephalon of normals, parkinson patients, and schizophrenics. Biol. Psych. 1983; 18:951
969.
Brandt GN, Bonelli RM. Structural Neuroimaging of the basal ganglia in schizophrenic patients: a
review. Wien. Med. Wochenschr. 2008; 158:8490. [PubMed: 18330524]
Brauer K, Husser M, Hrtig W, Arendt T. The core-shell dichotomy of nucleus accumbens in the
rhesus monkey as revealed by double-immunofluorescence and morphology of cholinergic
interneurons. Brain Res. 2000; 858:151162. [PubMed: 10700608]
Breier A, Su TP, Saunders R, et al. Schizophrenia is associated with elevated amphetamine-induced
synaptic dopamine concentrations: evidence from a novel positron emission tomography method.
Proc. Natl. Acad. Sci. U.S.A. 1997; 94:25692574. [PubMed: 9122236]
Buchsbaum MS, Christian BT, Lehrer DS, Narayanan TK, Shi B, Mantil J, Kemether E, Oakes TR,
Mukherjee J. D2/D3 dopamine receptor binding with [F-18] fallypride in thalamus and cortex of
patients with schizophrenia. Schizophr. Res. 2006; 85:232244. [PubMed: 16713185]
Buchsbaum MS, Hazlett EA. Positron emission tomography studies of abnormal glucose metabolism
in schizophrenia. Schizophr. Bull. 1998; 24:343364. [PubMed: 9718628]
Buchsbaum MS, Potkin SG, Siegel BV Jr. Lohr J, Katz M, Gottschalk LA, Gulasekaram B, Marshall
JF, Lottenberg S, Teng CY. Striatal metabolic rate and clinical response to neuroleptics in
schizophrenia. Arch. Gen. Psychiatry. 1992; 49:966974. [PubMed: 1449383]
Byne W, Hazlett EA, Buchsbaum MS, Kemether E. The thalamus and schizophrenia: current status.
Acta. Neuropathol. 2009; 117:347368. [PubMed: 18604544]
Carlsson A. The current status of the dopamine hypothesis of schizophrenia.
Neuropsychopharmacology. 1988; 1:179186. [PubMed: 3075131]
Carlsson A, Lindqvist M. Effect of Chlorpromazine or Haloperidol on Formation of
3methoxytyramine and Normetanephrine in Mouse Brain. Acta. Pharmacol. Toxicol. (Copenh).
1963; 20:140144. [PubMed: 14060771]
Carpenter MB, Baton RR 3rd, Carleton SC, Keller JT. Interconnections and organization of pallidal
and subthalamic nucleus neurons in the monkey. J. Comp. Neurol. 1981; 197:579603. [PubMed:
7229129]
Carpenter WT Jr. Heinrichs DW, Wagman AM. Deficit and nondeficit forms of schizophrenia: the
concept. Am. J. Psych. 1988; 145:587583.

Carpenter MB, Peter P. Nigrostriatal and nigrothalamic fibers in the rhesus monkey. J. Comp. Neurol.
1972; 144:93115. [PubMed: 4623850]
Charara A, Smith Y, Parent A. Glutamatergic inputs from the pedunculopontine nucleus to midbrain
dopaminergic neurons in primates: Phaseolus vulgaris-leucoagglutinin anterograde labeling

combined with postembedding glutamate and GABA immunohistochemistry. J. Comp. Neurol.
1996; 364:254266. [PubMed: 8788248]
Civelli O, Bunzow JR, Grandy DK, Zhou QY, Van Tol HH. Molecular biology of the dopamine
receptors. Eur. J. Pharmacol. 1991; 207:277286. [PubMed: 1783000]
Clinton SM, Ibrahim HM, Frey KA, Davis KL, Haroutunian V, Meador-Woodruff JH. Dopaminergic
abnormalities in select thalamic nuclei in schizophrenia: involvement of the intracellular signal
integrating proteins calcyon and spinophillin. Am. J. Psychiatry. 2005; 162:18591871. [PubMed:
16199832]
Clinton SM, Meador-Woodruff JH. Thalamic dysfunction in schizophrenia: neurochemical,
neuropathololical, and in vivo imaging abnormalities. Schizophr. Res. 2004; 69:237253.
[PubMed: 15469196]
Cobb WS, Abercrombie ED. Relative involvement of globus pallidus and subthalamic nucleus in the
regulation of somatodendritic dopamine release in substantia nigra is dopamine-dependent.
Neuroscience. 2003; 119:777786. [PubMed: 12809698]
Conley, RR.; Kelly, DL. Pharmacologic treatment of schizophrenia. 1st edition2000. Professional
Communications
Conley RR, Kelly DL. Management of treatment resistance in schizophrenia. Biol. Psychiatry. 2001;
50:898911. [PubMed: 11743944]
Coppens HJ, Slooff CJ, Paans AM, Wiegman T, Vaalburg W, Korf J. High central D2-dopamine
receptor occupancy as assessed with positron emission tomography in medicated but therapy-
resistant schizophrenic patients. Biol. Psychiatry. 1991; 29:629634. [PubMed: 1675892]
Cossette M, Lecomte F, Parent A. Morphology and distribution of dopaminergic neurons intrinsic to
the human striatum. J. Chem. Neuroanat. 2005; 29:111. [PubMed: 15589697]
Cote PY, Sadikot AF, Parent A. Complementary distribution of calbindin D-28K and parvalbumin in
the basal forebrain and midbrain of the squirrel monkey. Eur. J. Neurosci. 1991; 12:13161329.
[PubMed: 12106229]
Cousins DA, Butts K, Young AH. The role of dopamine in bipolar disorder. Bipolar Disorde. 2009;
11:787806.
Coyle JT. Glutamate and schizophrenic: beyond the dopamine hypothesis. Cell Mol. Neurobio. 2006;
26:365384. (2006).
Cragg SJ, Baufreton J, Xue Y, Bolam JP, Bevan MD. Synaptic release of dopamine in the subthalamic
nucleus. Eur. J. Neurosci. 2004; 20:17881802. [PubMed: 15380000]
Creese I, Burt DR, Snyder SH. Dopamine receptor binding predicts clinical and pharmacological
potencies of antischizophrenic drugs. Science. 1976; 192:481483. [PubMed: 3854]
Dahlstrom A, Fuxe K. Evidence for the existence of monoamine-containing neurons in the central
system. I. Demonstration of monoamines in the cell bodies of brain stem neurons. Acta. Physiol.
Scand. 1964; 232:155.
Davis KL, Kahn RS, Ko G, Davidson M. Dopamine in schizophrenia: a review and
reconceptualization. Am. J. Psychiatry. 1991; 148:14741486. [PubMed: 1681750]
Davies N, Russell A, Jones P, Murray RM. Which characteristics of schizophrenia predate psychosis?
J. Psychiatr. Res. 1998; 32:121131. [PubMed: 9793865]
De Almeida J, Palacios JM, Mengod G. Distribution of 5-HT and DA receptors in primate prefrontal
cortex: implications for pathophysiology and treatement. Prog. Brain Res. 2008; 172:10115.
[PubMed: 18772029]
De Keyser J, Claeys A, De Backer JP, Ebinger G, Roels F, Vauquelin G. Autoradiographic
localization of D1 and D2 dopamine receptors in the human brain. Neurosci. Lett. 1988; 91:142
147. [PubMed: 2972942]
De la Fuente-Sandoval C, Favila R, Alvarado P, Len-Ortiz P, Daz-Galvis L, Amezcua C, Garca-
Muoz E, Graff-Guerrero A. Glutamate increase in the associative striatum in schizophrenia: a

longitudinal magnetic resonance spectroscopy preliminary study. Gac. Med. Mex. 2009; 145:109
13. [PubMed: 19518017]
Delay J, Deniker P, Harl JM. Therapeutic use in psychiatry of phenothiazine of central elective action
(4560 RP). Ann. Med. Psychol. (Paris). 1952; 110:112117. [PubMed: 12986408]
DeLisi LE, Shaw SH, Crow TJ, et al. A genome-wide scan for linkage to chromosomal regions in 382
sibling pairs with schizophrenia or schizoaffective disorder. Am. J. Psychiatry. 2002; 159:803
812. [PubMed: 11986135]
Deniau JM, Chevalier G. Disinhibition as a basic process in the expression of striatal functions. II. The
striato-nigral influence on thalamocortical cells of the ventromedial thalamic nucleus. Brain Res.
1985; 334:227233. [PubMed: 3995318]
Deniau JM, Mailly P, Maurice N, Charpier S. The pars reticulata of the substantia nigra: a window to
basal ganglia output. Prog. Brain Res. 2007; 160:151172. [PubMed: 17499113]
Descarries L, Watkins KC, Garcia S, Bosler O, Doucet G. Dual character, asynaptic and synaptic, of
the dopamine innervation in adult rat neostriatum: A quantitative autoradiographic and
immunocytochemical analysis. J. Comp. Neurol. 1996; 375:167186. [PubMed: 8915824]
Dreher J-C, Kohon P, Kolachana B, Weinberger DR, Berman KF. Variation in dopamine genes
influences responsivity of the human reward system. Proc. Natl. Acad. Sci. U.S.A. 2009; 106:617
622. [PubMed: 19104049]
Dunlop BW, Nemeroff CB. The role of dopamine in the pathophysiology of depression. Arch. of Gen.
Psych. 2007; 64:32337.
Fatemi SH, Folsom TD. The neurodevelopmental hypothesis of schizophrenia, revisited. Schizophr.
Bull. 2009; 35:528548. [PubMed: 19223657]

Fattal O, Budur K, Vaughan AJ, Franco K. Review of the literature on major mental disorders in adult
patients with mitochondrial diseases. Psychosomatics. 2006; 47:17. [PubMed: 16384802]
Francois C, Yelnik J, Tande D, Agid Y, Hirsch EC. Dopaminergic cell group A8 in the monkey:
anatomical organization and projections to the striatum. J. Comp. Neurol. 1999; 414:334347.
[PubMed: 10516600]
Frankle WG, Laruelle M, Haber SN. Prefrontal cortical projections to the midbrain in primates:
evidence for a sparse connection. Neuropsychopharmacology. 2006; 31:16271636. [PubMed:
16395309]
Garcia-Cabezas MA, Rico B, Sanchez-Gonzalez MA, Cavada C. Distribution of the dopamine
innervation in the macaque and human thalamus. Neuroimage. 2007; 34:965984. [PubMed:
17140815]
Garris PA, Ciolkowski EL, Pastore P, Wightman RM. Efflux of dopamine from the synaptic cleft in
the nucleus accumbens of the rat brain. J. Neurosci. 1994; 14:60846093. [PubMed: 7931564]
Gerfen CR. The neostriatal mosaic: compartmentalization of corticostriatal input and striatonigral
output systems. Nature. 1984; 311:461464. [PubMed: 6207434]
Gerfen CR. The neostriatal mosaic: Striatal patch-matrix organization is related to cortical lamination.
Science. 1989; 246:385388. [PubMed: 2799392]
Gerfen CR. The neostriatal mosaic: multiple levels of compartmental organization in the basal ganglia.
Annu. Rev. Neurosci. 1992; 15:285320. [PubMed: 1575444]
Gerfen CR. Molecular effects of dopamine on striatal-projection pathways. Trends Neurosci. 2000;
23:S6470. [PubMed: 11052222]
Gerfen CR, Herkenham M, Thibault J. The neostriatal mosaic: II. Patch- and matrix-directed
mesostriatal dopaminergic and non-dopaminergic systems. J. Neurosci. 1987; 7:39153934.
[PubMed: 2891799]
Gerfen CR, McGinty JF, Young WS 3rd. Dopamine differentially regulates dynorphin, substance P,
and enkephalin expression in striatal neurons: in situ hybridization histochemical analysis. J.
Neurosci. 1991; 11:10161031. [PubMed: 1707092]
Goldman-Rakic PS. The physiological approach: functional architecture of working memory and
disordered cognition in schizophrenia. Biol. Psychiatry. 1999; 46:650661. [PubMed: 10472417]
Graveland GA, DiFiglia M. The frequency and distribution of medium-sized neurons with indented
nuclei in the primate and rodent neostriatum. Brain Res. 1985; 327:307311. [PubMed: 3986508]

Graybiel AM. Correspondence between the dopamine islands and striosomes of the mammalian
striatum. Neurosci. 1984; 13:11571187.
Graybiel, AM.; Flaherty, AW.; Gimenez-Amaya, JM. Striosomes and matrisomes.. In: Bernadi, G.,
editor. The basal ganglia III. Plenum Press; New York: 1991. p. 3-12.
Graybiel AM, Hickey TI. Chemospecificity of ontogenetic units in the striatum: Demonstration by
combining [3H]thymidine neuronography and histochemical staining. Proc. Natl. Acad. Sci.
U.S.A. 1982; 79:198202. [PubMed: 6172791]
Graybiel AM, Ragsdale CW Jr. Histochemically distinct compartments in the striatum of human,
monkey and cat demonstrated by acethycholinesterase staining. Proc. Natl. Acad. Sci. U.S.A.
1978; 75:57235726. [PubMed: 103101]
Groenewegen HJ, Wright CI, Beijer AV, Voorn P. Convergence and segregation of ventral striatal
inputs and outputs. Ann. N. Y. Acad. Sci. 1999; 877:4963. [PubMed: 10415642]
Haber SN. The primate basal ganglia: parallel and integrative networks. J. Chem. Neuroanat. 2003;
26:317330. [PubMed: 14729134]
Haber SN, Fudge JL, McFarland NR. Striatonigrostriatal pathways in primates form an ascending
spiral from the shell to the dorsolateral striatum. J. Neurosci. 2000; 20:23692382. [PubMed:
10704511]
Haber SN, Kim K-S, Mailly P, Calzavara R. Reward-related cortical inputs define a large striatal
region in primates that interface with associative cortical connections, providing a substrate for
incentive-based learning. J. Neurosci. 2006; 26:83688376. [PubMed: 16899732]
Haber SN, McFarland NR. The concept of the ventral striatum in nonhuman primates. Ann. N. Y.
Acad. Sci. 1999; 877:3348. [PubMed: 10415641]

Halliday, G. Substantia nigra and locus coeruleus.. In: Paxinos, G.; May, JK., editors. The human
nervous system. Elsevier; Amsterdam: 2004. p. 449-463.
Harrison PJ. The neuropathology of schizophrenia. A critical review of the data and their
interpretation. Brain. 1999; 122:593624. [PubMed: 10219775]
Harrison PJ, Weinberger DR. Schizophrenia genes, gene expression, and neuropathology: on the
matter of their convergence. Mol. Psychiatry. 2005; 10:4068. [PubMed: 15263907]
Hedreen JC. Tyrosine hydroxylase-immunoreactive elements in the human globus pallidus and
subthalamic nucleus. J. Comp. Neurol. 1999; 409:400410. [PubMed: 10379826]
Hedreen JC, DeLong MR. Organization of striatopallidal, striatonigral, and nigrostriatal projections in
the macaque. J. Comp. Neurol. 1991; 304:569595. [PubMed: 2013650]
Heimer, L. The olfactory cortex and the ventral striatum.. In: Livingston, KE.; Hornikiewicz, O.,
editors. Limbic mechanisms: the continuing evolution of the limbic system concept. Plenum; New
York: 1978. p. 95-187.
Hietala J, Syvlahti E, Vuorio K, et al. Presynaptic dopamine function in striatum of neuroleptic-naive
schizophrenic patients. Lancet. 1995; 346:11301131. [PubMed: 7475604]
Hietala J, Syvlahti E, Wilkman H, et al. Depressive symptoms and presynaptic dopamine function in
neuroleptic-nave schizophrenia. Schizophr. Res. 1999; 35:4150. [PubMed: 9988840]
Hirvonen J, van Erp TG, Huttunen J, et al. Brain dopamine D1 receptors in twins discordant for
schizophrenia. Am. J. Psychiatry. 2006; 163:17471753. [PubMed: 17012685]
Holcomb HH, Cascella NG, Thaker GK, Medoff DR, Dannals RF, Tamminga CA. Functional sites of
neuroleptic drug action in the human brain: PET/FDG studies with and without haloperidol. Am. J.
Holt DJ, Graybiel AM, Saper CB. Neurochemical architecture of the human striatum. J. Comp.
Neurol. 1997; 384:125. [PubMed: 9214537]
Holt DJ, Herman MM, Hyde TM, Kleinman JE, Sinton CM, German DC, Hersh LB, Graybiel AM,
Saper CB. Evidence for a deficit in cholinergic interneurons in the striatum in schizophrenia.
Hong S, Hikosaka O. The globus pallidus sends reward-related signals to the lateral habenula. Neuron.
2008; 60:720729. [PubMed: 19038227]
Howes OD, Kapur S. The dopamine hypothesis of schizophrenia: version III--the final common
pathway. Schizophr. Bull. 2009; 35:549562. [PubMed: 19325164]

Huot P, Parent A. Dopaminergic neurons intrinsic to the striatum. J. Neurochem. 2007; 101:1441
1447. [PubMed: 17286588]
Huttunen J, Heinimaa M, Svirskis T, et al. Striatal dopamine synthesis in first degree relatives of
patients with schizophrenia. Biol. Psych. 2008; 63:114117.

Hwang J, Lyoo IK, Dager SR, Friedman SD, Oh JS, Lee JY, Kim SJ, Dunner DL, Renshaw PF. Basal
ganglia shape alterations in bipolar disorder. Am. J. Psychiatry. 2006; 163:276285. [PubMed:
16449482]
Iversen SD, Iversen LL. Dopamine: 50 years in perspective. Trends Neurosci. 2007; 30:188193.
[PubMed: 17368565]
Jensen J, Willeit M, Zipursky RB, Savina I, Smith AJ, Menon M, Crawley AP, Kapur S. The
formation of abnormal associations in schizophrenia: neural and behavioral evidence.
Joel D, Weiner I. The connections of the dopaminergic system with the striatum in rats and primates:
an analysis with respect to the functional and compartmental organization of the striatum.
Juckel G, Schlagenhauf F, Koslowski M, et al. Dysfunction of ventral striatal reward prediction in
schizophrenic patients treated with typical, not atypical, neuroleptics. Psychopharmacology.
2006; 187:222228. [PubMed: 16721614]
Kane JM, Honigfeld G, Singer J, Meltzer H. Clozapine in treatment-resistant schizophrenics.
Psychopharmacol. Bull. 1988; 24:6267. [PubMed: 3290950]
Kelley JJ, Gao XM, Tamminga CA, Roberts. The effect of chronic haloperidol treatment on dendritic
spines in the rat striatum. Exp. Neurol. 1997; 146:471478. [PubMed: 9270058]
Kessler RM, Woodward ND, Riccardi P, Li R, Ansari MS, Anderson S, Dawant B, Zald D, Meltzer
HY. Dopamine D (2) Receptor Levels in Striatum, Thalamus, Substantia Nigra, Limbic Regions,
and Cortex in Schizophrenic Subjects. Biol. Psychiatry. 2009; 65:102431. [PubMed: 19251247]
Kim JS, Kornhuber HH, Schmid-Burgk W, Holzmuller B. Low cerebrospinal fluid glutamate in
schizophrenic patients and a new hypothesis on schizophrenia. Neurosci. Lett. 1980; 20:379382.
[PubMed: 6108541]
Kirkpatrick B, Buchanan RW, Ross DE, Carpenter WT Jr. A separate disease within the syndrome of
schizophrenia. Arch. Gen. Psychiatry. 2001; 58:165171. [PubMed: 11177118]
Kita H. Globus pallidus external segment. Prog. Brain Res. 2007; 160:111133. [PubMed: 17499111]
Kleinman JE, Hong J, Iadarola M, Govoni S, Gillin CJ. Neuropeptides in human brain -- postmortem
studies. Biol. Psychiatry. 1985; 9:9195.
Knutson B, Adams CM, Fong GW, Hommer D. Anticipation of increasing monetary reward
selectively recruits nucleus accumbens. J. Neurosci. 2001; 21:RC159. [PubMed: 11459880]
Knutson B, Cooper JC. Functional magnetic resonance imaging of reward prediction. Curr. Opin.
Neurol. 2005; 18:411417. [PubMed: 16003117]
Kolomeets NS, Uranova NA. Synaptic contacts in schizophrenia: study with immunocytochemical
identification of dopaminergic neurons. Zh. Nevrol. Psikhiatri. Im. S. S. Korsakova. 1997;
97:3943.
Kolomeets NS, Uranova NA. Synaptic contacts in schizophrenia: study with immunocytochemical
identification of dopaminergic neurons. Neurosci. Behav. Physiol. 1999; 29:217221. [PubMed:
10432512]
Korpi ER, Kleinman JE, Goodman SI, Phillips I, DeLisi LE, Linnoila M, Wyatt RJ. Serotonin and 5-
hydroxyindoleacetic acid in brains of suicide victims. Comparison in chronic schizophrenic
patients with suicide as cause of death. Arch. Gen. Psychiatry. 1986; 43:594600. [PubMed:
2423050]
Kreczmanski P, Heinsen H, Mantua V, Woltersdorf F, Masson T, Ulfig N, Schmidt-Kastner R, Korr
H, Steinbusch HW, Hof PR, Schmitz C. Volume, neuronal density and total neuron number in
five subcortical regions in schizophrenia. Brain. 2007; 130:678692. [PubMed: 17303593]
Kung L, Conley R, Chute DJ, Smialek J, Roberts RC. Synaptic changes in the striatum of
schizophrenic cases: a controlled postmortem ultrastructural study. Synapse. 1998; 28:125139.
[PubMed: 9450513]

Kung L, Roberts RC. Mitochondrial pathology in human schizophrenic striatum: a postmortem

ultrastructural study. Synapse. 1999; 31:6775. [PubMed: 10025685]
Lahti RA, Cochrane EV, Roberts RC, Conley RR, Tamminga CA. [3H] neurotensin receptor densities
in human postmortem brain tissue obtained from normal and schizophrenic persons. An
autoradiographic study. J. Neural Transm. 1998; 105:507516. [PubMed: 9720978]
Lahti RA, Roberts RC, Tamminga CA. D2-family receptor distribution in human postmortem tissue:
an autoradiographic study. NeuroReport. 1995; 6:25052512. [PubMed: 8741751]
Langer LF, Graybiel AM. Distinct nigrostriatal projection systems innervate striosomes and matrix in
the primate striatum. Brain Res. 1989; 498:344350. [PubMed: 2477114]
Laruelle M, Abi-Dargham A, Gil R, Kegeles L, Innis R. Increased dopamine transmission in
schizophrenia: relationship to illness phases. Biol. Psychiatry. 1999; 46:5672. [PubMed:
10394474]
Laruelle M, Abi-Dargham A, van Dyck CH, et al. Single photon emission computerized tomography
imaging of amphetamine-induced dopamine release in drug-free schizophrenic subjects. Proc.
Natl. Acad. Sci. U.S.A. 1996; 93:92359240. [PubMed: 8799184]
Lavoie B, Parent A. Immunohistochemical study of the serotoninergic innervation of the basal ganglia
in the squirrel monkey. J. Comp. Neurol. 1990; 299:116. [PubMed: 2212111]
Lavoie B, Parent A. Pedunculopontine nucleus in the squirrel monkey: cholinergic and glutamatergic
projections to the substantia nigra. J. Comp. Neurol. 1994; 344:232241. [PubMed: 7915727]
Lee KJ, Lee JS, Correl CU, Wee H, Yoo SY, Jeong JM, Lee DS, Lee SI, Kwong JS. Loss of
asymmetry in D2 receptors of putamen in unaffected family members at increased genetic risk
for schizophrenia. Acta. Psychiatr. Scand. 2008; 118:200208. [PubMed: 18699953]

Lvesque JC, Parent A. GABAergic interneurons in human subthalamic nucleus. Mov. Disorders.
2005; 20:574584.
Lewis DA. GABAergic local circuit neurons and prefrontal cortical dysfunction in schizophrenia.
Brain Res. Brain Res. Rev. 2000; 31:270276. [PubMed: 10719153]
Lewis DA, Hashimoto T, Morris HM. Cell and receptor type-specific alterations in markers of GABA
neurotransmission in the prefrontal cortex of subjects with schizophrenia. Neurotox. Res. 2008;
14:237248. [PubMed: 19073429]
Lewis DA, Sweet RA. Schizophrenia from a neural circuitry perspective: advancing toward rational
pharmacological therapies. J. Clin. Invest. 2009; 119:706716. [PubMed: 19339762]
Liddle PF. The symptoms of chronic schizophrenia. A re-examination of the positive-negative
dichotomy. Br. J. Psychiatry. 1987; 151:145151. [PubMed: 3690102]
Lindstrom LH, Gefvert O, Hagberg G, Lundberg T, Bergstrom M, Hartvig P, Langstrom B. Increased
dopamine synthesis rate in medial prefrontal cortex and striatum in schizophrenia indicated by L-
(-11C) DOPA and PET. Biol. Psychiatry. 1999; 46:681688. [PubMed: 10472420]
Lynd-Balta E, Haber SN. Primate striatonigral projections: a comparison of the sensorimotor-related
striatum and the ventral striatum. J. Comp. Neurol. 1994; 345:562578. [PubMed: 7962700]
Lyon GJ, Abi-Dargham A, Moore H, Lieberman JA, Javitch JA, Sulzer D. Presynaptic regulation of
dopamine transmission in schizophrnenia. Schizophr. Bull. Jun 12.2009 [Epub ahead of print].
Mai JK, Berger K, Sofroniew MV. Morphometric evaluation of neurophysin-immunoreactivity in
human brain: pronounced inter-individual variability and evidence for altered staining patterns in
schizophrenia. J. Hirnforsch. 1993; 34:133154. [PubMed: 8228177]
Mamah D, Wang L, Barch D, de Erausquin GA, Gado M, Csernansky JG. Structural analysis of the
basal ganglia in schizophrenia. Schizophr. Res. 2007; 89:5971. [PubMed: 17071057]
Marani E, Heida T, Lakke EA, Usunoff KG. The subthalamic nucleus. Part 1: development, cytology,
topography and connections. Adv. Anat. Embryol. Cell Biol. 2008; 198:1113. [PubMed:
18727483]
McFarland NR, Haber SN. Thalamic relay nuclei of the basal ganglia form both reciprocal and
nonreciprocal cortical connections, linking multiple frontal cortical areas. J. Neuroscience. 2002;
22:81178132.
Melchitzky DS, Erickson SL, Lewis DA. Dopamine innervation of the monkey mediodorsal thalamus:
Location of projection neurons and ultrastructural characteristics of axon terminals.

Meltzer HY. Clinical studies on the mechanism of action of clozapine: the dopamine-serotonin
hypothesis of schizophrenia. Psychopharmacology (Berl). 1989; 99(Suppl):S1827. [PubMed:
2682729]
Meredith GE, Baldo BA, Andrezjewski ME, Kelley AE. The structural basis for mapping behavior
onto the ventral striatum and its subdivisions. Brain Struct. Funct. 2008; 213:1727. [PubMed:
18256852]
Mitelman SA, Shihabuddin L, Brickman AM, Hazlett EA, Buchsbaum MS. Volume of the cingulate
and outcome in schizophrenia. Schizophr. Res. 2005; 72:91108. [PubMed: 15560955]
Mueller HT, Haroutunian V, Davis KL, Meador-Woodruff JH. Expression of the ionotropic glutamate
receptor subunits and NMDA receptor-associated intracellular proteins in the substantia nigra in
schizophrenia. Brain Res. Mol. Brain Res. 2004; 121:6069. [PubMed: 14969737]
Murray GK, Corlett PR, Clark L, Pessiglione M, Blackwell AD, Honey G, Jones PB, Bullmore ET,
Robbins TW, Fletcher PC. Substantia nigra/ventral tegmental reward prediction error disruption
in psychosis. Mol. Psychiatry. 2008; 239:267276.
Nagaska G. Zur Pathologie der extrapyramidalen Zentren bei Schizophrenie. Arb. Neur. Inst. Wien.
1925; 27:363396.
Nambu A. A new dynamic model of the cortico-basal ganglia loop. Prog. Brain Res. 2004; 143:4616.
[PubMed: 14653188]
Nambu A. Globus pallidus internal segment. Prog. Brain Res. 2007; 160:135150. [PubMed:
17499112]
Nambu A, Tokuno H, Takada M. Functional significance of the cortico-subthalamopallidal
hyperdirect pathway. Neurosci. Res. 2002; 43:1117. [PubMed: 12067746]

Nauta HJ, Cole M. Efferent projections of the subthalamic nucleus: an autoradiographic study in
monkey and cat. J. Comp. Neurol. 1978; 180:116. [PubMed: 418083]
Nieuwenhuys, R.; Voogd, J.; van Huijzen, C. Telencephalon: basal ganglia.. In: Nieuwenhuys, R.;
Voogd, J.; van Huijzen, C., editors. The human central nervous system. Springer; Berlin: 2008. p.
427-489.
Nirenberg MJ, Vaughan RA, Uhl GR, Kuhar MJ, Pickel VM. The dopamine transporter is localized to
dendritic and axonal plasma membranes of nigrostriatal dopaminergic neurons. J. Neurosci.
1996; 16:436447. [PubMed: 8551328]
Nozaki S, Kato M, Takano H, et al. Regional dopamine synthesis in patients with schizophrenia using
L-[beta-11C]DOPA PET. Schizophr. Res. 2009; 108:7884. [PubMed: 19056247]
Nudmamud-Thanoi S, Piyabhan P, Harte MK, Cahir M, Reynolds GP. Deficits of neuronal
glutamatergic markers in the caudate nucleus in schizophrenia. J. Neural. Transm. Suppl. 2007;
72:281285. [PubMed: 17982904]
Oke AF, Adams RN. Elevated thalamic dopamine: possible link to sensory dysfunctions in
schizophrenia. Schizophr. Bull. 1987; 13:589604. [PubMed: 2830663]
Owen R, Owen F, Poulter M, Crow TJ. Dopamine D2 receptors in substantia nigra in schizophrenia.
Brain Res. 1984; 299:152154. [PubMed: 6144367]
Palacios JM, Camps M, Cortes R, Probst A. Mapping dopamine receptors in the human brain. J.
Neural. Transm. Suppl. 1988; 27:227235. [PubMed: 2969952]
Paradiso S, Andreasen NC, Crespo-Facorro D, O'Leary DS, Watkins GL, Boles Ponto LL, Hichwa
RD. Emotions in unmedicated patients with schizophrenia during evaluation with positron
emission tomography. Am. J. Psychiatry. 2003; 160:17751783. [PubMed: 14514490]
Parent A, Fortin M, Ct PY, Cicchetti F. Calcium-binding proteins in primate basal ganglia.
Neurosci. Res. 1996; 25:309334. [PubMed: 8866512]
Parent A, Hazrati LN. Functional anatomy of the basal ganglia. I. The cortico-basal ganglia-thalamo-
cortical loop. Brain Res. Brain Res. Rev. 1995; 20:91127. [PubMed: 7711769]
Parent M, Parent A. The microcircuitry of the primate subthalamic nucleus. Parkinsonism Relat.
Disord. Suppl. 2007; 3:S292295.
Parent A, Sato F, Wu Y, Gauthier J, Levesque M, Parent M. Organization of the basal ganglia: the
importance of axonal collateralization. Trends Neurosci. 2000; 23:S2027. [PubMed: 11052216]

Parent A, Smith Y. Organization of efferent projections of the subthalamic nucleus in the squirrel
monkey as revealed by retrograde labeling methods. Brain Res. 1987; 436:296310. [PubMed:
3435830]
Penny GR, Wilson CJ, Kitai ST. Relationship of the axonal and dendritic geometry of spiny projection
neurons to the compartmental organization of the neostriatum. J. Comp. Neurol. 1988; 269:275
289. [PubMed: 2833538]
Perez-Costas E, Melendez-Ferro M, Gao XM, Conley R, Roberts RC. Decreased expression of
tyrosine hydroxylase in the substantia nigra of schizophrenia brains. Schizophr Bull. 2007;
33:266.
Perez-Costas, E.; Melendez-Ferro, M.; Rice, MW.; Roberts, RC. Dopamine pathology in
schizophrenia: Analysis of total and active form of tyrosine hydroxylase in the substantia nigra..
2009 Neuroscience Meeting Planner.; Chicago, IL: Society for Neuroscience. 2009; Program No.
340.2/N23Online
Pieczenik SR, Neustadt J. Mitochondrial dysfunction and molecular pathways of disease. Exp. Mol.
Pathol. 2007; 83:8492. [PubMed: 17239370]
Porritt MJ, Batchelor PE, Hughes AJ, Kalnins R, Donnan GA, Howells DW. New dopaminergic
neurons in Parkinson's disease striatum. Lancet. 2000; 356:4445. [PubMed: 10892768]
Powers RE. The neuropathology of schizophrenia. J. Neuropathol. Exp. Neurol. 1999; 58:679690.
[PubMed: 10411337]
Prensa L, Cossette M, Parent A. Dopaminergic innervation of human basal ganglia. J. Chem.
Neuroanat. 2000; 20:207213. [PubMed: 11207419]
Prensa L, Gimenez-Amaya JM, Parent A. Chemical heterogeneity of the striosomal compartment in

the human striatum. J. Comp. Neurol. 1999a; 413:603618. [PubMed: 10495446]
Prensa L, Parent A. The nigrostriatal pathway in the rat: A single-axon study of the relationship
between dorsal and ventral tier nigral neurons and the striosome/matrix striatal compartments. J.
Neurosci. 2001; 21:72477260. [PubMed: 11549735]
Prensa L, Parent A, Gimenez-Amaya JM. Compartmentalized organization of human corpus striatum.
Rev. Neurol. 1999b; 28:512519. [PubMed: 10229968]
Prince JA, Blennow K, Gottfries CG, Karlsson I, Oreland L. Mitochondrial function is differentially
altered in the basal ganglia of chronic schizophrenics. Neuropsychopharmacology. 1999; 21:372
379. [PubMed: 10457534]
Pulver AE. Search for schizophrenia susceptibility genes. Biol. Psychiatry. 2000; 47:221230.
[PubMed: 10682219]
Pulver AE, Mulle J, Nestadt G, et al. Genetic heterogeneity in schizophrenia: stratification of genome
scan data using co-segregating related phenotypes. Mol. Psychiatry. 2000; 5:650653. [PubMed:
11126395]
Raju DV, Shah DJ, Wright TM, Hall RA, Smith Y. Differential synaptology of vGluT2-containing
thalamostriatal afferents between the patch and matrix compartments in rats. J. Comp. Neurol.
2006; 499:231243. [PubMed: 16977615]
Rajarethinam R, Upadhyaya A, Tsou P, Upadhyaya M, Keshavan MS. Caudate volume in offspring of

patients with schizophrenia. Br. J. Psychiatry. 2007; 191:258259. [PubMed: 17766768]
Remington G. Alterations of dopamine and serotonin transmission in schizophrenia. Prog. Brain Res.
2008; 172:117140. [PubMed: 18772030]
Roberts RC, Conley RR, Kung L, Peretti FJ, Chute DJ. Reduced striatal spine size in schizophrenia: a
postmortem ultrastructural study. NeuroReport. 1996; 7:12141218. [PubMed: 8817535]
Roberts RC, Knickman JK. The ultrastructural organization of the patch matrix compartments in the
human striatum. J. Comp. Neurol. 2002; 452:128138. [PubMed: 12271487]
Roberts RC, Roche JK, Conley RR. Synaptic differences in the postmortem striatum of subjects with
schizophrenia: a stereological ultrastructural analysis. Synapse. 2005a; 56:185197. [PubMed:
15803499]
Roberts RC, Roche JK, Conley RR. Synaptic differences in the patch matrix compartments of subjects
with schizophrenia: a postmortem ultrastructural study of the striatum. Neurobiol. Dis. 2005b;
20:324335. [PubMed: 16242639]

Roberts RC, Roche JK, Conley RR. Differential synaptic changes in the striatum of subjects with
undifferentiated versus paranoid schizophrenia. Synapse. 2008; 62:616627. [PubMed:
18509852]
Roberts RC, Roche JK, Conley RR, Lahti AC. Dopaminergic synapses in the caudate of subjects with
schizophrenia: relationship to treatment response. Synapse. 2009; 63:520530. [PubMed:
19226604]
Rolls ET, Grabenhorst F, Franco L. Prediction of subjective affective state from brain activations. J.
Neurophysiol. 2009; 101:12941308. [PubMed: 19109452]
Sadikot AF, Parent A, Smith Y, Bolam JP. Efferent connections of the centromedian and
parafascicular thalamic nuclei in the squirrel monkey: A light and electron microscopic study of
the thalamostriatal projection in relation to striatal heterogeneity. J. Comp. Neurol. 1992;
320:228242. [PubMed: 1619051]
Sanchez-Gonzalez MA, Garcia-Cabezas MA, Rico B, Cavada C. The primate thalamus is a key target
for brain dopamine. J. Neurosci. 2005; 25:60766083. [PubMed: 15987937]
Sato F, Lavallee P, Levesque M, Parent A. Single-axon tracing study of neurons of the external
segment of the globus pallidus in primate. J. Comp. Neurol. 2000a; 417:1731. [PubMed:
10660885]
Sato F, Parent M, Levesque M, Parent A. Axonal branching pattern of neurons of the subthalamic
nucleus in primates. J. Comp. Neurol. 2000b; 424:142152. [PubMed: 10888744]
Schlagenhauf F, Sterzer P, Schmack K, Ballmaier M, Rapp M, Wrase J, Juckel G, Gallinat J, Heinz A.
Reward feedback alterations in unmedicated schizophrenia patients: relevance for delusions.
Biol. Psychiatry. 2009; 65:10321039. [PubMed: 19195646]
Schultz W. Predictive reward signal of dopamine neurons. J. Neurophysiol. 1998; 80:127. [PubMed:
9658025]
Schultz W. Getting formal with dopamine and reward. Neuron. 2002; 36:241263. [PubMed:
12383780]
Seeman P, Kapur S. Schizophrenia: more dopamine, more D2 receptors. Proc. Natl. Acad. Sci. U. S.
A. 2000; 97:76737675. [PubMed: 10884398]
Seeman P, Lee T, Chau-Wong M, Wong K. Antipsychotic drug doses and neuroleptic/dopamine
receptors. Nature. 1976; 261:717719. [PubMed: 945467]
Selemon LD, Goldman-Rakic PS. The reduced neuropil hypothesis: A circuit based model of
schizophrenia. Biol. Psychiatry. 1999; 45:1725. [PubMed: 9894571]
Sesack SR, Aoki C, Pickel VM. Ultrastructural localization of D2 receptor-like immunoreactivity in
midbrain dopamine neurons and their striatal targets. J. Neurosci. 1994; 14:88106. [PubMed:
7904306]
Sheitman BB, Lieberman JA. The natural history and pathophysiology of treatment resistant
schizophrenia. J. Psychiatr. Res. 1998; 32:143150. [PubMed: 9793867]
Shink E, Bevan MD, Bolam JP, Smith Y. The subthalamic nucleus and the external pallidum: two
tightly interconnected structures that control the output of the basal ganglia in the monkey.

Simpson MD, Slater P, Royston MC, Deakin JF. Regionally selective deficits in uptake sites for
glutamate and gamma-aminobutyric acid in the basal ganglia in schizophrenia. Psychiatry Res.
1992; 42:273282. [PubMed: 1353892]
Smith Y, Bennett BD, Bolam JP, Parent A, Sadikot AF. Synaptic relationships between dopaminergic
afferents and cortical or thalamic input in the sensorimotor territory of the striatum in monkey. J.
Comp. Neurol. 1994; 344:119. [PubMed: 7914894]
Smith Y, Bevan MD, Shink E, Bolam JP. Microcircuitry of the direct and indirect pathways of the
basal ganglia. Neuroscience. 1998; 86:353387. [PubMed: 9881853]
Smith Y, Hazrati LN, Parent A. Efferent projections of the subthalamic nucleus in the squirrel monkey
as studied by the PHA-L anterograde tracing method. J. Comp. Neurol. 1990; 294:306323.
[PubMed: 2332533]
Smith Y, Kieval JZ. Anatomy of the dopamine system in the basal ganglia. TINS. 2000; 23:S2833.
[PubMed: 11052217]

Smith Y, Parent A. Differential connections of caudate nucleus and putamen in the squirrel monkey
(Saimiri Sciureus). Neuroscience. 1986; 18:347371. [PubMed: 3736862]
Smith Y, Raju DV, Pare JF, Sidibe M. The thalamostriatal system: a highly specific network of the
basal ganglia circuitry. Trends Neurosci. 2004; 27:520527. [PubMed: 15331233]

Smith Y, Villalba R. Striatal and extrastriatal dopamine in the basal ganglia: an overview of its
anatomical organization in normal and Parkinsonian brains. Mov. Disord. 2008; 23:S534547.
[PubMed: 18781680]
Staal WG, Hulshoff Pol HE, Schnack HG, van Haren NE, Seifert N, Kahn RS. Structural brain
abnormalities in chronic schizophrenia at the extremes of the outcome spectrum. Am. J.
Stern RG, Kahn RS, Davidson M. Predictors of response to neuroleptic treatment in schizophrenia.
Psychiatr. Clin. North Am. 1993; 16:31338. [PubMed: 8101371]
Suhara T, Okubo Y, Yasuno F, et al. Decreased dopamine D2 receptor binding in the anterior cingulate
cortex in schizophrenia. Arch. Gen. Psychiatry. 2002; 59:2530. [PubMed: 11779278]
Takahashi H, Higuchi M, Suhara T. The role of extrastriatal dopamine D2 receptors in schizophrenia.
Biol. Psychiatry. 2006; 59:919928. [PubMed: 16682269]
Tallerico T, Novak G, Liu IS, Ulpian C, Seeman P. Schizophrenia: elevated mRNA for dopamine D2
(Longer) receptors in frontal cortex. Mol. Brain Res. 2001; 87:160165. [PubMed: 11245917]
Taylor SF, Liberzon I, Decker LR, Koeppe RA. A functional anatomic study of emotion in
schizophrenia. Schizophr. Res. 2002; 58:159172. [PubMed: 12409155]
Taylor SF, Phan KL, Britton JC, Liberzon I. Neural response to emotional salience in schizophrenia.

Tepper JM, Abercrombie ED, Bolam JP. Basal ganglia macrocircuits. Prog. Brain Res. 2007; 160:17.
Tepper JM, Bolam JP. Functional diversity and specificity of neostriatal interneurons. Curr. Opin.
Neurobiol. 2004; 14:685692. [PubMed: 15582369]
Tepper JM, Lee CR. GABAergic control of substantia nigra dopaminergic neurons. Prog. Brain Res.
2007; 160:189208. [PubMed: 17499115]
Toru M, Watanabe S, Shibuya H, Nishikawa T, Noda K, Mitsushio H, Ichikawa H, Kurumaji A,
Takashima M, Mataga N, Ogawa A. Neurotransmitters, receptors and neuropeptides in post-
mortem brains of chronic schizophrenic patients. Acta Psychiatr. Scand. 1988; 78:121137.
[PubMed: 2906213]
Uranova NA, Casanova MF, DeVaughn NM, Orlovskaya DD, Denisov DV. Ultrastructural alterations
of synaptic contacts and astrocytes in postmortem caudate nucleus of schizophrenic patients.
Schizophr Res. 1996; 22:8183. [PubMed: 8908694]
Uranova NA, Levite OI. Ultrastructure of the substantia nigra in schizophrenia. Zh. Nevropatol.
Psikhiatr. Im. S. S. Korsakova. 1987; 87:10171024. [PubMed: 3673380]
Uranova N, Orlovskaya D, Vikhreva O, Zimina I, Kolomeets N, Vostrikov V, Rachmanova V.
Electron microscopy of oligodendroglia in severe mental illness. Brain Res. Bull. 2001; 55:597
610. [PubMed: 11576756]
Uranova NA, Vostrikov VM, Vikhreva OV, Zimina IS, Kolomeets NS, Orlovskaya DD. The role of
oligodendrocyte pathology in schizophrenia. Int. J. Neuropsychopharmacol. 2007; 10:537545.
[PubMed: 17313698]
van der Kooy D, Fishell G. Neuronal birthdate underlies the development of striatal compartments.
Brain Res. 1987; 401:155161. [PubMed: 3028569]
Walker RH, Arbuthnott GW, Baughman RW, Graybiel AM. Dendritic domains of medium spiny
neurons in the primate striatum: relationships to striosomal borders. J. Comp. Neurol. 1993;
337:614628. [PubMed: 8288774]
Walker EF, Diforio D, Baum K. Developmental neuropathology and the precursors of schizophrenia.
Acta. Psychiatr. Scand. Suppl. 1999; 395:1219. [PubMed: 10225328]
Wanat MJ, WIlluhn I, Clark JJ, Phillips PE. Phasic dopamine release in appetitive behaviors and drug
addiction. Curr. Drug Abuse Rev. 2009; 2:195213. [PubMed: 19630749]
White NM, Hiroi N. Preferential localization of self-stimulation sites in striosomes/patches in the rat
striatum. Proc. Natl. Acad. Sci. USA. 1998; 95:64866491. [PubMed: 9600993]

Wichmann T, DeLong MR. Functional and pathophysiological models of the basal ganglia. Curr.
Opin. Neurobiol. 1996; 6:751758. [PubMed: 9000030]
Wilson, CJ. Basal ganglia.. In: Shepherd, GN., editor. The synaptic organization of the brain. Oxford
University Press; Oxford: 2004. p. 361-413.

Wong DF, Wagner HN Jr. Tune LE, Dannals RF, Pearlson GD, Links JM, Tamminga CA, Broussolle
EP, Ravert HT, Wilson AA. Positron emission tomography reveals elevated D2 dopamine
receptors in drug-naive schizophrenics. Science. 1986; 234:15581563. [PubMed: 2878495]
Yung KK, Bolam JP, Smith AD, Hersch SM, Ciliax BJ, Levey AI. Immunocytochemical localization
of D1 and D dopamine receptors in the basal ganglia of the rat: light and electron microscopy.
Yung KK, Smith AD, Levey AI, Bolam JP. Synaptic connections between spiny neurons of the direct
and indirect pathways in the neostriatum of the rat: evidence from dopamine receptor and
neuropeptide immunostaining. Eur. J. Neurosci. 1996; 8:861869. [PubMed: 8743734]
Zhou FW, Jin Y, Matta SG, Xu M, Zhou FM. An ultra-short dopamine pathway regulates basal
ganglia output. J. Neurosci. 2009; 29:1042510435.

Figure 1.
Electron micrographs of tyrosine hydroxylase (TH) immunocytochemistry in postmortem
human caudate nucleus. Several synaptic arrangements are shown. Note that the synapses
formed by the TH-labeled synapses are short in length and non-perforated. A) TH-labeled
axons (straight black arrows outlined in black) are adjacent to unlabeled axon terminals (at)
that are forming asymmetric synapses (black arrows). A TH-labeled terminal makes a
symmetric synapse (curved white arrow outlined in black). B) Boxed area in panel A is
enlarged to show the symmetric synapse. C) Three TH-labeled boutons (black arrow with
white outline) are adjacent to a spine which receives a symmetric TH-labeled synapse
(curved white arrow outlined in black) and an asymmetric synapse (black arrow) from an
unlabeled terminal (at). D) TH-labeled axon makes a symmetric synapse (arrow) en passant
with a dendrite (den). Sp, spines. Scale bars in A-D: 0.5m. Figures A, B and D are
modifications of our previously published figure 1 from Roberts et al., (2009), while Figure
C is a modification of our previously published figure 4 from Kung et al., (1998).

Costas Et Al. 2010 Basal Ganglia Pathology in Schizophrenia - Dopamine Connections and Anomalies

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Costas Et Al. 2010 Basal Ganglia Pathology in Schizophrenia - Dopamine Connections and Anomalies

Uploaded by

Copyright:

Available Formats

NIH Public Access

J Neurochem. 2010 April ; 113(2): 287302. doi:10.1111/j.1471-4159.2010.06604.x.

BASAL GANGLIA PATHOLOGY IN SCHIZOPHRENIA: DOPAMINE

South Birmingham, AL 35294 Phone: 2059969373 Fax: 2059969377 rcusidor@uab.edu.

Basal ganglia anatomy

The caudate nucleus and putamen present a further level of heterogeneity: a

J Neurochem. Author manuscript; available in PMC 2011 April 1.

The nucleus accumbens and ventral striatum

shell (Meredith et al., 2008).

The globus pallidus

J Neurochem. Author manuscript; available in PMC 2011 April 1.

The subthalamic nucleus

Basal ganglia pathways

J Neurochem. Author manuscript; available in PMC 2011 April 1.

Sato et al, 2000a,b).

Dopamine in the basal ganglia

J Neurochem. Author manuscript; available in PMC 2011 April 1.

dopaminergic system is compromised in illnesses such as Parkinson's disease (Porritt et al.,

There is a topographical organization for dopaminergic connections in which projections

Dopaminergic innervation to the striatum is heterogeneous with different cell groups

J Neurochem. Author manuscript; available in PMC 2011 April 1.

J Neurochem. Author manuscript; available in PMC 2011 April 1.

Reward and the dopamine system

Basal ganglia pathology in schizophrenia

J Neurochem. Author manuscript; available in PMC 2011 April 1.

(Fattal et al., 2006; Pieczenik and Neustadt, 2007).

The chronic undifferentiated subjects also had an increased density of glutamatergic-type

J Neurochem. Author manuscript; available in PMC 2011 April 1.

glutamatergic synapses in various subtypes of subjects with schizophrenia (de la Fuente-

Substantia nigra pathology

Dopamine anomalies in the basal ganglia and connected structures in

Dysregulation of the dopamine system plays a critical role in psychosis, diminished

J Neurochem. Author manuscript; available in PMC 2011 April 1.

Dopamine levels and treatment response/resistance

Numerous neuroimaging studies have shown a relationship between pathophysiology and

J Neurochem. Author manuscript; available in PMC 2011 April 1.

striatal response compared to poor responders (Buchsbaum et al., 1992). Enhanced

Dopamine and reward

cumulative evidence suggests multiple problems in the basal ganglia in schizophrenia,

J Neurochem. Author manuscript; available in PMC 2011 April 1.

The authors declare not having conflicts of interest.

J Neurochem. Author manuscript; available in PMC 2011 April 1.

30:194202. [PubMed: 17408759]

J Neurochem. Author manuscript; available in PMC 2011 April 1.

dopaminergic neurons in primates: Phaseolus vulgaris-leucoagglutinin anterograde labeling

J Neurochem. Author manuscript; available in PMC 2011 April 1.

Bull. 2009; 35:528548. [PubMed: 19223657]

J Neurochem. Author manuscript; available in PMC 2011 April 1.

Acad. Sci. 1999; 877:3348. [PubMed: 10415641]

J Neurochem. Author manuscript; available in PMC 2011 April 1.

patients with schizophrenia. Biol. Psych. 2008; 63:114117.

J Neurochem. Author manuscript; available in PMC 2011 April 1.

Kung L, Roberts RC. Mitochondrial pathology in human schizophrenic striatum: a postmortem

for schizophrenia. Acta. Psychiatr. Scand. 2008; 118:200208. [PubMed: 18699953]

J Neurochem. Author manuscript; available in PMC 2011 April 1.

hyperdirect pathway. Neurosci. Res. 2002; 43:1117. [PubMed: 12067746]

J Neurochem. Author manuscript; available in PMC 2011 April 1.

Prensa L, Gimenez-Amaya JM, Parent A. Chemical heterogeneity of the striosomal compartment in

Rajarethinam R, Upadhyaya A, Tsou P, Upadhyaya M, Keshavan MS. Caudate volume in offspring of

J Neurochem. Author manuscript; available in PMC 2011 April 1.

Neuroscience. 1996; 73:335357. [PubMed: 8783253]

J Neurochem. Author manuscript; available in PMC 2011 April 1.

basal ganglia circuitry. Trends Neurosci. 2004; 27:520527. [PubMed: 15331233]