XVI-7
Functional Anatomy of Substance-Related Disorders
R.A. Wise and E.L. Gardner
For the most part, the functional anatomy relevant to substance
abuse disorders remains to be identified. One problem is that
the field of substance-related disorders is not yet well defined.
For the purposes of the present chapter, the substances under
discussion will be drugs of potential abuse. However, the category
of ‘food’ includes at least two classes of substances — sweets and
lipids — that can also be abused. The case of food underlines an
important principle: substance abuse need not involve the kinds of
physiological dependence that have been assumed in the case of
drug addiction. Food is ‘abused’ only when it is taken above and
beyond any obvious physiological need. Current evidence suggests
significant overlap in the brain circuitry relevant to foraging for
food and foraging for drugs of abuse. For the most part, such
circuitry has been identified as critical for the substance of interest
to serve as a reward or ‘reinforcer’. The terms reward and reinforcer
are descriptive, not explanatory; they merely identify substances or
events that are habit-forming.
The concept of habit is central to the topic of substance abuse.
Again, the term is descriptive rather than explanatory. All substance
abuse reflects the habitual intake of a substance. Some habits are
benign, such as the habit of eating a small portion of pastry or ice
cream following a meal. We invoke the notion of substance abuse
in relation to habits that are pursued compulsively despite negative
consequences. The consequences most obviously associated with
substance abuse are addiction and obesity. The transition from
recreational drug use to addiction is gradual, just as is the transition
from overweight to obese, and we have no evidence to suggest that
the mechanisms of modest food or drug intake differ in anatomical
loci from those of excessive intake. Thus our current knowledge
of the neuroanatomy of substance abuse is based largely on our
understanding of why individuals take food and drug substances in
the first place.
In one sense, the task of identifying the neuroanatomy of drug
abuse is an easier one than that of identifying the neuroanatomy
of feeding: most drugs of abuse act at receptors that have been
identified and localized in the depths of the brain. Unlike foods,
drug rewards do not rely on peripheral sensory pathways to
reach the brain mechanisms serving motivational function. While
addictive drugs act on multiple receptor populations, and while
only a fraction of these populations serve motivational functions,
by injecting drugs directly into the brain and comparing the
effectiveness at different injection sites, we are able to identify
chemical trigger zones for the habit-forming actions of several drugs
of abuse. These trigger zones and the pathways that connect them
can serve as a first step towards identifying the brain structures
involved in substance-related disorders.
A classic issue in the field of drug abuse is the role of drug
dependence. Clear-cut dependence syndromes can develop with
chronic use of opiates, alcohol, barbiturates and benzodiazepines
(Kalant, 1977), and more subtle dependence syndromes can develop
with use of nicotine (Shiffman, 1979), cannabis (Jones, 1980) or
Biological Psychiatry : Edited by H. D’haenen, J.A. den Boer and P. Willner. ISBN 0-471-49198-5
 2002 John Wiley & Sons, Ltd.
cocaine (Jones, 1984). Addiction theory has, at least until recently,
been dominated by the assumption that the self-medication of
withdrawal distress differentiates between addiction and the so-
called ‘recreational’ use of drugs. The present chapter thus begins
with a discussion of some of the issues and neuroanatomy of drug
dependence before turning to the topic of the neuroanatomy of drug
reward.
NEUROANATOMY OF DRUG DEPENDENCE
Drug dependence develops with chronic drug use and is revealed in
‘withdrawal symptoms’ that are seen upon interruption of drug use.
There is no common denominator of the range of drug dependence
phenomena; the symptoms produced by withdrawal from a given
drug depend on the specific actions of that drug. Generally, the
withdrawal symptoms associated with a given drug are opposite to
the symptoms of intoxication with that drug. Thus withdrawal from
stimulants is generally associated with depression and withdrawal
from depressants is generally associated with agitation. As a
general rule, dependence is seen as resulting from ‘compensatory’
mechanisms: mechanisms that resist intoxication and tend, over
time, to re-establish normal equilibrium. These compensations also
result in tolerance (progressive desensitization) to the intoxicating
effects of the drug and when the drug is withdrawn the unopposed
compensations produce the objective signs of the withdrawal
syndrome. If a system has no tonic endogenous input, it is possible
to observe tolerance of the response to an exogenous drug in
the absence of any overt symptoms when the drug is withdrawn.
Usually, however, tolerance and dependence go together.
To the degree that drugs of different classes share common
actions, they tend to establish overlapping tolerance and dependence
syndromes and they are at least partially effective at alleviating each
other’s withdrawal symptoms. The ability of one drug to cause tol-
erance that extends to another drug is termed ‘cross-tolerance’; the
ability of one drug to alleviate the withdrawal symptoms associated
with another drug is termed ‘cross-dependence’. Even drugs such
as opiates, alcohol and barbiturates, which produce partial cross-
tolerance and partial cross-dependence, have some actions — and
thus cause some adaptations — that are not shared (Kalant, 1977).
There is a good deal of cross-tolerance between depressant drugs
(opiates, alcohol, barbiturates and benzodiazepines) but little if any
between depressant drugs of abuse and stimulant drugs of abuse
(Wise, 1987).
‘Somatic’ Dependence Signs
Pursuit of the anatomy of drug dependence mechanisms has
been fuelled by classic addition theory, which held that the self-
medication of withdrawal distress was a central if not a defining
510 CLINICAL SYNDROMES: SUBSTANCE-RELATED DISORDERS
property of addiction (Tatum et al., 1929; Himmelsbach, 1943; Lin-
desmith, 1947; Goldstein and Goldstein, 1961; Collier, 1966; Jaffe
and Sharpless, 1968). Inasmuch as the withdrawal symptoms asso-
ciated with such drugs as opiates and alcohol are unpleasant, and
inasmuch as addicts report that they are ‘sick’ during withdrawal
and that they take their drug to get ‘well’, this theory had obvious
face validity. From the perspective of classic addiction theory, the
anatomy of drug dependence should be the anatomy of the brain cir-
cuits regulating thermoregulation, autonomic function and the other
somatic signs of drug withdrawal — the signs that addicts report as
aversive and liken to some of the symptoms of influenza.
Our best knowledge of neuroanatomy of such dependence
phenomena involves opiate dependence. In part, this is because
the opiate withdrawal syndrome has frequently served as the model
of other addictions. In part, it is because opiates can be injected
directly into the brain sites where they have various actions and
where they remain reasonably localized for many minutes. In part,
it is because opiate withdrawal symptoms can be precipitated by
administration of opiate antagonists, which can also be restricted
to localized brain areas. Localization is relative, of course; drugs
injected into the brain can diffuse to adjacent structures, to the
ventricular system and into the circulation, from which they can
reach distant targets of action. Adequate localization of the effects
of direct drug injections into the brain requires the demonstration
that higher doses are required to produce the same effects when
the injections are in adjacent regions, into the ventricles or into
the circulation. This is a requirement that is frequently not met in
studies involving central drug injections.
Localized brain injections of opiates and opiate antagonists have
been used to identify sites at which opiates act to cause the various
symptoms of opioid intoxication and subsequent withdrawal, and
where opiate antagonists precipitate the various somatic symptoms
of the opiate withdrawal syndrome in dependent laboratory animals.
The somatic symptoms include diarrhoea, ear blanching, ptosis,
teeth chattering, ‘wet dog’ shakes, seminal emissions and in rats,
attempts to escape from the test chamber. The human symptoms are
similar: lacrimation, rhinorrhoea, yawning, sweating, restless sleep,
dilated pupils, tremor, nausea and vomiting, diarrhoea, increased
heart rate and blood pressure, chills, abdominal cramping, muscle
spasms and sexual orgasm (both male and female).
The brain mechanism of a given somatic withdrawal symptom
is the brain mechanism involved in the normal function that is
distorted by intoxication and subsequent withdrawal. The diarrhoea
during opiate withdrawal reflects an adaptation in the mechanism
responsible for the constipation during opiate intoxication: the
mechanism of µ-opioid inhibition of intestinal contractility. During
intoxication the intestine relaxes; during withdrawal it contracts
and expels the accumulated faeces. In the case of each withdrawal
symptom, a mechanism specific to that symptom is involved. The
sweats and chills of opiate withdrawal reflect the actions of opiates
and opiate withdrawal on the mechanisms of regulation of body
temperature. Thus the anatomy of opiate withdrawal is, essentially,
the anatomy of opiate action. Not surprisingly, very many brain
structures are implicated in the full range of opiate and other drug
dependence symptoms.
Among the first opiate withdrawal symptoms to be associated
with specific brain regions were the somatic signs of ptosis, teeth
chattering, wet dog shakes, and escape behaviour. These symptoms
can be precipitated in opiate-dependent rats by injections of opiate
antagonists into the ventricular system of the brain (Laschka et al.,
1976a). If the cerebral aqueduct is blocked so that antagonists
injected into the lateral or the third ventrical do not have easy
access to the fourth ventral, it is injections into the fourth ventricle
(Laschka et al., 1976b) that are most effective. Injections into
the nucleus locus coeruleus, at the lateral floor of the fourth
ventrical, are similarly effective (Maldonado et al., 1992). If the
opiates themselves are infused locally into the periaqueductal grey
matter or into the fourth ventricle, which is fed by the aqueduct,
systemic naloxone precipitates the somatic signs of teeth chattering
and escape behaviours (Wei and Loh, 1976; Wei, 1981; Bozarth
and Wise, 1984). One hypothesis holds that these symptoms are
responses to the fluctuations of body temperature that accompany
opiate withdrawal and result from opiate-induced disturbance of
temperature-regulating mechanisms (Wei et al., 1974).
Of the sites that are readily reached by drug injections into the
fourth ventricle, nucleus locus coeruleus and the periaqueductal
grey have received most attention. The noradrenergic neurones of
the locus coeruleus are inhibited by morphine; this inhibition under-
goes tolerance with repeated application (Aghajanian, 1978). In
opiate-dependent animals, the opiate antagonist naloxone precip-
itates accelerated firing of these neurones (Aghajanian, 1978); at
least part of this hyperactivity appears to involve adaptations of
the locus coeruleus itself (Ivanov and Aston-Jones, 2001). Part of
this hyperactivity results from altered neuronal input to these cells
(Akaoka and Aston-Jones, 1991). Thus while the cells of the locus
coeruleus appear to be one anatomical substrate of dependence, the
cells that provide input to the locus coeruleus are another. Presum-
ably, the many cells that receive input from the locus coeruleus are
yet other such substrates.
Indeed, most of the brain is involved directly or indirectly in
the opiate dependence syndrome. Signs of abnormal activity in
opiate-withdrawn animals are seen in the abnormal expression of
early immediate genes in a variety of brain areas associated with
autonomic function. Among these are the locus coeruleus and the
A5 noradrenergic cell group, the nucleus of the solitary tract, the
parabrachial nuclei, and the caudal and rostral ventrolateral medulla
(Stornetta et al., 1993). Moreover, it is not just autonomic control
systems that are altered by opiate dependence. Indeed, studies of
early immediate gene expression confirm that opiate withdrawal is
accompanied by abnormal neuronal activity in multiple structures
and at all levels of the neuraxis. Among additional sites where
immediate early genes are activated during opiate withdrawal are
the paraventricular nucleus of the hypothalamus, amygdala, ven-
tral tegmentum, nucleus accumbens, neostriatum, cerebral cortex,
hippocampus, thalamus, cerebellum and various layers of the spinal
cord (Hayward et al., 1990; Stornetta et al., 1993; Beckmann et al.,
1995; Rohde et al., 1996).
The fact that opiate withdrawal effects are widespread in the cen-
tral nervous system makes a general search for an anatomical basis
of opiate dependence a questionable enterprise. The problem is
confounded when other drugs of abuse are considered, particularly
because there is no common denominator to stimulant and depres-
sant somatic dependence signs (Wise, 1987). The affected circuitry
is not only widespread; it also differs from drug to drug. Even
when we restrict consideration to the opiates, dependence appears
to be more easily characterized in neurochemical than in anatomical
terms. Opiate receptors are G-protein-coupled, and the exposure of
G-protein-coupled receptors to agonists usually results in desensiti-
zation of the receptor (Ferguson et al., 1998; Pitcher et al., 1998).
Other drugs of abuse also act on (e.g., cannabis) or via (e.g.,
cocaine, amphetamine and, more indirectly, nicotine) G-protein-
coupled receptors. Rebounding supersensitivity of such receptors
will, where the receptor usually receives endogenous input, result
in withdrawal symptoms. This fact appears to confirm what has
already been suggested: every site of opiate action can contribute
to the complex phenomenon of opiate dependence. Localization of
the mechanisms of opiate or other drug dependence thus requires
a symptom-by-symptom characterization that may never be com-
pleted. Interest in drug withdrawal symptoms has thus tended to
focus on the specific symptoms most likely to contribute to the
motivation for drug self-administration.
Classic addiction theory — with its myriad withdrawal symp-
toms and syndromes — has always had as a primary weakness that
it does not explain why non-dependent subjects initiate sufficient
 FUNCTIONAL ANATOMY
drug intake to become dependent, nor does it explain why detox-
ified addicts are re-addicted so quickly. Broad dependence theory
has thus been challenged by workers who hypothesize that it is the
generation of drug-induced positive reinforcement and euphoria,
rather than the alleviation of withdrawal-induced dysphoria, that
motivates compulsive drug-seeking in addicts (McAuliffe and Gor-
don, 1974; Bijerot, 1980; Wise and Bozarth, 1987; Gardner, 1992;
Robinson and Berridge, 1993; Di Chiara, 1998). This view gained
support from the fact that stimulant drugs like cocaine, nicotine and
cannabis can be taken compulsively despite withdrawal symptoms
quite different from and much weaker than those associated with
depressant drugs (Shiffman, 1979; Jones, 1980, 1984). Further sup-
port came from studies showing that lower animals would learn
to take morphine, heroin, amphetamine, cocaine and related drugs
compulsively even if they were not first made dependent. Indeed,
animals will self-administer opiates in doses and limited access con-
ditions that cause no overt somatic withdrawal symptoms (Deneau
et al., 1969; Woods and Schuster, 1971). Confirmation that opiates
are strongly habit-forming independent of their ability to induce
physical dependence came from the demonstration that rats self-
administer morphine into the ventral tegmental area of the brain,
a site at which infusions of doses that are effective elsewhere fail
to produce somatic signs of dependence, but not into the periaque-
ductal grey, where infusions do cause somatic dependence signs
(Bozarth and Wise, 1984). With the waning influence of depen-
dence theory, interest in the neuroanatomy of somatic dependence
signs has also waned, and dependence theory has come to focus on
intoxication-induced neuroadaptations within the specific circuitry
of drug reward.
Reward-Relevant Dependence Signs
With the realization that opiate dependence was not a necessary
condition for compulsive opiate self-administration, the assumption
that some form of physical dependence must explain compulsive
self-administration of addictive drugs became less attractive and
classic addiction theory became overshadowed by theories that
focused on the positive reinforcing properties of drugs for non-
dependent subjects (Fibiger, 1978; Wise, 1978, 1988; Wise and
Bozarth, 1987; Di Chiara and Imperato, 1988; Gardner, 1992;
Robinson and Berridge, 1993). The brain circuitry contributing
importantly to the positive reinforcing properties of drugs of abuse
has been a target of intensive investigation and is discussed in some
detail in the next section. With the accumulating evidence as to the
neural substrates of drug reward has come a focusing of dependence
theory on those specific substrates. In the modern reformulation
of dependence theory, neuroadaptations in the reward circuitry
itself are posited to account for states of generalized depression
and anhedonia and it is hypothesized that it is the self-medication
of such states that adds the compulsive dimension to drug self-
administration (Solomon and Corbit, 1973; Leith and Barrett, 1976;
Kokkinidis et al., 1980; Dackis and Gold, 1985; Kokkinidis and
McCarter, 1990; Frank et al., 1992; Koob and Bloom, 1988).
The first suggestion that drugs of abuse might desensitize the
mechanisms of reward came from studies of the effects of drugs on
rewarding electrical stimulation of the brain. While drugs of abuse
usually potentiate the rewarding effects of lateral hypothalamic and
related brain stimulation (Wise, 1996b), reward thresholds are ele-
vated following withdrawal from chronic exposure to amphetamine
(Leith and Barrett, 1976; Kokkinidis et al., 1980; Wise and Munn,
1995), cocaine (Frank et al., 1988, 1992; Kokkinidis and McCarter,
1990; Markou and Koob, 1991), ethanol (Schulteis et al., 1995) and
nicotine (Watkins et al., 2000). The period of elevation lasts, how-
ever, only a few days, far short of the period when peak craving
for opiates (Shalev et al., 2001) or cocaine (Grimm et al., 2001)
occurs.
511
A variety of neuroadaptations have been found within the
mesolimbic dopamine system and its primary terminal field, the
nucleus accumbens. These loci are central to current knowledge
of brain reward circuitry, and neuroadaptations in these loci are
of potential relevance to drug dependence. The known neuroad-
aptations range from morphological changes (Beitner-Johnson and
Nestler, 1991; Beitner-Johnson et al., 1992; Sklair-Tavron et al.,
1996) to changes in neurotransmitter sensitivity (Bell et al., 2000;
Henry and White, 1991) and changes in intracellular signalling
cascades and transcription factors (Cha et al., 1997; Chen et al.,
1997; Fitzgerald et al., 1996; Hope et al., 1992; Kelz et al., 1999;
Nestler et al., 1990; Terwilliger et al., 1991). Some of these
changes are associated with decreased sensitivity — tolerance — to
the drug, while others are associated with increased sensitiv-
ity — sensitization. Mechanisms of tolerance are consistent with
traditional dependence theory, but mechanisms of sensitization are
opposite to those associated with dependence theory, and the find-
ing that addictive drugs can sensitize the nervous system to the
drug’s rewarding action raises another challenge to dependence the-
ory and the question of whether its anatomy is part of the anatomy
of substance abuse.
Sensitization in Reward Pathways
Dependence theory is predicated upon the notion that increasing
amounts of the drug are needed to ameliorate withdrawal symptoms.
Dependence theory thus requires that the effects of repeated drug
experience decrease the sensitivity of the brain to the addictive
drug, and bias normal brain function in the opposite direction
from the acute drug state (Solomon and Corbit, 1973; Koob et al.,
1989). Some drug effects — in particular those associated with
somatic withdrawal symptoms — do appear to desensitize with
chronic drug treatment. The reward-specific effects of amphetamine
(Lett, 1989; Piazza et al., 1990; Lorrain et al., 2000), cocaine (Lett,
1989; Horger et al., 1990; Shippenberg and Heidbreder, 1995) and
morphine (Lett, 1989; Shippenberg et al., 1996), however, appear to
undergo sensitization, at least with intermittent repeated treatment.
Thus while it is true that tolerance to the rewarding effects of
cocaine can occur within a binge of cocaine self-administration
(Emmett-Oglesby and Lane, 1992; Li et al., 1994), sensitization
to the rewarding effects of cocaine appear to occur between such
binges. While tolerance usually decreases within a few days of the
last drug administration, sensitization to intermittent psychomotor
stimulants is very long lasting (Robinson and Becker, 1986).
The finding that between-session sensitization is much stronger
and longer-lasting than any obvious signs of tolerance to the
rewarding effects of these drugs has led to yet another positive
reinforcement perspective on addiction (Robinson and Berridge,
1993). This perspective has again raised the question of whether
drug dependence phenomena play the significant role in addiction
that has been suggested by dependence theory. The sensitization-
of-reward findings directly challenge all forms of dependence
or opponent process theory and raise, again, serious questions
about the relevance of the neuroanatomy of dependence to the
neuroanatomy of substance abuse. While it is clear that there
are drug-induced neuroadaptations within the reward system itself,
the importance of drug-opposite or drug-like neuroadaptations for
drug self-administration require direct experiments that have only
recently begun (Carlezon et al., 1998; Kelz et al., 1999).
NEUROANATOMY OF DRUG REWARD
While it does not make obvious sense to discuss a ‘trigger zone’
for the rewarding effect of such natural incentives as food or
sexual contact, it is well established that food, like the psychomotor
512 CLINICAL SYNDROMES: SUBSTANCE-RELATED DISORDERS
stimulants and a number of other drugs of abuse, depends upon
dopamine neurotransmission for its rewarding effects (Wise et al.,
1978; Spyraki et al., 1982; Ettenberg and Camp, 1986). The
major dopamine systems originate in the midbrain and have long-
axon projections to the forebrain. These neurones originate as
one embryonic group, but the somata spread laterally from the
midline and are somewhat arbitrarily subdivided into a nigrostriatal
system, originating primarily in the substantia nigra and projecting
primarily to the caudate nucleus, and a mesocorticolimbic system,
originating primarily in the more medial ventral tegmental area
and projecting primarily to the frontal and cingulate cortices, the
septum, hippocampus, amygdala and the nucleus accumbens. Of
the various dopaminergic terminal fields, the nucleus accumbens
is most clearly seen as serving motivational function (Mogenson
et al., 1980). It appears to house trigger zones — regions where the
drug binds and initiates its relevant pharmacological action — for
the rewarding effects of at least three classes of addictive drug.
Nucleus Accumbens
The nucleus accumbens appears to be the primary site of rewarding
action for amphetamine, one of two sites of rewarding action
for cocaine and for phencyclidine, and one of two sites of
putative rewarding action for addictive opiates. The mechanisms
of rewarding action of amphetamine and cocaine are secondary to
their actions at the dopamine transporter, by which they elevate
nucleus accumbens dopamine levels, whereas phencyclidine and
morphine have rewarding actions due to their actions at receptors
for the neurotransmitter glutamate or for one or more of the
endogenous opioid peptides, respectively. The rewarding action of
each appears to result in decreased activity in the medium-sized
spiny neurones that comprise the output neurones of the nucleus
accumbens. While much less is known about the habit-forming
actions of cannabis, alcohol, barbiturates, benzodiazepines and
caffeine, there are reasons to suspect that the nucleus accumbens
also plays a part in the habit-forming effects of these potentially
addictive agents.
Phencyclidine
Phencyclidine (PCP) is a non-competitive antagonist at the NMDA-
type excitatory amino acid receptor, where it blocks some of the
excitatory effects of glutamate (Chaudieu et al., 1989; Ohmori
et al., 1992). It is also, at higher concentrations, a dopamine
uptake inhibitor (Gerhardt et al., 1987). It is self-administered
compulsively by a small but stable subset of humans (Crider,
1986); it is also self-administered by laboratory animals (Balster
et al., 1973), but not with the vigour or reliability that characterizes
intravenous heroin or cocaine self-administration (Collins et al.,
1984). PCP has mixed rewarding and aversive actions when given
systemically (Barr et al., 1985; Crider, 1986; Iwamoto, 1986), but
has straightforward rewarding actions when given directly into the
shell portion of the nucleus accumbens (Carlezon and Wise, 1996).
PCP shares this rewarding action with NMDA antagonists that
do not affect dopamine uptake, and the rewarding action of these
agents in the nucleus accumbens is not attenuated by sulpiride, a D2
dopamine antagonist that attenuates the rewarding effects of nucleus
accumbens injections of the dopamine uptake inhibitor nomifensine
(Carlezon and Wise, 1996). Thus PCP has dopamine-independent
rewarding actions at the NMDA receptor, where it binds at 10 times
lower concentration than is required for its binding at the dopamine
transporter (Chaudieu et al., 1989; Ohmori et al., 1992).
Before accepting the assumption that intracranial injections of
a drug identify the systems where it acts, one should require
convincing evidence that the drug is not diffusing from the site
of injection to a distal site of action. A central drug injection
can reach a distant site of action in three ways. First, it may
simply diffuse through the extracellular space to adjacent structures.
Only if injections into surrounding structures are less effective
and occur with greater latency can we conclude that a drug is
acting in a given target site. Second, drugs that readily cross
the blood– brain barrier can reach distal sites of action via the
circulation. The obvious safeguard against this possibility is the
demonstration that the same low doses are ineffective when given
intravenously. Finally drugs injected under hydraulic pressure can
follow the pressure gradient up the cannula shaft, and, if the cannula
penetrates a ventricle, to the ventricular pressure sink through
which it can reach distal circumventricular organs. This artefact
led to misinterpretation of several studies involving the effects
of central hormone and neurotransmitter injections on drinking
behaviour (Johnson and Epstein, 1975). In the case of intracranial
self-administration of PCP, fluid egress up the cannula shaft is
the most likely of these possibilities. The lateral ventricle is just
above the nucleus accumbens, and a vertical penetration to the
shell of the nucleus accumbens usually involves penetration of the
ventricle, establishing a pressure gradient from the cannula tip to
the ventricular system (where fluid flows naturally from the lateral
to the third and fourth ventricles and cerebrospinal aqueduct. The
demonstration that PCP is self-administered into the shell of the
nucleus accumbens (Carlezon and Wise, 1996) has two controls
that increase confidence that the drug’s rewarding action is in the
nucleus accumbens. First, an angled cannula was used to avoid
penetration of the ventricle. Second, rats did not self-administer
PCP to a site in the core of the nucleus accumbens, 1 mm dorsal
and slightly lateral — along the same cannula track — to the positive
reward sites in the shell of the accumbens. Such essential controls
(Routtenberg, 1972; Wise and Hoffman, 1992) are lacking in most
central injection studies, and this fact leaves interpretation of several
central injection studies in doubt.
Amphetamine
Amphetamine binds to and reverses monoamine transporters, caus-
ing release of noradrenaline (norepinephrine), dopamine and sero-
tonin. The first evidence of a role for dopamine in drug reward came
from studies in which intravenous amphetamine self-administration
was disrupted by treatment with dopamine-selective (but not
noradrenaline-selective) receptor antagonists (Yokel and Wise,
1975, 1976; Risner and Jones, 1976). Lesions of the nucleus accum-
bens, like treatment with dopamine receptor blockers, attenuate
intravenous amphetamine self-administration (Lyness et al., 1979).
Amphetamine is self-administered directly into the nucleus accum-
bens but not into the lateral ventricles (Hoebel et al., 1983); this
self-administration of amphetamine is not evident if amphetamine is
co-injected with dopamine antagonists (Phillips et al., 1994). Local
injections of amphetamine into this region but not adjacent regions
also establish conditioned place preferences (Carr and White, 1983).
Thus the nucleus accumbens is a critical site for the habit-forming
actions of amphetamine; amphetamine’s rewarding action depends
on the activation of local dopamine receptors by the extracellular
dopamine that accumulates (Zetterström et al., 1981) because of
amphetamine’s action at the dopamine transporter.
Once a period of amphetamine self-administration has been
initiated, extracellular dopamine concentration appears to regulate
the frequency of continued responding. Rats tend to respond to
amphetamine until their nucleus accumbens dopamine levels are
elevated three- to five-fold; they then wait until prior injections
are partially metabolized and their dopamine levels have fallen
to approximately twice-normal levels before responding again
(Ranaldi et al., 1999). Thus dopamine actions in the nucleus
accumbens are not only critical for whether or not amphetamine is
rewarding; they also appear to determine how long a given injection
will satiate an animal.
 FUNCTIONAL ANATOMY
Cocaine
Cocaine, like amphetamine, is rewarding through its ability to ele-
vate nucleus accumbens dopamine levels (de Wit and Wise, 1977;
Risner and Jones, 1980). Whereas amphetamine is a dopamine
releaser, cocaine is a dopamine uptake inhibitor (Heikkila et al.,
1975a, 1975b). While cocaine appears to be more effective as
a reinforcer when injected into the frontal cortex (Goeders and
Smith, 1983), if animals are given sufficient exposure they will self-
administer it directly into the nucleus accumbens (Carlezon et al.,
1995), where dopamine-selective lesions attenuate the rewarding
effects of intravenous cocaine (Roberts et al., 1977, 1980). More-
over, frontal cortex injections of cocaine appear to be reward-
ing because they trans-synaptically elevate nucleus accumbens
dopamine levels (Goeders and Smith, 1993). Nomifensine, a more
selective (Samanin et al., 1975) and efficacious (Nomikos et al.,
1990) dopamine uptake inhibitor, is also rewarding in the shell
(but not the core) of the nucleus accumbens, and its effective-
ness is blocked by co-administration of the D2 dopamine antagonist
sulpiride (Carlezon et al., 1995). This suggests that it is not the local
anaesthetic action of cocaine (Ritchie and Greene, 1985) in nucleus
accumbens that accounts for its rewarding actions there. Self-
administered doses of cocaine, like self-administered amphetamine,
elevate nucleus accumbens dopamine levels (Hurd et al., 1989; Pet-
tit and Justice, 1989) and maintain them at levels two or more times
above normal baseline levels (Wise et al., 1995b).
Opiates
It is also thought that opiates trigger rewarding actions in the
nucleus accumbens. Morphine (Olds, 1982) and the endogenous
opioid met-enkephalin (Goeders et al., 1984) are reported to be
self-administered into this region, and morphine injections into
this region are reported to cause conditioned place preferences
(van der Kooy et al., 1982). Some concern must remain, however,
as to whether opiate injections into this brain region have their
rewarding actions locally (Wise, 1989). In studies where nucleus
accumbens self-administration or conditioned place preference has
been reported, anatomical controls that would rule out drug efflux
to the ventricular system or adjacent sites have not been reported.
This is troublesome because much lower doses of morphine are self-
administered or cause conditioned place preferences when injected
into other brain sites (Bozarth and Wise, 1981, 1982; Bozarth,
1987; Olmstead and Franklin, 1997). Moreover, some workers have
reported nucleus accumbens opiates to be ineffective in each of
these reward paradigms (Bozarth and Wise, 1982; Schildein et al.,
1998; Zangen et al., 2000).
It is tempting, nonetheless, to suspect that opiates at high
enough concentrations can induce rewarding effects at nucleus
accumbens opiate receptors. There are several populations of opioid
receptors in nucleus accumbens, and µ- and δ-opioids inhibit
nucleus accumbens medium spiny neurones (Hakan and Henriksen,
1989; Jiang and North, 1992). There are µ-opioid receptors on
the medium spiny output neurones of the nucleus accumbens
(Wang et al., 1997). Activation of these receptors is thought to
inhibit medium spiny neurone activity much as does dopamine and
systemic morphine (Hakan and Henriksen, 1989). In addition, there
are both µ- and δ-opioid receptors on the presynaptic terminals of
corticolimbic glutamate inputs to the nucleus accumbens. Actions
at each of these receptor subtypes appear to inhibit release of the
excitatory amino acid glutamate onto medium spiny neurones (Jiang
and North, 1992), much as does blockade of NMDA receptors
by PCP. The two compounds that have been reported to be
self-administered into the nucleus accumbens, morphine and met-
enkephalin, each activate both µ- and δ-opioids. There are also
κ-opioid receptors in the nucleus accumbens, but κ-opioids are
513
aversive and act at the dopamine transporter to decrease dopamine
release (Thompson et al., 2000).
Cannabinoids
While there are no behavioural studies in which local injections
of cannabinoids were used to localize a rewarding site of action,
there is evidence that cannabinoids can influence the mesolimbic
dopamine system. The major psychoactive constituent of marijuana
and hashish is 9 -tetrahydrocannabinol (THC). Partly for reasons of
solubility, this substance appears to have its greatest abuse liability
when smoked. Recently, however, intravenous self-administration
of THC has been demonstrated in squirrel monkeys (Tanda et al.,
2000) and intravenous self-administration of a synthetic cannabi-
noid has been shown in mice (Martellotta et al., 1998). Systemic
treatment with THC can also establish conditioned place prefer-
ences (Lepore et al., 1995; Valjent and Maldonado, 2000).
THC elevates nucleus accumbens dopamine levels when given
either systemically (Chen et al., 1990) or directly into the nucleus
accumbens (Chen et al., 1993), and it enhances potassium-induced
dopamine release in much the same way as do dopamine uptake
inhibitors (Ng Cheong Ton et al., 1988). Such elevations appear to
occur selectively in the shell of the nucleus accumbens (Tanda et al.,
1997a). When THC is given in combination with haloperidol, the
dopamine release normally caused by haloperidol-induced blockade
of dopamine autoreceptors is enhanced, as it is by dopamine uptake
inhibitors (Gardner et al., 1990). Finally, THC’s effect on nucleus
accumbens levels of the dopamine metabolite 3-methoxytyramine
resembles the effects of a dopamine uptake inhibitor (Heal et al.,
1990) like cocaine or nomifensine (Chen et al., 1994). It would
thus seem that at least some part of the habit-forming effects of
THC is triggered in the nucleus accumbens or somehow depends
on nucleus accumbens dopaminergic function.
Alcohol
Ethanol elevates nucleus accumbens dopamine levels (Imperato and
Di Chiara, 1986; Gonzales and Weiss, 1998; Weiss et al., 1993),
and intra-accumbens microinjections of the dopamine D2 receptor
antagonist raclopride produce dose-orderly decreases in ethanol
self-administration (Samson et al., 1993). Thus it seems likely that
alcohol has habit-forming actions mediated in part by the nucleus
accumbens. In this case, however, there is no evidence to suggest
that alcohol’s interface with drug reward circuitry is within the
nucleus accumbens.
Caffeine
The only links between caffeine and drug reward circuitry are
extremely speculative. There is no direct experimental evidence on
caffeine’s central sites of rewarding action. Indeed, although reports
do exist of successful caffeine self-administration in laboratory rats
(e.g., Collins et al., 1984), monkeys (e.g., Deneau et al., 1969)
and baboons (e.g., Griffiths et al., 1979), the bulk of the existing
literature suggests that caffeine self-administration in laboratory
animals is inconsistent and sporadic at best (see reviews by Griffiths
and Woodson, 1988; Griffiths and Mumford, 1995; Howell et al.,
1997). More consistently, caffeine has been reported to augment
the reinforcing properties (e.g., Schenk et al., 1994; Shoaib et al.,
1999), prolong extinction of self-administration (e.g., Kuzmin et al.,
1999) and trigger reinstatement of extinguished self-administration
(Schenk and Partridge, 1999) of other addictive drugs.
Caffeine is an antagonist at adenosine A1 and A2 receptors,
and its behavioural effects appear to be mostly mediated by
such actions (Fredholm et al., 1999). As adenosine A1 (Goodman
and Snyder, 1982; Fastbom et al., 1987) and A2A (Dixon et al.,
514 CLINICAL SYNDROMES: SUBSTANCE-RELATED DISORDERS
1996; Rosin et al., 1998) receptors are densely distributed in the
nucleus accumbens, as A2A receptors are extensively co-localized
with dopamine D2 receptors and preproenkephalin mRNA in
accumbens medium spiny neurones (Svenningsson et al., 1997,
1998), and as A2A receptors are also co-localized (sparsely to be
sure, but significantly above background levels) with dopamine
D1 receptors in the accumbens (Svenningsson et al., 1997, 1998),
it may be surmised that adenosine receptor activation in the
accumbens modulates meso-accumbens dopaminergic function.
Indeed, considerable evidence exists that A1 or A2A receptor
activation inhibits dopaminergic function mediated through either
the D1 or D2 receptor, and that adenosine antagonism enhances
meso-accumbens dopaminergic function (e.g., Turgeon et al., 1996;
Le Moine et al., 1997; Moreau and Huber, 1999; Svenningsson
et al., 1999; Poleszak and Malec, 2000). In a standard drug
discrimination assay in monkeys, adenosine antagonism generalizes
dose-dependently and completely to eight different dopamine
receptor agonists that encompass a variety of mechanisms and sites
of action, both pre- and postsynaptic (Holtzman, 1999). Further,
the discriminative stimulus properties of the non-selective A1 /A2
adenosine antagonist CGS-15943 are blocked dose-dependently and
completely by the dopamine D1 antagonist SCH-23390 and the
D2 antagonist eticlopride (Holtzman, 1999). Congruently, caffeine
enhances dopamine turnover in the striatum (Waldeck, 1972, 1975;
Watanabe and Uramoto, 1986) and enhances striatal dopamine
release in freely moving rats as measured by in vivo voltammetry
(Morgan and Vestal, 1989). Recent evidence suggests that adenosine
and dopamine receptors form heterodimers in medium spiny
neurones (Franco et al., 2000). All of these interesting findings
notwithstanding, it is only by tentative and arbitrary decision-
making that we include caffeine with habit-forming drugs having
rewarding sites of action in the nucleus accumbens. There is no
evidence that caffeine has its rewarding action at trigger zones in
the nucleus accumbens, and it is listed here simply because we
could suggest no more relevant place for it.
Ventral Tegmental Area
Opiates
A good deal of evidence suggests that the primary site of rewarding
action of opiates is in the ventral tegmental area, where µ-opioids
disinhibit the mesocorticolimbic dopamine system by inhibiting the
GABAergic cells that normally hold their dopaminergic neighbours
under inhibitory control (Johnson and North, 1992). First, µ- and
δ-opioids are self-administered into the ventral tegmental area
but not into an area just dorsal to it (Bozarth and Wise, 1981;
Welzl et al., 1989; Devine and Wise, 1994; Zangen et al., 2000).
The µ-opioid DAMGO is 100 times more potent than the δ-
opioid DPDPE. Ventral tegmental injections of these substances
elevate nucleus accumbens dopamine levels (Leone et al., 1991;
Devine et al., 1993), and DAMGO is here again 100 times more
potent than DPDPE. Opiate antagonists injected into the ventral
tegmental area decrease the rewarding effects of intravenous heroin,
although there is disagreement as to whether they do so more
potently than antagonists injected into the nucleus accumbens (Britt
and Wise, 1983; Vaccarino et al., 1985). Opioid doses that are
ineffective in the nucleus accumbens establish intracranial self-
administration and conditioned place preferences in the ventral
tegmental area (Bozarth, 1987; Olmstead and Franklin, 1997;
Zangen et al., 2000). Indeed, in other behavioural tests opioids
have stronger behavioural effects when injected into the ventral
tegmental area than when injected into the nucleus accumbens
(Broekkamp et al., 1976; Kalivas et al., 1983; Jenck et al., 1987;
West and Wise, 1988; Zangen et al., 2000) unless the nucleus
accumbens is pharmacologically or neurotoxically deprived of
dopamine (Stinus et al., 1985, 1986).
It is clear that self-administered intravenous doses of heroin
are sufficient to activate the mesolimbic dopamine system, as
self-administered intravenous heroin elevates nucleus accumbens
dopamine much as do self-administered amphetamine and cocaine
(Wise et al., 1995a). Thus — since it is unlikely that medium spiny
neurones in the nucleus accumbens can discriminate the dopamine
overflow that results from heroin’s action at the dopamine cell
bodies from that resulting from amphetamine’s or cocaine’s actions
at the dopamine transporter — it seems clear that opiate actions
triggered in the ventral tegmental area must contribute significantly
to the rewarding effects of intravenous heroin. This suggestion
is strengthened by the fact that the initiation of the next within-
session lever-press for intravenous heroin, like those for intravenous
amphetamine and cocaine, can be predicted by the fall of nucleus
accumbens dopamine levels to a trigger point about twice the
normal dopamine concentration (Pocock et al., 1994).
Nicotine
Nicotine also triggers its rewarding actions in the ventral tegmental
area. Here the critical receptors are on the dopaminergic neu-
rones themselves (Clarke and Pert, 1985). Intravenous nicotine
self-administration is blocked by dopamine antagonists and neu-
rotoxins as well as by chlorisondamine (Corrigall et al., 1992), a
nicotinic channel blocker that is taken up and concentrated within
the dopaminergic cell bodies of the ventral tegmental area and
substantia nigra (El-Bizri et al., 1995). Nicotine increases dopamin-
ergic cell firing (Grenhoff et al., 1986; Mereu et al., 1987) and
elevates dopamine levels in the nucleus accumbens (Imperato et al.,
1986). Thus nicotine, like amphetamine, cocaine and morphine,
appears to be habit-forming because it elevates dopamine levels in
the nucleus accumbens.
Nicotine also elevates dopamine levels when infused directly into
the nucleus accumbens, where the cholinergic agonist carbachol is
self-administered (Ikemoto et al., 1998a). However, as is the case
with ventral tegmental and nucleus accumbens administration of
opioids, nucleus accumbens actions of nicotine appear to be weaker
than the ventral tegmental actions of nicotine (Benwell et al., 1993;
Nisell et al., 1994) and thus seem unlikely to account for the
rewarding effects of systemic nicotine (Corrigall et al., 1992).
Cannabinoids
Like morphine, THC has actions in the ventral tegmental area
(VTA) as well as in the nucleus accumbens. First, it stimulates
dopaminergic cell firing and this effect is not blocked — while
at least part of the elevations seen in dialysis studies are (Chen
et al., 1990; Tanda et al., 1997a) — by opiate antagonists (French,
1997; Melis et al., 2000). Second, local application of THC to
the ventral tegmental area elevates ventral tegmental but not
nucleus accumbens dopamine levels (Chen et al., 1993). This
effect is tentatively interpreted as a reflection of the inhibition
of dendritically released dopamine; it is not known if this local
effect of THC in the VTA is naloxone-sensitive. Local injections
of cannabinoids into the VTA have not been tested in behavioural
paradigms.
Alcohol
Ethanol increases the firing rate of dopamine neurones in the
rat VTA (Gessa et al., 1985; Brodie et al., 1990) and it is
self-administered directly into the VTA (McBride et al., 1993;
Gatto et al., 1994; Rodd-Henricks et al., 2000). This intracra-
nial self-administration of ethanol was seen in selectively bred
alcohol-preferring and ordinary Wistar rats, but not in selec-
tively bred alcohol-non-preferring rats. The animals performing
 FUNCTIONAL ANATOMY
such intracranial ethanol self-administration show lever discrimina-
tion, extinction of self-administration when vehicle is substituted
for ethanol, and reinstatement of self-administration responding
on the active lever when ethanol is once again made available
(Rodd-Henricks et al., 2000). Sites dorsal to the VTA do not
support ethanol self-administration (Gatto et al., 1994). In a map-
ping study, posterior ventral tegmental sites were found to sup-
port ethanol self-administration; anterior ventral tegmental sites
did not (Rodd-Henricks et al., 2000). As noted by McBride et al.
(1999), intracranial ethanol self-administration may involve brain
serotonin (5HT) mechanisms, especially 5HT3 receptors. Ethanol
potentiates the depolarizing effects of 5HT at the 5HT3 receptor
(Lovinger and White, 1991), and local 5HT3 agonist microinfusion
increases somatodendritic dopamine release in the VTA (Camp-
bell et al., 1996), suggesting that activation of 5HT3 receptors
in the VTA may activate meso-accumbens dopamine neurones.
Most provocatively, local 5HT3 antagonist microinfusion prevents
ethanol-induced somatodendritic dopamine release in the ventral
tegmental area (Campbell et al., 1996), suggesting that ethanol’s
action on meso-accumbens dopamine neurones is mediated via VTA
5HT3 receptors. Ethanol’s actions on meso-accumbens dopamine
neurones may also involve GABAA -(Harris et al., 1995) or NMDA-
mediated (Weight et al., 1991) mechanisms.
Barbiturates and Benzodiazepines
Barbiturates and benzodiazepines are self-administered and can be
abused by humans. These drugs are also self-administered in ani-
mal models, more readily in primates than in rodents (Ator and
Griffiths, 1987). Neither self-administration nor conditioned place
preferences have been established with intracranial injections; thus
notions of the sites of rewarding action for these drugs are largely
based on evidence that barbiturates and benzodiazepines act via an
interaction with GABAA receptors (e.g., Korpi et al., 1997; Chebib
and Johnston, 1999). Inasmuch as opiates are thought to have
rewarding actions by decreasing GABAA inhibition of dopamin-
ergic neurones in the VTA, one possibility is that barbiturates and
benzodiazepines have dopamine-dependent rewarding actions in the
VTA. This fits with the finding that dopaminergic lesions of the
nucleus accumbens produced by microinjections of the dopamin-
ergic cytotoxin 6-hydroxydopamine block diazepam-induced con-
ditioned place preference (Spyraki and Fibiger, 1988). However,
the GABAergic synaptology of the ventral region area is com-
plex, as GABAergic neurones comprise not only afferents to but
also efferents from this region. Recent evidence suggests that some
GABAergic drug actions are reflected in dopaminergic output and
others are reflected in non-dopaminergic output (Laviolette and van
der Kooy, 2001).
Non-Dopamine Output from the VTA
The view that rewarding brain stimulation, natural rewards like
those of food and sexual contact, and several drug rewards owe
their ability to control behaviour to the fact that they elevate
mesolimbic dopamine levels is widely but not uniformly accepted
(Wise, 1996b; but see Koob and Goeders, 1989; Bechara et al.,
1998). Several recent findings suggest that the dopaminergic output
of the VTA is not the only contribution of this region to reward
function.
First, ventral tegmental microinjections of a D1 -type dopamine
antagonist reduce the rewarding effects of intravenous cocaine
(Ranaldi and Wise, 2001). D1 -type dopamine receptors are not
expressed by the dopaminergic neurones of the VTA or adjacent
substantia nigra themselves; rather, the D1 receptor populations
in this brain region are thought to be localized primarily to
the terminals of GABAergic inputs to this region (Altar and
515
Hauser, 1987; Beckstead, 1988). The evidence for this localization,
however, is based on the adjacent substantia nigra, where D1
receptor-expressing GABAergic terminals synapse primarily on
GABAergic output neurones of the zona reticulata. There is dense
expression of D1 receptors in the zona reticulata of substantia
nigra, and sparse expression in the zona compacta and VTA. This
density parallels the density of GABAergic cell bodies and of
GABAergic input in terminals that co-localize dynorphin, which
identifies the D1 -expressing GABAergic medium spiny neurones
of the striatum. This evidence suggests, very indirectly, that the D1
receptors in the VTA and zona compacta are likely to be localized
to GABAergic inputs to GABAergic rather than to dopaminergic
targets. Ventral tegmental administration of D1 -type agonists causes
increased glutamate as well as increased GABA efflux, however,
raising the possibility that D1 receptors may also be expressed on
glutamatergic input to the VTA (Kalivas and Duffy, 1995).
The GABAergic anatomy of the VTA and substantia nigra
is complex. The substantia nigra, and to a lesser extent the
VTA, contains GABAergic neurones with dominant projections
to the pedunculopontine tegmental nuclei (Gerfen et al., 1982),
and to the superior colliculus and medial thalamus (Williams and
Faull, 1988). GABAergic cells of the VTA also project to the
nucleus accumbens (Van Bockstaele and Pickel, 1995). GABAergic
neurones also project to and inhibit (Johnson and North, 1992)
their dopaminergic neighbours; it was originally suspected that this
inhibition was accomplished by GABAergic local circuit neurones
(Grace and Bunney, 1985), but recent evidence suggests that it
is collaterals from GABAergic projection neurones that account
for the tonic inhibition of nearby dopaminergic neurones (Tepper
et al., 1995).
Three lines of recent investigation suggest heterogeneity of
GABAergic participation in reward function. First, Ikemoto et al.
(1997b) have found that rats will self-inject the GABAA antagonist
picrotoxin into the anterior but not the posterior VTA, and
that this behaviour is disrupted by co-infusion of the GABAA
agonist muscimol. However, when injected into the posterior
VTA, muscimol is rewarding (Ikemoto et al., 1998b). Zangen et al.
(2000) also found evidence of rostral–caudal differences in ventral
tegmental reward; they report that endomorphin-1, the endogenous
ligand for the µ-opioid receptor (the rewarding effects of which
are thought to be mediated by µ-opioid receptors on GABAergic
neurones: Johnson and North, 1992), is vigorously self-administered
into the posterior VTA but much less vigorously self-administered
into the anterior VTA. Laviolette and van der Kooy (2001) have
reported that the rewarding effects of ventral tegmental injections
of the GABAA agonist muscimol are dopamine-dependent whereas
the rewarding effects of ventral tegmental injections of the GABAA
antagonist bicuculline are dopamine-independent.
Medial Prefrontal Cortex
Cocaine
Cocaine is self-administered directly into the medial prefrontal
cortex (Goeders and Smith, 1983, 1986). It is difficult to imagine
how injections into this area could diffuse to the nucleus accumbens,
the other area implicated in cocaine reward. The self-administration
of cocaine in this region is dopamine-dependent, as co-infusion of
the D2 dopamine antagonist sulpiride blocks the effect (Goeders
et al., 1986). It is not at all clear, however, that cocaine is effective
in the frontal cortex — as it is in the nucleus accumbens — because
of its ability to block the dopamine transporter. The dopamine
transporter is sparsely distributed in the frontal cortex (Garris and
Wightman, 1994; Sesack et al., 1998), where it is the noradrenaline
transporter that seems to be most strongly implicated in dopamine
clearance (Tanda et al., 1997b; Yamamoto and Novotney, 1998;
516 CLINICAL SYNDROMES: SUBSTANCE-RELATED DISORDERS
Morón et al., 2001). The noradrenaline transporter has greater
affinity for dopamine than does the dopamine transporter, and in the
frontal cortex, unlike nucleus accumbens, it is abundant. Thus it is
probably cocaine’s ability to block the noradrenaline transporter in
the frontal cortex that accounts for its self-administration into this
area. Whatever the local site of action, self-administered cocaine in
the frontal cortex causes elevation of dopamine levels in the nucleus
accumbens, and this presumably trans-synaptic effect is thought to
be necessary for cocaine’s rewarding effects in the frontal cortex
(Goeders and Smith, 1993).
Phencyclidine
Phencyclidine is also self-administered into the medial prefrontal
cortex (Carlezon and Wise, 1996), where direct electrical stimula-
tion is also rewarding (Routtenberg and Sloan, 1972; Corbett et al.,
1982). In this case the mechanism of action is not well under-
stood, but it should be noted that the prefrontal cortex is intimately
linked to the mesolimbic dopamine system. The ventral tegmen-
tal dopaminergic neurones project to the medial prefrontal cortex,
where they synapse on GABAergic interneurones and on the pyra-
midal cells that are the cortical output neurones (Goldman-Rakic
et al., 1989; Sesack et al., 1995). The prefrontal cortex neurones, in
turn, project to both the nucleus accumbens and the VTA (Christie
et al., 1985; Sesack et al., 1989; Sesack and Pickel, 1992). The pri-
mary neurotransmitter of these neurones is glutamate (Druce et al.,
1982; Sandberg et al., 1985), and they co-localize the neuropeptide
cholecystokinin (CCK) (Meyer et al., 1982; Hökfelt et al., 1988).
These neurones are of interest because the release of CCK in both
VTA and nucleus accumbens is more proportional to the strength
of rewarding electrical stimulation of the prefrontal cortex than is
the release of either dopamine or glutamate in either structure (You
et al., 1998).
Conceptual Nervous System of Addiction
While only a portion of the anatomy of substance abuse is known,
a preliminary sketch of several important links in the rewarding
effects of drugs can be suggested. At its core is the mesolimbic
dopamine system with its cells of origin in the VTA and its most
important terminals in the nucleus accumbens. The trigger zones for
the habit-forming actions of nicotine and opiates are in the VTA;
the critical receptors are expressed by dopaminergic neurones and
GABAergic neurones, respectively. The endogenous ligand for the
µ-opioid receptor in this region is endomorphin-1, which projects to
the VTA from the cells in either the hypothalamus or the nucleus of
the solitary tract (Martin-Schild et al., 1999); the endogenous ligand
for the nicotinic receptor in this region is acetylcholine, which
is released in the VTA by projections from the pedunculopontine
tegmental nucleus (Oakman et al., 1995).
Trigger zones for the habit-forming actions of amphetamine,
cocaine and phencyclidine are in the nucleus accumbens. The
binding sites for amphetamine and cocaine are the dopamine
transporters on dopaminergic nerve terminals in this region; the
trigger zone for phencyclidine seems to be the NMDA receptor
on medium spiny neurones. The endogenous transmitter mediating
the rewarding effects of amphetamine and cocaine is dopamine; it
appears to require synergistic effects (see, e.g., Clark and White,
1987) of both D1 -type and D 2 -type receptors for dopamine to be
rewarding (Ikemoto et al., 1997a). The endogenous transmitter that,
when blocked, accounts for the rewarding effects of phencyclidine
would appear to be glutamate; glutamatergic afferents to the nucleus
accumbens arise from a variety of cortical structures.
Additional trigger zones for cocaine and phencyclidine effects
are found in the medial prefrontal cortex; the receptor mediating
the rewarding effects of phencyclidine again appears to be the
NMDA receptor. It is not clear what binding site mediates the
rewarding effects of cocaine in the medial prefrontal cortex.
While the rewarding effects of cocaine in this region appear
to be dopamine-dependent, since they are blocked by the D2
dopamine antagonist sulpiride and are eliminated by dopamine-
specific neurotoxic lesions (Goeders et al., 1986; Goeders and
Smith, 1986), cocaine does not appear to have its rewarding effects
as a result of actions at the dopamine transporter because this
transporter is sparsely distributed in this region. Rather, cocaine’s
ability to elevate frontal cortex dopamine concentration appears
to depend on its blockade of the noradrenaline transporter, which
apparently takes up dopamine into noradrenergic nerve terminals.
The findings reviewed above suggest a common reward circuitry
associated with a broad range of addictive drug classes. At the
core of the circuitry are the mesolimbic dopamine system and
the descending anatomical cascade of GABAergic neurones that
dominate the efferent pathway from nucleus accumbens. While this
unifying theme is attractive, the evidence for actions of different
drugs in this system is consistent but minimal in several cases. A
good deal of additional evidence will be needed, either to tie each of
these drugs unequivocally to the suggested circuitry or to establish
separate, parallel, reward circuitry for the drug classes for which
current evidence remains limited. Moreover, we are hardly closer
now than we were 20 years ago (Nauta et al., 1978; Mogenson
et al., 1980) to understanding how the activity of these segments of
motivational circuitry interfaces with and controls the mechanisms
of behavioural action.
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