Professional Documents
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Colin Haile
Neuroscience Winter 2004
Lecture Notes: IV
LECTURE 36: Olfaction and Gustation
Olfactory System
• The olfactory system mediates the special visceral afferent (SVA) modality of
smell via the olfactory nerve (CN I).
• It is the only sensory system that has no pre-cortical relay in the thalamus.
• It eventually projects to the thalamus, hypothalamus, amygdala and
hippocampal formation.
Olfactory Pathway
• Olfactory cells are chemoreceptors numbering about 25 million on each side
of the nose.
• They are replaced throughout life and regenerate.
• Olfactory cells are found in the nasal mucosa and are first-order neurons in
the olfactory pathway.
• They are unmyelinated bipolar neurons whose central processes are CN I.
• They have axons that enter the olfactory bulb and synapse in the olfactory
glomeruli with mitral and tufted cells.
• Cribriform plate of the ethmoid bone, as seen from inside a human skull.
• Olfactory fila pass through small holes (arrows) in the plate to reach the
olfactory bulb.
The Vomeronasal Organ – menstrual synchronization
Location of Olfactory Epithelium
• Olfactory epithelium is located on the lateral wall of the nasal cavity and
continues across the roof of the cavity into a patch of similar size on the nasal
septum.
• Odorants can reach this epithelium either through the nostrils or by way of
the oropharynx.
CN I: Olfaction
• Axons of the olfactory nerves are unmyelinated C fibers and are among the
smallest and slowest in the nervous system.
• Olfactory epithelium is also innervated by CN V (trigeminal) which detects
noxious or painful stimuli such as ammonia.
Chemosensory Transduction in Olfactory Receptor Cells
• Odorant molecules bind to receptors located on cilia of the olfactory receptor
neurons.
• When the receptors are activated, they activate G-proteins (Golf) which
activates adenylate cyclase.
• There is an increase in intracellular cAMP that opens Na+ channels in the
olfactory receptor membrane and produces a depolarizing receptor
potential.
• The receptor potential depolarizes the initial segment of the axon to
threshold, and action potentials are generated.
Glomeruli and Neurons of the Olfactory Bulb
• Most glomeruli in this drawing contain only one type of neural process,
either axon terminals of olfactory receptor neurons (go), dendrites of mitral
cells (gm), or dendrites of tufted cells (gt).
• In reality, each glomerulus contains all of these, together with processes of
interneurons.
Sorting of Olfactory Nerve Fibers Among Glomeruli
• Olfactory receptors are of different types, each type characterized by one or
a few receptor proteins and a restricted range of odor sensitivities
(represented as different colors), are intermingled with each other in a given
area of olfactory epithelium.
• The axon terminals of any given type all converge on one or two glomeruli
(which in reality would contain thousands of axon terminals and the
dendrites of dozens of mitral and tufted cells).
Olfactory Pathway
• The olfactory bulb lies on the cribriform plate of the ethmoid bone and
receives the olfactory nerve.
• It contains mitral and tufted cells (second-order neurons) that project via the
olfactory tract and the lateral olfactory stria to the primary olfactory cortex
and the amygdaloid nucleus.
Olfactory Pathway
• Olfactory tract contains the anterior olfactory nucleus which gives rise to the
medial and lateral olfactory striae.
• It projects to the contralateral olfactory tract via the anterior commissure.
• The lateral olfactory stria projects to the primary olfactory cortex and the
amygdaloid nucleus.
• The primary olfactory cortex overlies the uncus of the parahippocampal
gyrus (area 34).
• It receives input from the lateral olfactory stria and consists of prepiriform
and periamygdaloid cortices.
• The olfactory cortex projects to the medial dorsal nucleus of the thalamus,
via the amygdaloid nucleus to the hypothalamus and via the entorhinal
cortex (area 28) to the hippocampal formation.
• The mediodorsal nucleus of the thalamus projects to the orbitofrontal cortex,
where the conscious perception of smell takes place.
Clinical Correlations
• Anosmia: the loss of smell may occur as a result of a lesion of the olfactory
nerve (anosmia is unilateral).
• Olfactory nerves may be damaged by fractures of the cribriform plate, by
meningitis, meningiomas, gliomas, or by abscesses of the frontal lobes.
• Olfactory hallucinations may be a consequence of lesions of the
parahippocampal uncus.
• Foster Kennedy Syndrome results from a meningioma of the olfactory
groove, which compresses the olfactory tract and the optic nerve.
• It results in ipsilateral anosmia, optic atrophy, and contralateral
papilledema.
• Fractures of the cribriform plate of the ethmoid bone may result in anosmia
and cerebrospinal rhinorrhea.
Gustatory System
• The gustatory system mediates the somatic visceral afferent (SVA) modality
of taste.
• It mediates gustation, which like olfaction, is a chemical sense.
• Taste receptor cells line the taste buds that are located on specialized
papillae.
• The receptor cells are covered with microvilli, which increase the surface
area for binding taste chemicals.
• In contrast to olfactory receptor cells, taste receptors are not neurons.
Distribution of Taste Buds and Innervation
• The anterior two-thirds of the tongue:
– detects salty and sweet sensations.
– Is innervated by CN VII (chorda tympani).
• The posterior one-third of the tongue:
– Has circumvallate and foliate papillae.
– Detects sour and bitter sensations.
– Is innervated by CNIX (glossopharyngeal).
• The back of the throat and the epiglottis are innervated by CNX.
Morphology of Taste Buds
Transduction in Taste Receptor Cells
• (A) Tastant molecules activate the transduction machinery in the apical
microvilli of a taste cell (1) cause production of a depolarizing receptor
potential
• (2) entry of Ca2+ through voltage-gated CA2+ channels (3) release of
transmitter onto a peripheral nerve ending (4) and increased firing of the
nerve fiber (5).
• (B) Na+ ions (salty taste) flow directly into Na+ channels. (C), Protons (sour
taste, H+) either flow through Na+ channels (1) or cause normally open K+
channels (2) to close (3).
• The decreased K+ conductance causes the membrane potential to move
toward the Na+ equilibrium potential (i.e. depolarize).
• (D) Sweet substances all bind to G protein-coupled receptors (1).
• Dissociation of the G-protein from some of these receptors (3) activates an
enzyme (4) whose product (cAMP) leads to the closing of K+ channels (5)
that are normally open (2).
• (E) Some bitter substances bind (2) to normally open K+ channels (1),
causing them to close (3).
• Other bitter substances bind to G protein-coupled receptors (4).
• Dissociation of the G-protein (5) activates an enzyme (6) whose product leads
to the release of Ca2+ (8) from intracellular stores (7).
Gustatory Pathway
• Taste receptor cells are chemoreceptors; modified epithelia cells, not
neurons.
• They are continuously being regenerated and are located in the taste buds of
the tongue, epiglottis and palate.
• Taste receptor cells are innervated by SVA fibers of the facial nerve (CN
VII), the glossopharyngeal nerve (CNIX) and the vagal nerve (CN X).
• Taste buds on the tongue detect certain sensations:
• sweetness at the apex of the tongue
• saltiness posterolateral to the apex of the tongue
• bitterness on the circumvallate papillae
• sourness on the anterior two-thirds of the dorsal surface of the tongue
Innervation of Taste Buds
• Innervation of taste buds in different parts of the oral cavity by the facial
(VII), glossopharyngeal (IX) and vagus (X) nerves.
• The central processes of all three terminate in rostral parts of the nucleus of
the solitary tract. CT, Chorda tympani nerve; GG, geniculate ganglion; GP,
greater petrosal nerve; IG IX, inferior ganglion of the glossopharyngeal
nerve; IG X, inferior ganglion of the vagus.
Taste Pathway in the CNS
• Second-order neurons are located in the nucleus of the solitary tract.
• Second-order neurons feed into reflexes both by direct projection (e.g. to the
nearby dorsal motor nucleus of the vagus, DMN X) and by connections with
the reticular formation (RF).
The projection from the parabrachial nucleus to the hypothalamus (H) and
amygdala (A) is dashed because, although it is present in most mammals, its
presence in primates is doubtful.
Firing Patterns of Neurons and Taste
• Information about taste is coded by the pattern of activity in populations of
neurons.
• Responses of a single gustatory neurons in the nucleus of the solitary tract
(A) and the orbital cortex (B) of monkeys to tastants applied at the time
indicated by the vertical dashed lines.
• The brainstem neuron responds to multiple tastants, but the cortical neuron
is more selective.
Clinical Correlation
• Ageusia (gustatory anesthesia or lack of the sense of taste) is most commonly
caused by heavy smoking.
• Ageusia is most frequently associated with peripheral lesions of CN VII
(Bell’s palsy and diseases of the middle ear) and CN IX.
• All parts of the cerebral cortex send axons to the caudate nucleus and the
putamen.
• Each part of the cerebral cortex projects to a specific part of the caudate
putamen complex.
• Most of the projections are from the cortex of the same side.
• The largest input is from the sensory-motor cortex. Glutamate is the
neurotransmitter of the corticostriate fibers.
• Neurons in the substantia nigra send axons to the caudate nucleus and the
putamen and use dopamine at their terminals. These fibers are INHIBITORY.
• Ascending fibers from the brainstem end in the caudate nucleus and
putamen and use serotonin which is INHIBITORY.
• Striatopallidal fibers pass from the caudate nucleus and putamen to the globus
pallidus. They use GABA as their transmitter.
• Striatonigral fibers pass from the caudate nucleus and putamen to the
substantia nigra.
• Some of the fibers are GABAergic or use acetylcholine as the neurotransmitter
whereas others use Substance P.
Connections of the Globus Pallidus
• Pallidofugal fibers can be divided into groups:
• ansa lenticularis: which pass to the thalamic nuclei
• fasciculus lenticularis: which pass to the subthalamus
• pallidotegmental fibers: which terminate in the caudal tegmentum of the
midbrain
• pallidosubthalamic fibers: which pass to the subthalamic nuclei.
Summary of Neurotransmitters Utilized in the Basal Ganglia
Substantia nigra Caudate and Putamen
Dopamine
Caudate and Putamen Globus Pallidus and SN
GABA
Cortex Caudate and Putamen
Glutamate
• The word limbic means ‘border’ or ‘margin’ and the term limbic system was
loosely used to include a group of structures that lie in the border zone between
the cerebral cortex and the hypothalamus.
• Now however, it is known that the limbic system is involved with many other
structures beyond the border zone in the control of emotion, behavior, drive and
memory.
• Thus, the limbic system (or lobe) is the anatomical substrate for drive-related
and emotional behaviors.
• The limbic system is considered to be an anatomical substrate underlying
behavioral and emotional expression.
• It plays a role in:
• Feeling
• Feeding
• Fighting
• Fleeing
• And, Fu…..well…you know.
• It expresses itself through the hypothalamus via the autonomic nervous system
(ANS).
• Anatomically, the limbic structures include:
• cingulate
• parahippocampal gyrus
• hippocampal formation
• amygdaloid nucleus
• mammillary bodies
• anterior thalamic nucleus
Limbic System: Connecting Pathways
• The alveus, fimbria, fornix, mammillothalamic tract and the stria terminalis
constitute the connecting pathways of this system.
Hippocampal Formation
The hippocampal formation consists of the hippocampus the dentate gyrus and the
parahippocampal gyrus.
• The hippocampus is a curved elevation of gray matter that extends throughout
the entire length of the floor of the inferior horn of the lateral ventricle.
• It is named hippocampus because it resembles a sea horse in coronal section.
• The convex ventricular surface is covered with ependyma, beneath lies a thin
layer of white matter called the alveus.
• The alveus consists of nerve fibers that have originated in the hippocampus and
these converge medially to form a bundle called the fimbria.
• The hippocampus itself is divided up into section called “CA” fields or
sections.
• The dentate gyrus and the hippocampus proper have the form of two
interlocking Cs.
• The hippocampus is also sometimes called “Ammon’s horn” (or cornu
ammonis after an Egyptian deity with ram’s horns) because of the way the
hippocampus curve downward and outward from the hippocampal rudiment into
the temporal lobes.
• The fimbria becomes continuous with the crus of the fornix.
• The hippocampus terminates posteriorly beneath the splenium of the corpus
callosum.
• The anterior end is called the pes hippocampus.
• The dentate gyrus is a narrow notched band of gray matter that lies between the
fimbria of the hippocampus and the parahippocampal gyrus.
• Posteriorly, the dentate gyrus accompanies the fimbria almost to the splenium
of the corpus callosum and becomes continuous with the indusium griseum.
• The indusium griseum is a thin, vestigial layer of gray matter that covers the
superior surface of the corpus callosum.
• The parahippocampal gyrus lies between the hippocampal fissure and the
collateral sulcus and is continuous with the hippocampus along the medial edge
of the temporal lobe.
Afferents to the Hippocampus
• The major afferent to the hippocampus (H) is the entorhinal cortex, which in
turn collects inputs from the cingulate, temporal, and orbital cortices and from
the amygdala (Am) and olfactory cortex.
• Other inputs arrive from the septal nuclei and hypothalamus and from the
contralateral hippocampus enter via the fornix.(A, anterior thalamic nucleus)
Efferents from the Hippocampus
• The major efferent pathway is the fornix, through which fibers reach an
assortment of anteriorly situated forebrain structures. Many fibers pass directly
from the subiculum to the entorhinal cortex, to the amygdala, or backward
along the cingulum to the cingulate gyrus (A, anterior thalamic nucleus).
The Amygdala
• The amygdaloid nucleus is named because it resembles an almond.
• It is situated partly anterior and partly superior to the tip of the inferior horn of
the lateral ventricle.
• It is fused with the tip of the tail of the caudate nucleus, which passes anteriorly
in the roof of the inferior horn of the lateral ventricle.
• The amygdala lies beneath the uncus of the limbic lobe at the anterior end of the
hippocampus and inferior horn of the lateral ventricle.
• It merges with the periamygdaloid cortex, which forms part of the surface of
the uncus.
• The amygdala is centrally involved in emotional responses thus receives a
great deal of sensory input in a highly processed form.
• It receives somatosensory, visual, auditory and all types of visceral inputs.
Afferents to the Amygdala
• Afferents to the amygdala arrive via four routes: from the hypothalamus (Hy),
the septal nuclei (s) through the stria terminalis, from the thalamus (T) and
hypothalamus (Hy) and from orbital and anterior cingulate cortex, olfactory
bulb and olfactory cortex and directly from the hippocampus.
Efferents from the Amygdala
• Efferents from the amygdala take three routes: the stria terminalis which
reaches the septal nuclei (S) and hypothalamus (Hy); the ventral amygdalofugal
pathway to the hypothalamus, thalamus (T) frontal and insular cortex,
olfactory structures and other sites; direct projections to the hippocampus (H),
entorhinal cortex (E) and temporal and neocortical areas.
Connecting Pathways of the Limbic System
These pathways are the alveus, the fimbria, the fornix and the mammillothalamic tract
and the stria terminalis.
• The alveus consists of a thin layer of white matter that lies on the superior or
ventricular surface of the hippocampus.
• It is composed of nerve fibers that originate in the hippocampal cortex.
• Fibers converge on the medial border of the hippocampus to form a bundle
called the fimbria.
• The fimbria now leaves the posterior end of the hippocampus as the crus of the
fornix.
• The crus from each side curves posteriorly and superiorly beneath the splenium
of the corpus callosum and around the posterior surface of the thalamus.
• The two crura converge to form the body of the fornix which is applied closely
to the undersurface of the corpus callosum.
• As the crura come together, they are connected by transverse fibers called the
commissure of the fornix.
• These fibers decussate and join the hippocampi of the two sides.
• Anteriorly, the body of the fornix is connected to the undersurface of the corpus
callosum by the septum pellucidum.
• Inferiorly, the body of the fornix is related to the tela choroidea and the
ependymal roof of the fourth ventricle.
• The body of the fornix splits anteriorly into two anterior columns each of which
curves anteriorly and inferiorly over the interventricular foramen (foramen of
Monroe).
• Then each column disappears into the lateral wall of the third ventricle to
reach the mammillary body.
• The mammillothalamic tract provides important connections between the
mammillary body and the anterior nuclear group of the thalamus.
• The stria terminalis emerges from the posterior aspect of the amygdaloid
nucleus and runs as a bundle of nerve fibers posteriorly in the roof of the inferior
horn of the lateral ventricle.
• Mammillothalamic tract: Projection from the mammillary body to the anterior
nucleus of the thalamus.
• Part of the Papez circuit.
• Stria terminalis: Efferent from the amygdala to the septal nuclei, basal
forebrain and hypothalamus.
Structure of the Hippocampus and the Dentate Gyrus
• The cortical structure of the parahippocampal gyrus is six-layered. As the
cortex is traced into the hippocampus there is a gradual transition from a six to a
three-layered arrangement.
• These three layers are the:
• superficial molecular layer, consisting of many small neurons,
• pyramidal layer, consisting of many large pyramid-shaped neurons and the
inner
• polymorphic layer, which is similar in structure to the polymorphic layer of the
cortex seen elsewhere.
Functions of the Limbic System
• The limbic system via the hypothalamus and its connections with the outflow of
the ANS and its control of the endocrine system, influences many aspects of
emotional behavior.
• These include particularly the reactions of fear and anger and the emotions
associated with sexual behavior.
• Memory: the hippocampus is concerned with converting recent memory to
long term memory.
• Lesions of the hippocampus result in the individual not being able to store long-
term memories.
• Memory before the lesion are not affected (retrograde).
• This is called anterograde amnesia.
Papez Circuit
• James Papez pointed out in 1937 that this loop provided for interactions among
the neocortex, limbic structures, and the hypothalamus and proposed that it
might be the anatomical substrate for emotional experience.
• Beginning in the hippocampus, the pathway proceeds through the fornix to the
mammillary body, from there in sequence to the anterior thalamic nucleus, the
cingulate gyrus and part of the parahippocampal gyrus (entorhinal cortex) and
finally back to the hippocampus.
CLINICAL NOTES
Schizophrenia
• The symptoms of schizophrenia include chronically disordered thinking,
blunted affect, and emotional withdrawal.
• Paranoid delusions and auditory hallucinations may be present as well.
• Present-day anti-psychotics block dopamine receptors (e.g. phenothiazine) in
discrete areas of the limbic system, in turn, lessening the worst symptoms of the
disease.
• Unfortunately, these drugs have major motor side effects on dopaminergic
receptors (primarily D2) within the extrapyramidal system, producing
abnormal involuntary movements (tardive dyskinesia)
• Research of late has focused on other receptors that may be involved in
symptoms associated with schizophrenia (glutamatergic, AMPA,NMDA
receptors).
Destruction of the Amygdaloid Complex
• Unilateral or bilateral destruction of the amygdala in patients suffering from
aggressive behavior in many cases results in:
– decrease in aggressiveness (docility),
– emotional instability
– restlessness
– Hyperphagia (food)
– Hypersexuality
• Kluver-Bucy syndrome: results from bilateral ablation of the anterior
temporal lobes, included the amygdaloid nuclei.
• It causes psychic blindness (visual agnosia), hyperphagia, placidity,
hypersexuality.
Cingulate Gyrus
• Lesions of the cingulate gyrus results in:
– akinesia
– mutism
– apathy
– indifference to pain
Mamillary Bodies and Thalamus
• Mamillary bodies and the mediodorsal nucleus of the thalamus are damaged
by chronic alcoholism and thiamine (B1) deficiency which results in
Korsakoff’s Syndrome (amnestic-confabulatory syndrome).
• This syndrome is a late chronic stage of Wernicke encephalopathy.
• Clinical signs include memory disturbances (amnesia), confabulation, and
temporospatial disorientation.
Temporal Lobe Epilepsy
• The hippocampus is the most epileptogenic part of the cerebrum.
• Temporal lobe epilepsy may be preceded by an aura of acoustic or olfactory
experience.
• The olfactory aura is usually an unpleasant odor.
• The patient is often confused, anxious, and docile and may perform automatic
and complicated movements, such as undressing in public or driving a car and
then following the seizure may have no memory of what occurred.
Lesions in Limbic Structures
• Bilateral transection of the fornix may cause an acute amnestic syndrome—the
inability to consolidate short-term memory into long-term memory.
• Bilateral destruction or removal of the cingulate gyri causes loss of initiative
and inhibition as well as dulling of emotions.
– Memory is unaffected.
• Lesions of the anterior cingulate gyrus cause placidity.
• Cingulectomy is used to treat severe anxiety and depression.
Sedative-Hypnotics
• Sedatives are CNS depressants that include alcohol, barbiturates and
benzodiazepines.
• Sedative agents work primarily by increasing the activity of the inhibitory
neurotransmitter γ -aminobutyric acid (GABA).
• Hospitalization is required for those going through withdrawal syndrome
associated with these substances.
• Symptoms may include seizures and cardiovascular abnormalities which can
be life-threatening.
Alcohol
• Mead, a fermentation product of honey, is the oldest alcoholic beverage, having
existed in the Paleolithic age, about 8000 BC.
• Beer and wine were made by fermentation dating back to 3700 BC in Egypt.
• Distillation to obtain high alcohol concentrations was discovered in the Arab
world about 800 AD.
• The word “alcohol” is of Arabian origin, from the word that is transliterate as
alkuhl or al-koh’l (“something subtle”).
• Distillation of alcohol from fermented grain mixtures known as whisky became
popular in the Middle Ages (whisky comes from the Gaelic word usquebaugh
meaning “water of life”).
Alcohol: Epidemiology
• 50% of the population in the US have consumed alcohol within the last year.
• 85% have consumed alcohol in their lifetime.
• There is a 10-13% lifetime prevalence of abuse or dependence.
• The male:female ratio of abusers is at least 2:1.
• Higher rate of use occurs in Native Americans and Eskimos, the 21-34 year
old age group and residents of the Northeastern states.
• The lowest rate of use occurs in Utah because the Mormon religion prohibits
alcohol use.
Alcohol: Acute Problems
• Traffic accidents, homicide, suicide and rape are correlated with the concurrent
use of alcohol.
• Child physical and sexual abuse, spouse abuse, and elder abuse are also
associated with alcohol use.
Alcohol: Chronic Problems
• Thiamine deficiency resulting in Wernicke and Korsakoff syndromes is
associated with long-term use of alcohol.
• Liver dysfunction, gastrointestinal problems (e.g. ulcers), and reduced life
expectancy are also seen in heavy users of alcohol.
• Alcohol withdrawal delirium (delirium tremens or “the DTs”) may occur
during the first week of withdrawal from alcohol.
• It usually occurs in patients who have been drinking heavily for at least 5 years.
• DTs is life threatening; mortality rate is about 20%.
Fetal Alcohol Syndrome
• Fetal alcohol syndrome is seen in the offspring of women who drink during
pregnancy.
• Characteristics include facial abnormalities, reduced height and weight and
mental retardation.
• A childhood history of problems such as attention-deficit hyperactivity
disorder and conduct disorder correlate with alcoholism in the adult.
Alcohol Intoxication
• Legal intoxication is defined as 0.08%-0.15% blood alcohol concentration,
depending on individual state laws.
• Coma occurs at a blood alcohol concentrations 0.40%-0.50% in non-alcoholics.
Alcohol: Neurochemistry
• Unlike most other drugs of abuse, no single molecular target has been
identified as the mediator for the effects of alcohol.
• Data does support that alcohol produces its effects by increasing the fluidity of
membranes with short-term use.
• With long-term use however, membranes become rigid or stiff.
• Recently studies have found that alcohol exerts effects on ion channels.
• Specifically, nicotinic acetylcholine, serotonin 5-HT3 and GABAa receptors
are enhanced by alcohol.
• In contrast, ion channels associated with glutamate receptors or voltage-gated
calcium channels are inhibited.
Psychological and Physical Effects of Sedatives
• Mild elevation of mood.
• Decreased anxiety.
• Somnolence.
• Behavioral disinhibition.
• Sedation.
• Poor coordination.
• Respiratory depression.
Withdrawal Effects of Sedatives
• Mild depression of mood.
• Increased anxiety.
• Insomnia.
• Psychotic symptoms such as delusions and formication.
• Disorientation.
• Tremors, seizures and cardiovascular symptoms such as tachycardia and
hypertension.
Alcoholism: Treatment
• Alcoholics Anonymous (AA) and other voluntary peer support groups (12-
step programs).
• Disulfiram (Antabuse) to prevent use (causes a toxic reaction when alcohol is
ingested.
• Benzodiazepines for withdrawal symptoms.
• Thiamine (B1) for immediate emergency room treatment.
Sedatives: Barbiturates
• Barbiturates are used medically as sleep aids, sedatives, antianxiety agents
(tranquilizers), anticonvulsants, and anesthetics.
• Frequently used and abused barbiturates include amobarbital, pentobarbital,
and secobarbital.
• Barbiturates cause respiratory depression and have a low safety margin;
hence, they are drugs most commonly taken to commit suicide.
Sedatives: Benzodiazepines
• Benzodiazepines are used medially as tranquilizers, sedatives, muscle
relaxants, anticonvulsants, and anesthetics, and to treat alcohol withdrawal
(chlordiazepoxide and diazepam).
• Benzodiazepines have a high safety margin unless taken with another
sedative such as alcohol.
Benzodiazepine and Barbiturate Addiction: Treatment
• Hospitalization and gradual reduction in dosage of the abused drug by
substituting long-acting barbiturates (such as phenobarbital) for the more
commonly abused short acting types.
• Replacement with non-addictive antianxiety agents (i.e. buspirone [Buspar])
or sleep agent (i.e. zolpidem [Ambien]).
Opiates
• Theophrastus in the third century B.C. mentioned the use of opiates.
• In 1803, a German chemist isolated an active ingredient from opium which he
called morphine after the god of dreams, Morpheus.
• Opium is prepared by drying and powdering the milky juice taken from the seed
capsules of the opium poppy, Papaver somniferum, just prior to ripening.
• The majority of the world’s supply comes from Southeast Asia, India, China, Iran,
Turkey, Russia and southeastern Europe.
• In 1874, a minor chemical modification of the morphine molecule produced
the compound diacetylmorphine, or heroin.
• At the time, the new compound was promoted as a more potent, yet
nonaddicting substitute for morphine.
• We now know that heroin is converted to monoacetylmorphine and then to
morphine in the brain.
• Narcotics or opioid drugs include agents used medically as analgesics (e.g.
morphine) as well as drugs of abuse (e.g. heroin).
• Compared to morphine and methadone, abused opioids such as heroin are more
potent, cross the blood brain barrier more quickly, have a faster onset of
action and have more euphoric action.
• In contrast to barbiturate withdrawal, which may be fatal, death from
withdrawal of opioids is rare unless a serious physical illness is present.
Heroin: Epidemiology
• 0.2% of the population in the US have used heroin in the last year.
• 1.3% have used the drug in their lifetime.
• There is a higher use rate among people who live in large cities.
• The male:female ratio of users is 3:1.
Psychological and Physical Effects of Opioid Drugs
• Elevation of mood.
• Relaxation.
• Somnolence.
• Sedation.
• Analgesia.
• Respiratory depression (overdose may be fatal).
• Constipation.
• Pupil constriction.
Psychological and Physical Effects of Withdrawal from Opioid Drugs
• Depression of mood.
• Anxiety.
• Insomnia.
• Sweating and fever.
• Rhinorrhea (running nose).
• Piloerection (goose bumps).
• Yawning.
• Stomach cramps and Diarrhea.
• Pupil dilation.
Opioid Peptides
• Endorphins: are derived from pro-opiomelanocortin (POMC) the precursor of
adrenocorticotropic hormone (ACTH).
• Endorphins include β -endorphin (the major endorphin found in the brain).
They play a major role in endocrine function.
• Endorphinergic neurons are found almost exclusively in the hypothalamus
(arcuate and premamillary nuclei).
• These neurons project to the hypothalamus, amygdala, nucleus accumbens,
septal area, thalamus, and locus ceruleus (midbrain and pons).
• Enkephalins: are derived from proenkephalin and are the most widely
distributed and abundant opioid peptides.
• They are found in the highest concentrations in the globus pallidus.
• Enkephalins are also synthesized in striatal neurons, which project to the
globus pallidus.
• Enkephalins are located mainly in local circuits of the limbic and striatal systems
and play a role in pain suppression in the dorsal horn of the spinal cord.
• Enkephalins are co-localized with dopamine, norepinephrine, ACh, and
GABA.
• Dynorphins are derived from prodynorphin and follow, in general, the
distribution map for enkephalin.
• Dynorphins have high concentrations in the hypothalamus and amygdala.
Opioid Action
• The reinforcing effects of opioids are mediated by the mesolimbic DA system
through various opioid receptors (µ, delta and kappa).
Opioid Action: Mesolimbic DA System
• In the VTA, β -endorphin neurons (via µ-receptors) increase mesolimbic
activity by inhibiting inhibitory GABA neurons.
• The release of DA from mesolimbic nerve terminals is tonically inhibited by
dynorphin activity (via kappa-receptors).
• Basal DA release is determined by the balance between the two opioid
systems.
• D-1 receptors on cells in the nucleus accumbens that go to other brain areas,
such as the ventral pallidum, may ultimately be responsible for “motivational”
tonus (aversion, neutral state, positive reinforcement).
Opioid Actions in the Locus Ceruleus
• Opioids acutely inhibit LC neurons by increasing the conductance of K+ channels
via coupling with subtypes of Gi and/or Go and by decreasing an Na+-dependent
inward current via coupling with Gi/o and the consequent inhibition of adenylyl
cyclase.
• Reduced levels of cAMP decrease PKA and the phosphorylation of the
responsible channel or pump.
• Inhibition of the cAMP pathway also decreases phosphorylation of numerous
other proteins and thereby affects many additional processes in the neuron.
Opiate Addiction:Treatment
• Methadone or LAMM maintenance program.
• Narcotics anonymous (NA) or other 12-step program.
• Naloxone (blocks opiate receptors) to precipitate withdrawal and to maintain
abstinence.
• Clonidine for withdrawal symptoms.
• Methadone and 1-alpha-acetylmethodol acetate (LAMM) are synthetic opioids
used to treat heroin addiction.
• Both cause physical dependence and tolerance.
• These legal opioids are used as substitutes for heroin and to prevent
withdrawal symptoms.
• Methadone and LAMM are dispensed by federal health authorities.
• They can be taken orally.
• The IV method of drug delivery employed by heroin users contributes to the
spread of AIDS and Hepatitis B.
• Methadone and LAMM have a longer duration of action.
• They cause less euphoria and drowsiness, allowing people on maintenance
regimens to keep their jobs and avoid the criminal activity that is necessary to
maintain a costly heroin habit.
• Hallucinogens include:
• Cannabis (tetrahydrocannabinol, marijuana, hashish)
• Lysergic acid diethylamide (LSD)
• Psilocybin (from Psilocybin mushrooms)
• Mescaline (from Peyote cactus, L. williamsii)
• Phencyclidine (PCP, “angle dust”)
Cannabis sativa: Epidemiology
• 10% of the US population has used marijuana in the last year.
• 33% have used it in their lifetime.
• Marijuana is used more commonly than any other illegal psychoactive drug.
• Use has increased recently in the 12-25 year old age group.
• Linnaeus in 1753 gave a weed-like plant the name of Cannabis sativa.
• Historically, hemp has served an important function in many cultures as a
source of fiber for making rope, cloth, and paper.
• The first president of the US, George Washington, was a hemp farmer.
• There are over 60 compounds found in the plant which are collectively known
as cannabinoids.
• The word “marijuana” is from a Mexican word maraguanquo, meaning “an
intoxicating plant”.
• Tetrahydrocannabinol (THC) is the primary active compound found in
marijuana.
• In low doses, it increases appetite and relaxation and causes conjunctival
reddening.
• Chronic users experience lung problems associated with smoking and a
decrease in motivation characterized by lack of desire to work and increased
apathy.
Cannabinoid Receptor
• The cannabinoid receptor is a member of the G protein-linked family of
receptors and is linked to inhibitory Gi which inhibits adenylyl cyclase.
• The receptor is found in highest concentrations in the basal ganglia,
hippocampus, and the cerebellum with lower concentrations in the cerebral
cortex.
• Animals do not self-administer cannabinoids like other drugs of abuse.
• However, like other drugs of abuse, THC does indeed increase DA efflux in the
nucleus accumbens.
• Tolerance to cannabis does develop and psychological dependence has been
documented.
• Evidence for physiological dependence is not strong.
Medical Use of Marijuana
• Currently, cannabis is classified as a controlled substance with a high potential
for abuse with NO medical use recognized by the Drug Enforcement Agency
(DEA).
• However, it is used to treat various disorders such as:
– nausea secondary to chemotherapy
– multiple sclerosis
– chronic pain
– AIDS
– Glaucoma
• Opposition to using cannabis medically is based on the illicit recreational use of
the drug.
• Some states now allow the use of medial marijuana.
• However, physicians who prescribe the drug are subject to prosecution for a
federal crime.
Lysergic Acid Diethylamide (LSD)
• Lysergic Acid Diethylamide (LSD) is a compound synthesized in 1938 by the
Swiss chemist Albert Hoffmann while working at Sandoz in Basel.
• Searching mainly for vasoconstrictor useful in controlling headaches and
postpartum bleeding, LSD was shelved.
• Five years later, Hoffmann accidentally ingested a small amount of LSD
(possible absorbed it through his skin) and experienced the first LSD “trip”.
• After experiencing a kaleidoscope of effects that he felt were “rather pleasant”
he returned to his laboratory and intentionally ingested LSD (250ug).
• However, the dose he chose was several times more than adequate doses (50-
100ug) and his “trip” much more powerful.
• The first printed account of the phenomena associated with LSD intoxication was
in 1947 after Hoffman’s colleague Stoll sampled the drug.
• Stoll did studies on human subjects in a psychiatric clinic in Zurich.
• Sandoz then began to synthesize the compound (Delysid), and made it
available at no cost to medical researchers.
• LSD is presently a Schedule I drug, the most restrictive class of substances with
no medical value.
LSD: Basic Pharmacology
• LSD is the most potent psychoactive drug known and has an extremely high
safety margin.
• It can have effects at doses of 10-15ug; yet doses hundreds of times higher are
unlikely to be fatal.
• Animals will not self-administer LSD.
Psychological and Physical Effects of LSD
• Altered perceptual states (auditory and visual hallucinations, alterations of
body image, distortions of time and space).
• Elevation of mood.
• “Bad Trips” (panic reactions that may include psychotic symptoms).
• “Flashbacks”
• Impairment of complex motor activity.
• Cardiovascular symptoms.
• Sweating and tremor.
• There are few, if any, psychological withdrawal symptoms.
• There are few, if any, physical withdrawal symptoms.
• Users of LSD report visual and auditory illusions and synesthesias, which are
mixed sensations such as “seeing” smells or “hearing” colors after a small
dose.
• Senses are magnified and time is distorted.
• A negative response to LSD (i.e. a “bad trip”) consists of acute panicky feelings
in which one’s personality seems to be falling apart, with paranoia,
depression and feelings of confusion and fragmentation.
• Chronic adverse reactions include flashbacks, psychoses, depression, and
chronic personality changes.
• Flashbacks decrease over time whether they are treated or not.
• LSD exerts its effects by acting on the serotonergic system; specifically, post-
synaptic 5-HT receptors.
• 5-HT receptor antagonists block the effects of LSD, the most potent of which
(pirenperone and ritanserin) selectively block the 5-HT2a receptor subtype.
Hallucination Intoxication: Treatment
• Persons are treated for hallucinogen intoxication by psychological support for the
remainder of the trip; so called, talking down.
• Alternatively, or in conjunction, Diazepam (20mg/kg) is administered which
calms the patient.
Hallucinogen-Induced Psychosis
• Treatment does not differ from conventional treatment for other psychoses.
• Other drugs that have been used include: lithium carbonate, carbamazepine
and ECT therapy have been helpful.
• One hallmark of this disorder is that as opposed to schizophrenia (in which
negative symptoms and poor interpersonal relatedness may be found) patients
with hallucinogen-induced psychosis exhibit the positive symptoms of
hallucinations and delusions while retaining the ability to relate to the
psychiatrist.
Phencyclidine (PCP)
• Phencyclidine (PCP) also known as “angle dust” was developed and is
classified as a dissociative anesthetic.
• It was originally used as an anesthetic in humans.
• However, it was associated with disorientation, agitation, delirium and
unpleasant hallucinations on awakening.
• PCP is potent by any route of administration and is highly reinforcing.
• It carries a high risk of behavioral, physiological, and neurological toxicity.
• A related compound, Ketamine (Ketalar) also referred to as “special K” is still
used as a human anesthetic in the US.
• PCP was first used illicitly in San Francisco in the late 1960s.
Phencyclidine (PCP): Epidemiology
• The highest PCP use in the US is in Washington, DC where PCP accounts for
18% of all substance-related deaths.
• In Los Angeles, Chicago, and Baltimore, the comparable figure is 6%.
• Most users of PCP also use other substances such as alcohol, but also opiates,
marijuana, amphetamines and cocaine.
• PCP is frequently added to marijuana with severe untoward effects on the user.
• PCP is associated with 3% of substance abuse deaths and 32% of substance-
related emergency room visits nationally.
PCP Neuropharmacology
• PCP and Ketamine act as antagonists at the NMDA receptor subtype of
glutamate receptors.
• PCP binds to a site within the NMDA-associated Ca+ channel and prevents
the influx of Ca+ ions.
NMDA Glutamatergic Receptor
• The NMDA receptor complex possesses a glutamate recognition site to which
receptor agonists and competitive antagonists bind, as well as other binding sites
for glycine, polyamines such as spermine and spermidine, phencyclidine
(PCP) and related drugs, Mg2+, and Zn2+.
• Channel opening permits an influx of Na+ and Ca2+ ions, and an efflux of K+
ions.
PCP: Dopamine Interaction
• PCP-like drugs stimulate firing of Ventral Tegmental Area dopaminergic neurons.
• PCP also activates DAergic neurons of the VTA, which project to the
cerebral cortex and the limbic system.
• Activation of these neurons is mediates the reinforcing effects of the drug.
Phencyclidine Intoxication
Short-term PCP intoxication can have potentially severe complications and must be
considered a psychiatric emergency.
• Talking down, which may work for hallucinogen intoxication, is not useful
for PCP intoxication.
• Benzodiazepines and DA receptor antagonists are the drugs of choice for
controlling behavior pharmacologically.
• Physicians must monitor level of consciousness.
• Muscle spasms are best treated with diazepam.
Other Abused/Misused Substances
• Inhalants
• Anabolic Steroid Abuse
• Gamma Hydroxybutyrate (GHB)
• Nitrite Inhalants
• Nitrous Oxide
– panic disorder
– post-traumatic stress disorder (PTSD)
– generalized anxiety disorder
– social phobia
– obsessive-compulsive disorder (OCD)
– Three major schools of psychological theory have contributed theories explaining
the causes of anxiety.
– These include:
– psychoanalytic
– behavioral
– existential
Psychoanalytic Theories
• Anxiety is viewed as the result of psychic conflict between unconscious sexual
or aggressive wishes and corresponding threats from the superego or external
reality.
• In response to this signal, the ego mobilized defense mechanisms to prevent
unacceptable thoughts and feelings from emerging into conscious awareness.
• According to Psychoanalytic theory there are different types of anxiety that may
arise in development:
– Disintegration anxiety
– Persecutory or paranoid anxiety
– Castration anxiety (oedipal complex)
– Superego anxiety
Behavioral Theories
• Behavioral or learning theories of anxiety have spawned some of the most
effective treatments for anxiety disorders.
• According to these theories, anxiety is a conditioned response to specific
environmental stimuli (classical conditioning).
• They may have learned the anxiety response from their parents (social
learning theory).
• Treatment is usually a form of desensitization by repeated exposure to the
anxiogenic stimulus, coupled with cognitive therapy approaches.
Existential Theories
• Provide models for generalized anxiety disorder, in which there is no specifically
identifiable stimulus for a chronically anxious feeling.
• The central concept of existential theory is that people become aware of feelings
of profound nothingness in their lives, feelings that may be even more
discomforting than an acceptance of their inevitable death.
• Anxiety is their response to the vast void in existence and meaning.
Biological Theories
• Biological theories of anxiety have developed from preclinical studies with
animal models of anxiety, the study of patients in whom biological factors were
ascertained, the growing knowledge about basic neuroscience, and the actions of
psychotherapeutic drugs.
• One faction of the biological theorists posits that measurable biological changes
in patients with anxiety disorders reflect the results of psychological conflicts.
• The other posits that the biological events precede the psychological conflicts.
Autonomic Nervous System
• Stimulation of the ANS causes:
– cardiovascular (tachycardia)
– muscular (headache)
– gastrointestinal (diarrhea)
– respiratory (tachypnea)
• These peripheral manifestations of anxiety are neither specific to anxiety
disorders nor necessarily correlated with the subjective experience of anxiety.
• It is currently generally thought that the anxiety manifests itself through the CNS
before peripheral manifestations; except when a specific cause is present (e.g.
Pheochromocytoma).
• However, the ANS of some patients with anxiety disorder, especially those with
panic disorder, exhibit increased sympathetic tone, adapt slowly to repeated
stimuli, and respond excessively to moderate stimuli.
Neurotransmitters involved in Anxiety
• Three major neurotransmitters associated with anxiety on the bases of animal
studies and responses to drug treatment are norepinephrine (NE), serotonin
(5HT), and γ -aminobutyric acid (GABA).
• Animal models such as the conflict test and the Lick-suppression test (and
others) have helped determine pharmacotherapies for anxiety.
• In these models, anxiolytic drugs such as benzodiazepines facilitate adaptation
of the animal whereas other drugs (e.g.amphetamines) disrupt behavior.
Norepinephrine
• The general theory about the role of norepinephrine in anxiety disorders is that
affected patients may have a poorly regulated noradrenergic system with
occasional bursts of activity.
• The cell bodies of the noradrenergic system are primarily localized to the locus
ceruleus in the rostral pons and they project their axons to the cerebral cortex,
the limbic system, the brainstem and the spinal cord.
• Experiments in primates have demonstrated that stimulation of the LC produces
a fear response in the animals.
• In contrast, ablation of the same area inhibits or completely blocks the ability of
the animals to form a fear response.
• In patients with panic disorder, β -adrenergic agonists (isoproterenol [Isuprel])
and α 2-adrenergic antagonists (yohimbine [Yocon]) can provoke frequent and
severe panic attacks.
• In contrast, clonidine (Catapres), an α 2-adrenergic agonist, reduces anxiety
symptoms in some experimental and therapeutic situations.
A less consistent finding is that patients with anxiety disorders, particularly panic
disorder, have elevated CSF or urinary levels of the NE metabolite 3-methoxy-4-
hydroxyphenylglycol (MHPG).
Serotonin
• The identification of many serotonin receptor types has stimulated the search for
the role of 5HT in the pathogenesis of anxiety disorders.
• The effectiveness of buspirone (BuSpar), a 5HT1A agonist, in the treatment of
anxiety disorders also suggests a connection between 5HT and anxiety.
• Cell bodies of most 5HT neurons are located in the raphe nuclei in the rostral
brainstem and project to the cerebral cortex, the limbic system (especially the
amygdala and the hippocampus) and the hypothalamus.
• Several reports indicated that m-chlorophenylpiperazine (mCPP), a drug with
multiple serotonergic and non-serotonergic effects, and fenfluramine
(Pondimin), which causes the release of serotonin, cause increased anxiety in
patients with anxiety disorders.
• Anecdotal reports indicated that 5HTergic hallucinogens and stimulants (e.g.
LSD, MDMA) are associated with the development of both acute and chronic
anxiety disorders in heavy users of these drugs.
γ -aminobutyric acid (GABA)
• A role for GABA in anxiety disorders is most strongly supported by the
undisputed efficacy of benzodiazepines, which enhance the activity of GABA
at the GABAa receptor, in the treatment of some types of anxiety disorders.
• Although low-potency benzodiazepines are most effective for symptoms of
generalized anxiety disorder, high-potency benzodiazepines, such as
alprazolam (Xanax), are effective in the treatment of panic disorder.
• Pre-clinical studies in primates have found that ANS symptoms of anxiety
disorders are induced when a benzodiazepine inverse agonist, β -carboline-3-
carboxylic acid (BCCE), is administered, BCCE also causes anxiety in normal
control volunteers.
• A benzodiazepine antagonist, flumazenil, causes frequent severe panic
attacks in patients with panic disorder.
These data have led to the conclusion that some patients with anxiety disorders have
abnormal functioning of their GABAa receptors, although this connection has not
been shown directly.
Genetic Contribution
• Studies have produced solid data showing that at least some genetic component
contributes to the development of anxiety disorders.
• Almost HALF of all patients with panic disorder have at least one affected
relative.
• The figures for other anxiety disorders, although not as high, also indicate a
higher frequency of the illness in first-degree relatives of affected patients than
occurs in the relatives of non-affected persons.
• Data from twin studies support the hypothesis that anxiety disorders are at least
partially genetically determined.
Anxiety Disorders Due to a General Medical Condition
• A wide range of medical conditions can cause symptoms similar to those of
anxiety disorders.
• Hyperthyroidism, hypothyroidism, hypoparathyroidism, and vitamin B12
deficiency are frequently associated with anxiety symptoms.
• A pheochromocytoma produces epinephrine, which can cause paroxysmal
episodes of anxiety symptoms.
• Certain lesions of the brain and postencephalitic states reportedly produce
symptoms identical to those seen in obsessive-compulsive disorder.
• Other medical conditions, such as cardiac arrhythmia, can produce
physiological symptoms of panic disorder.
• Hypoglycemia can also mimic the symptoms of an anxiety disorder.
• The diverse medical conditions that can cause symptoms of anxiety disorder may
do so through a common mechanism: the noradrenergic system.
Major Types of Anxiety
• Panic Disorder
• Post-traumatic Disorder (PTSD)
• Generalized Anxiety Disorder
• Social Phobia
• Obsessive-Compulsive Disorder (OCD)
Panic Disorder
• Panic attacks are brief, recurrent, unexpected episodes of terror without a clearly
identifiable cause.
• The attacks are brief, lasting 15-30 minutes; rarely up to an hour.
• An essential feature of these attacks is that they are unexpected.
• They do not occur in situations that normally evoke fear or in which the
patient is the focus of other people’s attention.
• The attacks are characterized by: a sense of impending doom accompanied by an
intense over-activity of the sympathetic nervous system (referred to as a
sympathetic crisis):
• the heart races
• there is shortness of breath
• dizziness
• trembling or shaking of the hands and legs
• flushes or chills
• chest pain
• fear of dying or going crazy or of doing something uncontrolled
• Shortness of breath is characteristic of panic attacks but not of the acute terror
evident in battle, suggesting that panic attacks may represent a false alarm for
suffocation.
• In those patients that have panic disorder, a panic attack can be induced by the
infusion of sodium lactate into the blood or the inhalation of carbon dioxide
but not in normal subjects.
• Antidepressants that are effective against spontaneous panic attacks also prevent
the panic induced by the infusion.
• Yohimbine, a drug that activates central noradrenergic neurons (by blocking α2-
adrenergic receptors that serve as inhibiting autoreceptors), precipitates
panic attacks in patients but not in normal subjects.
• This indicates that panic attacks involve an abnormality in the biogenic amine
system of the brain.
Post-Traumatic Stress Disorder (PTSD)
• PTSD occurs in people after an extremely stressful event, such as life-
threatening combat or physical abuse.
• It is manifested in recurrent episodes of fear, often triggered by reminders of
the initial trauma.
• Memory for the traumatic experience remains powerful for decades and is
readily reactivated by a variety of stimuli and stressors.
• This is due to the recruitment of the noradrenergic system by the reactivating
stimuli.
• Vietnam War veterans with PTSD show heightened noradrenergic functioning.
• Excrete high levels of norepinephrine in their urine, presumably reflecting high
circulating catecholamine levels.
• Patients with PTSD are given yohimbine, they experience a type of panic attack:
an intense memory accompanied by autonomic symptoms, frightening
thoughts, emotional numbing and grief.
• This evidence is consistent with the idea that uncontrollable stress produces
substantial increases in noradrenergic functioning in the brain.
• Propranolol and clonidine (noradrenergic antagonists) greatly ameliorate the
symptoms of PTSD.
• A large percentage (50%) of patients with PTSD also show concurrent panic
disorder.
Generalized Anxiety Disorder
• Key feature of GAD is unrealistic or excessive worry, lasting for 6 months or
longer.
• The symptoms are:
– motor tension (trembling, twitching, muscle aches, restlessness)
– autonomic hyperactivity (palpitations, in creased heart rate, sweating,
cold hands)
– vigilance and scanning (feeling on edge, exaggerated startle response,
difficulty in concentrating).
• The disorder sometimes follows an episode of depression.
• Patients with GAD respond well to the benzodiazepines such as
chlordiazepoxide (Librium), and its derivative, diazepam (Valium) both bind
to the GABAa receptor.
Obsessive-Compulsive Disorder
• OCDs are usually chronic disorders with recurrent obsessions and
compulsions as the predominant features.
• Obsessions are persistent and intrusive ideas, thoughts, images, or impulses
that commonly fall into one of two categories: doubts or fears.
• Obsessive doubting penetrates daily life, for example, leaving patients repeatedly
unsure whether the apartment door was locked, whether the stove was turned off,
or whether their hands are clean enough.
• Obsessive fears focus on unrealistic and improbable dangers, such as the
prospect of killing someone driving a car or lighting the stove.
• To alleviate the anxiety and diminish the discomfort of the obsessive thoughts or
urges, the patient often begins to carry out compulsive acts.
• In contrast to obsessions (repetitive ideas), compulsions are repetitive acts.
• To be defined as a compulsion a behavior must be repeated excessively and the
repetition must not be realistically related to any environmental condition.
• The most common compulsions are handwashing, counting, checking,
touching, and pulling out of hair.
• OCD is though to reflect a disturbance of the basal ganglia.
• Some forms of OCD seem to be related to Tourette syndrome (hereditary
chronic motor tic disorder with its locus in the basal ganglia).
• Postencephalitic Parkinson disease
• Sydenham chorea
• Bilateral necrosis of the globus pallidus
• Huntington Disease
• These disorders are often associated with a component of obsessive-compulsive
disorder.
The head of the caudate nucleus and the pathway that connects the caudate with the
prefrontal (orbitofrontal) cortex and cingulate gyrus is hyperactive in obsessive-
compulsive disorder.
OCD: Treatment
• OCD is responsive to two types of treatments: specific behavioral therapies
based on conditioning and specific serotonin reuptake inhibitors (SSRIs).
• After effective treatment of the disease with either SSRIs or behavioral therapy,
hyperactivity of the caudate nucleus and orbitofrontal cortex decreases
significantly.
• In medicine the term disease refers to a cluster of symptoms and signs that
results from a specific cause and leads through a defined course to a specific
outcome.
• Ideally a diagnosis is based on two additional factors:
– (1) a clear and evident causative agent (whether the illness results from a
genetic abnormality, a viral or bacterial infection, toxins, tumors, or
stress) and
– (2) a plausible pathogenesis (a clear idea of the mechanism by which the
causative agent produces the disease).
• Unfortunately, unlike most other medial illnesses the causes and pathogenesis of
most mental illness have not, as of yet, been determined.
• This is especially the case in regards to schizophrenia.
• Schizophrenia is perhaps the most devastating mental disorder of humankind.
• It strikes about 1% of the population worldwide and affects men slightly more
frequently than women.
• In addition to the 1% with schizophrenia, an additional 2-3% of the general
population have schizotypal personality disorder, a milder form of
schizophrenia proper.
• Bleuler called a certain group of illnesses schizophrenia, a splitting of the mind.
• This condition is NOT to be confused with multiple or split personalities an
uncommon disease in which a person alternately assumes two or more identities.
• People with schizophrenia may show evidence of this splitting by having
inappropriate affect.
• For example, they may laugh while recounting a tragic event or may show no
emotion (flat affect) while describing a joyous occasion.
Schizophrenia: Symptoms
• Psychotic Episodes
• Mental states in which some of the patient’s thought processes are not able to
test reality correctly.
• The patient is unable to examine their beliefs and perceptions realistically and
to compare them to what is actually happening in the world.
• This is called loss of reality testing.
• Other symptoms include:
• disturbances of higher mental functioning,
• delusions (aberrant beliefs that fly in the face of facts and are not
changed by evidence that the beliefs are unreasonable)
• hallucinations (mostly auditory)
• incoherent thinking
• disordered memory
• confusion
One example, people with schizophrenia often hear internal voices that tell them things
that are not true, for example that their parents are trying to poison them.
Neuroanatomy of Hallucinations in Schizophrenia
• Studies have shown that the inferotemporal cortex is critically involved in the
recognition and discrimination of visual objects and is the area disturbed in
prosopagnosia, a disorder concerned with the recognition of faces.
• The output nuclei of the basal ganglia—the substantia nigra pars reticulata—
project via the thalamus to the inferotemporal cortex.
• The inferotemporal cortex is not only a source of input to the basal ganglia but
also a target of basal ganglia output.
• The basal ganglia can influence higher-order visual processing.
• In essence, abnormalities in the basal ganglia (DAergic) loop (substantial nigra
—thalamus—infratemporal cortex) may lead to alterations in visual perception,
including visual hallucinations characteristic in schizophrenia.
• In fact, visual hallucinations are a major side effect of L-DOPA and other
DAergic agents used in the treatment of Parkinson disease.
• Approximately 30% of patients with Parkinson disease treated in this manner
experience this side effect.
Thus, hallucinations in these patients may be due to excessive stimulation of DA
receptors in the visual striatum, which leads to a net INCREASE in activity in the
nucleus pars reticulata and thus abnormal increases in thalamic input to the
inferotemporal cortex.
• Brain imaging studies of schizophrenic patients experiencing hallucinations
support this hypothesis.
• Subjects display significant changes in blood flow at several brain sites that are
part of the inferotemporal system.
Prodromal Signs
• The first psychotic episode of schizophrenia is often preceded by prodromal
signs.
• These include:
– social isolation and withdrawal
– impairment in the normal fulfillment of expected roles
– odd behavior and ideas
– neglect of personal hygiene
– blunted affect
• The prodromal period is followed by one or more psychotic episodes that may
include loss of reality testing, memory disturbances, delusions, and
hallucinations.
• These periods are sometimes separated by long periods when the patient is not
overtly psychotic but behaves:
– eccentrically
– is socially isolated
– has a low level of emotional arousal (flat affect)
– impoverished social drive
– poverty of speech
– poor attention span
– lack of motivation
Positive and Negative Symptoms
• Symptoms of the nonpsychotic period are called negative symptoms because they
reflect the absence of certain normal social and interpersonal behaviors.
• In contrast, the striking abnormalities of psychotic episodes are called positive
symptoms because they reflect the presence of distinctively abnormal
behaviors.
• Negative symptoms are chronic features of the illness and are the most difficult
to manage.
Diagnosis
• Criteria for diagnosing schizophrenia require that a patient be continuously ill for
at least six months and that there be at least one psychotic phase followed by
a residual phase.
• During the psychotic episode one or more of the following three groups of
positive symptoms must be present:
• (1) Delusions (for example, the belief that one is being persecuted or that
one’s feelings, thoughts, and actions are controlled by an outside force)
• (2) Prominent hallucinations, usually auditory (for example, hearing
voices commenting on one’s actions)
• (3) Disordered thoughts, incoherence, loss of the normal association
between ideas, or marked poverty of speech accompanied by a loss of
emotional expression (flattening of affect).
Subtypes of Schizophrenia
• During psychotic episodes patients with schizophrenia may also exhibit unusual
postures, mannerisms, or rigidity.
• On the basis of these criteria and other differences, schizophrenia is often divided
into three subtypes:
– paranoid schizophrenia
– disorganized schizophrenia (hebephrenia)
– catatonic schizophrenia
• Paranoid schizophrenia is found more often in men in which systematic
delusions of persecutions predominate.
• Disorganized schizophrenia (hebephrenia) is a form characterized by early age
of onset, a wide range of symptoms, and a profound deterioration of personality.
• Posturing, grimacing and mirror gazing are symptomatic of this subtype.
• Catatonic schizophrenia, a rare form in which mutism and abnormal postures
dominate.
• The patient is usually immobile, demonstrating waxing flexibility.
• Appendages are often in an uncomfortably position and facial expression is
characterized by a Schnauzkrampf or frozen snout.
Genetic Predisposition
• Franz Kallmann discovered that the incidence of schizophrenia throughout the
world is uniformly about 1%, even though social and environmental factors
vary dramatically.
• He found however, that the incidence of schizophrenia among parents,
children, and siblings of patients with the disease is about 15%, strong
evidence the disease runs in families.
• Early this century, it was found that comparing the rates of illness in monozygotic
(identical) and dizygotic (fraternal) twins was found to be the best way to
analyze the contribution of genetics in schizophrenia.
• Monozygotic twins essentially have identical genomes; they share almost 100%
of each other’s genes.
• In contrast, dizygotic twins share only 50% of their genes are genetically
equivalent to siblings.
• If schizophrenia were caused entirely by genetic factors, monozygotic twins
would have an identical tendency to have the disease to develop.
• The tendency for twins to have the same illness is called concordance.
• Studies of twins have established that the concordance for schizophrenia in
monozygotic twins is about 45%, but in dizygotic twins only about 15%,
about the same as for other siblings.
• Studies of adoptees show that some of the blood relatives of adoptees with
schizophrenia show odd behavior even if they do not manifest signs of
schizophrenia.
• They are socially isolated, have poor rapport with people, ramble in their
speech, tend to be suspicious, have eccentric beliefs, and engage in magical
thinking.
• This group of symptoms is called schizotypal personality disorder, and is thought
to be a mild form of the disease, a nonpsychotic condition related to
schizophrenia.
• If schizophrenia were caused entirely by genetic abnormalities, then the
concordance rate for monozygotic twins, who share almost 100% of each
other’s genes, would be nearly 100%.
• The finding that the concordance rate in monozygotic twins is only about 45%
indicates that the genetic transmission is unusual and that genetic factors are
not the only cause.
Anatomical Abnormalities
• CT and MRI and cerebral blood flow studies have revealed that SOME patients
with schizophrenia have one or more of four major anatomical
abnormalities.
• First, early in the disease there is a reduction in blood flow to the left globus
pallidus suggestive of a disturbance in the system that connects the basal ganglia
to the frontal lobes.
• Second, there appears to be a disturbance in the frontal lobes themselves since
blood flow does not increase during tests of frontal lobe function involving
working memory as it does in normal subjects.
• Third, the cortex of the medial temporal lobe is thinner and the anterior
portion of the hippocampus is smaller than in normal people, especially on the
left side, consistent with a defect in memory.
• Finally, the lateral and third ventricles are enlarged and there is widening of
the sulci, especially in the thinner temporal lobe and in the frontal lobe,
reflecting a reduction in the volume of this lobe as well.
• Anatomical abnormalities have also been studied in monozygotic twin pairs of
where only one twin had schizophrenia.
• In 12 of 15 cases examined, the twin with schizophrenia had larger ventricle
compared to the normal twin.
• The twin also had a smaller anterior hippocampus on the left side, and this
reduction in hippocampal mass correlated highly with the reduction in blood
flow in the left prefrontal cortex.
Neural Substrate
• The smaller the hippocampal volume of the affected twin, the less the left
prefrontal cortex was activated during a cognitive task.
• These and several other findings suggest that the hippocampus, prefrontal
cortex, globus pallidus, are part of a cognitive system that is impaired in
schizophrenia.
Antipsychotic Drugs
• In the 1950s the French Neurosurgeon Henri Laborit, by trial and error,
discovered that chlorpromazine had a calming action in patients.
• He thought this drug may have a wider use in psychiatric patients.
• In 1951, John Delay and Pierre Deniker, discovered that chlorpromazine
calmed highly agitated and aggressive patients who had either schizophrenic
or manic depressive symptoms.
By the mid 1960s it was found that chlorpromazine (and drugs of the phenothiazine
class) mitigated or abolished delusions, hallucinations, and some types of disordered
thinking in schizophrenic patients.
These findings led to the delineation of a group of drugs, now called typical
antipsychotics, which include the phenothiazines (chlorpromazine), butyrophenones
(haloperidol) and the thioxanthenes.
• More recently a second group of drugs, the atypical antipsychotics (clozapine,
risperidone, olanzapine) have also proved useful in the treatment of
schizophrenia.
• Atypical antipsychotics are better than typical antipsychotics in treating negative
symptoms (cognitive effects) in schizophrenia, and they produce fewer side
effects on the extrapyramidal system.
How Do Antipychotics Work?
• The first clue in determining how these drugs worked was the side effects.
• The drugs often produce a syndrome resembling Parkinsonism.
• Arvid Carlsson first suggested that these drugs may block DA receptors and
that DA transmission could be an important part of the pathogenesis of
schizophrenia.
• Above: Having a similar structure to DA, chlorpromazine sits on the DA
receptor blocking it without triggering a response.
• Typical antipsychotic drugs have a high affinity for D2 receptors, which are
therefore thought to be one of the major sites of therapeutic actions of these
drugs.
• Indeed, clinical potency of the typical antipsychotic agents in patients with
schizophrenia is closely correlated with the affinity of these drugs for the D2
receptor.
Dopamine D2-like Receptors
• The D2 receptor is part of a family of related receptors (D2 group or D2-like
receptors) which include the D3, and D4 receptors.
• All three inhibit adenylyl cyclase and are expressed at particularly high levels in
neurons of the caudate nucleus, the putamen, and the nucleus accumbens.
• D2 receptors are also present in the amygdala, hippocampus, and parts of the
cerebral cortex.
• Since D2-like receptors are expressed in the caudate and putamen, these
receptors presumably contribute to the side effects of the antipsychotic drugs on
the extrapyramidal systems.
• The amygdala, hippocampus, and neocortex, however, are possible sites of
therapeutic action.
D3 Receptors: Atypical Antipsychotics
• The atypical antipsychotic agents, such as clozapine, bind to D3 and even more
effectively to D4 receptors.
• These two subtypes of the D2 group are expressed primarily in the limbic system
and cortex and are weakly expressed in the basal ganglia.
• This selective distribution may explain why the atypical antipsychotic agents do
not give rise to side effects in the extrapyramidal systems.
• Both the D2 and D3 receptors are of further interest because they are present on
DAergic neurons themselves, on both the cell body and the terminals.
• Here they act as inhibitory auto-receptors to control both the rate of firing of
the neuron and the release of DA by the action potential at the terminals.
Abnormalities in DAergic Transmission in Schizophrenia
• Excessive release of DA in the mesolimbic DA system may contribute to the
expression of schizophrenia.
• Drugs that increase the level of DA, such as L-dihydroxyphenylalanine (L-
DOPA), cocaine, and amphetamine, can induce psychotic episodes
resembling paranoid schizophrenia.
• Some of these drugs, such as amphetamine, also cause bizarre, repetitive
stereotyped behavior in monkeys.
• Antipsychotic drugs reverse not only amphetamine psychosis in humans but
also the bizarre behavioral syndrome in monkeys.
Neurobiological Substrate for Schizophrenia
• The DAergic mesolimbic system has its origin in the cell bodies of the VTA
(ventral tegmental area) which is medial and superior to the substantia
nigra.
• These cells project to the components of the limbic system:
• nucleus accumbens
• ventral striatum
• nuclei of the stria terminalis
• amygdala
• hippocampus
• lateral septal nuclei
• entorhinal cortex
• mesial frontal cortex
• anterior cingulate cortex
• The idea that the mesolimbic DA system is affected in schizophrenia is supported
by the finding that the earliest sign of brain disturbances in schizophrenia,
detectable with PET imaging, is a decrease in blood flow in a region of the
basal ganglia (globus pallidus).
• This disturbance is before the prominent frontal lobe deficit becomes evident.
• Among the projections of the mesolimbic system, those to the nucleus
accumbens are thought to be particularly important because of the extensive
connection of this nucleus to the limbic system.
• The nucleus accumbens receives and integrates inputs from the amygdala,
hippocampus, entorhinal area, anterior cingulate area, and parts of the
temporal lobe.
• After loss the dorsal prefrontal cortex, patients are poorly motivated, plan
poorly and have flattened affect.
• Patients with Parkinson’s disease who have lost DA neurons not only have a
motor disorder but also lack motivation and have flat affect and reduced
spontaneity, defects that can be reversed with DA agonists.
• Lesions that destroy the VTA cause demential and psychotic symptoms.
• Overactive modulation of the integration of the inputs to the nucleus accumbens
and of the output from it could contribute to positive symptoms of schizophrenia.
• The mesocortical DA system originates in the VTA and projects to the
neocortex, in particular the prefrontal cortex.
• The prefrontal cortex is involved in the temporal organization of behavior, in
motivation, planning, attention, and social behavior.
• This system may be important in the negative symptoms of schizophrenia,
symptoms that bear some resemblance to the defects seen after surgical
disconnection of the frontal lobes, especially the dorsal prefrontal cortex.
Neurobiological Substrate for Schizophrenia: Pulling It All Together
• An INCREASE in activity in the mesolimbic pathway (perhaps through the D2
and D3 receptors and particularly through D4 receptors) would account for the
positive symptoms.
• DECREASED activity of the mesocortical connections in the prefrontal cortex
would account for the negative symptoms.
Imbalance Between the Mesolimbic and Mesocortical Pathways
• According to this model, the imbalance between the cortical and subcortical
DA transmission underlies the development of schizophrenia.
• It has been proposed that activity in the mesocortical pathway to the prefrontal
cortex normally INHIBITS the mesolimbic pathway by FEEDBACK
INHIBITION and that the primary defect in schizophrenia is a REDUCTION
in this activity, which leads to disinhibition and overactivity in the mesolimbic
pathway.
Dopamine Doesn’t Explain It All
• Primary treatments for schizophrenia act on DAergic systems yet we do not know
for sure if these systems cause the disease.
• Pharmacological manipulation may produce changes that compensate for the
disease without directly affecting the disordered mechanism itself.
• For example, the primary defect in Parkinson’s Disease is a decrease in DA levels
but some symptoms can be alleviated by drugs that block cholinergic
transmission.
• In addition, although antipsychotic drugs occupy DA receptors very quickly after
administration the maximal therapeutic (antipsychotic) effects are often
delayed several weeks.
• Activity in certain neural circuits may need to adjust to a new level of modulation.
• The drugs or the resulting alterations in neuronal activity might produce changes
in gene expression, the consequences of which may not become manifest for
one or more weeks.
• These alterations may reflect changes in other neurotransmitter systems that
interact with DA such as 5HT.
• Indeed, most typical antipsychotics act on 5HT2 receptors at which lysergic
acid diethylamide (LSD) and other psychedelic hallucinogens also act.
• Long-term administration of antipsychotic agents leads to a downregulation of
5HT2 receptors that parallels in time course the therapeutic action of the
antipsychotic drugs.
Other Receptors Other Systems
• 20% of patients do not respond to DAergic drugs that block D2 receptors.
• These patients often respond to the atypical antipsychotic agents such as
clozapine, which is only a weak blocker of D2 receptors.
• Clozapine produces few, if any, Parkinson-like side effects, which
characteristically occur with blockade of D2 receptors.
• Clozapine and risperidone bind to D3 and D4 receptors.
• D3 and D4 receptors are limited to the limbic system in their distribution.
• Clozapine also blocks 5HT2a and α1 norepinephrine and H1 histamine
receptors.
• Phencyclidine (PCP) produces a psychosis that resembles the psychosis in
schizophrenia and exacerbates psychosis in patients with schizophrenia.
• Normal subjects given IV PCP experience depersonalization and feel
disconnected from their environment.
• They also have delusion of being controlled by external agents and have
auditory and visual hallucinations.
• PCP binds to two identified molecular targets in the brain:
• (1) the dopaminergic terminals in the nucleus accumbens
• (2) the N-methyl-D-aspartate (NMDA) class of glutamate receptors
• NMDA receptors are present on DAergic axon terminals in the prefrontal
cortex and enhance DA release from the terminals.
• PCP, when it binds to the NMDA receptors, inhibits release of DA.
• In contrast, at the DAergic terminals in the nucleus accumbens PCP increases
DA release and inhibits reuptake, much like amphetamine.
• Specific drugs developed to block NMDA receptors selectively (used for the
treatment of NMDA induced neurotoxicity after stroke or prolonged seizure
activity) have the undesirable side effect of producing psychosis, perhaps by
reducing the release of DA in the mesocortical pathway to the frontal lobe.
This evidence points towards other possible therapeutic targets besides DA (e.g. NMDA
receptors) for the treatment of schizophrenia.
• The common migraine headache lacks the classic aura, is usually bilateral and
periorbital, and is seen more frequently in clinical practice.
• The pain may be described as throbbing.
• As the pain persists, associated cervical muscle contractions can compound the
symptoms.
• Scalp tenderness is often present during the episode.
• Vomiting may occasionally terminate the headache.
Bedside Test
• A useful bedside test for both common and classic migraine is reducing
headache severity by compressing the ipsilateral carotid or superficial
temporal artery.
Precipitating Factors
• Migraine attacks can be precipitated by certain foods (tyramine-containing
cheeses, meat, nitrite preservatives, chocolate containing phenylethylamine
but not chocolate alone) and by food additive such as monosodium
glutamate.
• Fasting, emotion, menses, drugs (especially oral contraceptive agents and
vasodilators such as nitroglycerin) and bright lights may also trigger attacks.
Treatment
• Acute migraine attacks may respond to simple analgesics (aspirin,
acetaminophen, naproxyn).
• If not, they usually respond to ergot preparations or to the 5HT agonist
sumatriptan.
• Ergot alkaloids and 5HT agonists are potent vasoconstrictors and are
contraindicated in patients with significant hypertension or cardiac disease.
• Drugs used as prophylactics include propranolol, amitriptyline and valproic
acid.
• In addition, calcium channel antagonists such as verapamil or nicardepine are
also effective.
• SSRIs are NOT an effective therapy for migraine.
Cluster Headache
• Cluster headache is a common headache syndrome seen much more frequently
in men and women.
• Cluster headaches characteristically begin later in age compared to migraine
(25years).
• There is rarely a family history.
• The syndrome presents as clusters of brief, very severe, unilateral, constant
non-throbbing headaches that last from 10 min to less than 2 hours.
• Always unilateral and usually recur on the same side in a given patient.
• Commonly occur at night, awakening the patient from sleep, and recur daily,
often at nearly the same time of day for a cluster period of weeks to months.
• The headache may begin as a burning sensation over the lateral aspect of the
nose or as a pressure behind the eye.
• Ipsilateral conjunctival injection, lacrimation, nasal stuffiness, and Horner’s
syndrome are commonly associated with the attack.
• Episodes are often precipitated by alcohol or vasodilating drugs.
• Treatment is with sumatriptan, 100% oxygen and dihydroergotamine.
Tension-Type Headache
• Tension headache is the term used to describe chronic headaches of
inapparent cause that lack features characteristic of migraine or cluster
headache.
• The underlying pathophysiologic mechanism is unknown, and tension is
unlikely to be primarily responsible.
• It its classic form, tension headache is a chronic disorder that begins after age
20.
• It is characterized by frequent (often daily) attacks of non-throbbing, bilateral
occipital head pain that is not associated with nausea, vomiting, or
prodromal visual disturbance.
• The pain is sometimes likened to a tight band around the head.
LECTURE 47: The Neurological Exam
Class Handout