Harrison's Neurology in Clinical Medicine, 3rd Edition


Robert O. Messing Image John H. Rubenstein Image Eric J. Nestler

Psychiatric disorders are central nervous system diseases characterized by disturbances in emotion, cognition, motivation, and socialization. As a result of their high prevalence, early onset, and persistence, they contribute substantially to the burden of illness worldwide. Most psychiatric disorders are heterogeneous syndromes that currently lack well-defined neuropathology and bona fide biological markers. Therefore, diagnoses continue to be made solely from clinical observations using criteria in the Diagnostic and Statistical Manual of Mental Disorders of the American Psychiatric Association (2000), 4th edition, text revision (DSM-IVTR). Recent advances in neuroimaging are beginning to provide evidence of brain pathology, which may one day be used for diagnosis and for following treatment. Family, twin, and adoption studies have shown that all common psychiatric syndromes are highly heritable, with genetic risk comprising 20–90% of disease vulnerability. The epidemiology, genetics, and biology of four common psychiatric disorders—autism, schizophrenia, mood disorders, and drug addiction—are presented in this chapter. A detailed discussion of the clinical manifestations and treatment of schizophrenia and mood disorders can be found in Chap. 54. Further discussion of alcoholism can be found in Chap. 56, opiate addiction in Chap. 57, and cocaine and other drugs of abuse in Chap. 58.


The DSM-IVTR criteria for autism spectrum disorders (ASDs) require delays or abnormal functioning in social interactions, language as used in social communication, and symbolic or imaginative play, with onset prior to age 3. In addition to abnormal social behavior, ASDs are frequently, but not always, associated with reduced IQ and epilepsy. Individuals who exhibit some autism-like symptoms with relatively preserved cognitive functioning and language skills are described as having Asperger’s syndrome.


There has been a dramatic increase in the diagnosis of ASDs, from ~1/1000 (1950s–1990s) to a current level of ~1/150. Whether this increase reflects increased disease prevalence remains uncertain; ongoing studies are searching for genetic, environmental, and sociologic mechanisms that may have contributed to this change. In the 1950s–1960s, psychological factors were held to underlie autism. This conception was largely debunked by the 1970s, with the demonstration that prenatal rubella and phenylketonuria can cause ASDs, and with evidence for the genetic etiology of ASDs from twin studies. There is ongoing public concern that vaccines in general, or mercury-based preservatives in vaccines, can cause ASDs; however, large epidemiologic analyses have not supported this as an etiology. Whether environmental factors, such as perinatal infection and various toxins, for example, ethanol, illicit drugs, medications, and mutagenic agents, play a role is unclear.


ASDs show no defining neuroanatomic phenotype that would indicate neurodevelopmental abnormalities. However, structural neuroimaging and histologic studies of postmortem brain provide evidence for anatomic defects. There is a modest increase in cerebrum growth (~10%; affecting both the white and grey matter) during early childhood (years 1–3), with the largest effect in the frontal lobes; the growth rate then decreases with age. Cerebellar size is increased by about 7% in children under age 5 years, but is decreased in older patients, and there are reduced (~30%) numbers of cerebellar Purkinje neurons. Finally, there is reduced cell size and increased cell density in the limbic areas of the brain.


ASDs are highly heritable; concordance rates in monozygotic twins (~60–90%) are roughly tenfold higher than in dizygotic twins and siblings, and first-degree relatives show about fiftyfold increased risk for autism compared with prevalence in the general population. For unknown reasons, ASDs affect four times as many boys as girls. ASDs are also genetically heterogeneous. More than 20 known mutations, including copy number variations, account for about 10–20% of all cases, though none of these causes individually accounts for more than 1–2% (Table 53-1). Many of the genes linked to ASDs can also cause other illnesses. For instance, mutations in MeCP2, FMR1, and TSC1&2 (see Table 53-1 for abbreviations) can cause mental retardation without ASDs, and alleles of certain genes, for example, neurexin 1, are associated with both ASDs and schizophrenia. It is likely that many cases of ASDs result from more complex genetic mechanisms, including inheritance of multiple genetic variants or epigenetic modifications.

TABLE 53-1





Despite the genetic heterogeneity of ASDs, there are some common themes that may explain pathogenesis. These include mutations in proteins involved in the formation and function of synapses, control over the size and projections of neurons, production and signaling of neurotransmitters and neuromodulators, the function of ion channels, general cell metabolism, gene expression, and protein synthesis (see Table 53-1). Many of these mutations have a clear relationship to activity-dependent neural responses and can affect the development of neural systems that underlie cognition and social behaviors. They may be detrimental by altering the balance of excitatory vs. inhibitory synaptic signaling in local and extended circuits, and by altering the mechanisms that control brain growth. Another class of mutations affects genes (e.g., PTEN and Tsc) that negatively regulate signaling from several types of extracellular stimuli, including those transduced by receptor tyrosine kinases. Their dysregulation can have pleiotropic effects, including altering brain and neuronal growth as well as synaptic development and function. With further understanding of pathogenesis and the definition of specific ASD subtypes, there is reason to believe that effective therapies will be identified, as in the case of dietary treatments for phenylketonuria. In addition, work in mouse models (e.g., with fragile X or Rett syndrome mutations) has suggested that autismlike behavioral abnormalities can be reversed even in fully developed adult animals by reversing the underlying pathology, which holds out hope for many affected individuals.


Schizophrenia appears to be a heterogeneous collection of many distinct diseases, which remain poorly defined but linked by common clinical features. Three major symptom clusters are seen in schizophrenia: positive, negative, and cognitive symptoms. Positive symptoms include hallucinations and delusions, experiences that are not characteristic of normal mental life. Negative symptoms represent deficits in normal functions such as blunted affect, impoverished speech, asocial behavior, and diminished motivation. Cognitive symptoms include deficits in working memory and cognitive control of behavior that often prove extremely disabling. Current antipsychotic drugs are efficacious for positive symptoms only and generally lack efficacy for negative and cognitive symptoms.


Schizophrenia is common, affecting males and females roughly equally, with a worldwide prevalence of approximately 1%. Environmental risks are thought to include prenatal exposure to viral infection (influenza), prenatal poor nutrition, perinatal hypoxia, psychotropic drug use (in particular, cannabis), and psychological stress. Advanced paternal age, birth order, and season of birth have also been implicated. However, none of these environmental influences has a specific or strong association with most cases of schizophrenia.


The best-established neuropathologic finding in schizophrenia is enlargement of the lateral ventricles of the cerebral hemispheres. This is accompanied by a reduction in cortical thickness. These abnormalities are not specific to schizophrenia and are seen in many other conditions, including many neurodegenerative disorders. However, there is a general consensus that the reduction in cortical thickness in schizophrenia is associated with increased cell packing density and reduced neuropil (defined as axons, dendrites, and glial cell processes) without an overt change in neuronal cell number. Specific classes of interneurons in prefrontal cortex consistently show reduced expression of the gene encoding the enzyme glutamic acid decarboxylase 1 (GAD1), which synthesizes γ-aminobutyric acid (GABA), the principal inhibitory neurotransmitter in the brain. Functional imaging studies, by positron emission tomography (PET) or functional magnetic resonance imaging (MRI), show evidence of reduced metabolic or neural activity in the dorsolateral pre-frontal cortex at rest and when performing psychological tests of executive function, including working memory. Alleles of two candidate risk genes (catechol-O-methyltransferase [COMT] and metabotropic glutamate receptor 3 [mGluR3]) are reported to affect dorsolateral prefrontal cortex activity, but these findings need to be replicated in larger samples. Similar pathologic and brain imaging abnormalities are seen in several other brain regions, in particular, the hippocampus. There are also numerous reports of abnormalities in myelin and oligodendrocytes in the cerebral cortex of patients with schizophrenia.


Twins studies establish the heritability of schizophrenia, with co-inheritance at ~50% for monozygotic twins and ~10% for dizygotic twins. Genomewide linkage and association studies, and studies of copy number variation, have identified many regions and alleles that confer increased disease risk, particularly near genes on chromosome 22 (disrupted in schizophrenia 1 [DISC1], COMT, neuregulin 1, the neuregulin receptor ERBB4, and the DiGeorge [or velocardiofacial syndrome] region), and on chromosome 16p. The DiGeorge region deletions produce, in heterozygous form, a psychotic disorder with variable clinical features and a moderate to strong degree of penetrance. In contrast, the contribution of each of the individual genes to schizophrenia remains to be established with certainty. Moreover, the responsible genes within the DiGeorge region have not yet been identified. What is clear is that none of these other alleles produce schizophrenia with a high degree of penetrance. The current view in the field is that multiple rare alleles, many or most with limited penetrance, likely contribute to risk of schizophrenia. As for ASDs, the same allele may be a risk factor for multiple disorders. For instance, duplication of chromosome 16p is associated with both schizophrenia and autism, while DiGeorge region deletions and the DISC1 locus on chromosome 22 are associated with schizophrenia, autism, and bipolar disorder.


There are several prevailing hypotheses about neuro-chemical mechanisms underlying schizophrenia. A reduction in the function of cortical and perhaps hippocampal GABAergic interneurons fits with reduced expression of glutamic acid decarboxylase. However, it is unknown whether this is a primary or compensatory feature of the disorder. Nevertheless, defects in parvalbumin-expressing GABAergic interneurons are known to reduce gamma-frequency activity on the EEG, which is a feature of many people with schizophrenia. Reduced excitatory neurotransmitter (glutamate) function is posited based on psychotic and cognitive symptoms generated in humans exposed to ketamine or phencyclidine, which are non-competitive antagonists of the NMDA subtype of glutamate receptors. There are reports of altered levels of glutamate receptors or associated proteins in the brains of individuals with schizophrenia examined postmortem, but no findings have yet been widely replicated. Finally, overactivity of dopamine neurotransmission at D2-type dopamine receptors is proposed based on the ability of D2 antagonists (an action common to all current antipsychotic agents; see Chap. 54) to ameliorate the positive symptoms of schizophrenia. Excessive dopamine release in the striatum elicited by an acute dose of amphetamine has been demonstrated by PET imaging in some patients with schizophrenia. However, it is unclear whether this abnormality reflects the underlying illness or a lasting effect of antipsychotic medications. In contrast, reduced activity of dopamine at D1 dopamine receptors in the prefrontal cortex has been implicated in working memory deficits based on the cognitive effects of D1 receptor agonists and antagonists in the illness. Nevertheless, inferring something about disease pathogenesis from the actions of psychotropic drugs, for example, as with the glutamate and dopamine hypotheses, is fraught with artifact.

Efforts to understand how defects in these neurotransmitter systems might generate similar behavioral pheno-types have led to intriguing hypotheses. For instance, in the hippocampus, reduced glutamate transmission (based on a hypothesized deficit in glutamate release or glutamate receptors) onto GABAergic interneurons could lead to reduced glutamic acid decarboxylase expression, reduced gamma oscillations, and reduced inhibition onto excitatory neurons. These events in turn could lead to increased dopamine release from the ventral tegmental area, with dopamine antagonists thereby helping to reset the system to its nonpathologic state. It must be emphasized that these are working models only, and a true pathophysiology (or pathophysiologies) for schizophrenia remains to be established.

Overlaid on these neurotransmitter-based hypotheses is speculation as to how mutations in any of several genes implicated, however tentatively, in schizophrenia lead to the associated pathologic and behavioral abnormalities. DISC1 was originally discovered based on its association with schizophrenia in an Icelandic family. However, as stated earlier, DISC1 has since been variably associated with other neuropsychiatric conditions and its role in schizophrenia remains uncertain. The DISC1 protein has been implicated in several cellular functions, including neuronal growth and maturation, neurite outgrowth, and even the proliferation of new neurons during development. Neuregulin 1 (NRG1), a member of the EGF family of growth factors, and its receptor ERBB4 have also been implicated in schizophrenia in several genetic studies. Interestingly, NRG1 and ERBB4 play important roles in the maturation of GABAergic interneurons in cerebral cortex, and regulate dopamine transmission to several limbic brain regions. Moreover, loss of NRG1-ERBB4 in mice leads to reduced neuropil, thus phenocopying a pathologic finding in schizophrenia. Another gene of potential interest encodes Reelin, a secreted extracellular matrix serine protease. There are unconfirmed reports of association of schizophrenia with the Reelin locus on chromosome 7, and of reduced Reelin expression in the cerebral cortex of schizophrenic subjects, possibly related to increased methylation of the Reelin gene promoter. Reelin is important during development in the migration of newly born neurons to their appropriate layers of cerebral cortex. In the adult brain, the protein is enriched in cortical GABAergic interneurons and has been implicated in regulating NMDA glutamate receptor function. It is, therefore, easy to imagine how abnormalities in DISC1, NRG1, or Reelin may be related to GABAergic, glutamatergic, and dopaminergic mechanisms in schizophrenia, and to associated pathologic abnormalities, but all such connections are currently speculative.


Mood disorders are divided into depressive and bipolar disorders. Depressive disorders include the major depressive disorders, dysthymia, and more minor forms of depression. These disorders are heterogeneous syndromes, each composed of several diseases with presumably distinct pathophysiologies that remain to be elucidated.


Mood disorders are common, with a prevalence of ~1–2% for bipolar disorder, ~5% for major depression, and ~15–20% for milder forms of depression. Between 40–50% of the risk for depression appears to be genetic. Nongenetic factors as diverse as stress and emotional trauma, viral infections, and even stochastic (random) processes during brain development have been implicated in the etiology. Depressive syndromes can occur in the context of general medical conditions such as endocrine disturbances (hyper- or hypocortisolemia, hyper- or hypothyroidism), autoimmune diseases, Parkinson’s disease, traumatic brain injury, certain cancers, asthma, diabetes, and stroke. Depression and obesity/metabolic syndrome are important risk factors for each other. In predisposed individuals, stressful life events can lead to clear-cut depressive episodes, while severe stress can induce posttraumatic stress disorder (PTSD), instead of depression. Bipolar disorder is characterized by episodes of mania and depression and is one of the most heritable of psychiatric illnesses, with genetic risk of ~80%. Stress and disrupted circadian rhythms can promote the manic episodes, during which patients exhibit extremely elevated mood, abnormal thought patterns, and sometimes psychosis. Several of these clinical signs can resemble certain features of schizophrenia; indeed, recent epidemiologic and genetic research has questioned the DSM-IVTR designations of bipolar disorder, schizophrenia, and schizoaffective disorder as distinct syndromes.


Brain imaging studies in humans are defining the neural circuitry of mood within the brain’s limbic system (Fig. 53-1). Integral to this system are the nucleus accumbens (important for brain reward—see later in the chapter under Substance Use Disorders), amygdala, hippocampus, and regions of prefrontal cortex. Given that many symptoms of depression (so-called neurovegetative symptoms) involve physiologic functions, a key role for the hypothalamus is also presumed. Depressed individuals show a small reduction in hippocampal size. PET and functional MRI have revealed increased activation of the amygdala by negative stimuli and reduced activation of the nucleus accumbens by rewarding stimuli. There is also evidence for altered activity in prefrontal cortex, for example, hyperactivity of subgenual area 25 in anterior cingulate cortex. Deep brain stimulation (DBS) of either the nucleus accumbens or subgenual area 25 elevates mood in normal and depressed individuals. While there are numerous reports of pathologic findings within these various regions postmortem, there is to date no defined neuropathology of depression.



Neural circuitry of depression and addiction. The figure shows a simplified summary of a series of limbic circuits in brain that regulate mood and motivation and are implicated in depression and addiction. Shown in the figure are the hippocampus (HP) and amygdala (Amy), regions of pre-frontal cortex, nucleus accumbens (NAc), and hypothalamus (Hyp). Only a subset of the known interconnections among these brain regions is shown. Also shown is the innervation of several of these brain regions by monoaminergic neurons.

The ventral tegmental area (VTA) provides dopaminergic input to each of the limbic structures. Norepinephrine (from the locus coeruleus or LC) and serotonin (from the dorsal raphe [DR] and other raphe nuclei) innervate all of the regions shown. In addition, there are strong connections between the hypothalamus and the VTA-NAc pathway. Important peptidergic projections from the hypothalamus include those from the arcuate nucleus that release β-endorphin and melanocortin and from the lateral hypothalamus that release orexin.


Although depression and bipolar disorder are highly heritable, the specific genes that comprise this risk remain unknown. As noted earlier, some of the genes implicated in autism or schizophrenia seem to cause bipolar disorder in some families. Large genomewide association studies have identified genes for diacylglycerol kinase η (DGKH), ankyrin G (ANK3), an L-type voltage-gated calcium channel (CACNA1C), and a gene-rich region on chromosome 16p12 as being associated with bipolar disorder, but these findings await confirmation by additional studies. Numerous susceptibility genes have also been implicated in linkage and association studies, but none has yet been definitively established as a bona fide depression gene. However, a few genes with variants that may modify depression risk are worthy of mention since they may be linked to mechanisms of pathogenesis (discussed later). These include genes for the type 1 receptor for corticotrophin-releasing factor (CRHR1); the glucocorticoid receptor gene (GR); FKBP5, which encodes a chaperone protein for the glucocorticoid receptor; the serotonin transporter gene (SLA6A4); the catechol-O- methyltransferase gene (COMT); and brain-derived neurotrophic factor (BDNF).


Human and animal research in depression has focused on the long-term effects of chronic stress on the brain and their reversal by antidepressant medications; prominent examples are discussed here. A subset of depressed patients show elevated levels of cortisol associated with increased production of corticotrophin-releasing factor from the hypothalamus and perhaps other brain regions (e.g., amygdala). In animals, sustained elevations in glucocorticoids impair hippocampal function, in part via direct damage to hippocampal neurons, which is consistent with reduced hippocampal volumes seen in some depressed humans. As the hippocampus exerts the major inhibitory influence over the hypothalamic-pituitary-adrenal axis, impairment of hippocampal function would lead to still further increases in glucocorticoid secretion, establishing a pathologic feed-forward loop.

Stress-induced damage to the hippocampus, and perhaps other limbic regions (e.g., amygdala), in animals is also mediated in part by reduced levels of BDNF and other growth factors and cytokines. Furthermore, stress leads to a decrease in the birth of new neurons in the adult hippocampus. Interestingly, antidepressant treatments reverse these effects of stress, and the antidepressant effects of these medications seem to depend, in part, on their ability to promote hippocampal neurogenesis in animal models of depression. The clinical ramifications of such observations are unproven, although similar regulation of adult hippocampal neurogenesis may be important for certain forms of learning and memory.

Another important target of stress in animals is the nucleus accumbens, where stress regulation of numerous signaling events (dopaminergic transmission and BDNF signaling are two examples) exert potent effects on depression-like behavioral abnormalities. While a reduction in BDNF in the hippocampus promotes depression-like behaviors, an induction of BDNF in the nucleus accumbens promotes depression; similar changes in BDNF expression have been observed in postmortem brains of depressed patients. Thus the role of BDNF in regulating mood is highly brain-region specific.

In contrast to depression, animal models of mania as well as bipolar disorder have proved much more elusive. Mice with loss-of-function mutations in the Clock or GluR6 glutamate receptor genes or transgenic mice that overexpress glycogen synthase kinase 3β (GSK3β) show manic-like behavioral abnormalities, although the relevance of these observations to human mania remains unknown.

The observation that tricyclic antidepressants (e.g., imipramine) inhibit serotonin and/or norepinephrine reuptake, and that monoamine oxidase inhibitors (e.g., tranylcypromine) are effective antidepressants, initially led to the view that depression is caused by a deficiency of these monoamines. However, this hypothesis has not been well substantiated, although variants in the serotonin transporter, and in the COMT gene, have been associated with altered mood states in some individuals. Nevertheless, these medications, particularly the tricyclics, have formed the basis of antidepressant discovery efforts, with virtually all of today’s marketed antidepressants being SSRIs (e.g., fluoxetine, sertraline, citalopram), serotonin, and norepinephrine reuptake inhibitors (SNRIs) (e.g., venlafaxine, duloxetine), or norepinephrine reuptake inhibitors (NRIs) (e.g., atomoxetine).

A cardinal feature of all antidepressant medications is that long-term administration is needed for their mood-elevating effects. This means that their short-term actions, namely promotion of serotonin or norepinephrine function, is not per se antidepressant but rather induces a cascade of adaptations in the brain that underlie their clinical effects. The nature of these therapeutic drug-induced adaptations has not been identified with certainty. Presumably, the rich innervation of the brain’s limbic circuitry by serotonin and norepinephrine (Fig. 53-1) provide the anatomic basis of their therapeutic actions.

Lithium is a highly effective drug for bipolar disorder, and competes with magnesium to inhibit magnesium-dependent enzymes, including GSK3β and several enzymes involved in phosphoinositide signaling leading to activation of protein kinase C. These findings have led to discovery programs focused on developing GSK3 and PKC inhibitors as potential novel treatments for mood disorders. Another commonly prescribed drug for bipolar disorder is valproic acid, which has pleio-tropic effects, including inhibition of histone deacetylases (HDACs). Histone acetylation promotes transcriptional activation through posttranslational modification of N-terminal lysine residues in histones and thereby causes chromatin decondensation. HDAC inhibitors have shown some antidepressant effects in animal models of depression. Another form of epigenetic control of gene expression is methylation of cytosine residues in DNA, which inhibits gene transcription. DNA methylation has been shown to be important for inherited maternal effects on emotional behavior. Thus, rats born to mothers that exhibit low levels of nurturing behavior show increased anxiety and reduced expression of hippo-campal glucocorticoid receptors due to increased methylation of the receptor gene. They pass these traits on to their offspring, but cross-fostering by mothers that display high levels of nurturing reverses them. As research into epigenetic mechanisms progresses, there is hope that it may become possible to identify specific depression-associated alterations in human chromatin.


The DSM-IVTR uses the terms substance dependence and substance abuse to describe substance use disorders. It is unfortunate that the term substance dependence instead of addiction is used, because dependence can develop without addiction, and addiction involves much more than dependence per se. Physical dependence develops through resetting of homeostatic cellular mechanisms to permit normal function despite the continued presence of a drug; when drug intake is terminated abruptly, a withdrawal syndrome emerges. Withdrawal from alcohol or other sedative-hypnotics causes nervous system hyper-activity, whereas withdrawal from psychostimulants produces fatigue and sedation. Tolerance is a reduction in response to a drug, which like dependence, develops after repeated use. It results from a change in drug metabolism (pharmacokinetic tolerance) or cell signaling (pharmacodynamic tolerance). It is important to recognize that many nonaddictive medications induce tolerance and physical dependence, including β-adrenergic antagonists (e.g., propranolol) and α2-adrenergic agonists (e.g., clonidine).

What sets drugs of abuse apart is their unique ability to produce euphoria, a positive emotional state characterized by intensely pleasant feelings that are rewarding and reinforcing since they motivate users to take the drug repeatedly. Tolerance develops to the rewarding properties of most abused drugs during periods of heavy use, which promotes the use of higher drug doses. In addition, psychological (or motivational) dependence develops through the resetting of cellular mechanisms within reward-related regions of the brain and leads to negative emotional symptoms resembling depression during drug withdrawal. Addictive drugs can also cause sensitization, an increased drug effect upon repeated use, as exemplified by the paranoid psychosis induced by chronic use of cocaine or other psychostimulants (e.g., amphetamine). Addiction, therefore, results from drug-induced changes in reward-related regions of the brain that lead to a complex mixture of tolerance, sensitization, and motivational dependence, in addition to powerful conditioning effects of these drugs mediated by the brain’s memory circuits.


Substance use disorders, especially those involving alcohol and tobacco, are very prevalent. The World Health Organization (WHO) estimates that more than 76 million people worldwide have alcohol use disorders and ~1.3 billion people smoke tobacco products (~1 billion men, 250 million women). The most widely used illicit drug in the United States is marijuana, with ~17% of 18–25-year-olds reporting regular use. Estimates of the annual economic burden of substance use disorders in the United States, including health- and crime-related costs and losses in productivity, exceed $500 billion.


Imaging studies in humans demonstrate that addictive drugs, as well as craving for them, activate the brain’s reward circuitry (discussed later). However, there is no established pathology associated with addiction risk. Patients who abuse alcohol or psychostimulants show reduced gray matter in the prefrontal cortex. Functional MRI or PET studies show reduced activity in anterior cingulate and orbitofrontal cortex during tasks of attention and inhibitory control. Damage to these cortical areas may contribute to addiction by impairing decision making and increasing impulsivity.


Substance use disorders are highly heritable, with genetic risk estimated to be 0.4 to 0.7; however, the specific genes that comprise this risk remain largely unknown. The best-established genetic contribution to addiction is the protective effect that mutations in alcohol-metabolizing enzymes have on risk for alcoholism. Mutations that increase alcohol dehydrogenase (ADH) activity and decrease aldehyde dehydrogenase (ALDH) activity are additive and promote accumulation of acetaldehyde following ingestion of alcohol. This produces intoxication at low doses and a flushing reaction that is unpleasant, resembling the reaction to disulfiram, a drug used to prevent relapse. These variants are common among people of East Asian descent, and individuals expressing these variants rarely abuse alcohol.

Genes that promote risk for addiction have begun to emerge from large family and population studies, but all genes identified to date represent only a very small fraction of the overall genetic risk for addiction. The best established susceptibility loci are regions on chromosomes 4 and 5 containing GABAA receptor gene clusters linked to alcohol use disorders and the nicotinic acetylcholine receptor gene cluster on chromosome 15 associated with nicotine and alcohol dependence. There are reports of numerous other addiction susceptibility genes (e.g., variants in COMT, the μ-opioid receptor, and the serotonin transporter), but further work is needed to validate these findings. In addition, several genes have been implicated in impulsivity, which is strongly associated with substance abuse. These include variants in genes for the D4 dopamine receptor, the dopamine transporter, monoamine oxidase A, COMT, and the 5-HT1B serotonin receptor.


Work in rodents and nonhuman primates has established the brain’s reward regions as key neural substrates for the acute actions of drugs of abuse and for addiction induced by repeated drug administration (Fig. 53-1). Midbrain dopamine neurons in the ventral tegmental area (VTA) function normally as rheostats of reward: They are activated by natural rewards (food, sex, social interaction) or even by the expectation of such rewards, and many are suppressed by the absence of an expected reward or by aversive stimuli. These neurons thereby transmit crucial survival signals to the rest of the limbic brain to promote reward-related behavior, including motor responses to seek and obtain the rewards (nucleus accumbens), memories of reward-related cues (amygdala, hippocampus), and executive control of obtaining rewards (prefrontal cortex).

Drugs of abuse alter neurotransmission through initial actions at different classes of ion channels, neurotransmitter receptors, or neurotransmitter transporters (Table 53-2). Although the initial targets differ, the actions of these drugs converge on the brain’s reward circuitry by promoting dopamine neurotransmission in the nucleus accumbens and other limbic targets of the VTA. In addition, some drugs promote activation of opioid and cannabinoid receptors, which modulate this reward circuitry. By these mechanisms, drugs of abuse produce powerful rewarding signals, which, after repeated drug administration, corrupt the brain’s reward circuitry in ways that promote addiction. Three major pathologic adaptations have been described. First, drugs produce tolerance and dependence in reward circuits, which promote escalating drug intake and a negative emotional state during drug withdrawal that promotes relapse. Second, sensitization to the rewarding effects of the drugs and associated cues is seen during prolonged abstinence and also triggers relapse. Third, executive function is impaired in such a way as to increase impulsivity and compulsivity, both of which promote relapse.

TABLE 53-2



Repeated intake of abused drugs induces specific changes in cellular signal transduction, synaptic strength (long-term potentiation or depression), and neuronal structure (altered dendritic branching or cell soma size) within the brain’s reward circuitry. These modifications are mediated in part by changes in gene expression, achieved by drug regulation of transcription factors (e.g., CREB [cAMP response element binding protein] and ΔFosB) and their target genes. Together, these drug-induced adaptations underlie alterations in numerous neurotransmitter systems (e.g., glutamate, GABA, dopamine), growth factors (e.g., BDNF), neuropeptides (e.g. corticotrophin releasing factor), and intracellular signaling cascades. These adaptations provide opportunities for developing treatments targeted to drug-addicted individuals. The fact that the spectrum of these adaptations partly differ depending on the particular addictive substance used creates opportunities for treatments that are specific for different classes of addictive drugs and that may, therefore, be less likely to disturb basic mechanisms that govern motivation and reward.

Increasingly, causal relationships are being established between individual molecular-cellular adaptations and specific behavioral abnormalities that characterize the addicted state. For example, acute activation of μ-opioid receptors by morphine or other opiates activates Gi/o proteins leading to inhibition of adenylyl cyclase, resulting in reduced cAMP production, protein kinase A (PKA) activation, and activation of the transcription factor CREB. Repeated administration of these drugs (Fig. 53-2) evokes a homeostatic response resulting in upregulation of adenylyl cyclases, increased production of cAMP, and increased activation of PKA and CREB. Such upregulation of cAMP signaling has been identified in the locus coeruleus, periaqueductal gray, VTA, and nucleus accumbens and contributes to opiate craving and signs of opiate withdrawal. The fact that endogenous opioid peptides do not produce tolerance and dependence while morphine and heroin do may relate to the recent observation that, unlike endogenous opioids, morphine and heroin are weak inducers of μ-opioid receptor desensitization and endocytosis. Therefore, these drugs cause prolonged receptor activation and inhibition of adenylyl cyclases, which provides a powerful stimulus for the upregulation of cAMP signaling that characterizes the opiate-dependent state.



Opiate action in the locus coeruleus (LC). Binding of opiate agonists to μ-opioid receptors catalyzes nucleotide exchange on Gi and Go proteins, leading to inhibition of adenylyl cyclase, neuronal hyperpolarization via activation of K+ channels, and inhibition of neurotransmitter release via inhibition of Ca2/+ channels. Activation of Gi/o also inhibits adenylyl cyclase (AC), reducing protein kinase A (PKA) activity and phosphorylation of several PKA substrate proteins, thereby altering their function. For example, opiates reduce phosphorylation of the cAMP response element-binding protein (CREB), which appears to initiate long-term changes in neuronal function. Chronic administration of opiates increases levels of AC isoforms, PKA catalytic (C) and regulatory (R) subunits, and the phosphorylation of several proteins, including CREB (indicated by red arrows). These changes contribute to the altered phenotype of the drug-addicted state. For example, the excitability of LC neurons is increased by enhanced cAMP signaling, although the ionic basis of this effect remains unknown. Activation of CREB causes upregulation of AC isoforms and tyrosine hydroxylase, the rate-limiting enzyme in catecholamine biosynthesis.