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By M. Kliff. Northwestern Michigan College.

Anxiety order rabeprazole with a mastercard, motor activation purchase rabeprazole pills in toronto, corticotropin-releasing hormone receptor-2 display anxiety-like and maternal-infant interactions in 5-HT1B knockout mice purchase 20mg rabeprazole amex. Nature Genetics 2000; Behav Neurosci 1999;113:587–601. Abnormal adapta- vocalizations in rat pups: effects of serotonergic ligands. Neurosci tions to stress and impaired cardiovascular function in mice Biobehav Rev 1998;23:215–227. Crhr2 reveals an anxiolytic role for corticotropin-releasing hor- 141. Increased exploratory stress: differential roles of CRFreceptors 1 and 2. J Neurosci activity and altered response to LSD in mice lacking the 5- 1999;19:5016–5025. Neurobehavioral analysis to probe functions of 5-HT receptors. Ann NY Acad Sci 1998; of 5-HT6 receptor null mutant mice. Behavioral effects of ovine corticotropin-releasing 145. Adaptive changes of serotonin with the CRF1 receptor: design of small molecule inhibitors, 5-HT2A receptors in mice lacking the serotonin transporter. Oral administration of a bility in mice lacking 5-HT2C receptors: a behavioral analysis. Proc Natl Acad Sci USA 2000; Res Rev 1999;29:196–217. Postnatal development Proc Natl Acad Sci USA 1996;93:10614–10619. Gene chips and arrays revealed: a primer lacking GAD65. Gene transfer altered responses to anxiolytics in mice deficient in the 65-kDa into neurones for the molecular analysis of behaviour: focus on isoform of glutamic acid decarboxylase. Benzodiazepine-insensi- morphine induced by viral-mediated gene transfer. Science tive mice generated by targeted disruption of the 2 subunit 1997;277:812–814. A gene promotes anxiety in mice—and also mine-deficient mice. Anxiety: at the phism in the regulatory region of the corticotropin-releasing intersection of genes and experience. Na- ing hormone promoter region polymorphisms in rheumatoid ture 1999;401:751–752. Dinucleotide repeat polymor- rosci 2000;3:529–530 phism at the CRH gene. Association of anxiety- mediated by specific -aminobutyric acid A receptor subtypes. Association between anxiety not anxiolytic properties of benzodiazepines are mediated by the disorders and a functional polymorphism in the serotonin trans- GABAA receptor 1 subtype. Role of the seroto- ment, plasticity and environment in the interpretation of pheno- nin transporter promoter polymorphism in anxiety-related typic changes in knockout mice. Corticotropin-releasing hormone and associated with the serotonin transporter (5-HTTLPR) poly- animal models of anxiety: gene-environment interactions. Accessing genetic information phenotypes for genetic studies. Am J Psychiatry 1998;155: with high-density DNA arrays. DREVETS The 1990s witnessed tremendous progress in the acquisition diating the anticipation, interpretation, or recollection of of knowledge about the molecular, cellular, and anatomic perceived stressors and threats. Advances in neuropharmacol- Emotional processing in general can be divided into eval- ogy and molecular biology have enabled elucidation of mul- uative, expressive, and experiential components (1). Evalua- tiple chemical neurotransmitter systems that play roles in tion of the emotional salience of a stimulus involves ap- fear and anxiety behavior. The anatomic circuits where these praisal of its valence (e. Emotional expression conveys the range of behavioral, selectivity of lesion analyses in experimental animals, and endocrine, and autonomic manifestations of the emotional by advances in neuroimaging technology, which have per- response, whereas emotional experience describes the sub- mitted mapping of the neurophysiologic correlates of emo- jective feeling accompanying the response. The findings of these investigations have their capacity for guiding behavior, all these aspects of emo- informed the design and interpretation of clinical neurosci- tional processing are modulated by complex neurobiological ence approaches aimed at investigating how dysfunction systems that prevent them from becoming persistent, exces- within these neurochemical and anatomic systems may re- sive, inappropriate to reinforcement contingencies, or other- sult in psychiatric conditions such as panic, posttraumatic wise maladaptive. This chapter reviews the pre- The emotional processes pertaining to fear and anxiety clinical and clinical data regarding the neural mechanisms that have been most extensively studied (largely because of underlying normal and pathologic anxiety and discusses their amenability to experimental manipulation) have in- their implications for guiding development of novel treat- volved pavlovian fear conditioning and fear-potentiated ments for anxiety disorders. These types of 'fear learning' have been shown to comprise experience-dependent forms of neural plasticity in an extended anatomic network that centers around the NEUROANATOMIC CIRCUITS SUPPORTING critical involvement of the amygdala (1,6). The structures FEAR AND ANXIETY that function in concert with the amygdala during fear learning include other mesiotemporal cortical structures, the Fear and anxiety normally comprise adaptive responses to sensory thalamus and cortices, the orbital and medial pre- threat or stress. These emotional-behavioral sets may arise frontal cortex (mPFC), the anterior insula, the hypothala- in response to exteroceptive visual, auditory, olfactory, or mus, and multiple brainstem nuclei (1,5,7). Much of this somatosensory stimuli or to interoceptive input through the network appears to participate in the general process of asso- viscera and the endocrine and autonomic nervous systems. Charney: Mood and Anxiety Disorder Research Program, National Institute of Mental Health, Bethesda, Maryland. Drevets: Section on Mood and Anxiety Disorders Imaging, Molec- ular Imaging Branch, National Institute of Mental Health, Bethesda, Mary- The anatomic systems supporting fear learning are organ- land. The projections from sensory thalamus to the LA are The former processes depend on monosynaptic projections thought to support rapid conditioning to simple visual and from the sensory thalamus to the amygdala, whereas the auditory features, presumably accounting for fear responses latter involve projections from sensory association cortices below the level of conscious awareness (31). Thus, lesioning and mesiotemporal cortical structures to the amygdala (1, the auditory cortex before conditioning does not prevent 12). These neural networks also respond to visceral input conditioning to single auditory tones. In contrast, projec- received both directly through the nucleus paragigantocellu- tions to the LA from the primary sensory and sensory associ- laris and the nucleus tractus solitarius (NTS) of the vagus ation cortices appear to be essential for some aspects of nerve and indirectly through the locus ceruleus (LC), the conditioned responding to more complex sensory stimuli (4, anterior insula, and the infralimbic and prelimbic cortices 32). Finally, neural activity within the amygdala is disruption of the projections from the auditory thalamus modulated by cortisol, norepinephrine (NE), and other and auditory cortex to the LA specifically prevents acquisi- neurotransmitters and by mnemonic input related to previ- tion of fear conditioning to auditory stimuli and fear-condi- ous conditioning and reinforcement experiences conveyed tioned responses to previous auditory CSs (33–35). The most extensive extranuclear projections of are responsive to auditory, visual, and somatic stimuli, thus the LA are composed of reciprocal projections to the basal enabling the LA to serve as a locus of convergence for infor- and accessory basal nuclei and the central nucleus of the mation about CS and US (19). Olfactory input, in contrast, amygdala (CE) (37,38). Lesions of either the LA or the directly projects to the periamygdaloid cortex from the ol- CE—but not of other amygdala nuclei—disrupt fear condi- factory bulb through the olfactory tract (20). The olfactory tioning to a tone CS, a finding suggesting that this direct tract also sends projections to the pyriform cortex and the projection from LA to CE is sufficient to mediate condition- entorhinal cortex, areas with reciprocal connections to the ing to simple sensory features (4). Although the periamygdaloid cortex neu- The projections from LA to the basal amygdaloid nuclei rons project to deeper amygdaloid nuclei, the specific path- also participate in forming long-lasting memory traces for ways conveying olfactory information through the amygdala fear conditioning (2,15,39).

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See the rent defined a physiologic receptor mechanism termed the chapters on GABA in previous editions of this book (1 best order for rabeprazole,4) generic 20 mg rabeprazole mastercard. GABAA receptor generic rabeprazole 20mg with visa, also pharmacologically defined by the an- Since its discovery in the CNS in the early 1950s (5,6), tagonist bicuculline, as well as picrotoxin, and the agonist GABA was shown to fulfill the criteria for establishment as muscimol (Fig. Thus, the GABAA receptor is a chlo- a neurotransmitter (Fig. It is synthesized by a specific ride channel regulated by GABA binding, and it is now enzyme, l-glutamic acid decarboxylase (GAD), in one step grouped in the superfamily of ligand-gated ion channel re- from l-glutamate. Thus, in addition to its role in protein ceptors, which includes the well-characterized nicotinic ace- synthesis, in cofactors such as folic acid and in hormones tylcholine receptor, present at the skeletal neuromuscular such as thyrotropin-releasing hormone, and its action as a junction (13,14). Much of the ron by virtue of stabilizing the membrane potential near glutamate and GABA used as neurotransmitter is derived the resting level. However, under conditions of high intra- from glial storage pools of glutamine (2,6). Two genes for cellular chloride, for example, in immature neurons with GAD have been cloned, and the two forms of the enzyme low capacity to maintain a chloride gradient, increasing are proposed to differ in their affinity for the cofactor pyri- chloride permeability can depolarize the membrane poten- tial. This depolarization could be sufficient to fire the cell, and it would be likely to activate certain voltage-gated ion channels, including calcium, that can, in turn, regulate RichardW. Olsen: DepartmentofMolecular andMedicalPharmacology, University of California Los Angeles School of Medicine, Los Angeles, Cali- other cellular events. Diagram showing the main features of the GABA syn- apse. Transporters are indicated by oval symbols, receptors and ion channels by rectangular sym- bols. A: Transporters: GAT-1, GAT-3, plasma membrane GABA transporters; VGAT, vesicular GABA transporter. B: Receptors: GABA-A, ionotropic GABA receptor; GABA-B, G-protein–coupled GABA receptor; KAINATE, presynaptic kainate receptor; MGLUR, metabotropic glutamate receptor. C: Ion channels: GIRK2, G-protein–coupled inwardly rectifying K channel; VDCC: voltage-depen- dent calcium channel. D: Enzymes: GABA-T, GABA transaminase; GAD, glutamic acid decarboxyl- ase; GS, glutamate synthetase. Such depolarizing such as benzodiazepines and anesthetics (19). The eventual GABAR action has been proposed as an important excita- cloning of a retinal-specific subunit cDNA that produced tory system in developing brain (16), and it may explain bicuculline-insensitive GABA chloride channels appeared to the well-known trophic action of GABA to promote both account for GABAC receptors (20). However, because of survival and differentiation during development (17). The coupling mecha- neither bicuculline nor baclofen sensitive and sometimes nism depends on the cell location, because several G-pro- called GABAC (19), and generally sensitive to the GABA tein–coupled effectors can be used, involving negative analogue cis-aminocrotonic acid. GABAC–type inhibition modulation of adenylate kinase and negative modulation of was shown to involve a rapid chloride conductance, as with inositol tris phosphate production. These lead to activation GABAA receptors; however, it was not only insensitive to of potassium channels or inhibition of voltage-gated cal- bicuculline, but also not modified by other GABAA drugs, cium channels (22). Presynaptic inhibition of GABA release Chapter 12: GABA 161 pharmacology (26,27). One or more polypeptides of 45 to 60 kd on sodium dodecylsulfate–polyacrylamide gel FIGURE 12. Considerable effort was therefore expended to determine whether different GABAB receptors could mediate these very different functions, possibly allowing the development of receptor subtype-specific drugs. Although some classic pharmacology studies supported this hypothesis (18, 22), it was the long-awaited cloning of the GABAB receptor (23) that established the true situation. The first receptor exists as two splice variants, and additional clones for GABAB receptor subtype genes have been isolated. Surprisingly, the GABABreceptors appear to exist as heterodimers, previously unknown for G-protein–coupled receptors. The dimers produce the diverse pharmacologic specificity for the GABA site and the diverse coupling mechanisms observed in nature (24). It seems that the pharmacology of GABAB receptors is in a very promising infancy. The chloride channel is shown as a pore in the center of five equivalent sub- RECEPTORS units, each with four membrane-spanning domains (see the iso- lated subunit at the bottom). Because of the existence of subunit The GABARs are the major players in CNS function and families, many such heteropentamer combinations are possible, each with multiple drug sites. Ligand sites: GABA: agonists (musci- relevance to psychopharmacology. These receptors, defined mol), antagonists (bicuculline); Benzodiazepine: agonists (fluni- by pharmacologists using electrophysiologic and other tech- trazepam), antagonists (flumazenil), inverse agonists (DMCM); niques (14,22), were identified in brain homogenates by Picrotoxin/Convulsant (TBPS); Barbituate (phenobarbitol); Steroid (alphaxalone, allopregnanolone); Volatile Anesthetic (halo- radioligand binding (25), and are shown to have the correct thane). Molecular biology specificity for GABA analogues expected from the neuro- of GABAAreceptors. The stituents of the GABAR by photoaffinity labeling with the GABAR strategy has certainly not been exhausted. ACTION OF BENZODIAZEPINES AND The GABAR proteins were purified using benzodiaze- BARBITURATES pine affinity chromatography (32), which allowed partial protein sequencing and expression cloning of two receptor The actions of several classes of CNS depressant drugs had genes (13). GABA-activated currents were demonstrated in for some time been suggested to involve enhancement of Xenopus oocytes using cDNAs for two polypeptides that inhibitory synaptic transmission. In particular, the anxio- contained the partial sequences within their coded sequence, lytic effects of benzodiazepines were shown probably to re- sult from potentiation of GABA action (37,38). At first, these were benzodiazepine receptors were discovered using radioligand thought (incorrectly) to correspond to the two bands seen binding to brain homogenates (1,4,39,40), it was quickly in the purified protein (32). These two subunits were related determined that the benzodiazepine binding sites were phys- to each other and also to the nicotinic acetylcholine receptor ically present on the GABAA receptor–chloride channel family of subunits, a finding indicating a superfamily of complex (28,41). The various types of drug binding site on receptor polypeptide genes and a likely heteropentameric the GABAAreceptor allosterically interact with each other in structure (Fig. Barbiturates and related sedatives also enhance as probes to clone additional family members with more or GABAAreceptor–mediated inhibition, and their pharmaco- less sequence homology to the first two. Those with high logic spectrum overlaps with that of the benzodiazepines homology were named with the same Greek letter, whereas and related substances, such as zolpidem, zopiclone, and those with less homology were given other Greek letters. The selective actions of benzodiaze- The current repertoire involves 1to6, 1to3, 1to3, pines not shown by barbiturates or vice versa are believed , , , , and 1 to 3 (21). There are also a few splice to arise from heterogeneity in GABA receptor sensitivity to variants; for example, 2 exists in two forms differing in an the drugs, and corresponding heterogeneity in brain regions, eight-amino acid insert in the intracellular loop that in- circuits, and functions. Further, some GABARs are insensi- cludes a substrate serine for protein kinase C (33). All the tive to benzodiazepines but not to barbiturates, as well as subunits are related to each other and have molecular additional nonoverlapping, nonGABA actions of high weights of about 50 kd. The purified receptor protein thus doses, especially barbiturates. In addition, the two classes of actually contains about a dozen subunit polypeptides, of drugs have a different mechanism of action at the molecular varying amount (6).

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At the different opiate receptor subtypes are expressed on dif- higher doses purchase generic rabeprazole from india, ethanol also inhibits the functioning of most ferent cells order rabeprazole 20mg line, resulting in different biological effects when voltage-gated ion channels order rabeprazole without a prescription. Morphine-like opiates, including heroin, are which ethanol affects these receptors and channels are not both analgesic and addictive, and interact with highest affin- yet certain; two types of mechanisms have been hypothe- ity with the -receptor. One possible mechanism attributes the effects of Morphine-like opiates suppress afferent nociceptive in- ethanol on receptors and channels to its generalized effects formation by acting on opiate receptors contained within on cell membranes, in which it is highly soluble. Certain 1370 Neuropsychopharmacology: The Fifth Generation of Progress ligand-gated and voltage-gated channels may be preferen- Serotonin also appears to be involved in ethanol con- tially affected by ethanol because, as complex multimeric sumption and reinforcement; ethanol consumption is gen- proteins, they may be particularly vulnerable to ethanol- erally curbed by experimental manipulations that increase mediated changes in their lipid environment. The alterna- serotonergic function, and experiments with rats selectively tive hypothesis is that ethanol interacts with specific hydro- bred for ethanol preference suggest that strong ethanol pref- phobic regions of these proteins to produce allosteric erence is associated with reduced serotonergic function. Mice lacking 5-HT1B serotonin recep- more specifically, in interaction with particular regions of tors consume higher levels of ethanol yet demonstrate less proteins, ethanol has been shown to allosterically regulate ataxia (21). A The anxiolytic and sedative effects of ethanol, like those of Nicotine barbiturates and benzodiazepines, are believed to result from Nicotine is the main psychoactive ingredient of tobacco and facilitation of the GABAA receptor, although the precise is responsible for the stimulant effects, reinforcement, and mechanism differs for each drug. For example, distinct dependence that result from tobacco use. Cigarette smoking binding sites on the receptor have been identified for barbi- rapidly delivers nicotine into the bloodstream. The convergence of actions fers from cocaine and opiates in that it is powerfully rein- of ethanol, barbiturates, and benzodiazepines on a single forcing in the absence of subjective euphoria. In addition, these agents nicotinic acetylcholine receptors (nAChRs). Nicotinic all produce cross-tolerance, thus permitting the use of ben- AChRs are ligand-gated cation channels located both pre- zodiazepines in ethanol detoxification protocols. Presynaptic nAChRs fa- Not all GABAA receptors are ethanol sensitive. The reinforcing effects of receptor complexes are heteropentamers comprised of com- nicotine depend on an intact mesolimbic dopamine system; binations of the various members of five distinct subunit nicotine-induced increases in locomotor behavior are also families. The subunit combinations vary in different cell blocked by destruction of mesolimbic dopamine nerve ter- types, leading to differences in the sensitivity of GABAA minals or cell bodies (22). Moreover, nicotine increases do- receptors to ethanol in different brain regions. Other actions of ethanol that are possibly relevant be involved in both nicotine-induced dopamine release and to its psychotropic effects include potentiation of the action reinforcement and in nicotine-induced locomotor activa- of serotonin at 5-HT3 receptors, which, like NMDA recep- tion (24,25). Systemic nicotine self-administration is dis- tors, are excitatory, cation-selective ion channels. Nicotine may also have some ability to stimu- effects of ethanol are partly explained by its ability to activate late dopamine release in the NAc, however, mediated by mesocorticolimbic dopamine circuitry (15), with enhanced presynaptic nAChRs located on dopamine terminals within release of dopamine in the NAc. Nicotinic AChRs on VTA dopamine neurons are this effect is mediated by disinhibition of dopamine neurons normally activated by cholinergic innervation from the at the level of the VTA or whether it occurs at the level of laterodorsal tegmental nucleus or the pedunculopontine nu- the NAc, nor is it known whether it is caused primarily by cleus. Finally, it is not know to what degree opioid, peptide system. Not only dopamine antagonists, but also serotonin, and other systems play a role in ethanol-mediated opiate antagonists, block nicotine-induced behaviors and reinforcement. Thus, for example, not only GABA recep- self-administration (26,27). These findings suggest a role A for endogenous opioid systems in the reinforcing effects of tor antagonists but also opiate antagonists, decrease ethanol nicotine, and raise the possibility that such antagonists may self-administration and ethanol-related behavioral effects in be of use in the treatment of nicotine addiction. The opiate antagonist naltrexone reduces ethanol self-administration in animals; moreover, naltrex- Cannabinoids one and other opioid receptor antagonists reduce ethanol consumption, relapse to active drinking, and craving clini- -9-Tetrahydrocannabinol (THC)is the major psychoac- cally (19,20). THC produces ef- Chapter 96: Molecular and Cellular Biology of Addiction 1371 fects in humans that range from mild relaxation, euphoria, contrast, hallucinogens, such as LSD, act at 5-HT2 seroto- analgesia, and hunger to panic attacks. THC MECHANISMS OF LONG-LIVED DRUG increases mesolimbic dopamine transmission in the NAc EFFECTS shell, probably via a -opioid receptor-mediated mecha- Homeostasis Versus Associative Learning nism because -receptor antagonists prevent the THC- induced dopamine increases in the brain mesolimbic area Diverse behaviors, symptoms, and signs of substance use (30). Cannabinoids have also been reported to inhibit exci- disorders coexist clinically, but depending on the drug and tatory glutamatergic neurotransmission in the substantia on the stage of the disorder, these may involve multiple nigra pars reticulata (31). THC binds to two cannabinoid receptors denoted CB1 Heuristically, the types of molecular mechanisms involved and CB2. Of the two, only the CB1 receptor is expressed in the long-lived effects of addictive drugs may be divided in the central nervous system, with high levels in the basal into two major classes: homeostatic adaptations and associa- ganglia and limbic system (32). These adaptations tend to dampen drug effects, thus receptor. The Despite ongoing debates about the addictiveness of can- adapted state of neurons or neural systems may be un- nabinoids in humans, there appear to be many compulsive masked on drug cessation, leading to the production of marijuana users. Withdrawal symptoms typically are not withdrawal symptoms, as illustrated in the following. Ho- reported with termination of long-term marijuana use, but meostatic adaptations typically occur within reversible withdrawal symptoms have been demonstrated in a labora- bounds, and with removal of the drug, tend to dissipate tory setting after four days of marijuana smoking (33). Relapse often occurs on re-exposure to cues with THC, a selective cannabinoid receptor antagonist pro- associated with drug use, consistent with an important role duced withdrawal symptoms that included head shakes, fa- for associative learning (36). Although homeostatic mecha- cial tremors, tongue rolling, biting, wet dog shakes, and nisms are thought to represent reversible global alterations ptosis (34). Neurobiologically, withdrawal effects include in the sensitivity of neurons or circuits to neurotransmitters increases in c-fos expression in the basal ganglia systems and or drugs, associative learning is thought to represent long- CRF release in the amygdala (35). The clear separation between homeostasis and associative learning Phencyclidine-Like Drugs that has been implied, however, is an oversimplification. For Phencyclidine (PCP or angel dust)and ketamine are related example, there is recent evidence that associative learning drugs classified as dissociative anesthetics. These drugs ex- mechanisms and compensatory adaptations may interact. Moreover, molecular adaptations that occur The reinforcing properties of PCP and ketamine are me- as a homeostatic response to drug bombardment may alter diated by the binding to specific sites in the channel of the the threshold for associative learning involving affected cells. NMDA glutamate receptor, where they act as noncompeti- tive NMDA antagonists. PCP is self-administered directly Recruitment of Different Molecular into the NAc, where its reinforcing effects are believed to Mechanisms Over Time result from the blockade of excitatory glutamatergic input to the same medium spiny NAc neurons inhibited by During the earliest periods of drug experimentation, meso- opioids, and also by increases in extracellular dopamine. In corticolimbic reward circuits are activated via different 1372 Neuropsychopharmacology: The Fifth Generation of Progress mechanisms by different classes of drugs. As noted, a shared property of addictive drugs is to promote dopamine release in multiple forebrain regions, including the NAc, but also including the dorsal striatum, amygdala, and hippocampus, in which dopamine release can act as a reinforcement signal, thus controlling learning processes (39,40). As drug use con- tinues, tolerance may occur, leading to dosage escalation. Depending on the drug, somatic dependence and/or emo- tional–motivational dependence my sustain drug seeking and drug use in attempts to avoid the aversive state of with- drawal. The emotional–motivational aspects of tolerance and dependence may largely occur within the mesocorticoli- mbic circuitry itself, but molecular adaptations occur in other circuits as well in a drug-specific manner reflecting the location of the target molecules for the given drug. Sen- sitization to some drug effects may occur, a phenomenon that is especially well documented for psychostimulants.

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