By N. Jose. Touro College.

Genetic correlation fascia dentata: identification of target structures on granule cells of inhibitory gating of hippocampal auditory evoked response by combining choline acetyltransferase immunocytochemistry and alpha-bungarotoxin-binding nicotinic cholinergic receptors and Golgi impregnation order 20 mg tadora with amex erectile dysfunction early 20s. Mechanisms of action of acetyl- inhibitory interneurons order tadora 20mg on-line erectile dysfunction doctor toronto. AGHAJANIAN AND ELAINE SANDERS-BUSH Serotonin, or 5-hydroxytryptamine (5-HT), has been impli- cellular aspects of individual 5-HT receptor subtypes and cated in almost every conceivable physiologic or behavioral their transduction mechanism, in addition to interactions function—affect, aggression, appetite, cognition, emesis, between different receptor subtypes within a single neuron endocrine function, gastrointestinal function, motor func- or region. The implications of this work in understanding tion, neurotrophism, perception, sensory function, sex, the global functions of the 5-HT system are discussed. Moreover, most drugs that are currently used for the treatment of psychiatric disorders (e. How is it possible for 5-HT to be involved in so many different processes? One answer lies in In the first half of the last decade, the cloning of the major the anatomy of the serotoninergic system, in which 5-HT known families of 5-HT receptors was accomplished. More cell bodies clustered in the brainstem raphe nuclei are posi- recently, attention has turned to issues of transcriptional tioned through their vast projections to influence all regions and post-transcriptional regulation. Another answer lies in the molecular diver- sity and differential cellular distribution of the many 5- RNA Processing HT receptor subtypes that are expressed in brain and other tissues. The 5′-flanking region of several 5-HT-receptor genes has During the past decade, molecular cloning techniques been cloned, and consensus sequences for transcription fac- have confirmed that putative 5-HT receptor subtypes, pre- tors have been identified in the promoter region (2–4). The dicted from radioligand binding and functional studies identification of these potential regulatory sites sets the stage (e. This knowledge has revolution- tion of gene transcription in vivo (5). A prominent form of ized contemporary research on the serotoninergic system. Alter- ization and immunocytochemical maps, studies of previ- native splicing is common and occurs for a number of 5- ously recognized 5-HT receptors could be directed more HT receptors, including the 5-HT2C, 5-HT4, and 5-HT7 precisely toward neurons and model cell lines that express receptors. The two splice variants of the 5-HT2C receptor these specific 5-HT receptor subtypes. Moreover, by the described in the literature encode severely truncated pro- use of cloning techniques, investigations could be initiated teins with no obvious function (6–8). In contrast, the splice to determine the functional role of previously unrecognized variants of the 5-HT4 receptor (5-HT4(a)–5-HT4(f)) and 5-HT receptors (e. Concur- 5-HT7 receptor (5-HT7(a)–5-HT7(d)) differ in length and rently, much progress has been made in delineating the composition in the carboxyl terminus (see refs. Marked species differences and perhaps regional subtypes. The focus of this review is on the molecular and differences lead to different patterns of splicing. Aghajanian: Departments of Psychiatry and Pharmacology, molecule. Splice variants of the 5-HT receptor have no 7 Yale University School of Medicine, New Haven, Connecticut. Elaine Sanders-Bush: Department of Pharmacology, Vanderbilt Univer- known functional differences. In contrast, a second form sity School of Medicine, Nashville, Tennessee. It is not known whether other ing properties of this ligand-gated ion channel (see ref. It seems likely that the RNA editing in mammalian systems was discovered 5-HT2C receptor would not be unique. However, screening about a decade ago and is defined as any modification, other methods for reliably detecting RNA editing are not avail- than alternative splicing, that occurs at the level of mRNA. Conse- editing generally involves the conversion of adenosine resi- quently, new edited substrates are slow to emerge. Such editing events have the potential to alter the genetic code at the level of RNA; the resulting is the Post-translational Regulation formation of multiple protein isoforms with altered func- tion. The discovery of RNA editing of the 5-HT receptor Receptor desensitization and down-regulation are common 2C provided the first, and so far only, example of editing of a adaptive responses to sustained agonist exposure. Editing of the human 5- widely accepted model of desensitization of G protein-cou- HT receptor mRNA involves five sites, A through E, pled receptors is based on extensive studies of the -adrener- 2C where adenosine is converted to inosine; inosine substitutes gic receptor, a G -linked receptor. In a simplified renditions for guanosine in the genetic code, thus generating different of the model, agonist binding to a cell surface receptor leads protein isoforms.

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Sen- sitization to some drug effects may occur 20 mg tadora with visa impotence effect on relationship, a phenomenon that is especially well documented for psychostimulants buy tadora 20mg low cost erectile dysfunction ear. Sensitization may act, inter alia, to increase the incentive salience of the drug, and thereby contribute to compulsive drug use (41). At the same time, multiple memory systems are affected by drugs of abuse (42)and, undoubtedly con- tribute to sustaining active drug use and late relapses (37). What follows are examples of different molecular processes that contribute to different aspects and stages of substance use disorders. These illustrations have been chosen based on the depth of available information, and likely relevance to the clinical situation in humans. Adaptations That Produce Tolerance and Somatic Dependence to Opiates FIGURE 96. Mechanism of opiate tolerance and dependence Opiates and ethanol produce somatic dependence and with- in the locus ceruleus: Acute administration of opiates increases drawal because their targets are expressed on cells and cir- outward K current, thereby hyperpolarizing locus ceruleus cells cuits that regulate bodily functions such as autonomic activ- (top). With chronic opiate use the cAMP signaling system is up- regulated, leading to PKA-dependent phosphorylation of the ity. Tolerance and dependence are generally thought to Na channel. In this state, the channel is more active, allowing represent homeostatic adaptations that compensate for Na ions to flow into the cell, increasingly the intrinsic excitability overstimulation by a drug or neurotransmitter. Up-regulation of the cAMP system also increases CREB Ser133 phosphorylation and CRE-dependent gene transcription. The molecular adaptations probably responsible for some aspects of tolerance and somatic dependence are best understood signaling mechanisms in opiate receptor-bearing cells (Fig. With repeat administration of mu agonist opiates such The locus ceruleus (LC), located in the dorsal pons, is as morphine or heroin, both tolerance and dependence the major noradrenergic nucleus of the brain and regulates emerge. There is a significant somatic component to heroin arousal, attention, and vigilance. It is involved in responses dependence as manifest by the classic heroin somatic with- to stress, and together with other noradrenergic cell groups drawal syndrome. It had initially been hypothesized that plays a role in regulation of the autonomic nervous system. Thus, despite continued op- turned out to be the case; rather opiate tolerance and depen- iate exposure, LC firing rates gradually return to their basal dence appear to be caused by adaptation in postreceptor levels. At this point, administration of an opioid receptor Chapter 96: Molecular and Cellular Biology of Addiction 1373 antagonist, such as naloxone or naltrexone, causes a dra- mice exhibited markedly reduced signs of withdrawal in- matic increase in LC firing rates. In animals, the period cluding complete absence of sniffing and ptosis (44,45). Opiate-induced syndrome, and drugs, such as the 2-adrenergic receptor up-regulation of PKA does not involve CREB and may be agonist clonidine, which inhibit LC firing, attenuate with- mediated posttranslationally. When the regulatory subunits are bound erance and dependence depend on the cyclic AMP (cAMP) by cAMP, the catalytic subunits are free to phosphor late pathway. In the LC, as in most other cell types, -opioid substrate proteins. However, free catalytic subunits of PKA receptor activation inhibits the cAMP pathway via Gi acti- are highly vulnerable to proteolysis, whereas inactive sub- vation and stimulates an inwardly rectifying K current by units bound to regulatory subunits are proteolysis-resistant. As the number of enzyme the actions of agonist opiates on these K and Na molecules increases, the kinase activity can be more readily channels expressed by LC neurons decrease the excitability activated by the low levels of cAMP. With long-term opiate administration, however, a homeostatic compensatory re- Adaptations That May Produce Tolerance sponse occurs: key components of the cAMP pathway be- and Somatic Dependence on Ethanol come up-regulated in LC neurons; thus, for example there Like opiates, ethanol produces somatic dependence and are increased concentrations of adenylyl cyclase and protein withdrawal, although the clinical syndrome is quite distinct, kinase A. This up-regulation increases the intrinsic excitabil- and potentially more dangerous. The molecular mecha- ity of LC neurons, by activating the cAMP-dependent Na nisms are less well understood than those underlying opiate current. The activation of this current may explain why LC tolerance and dependence, but the comparison is instruc- firing rates return to normal despite the continued presence tive. There is some evidence that homeostatic adaptations of an opiate (an example of tolerance). These observations occur in response to ethanol that decrease GABAA receptor may also explain the dramatic increase in LC firing that expression and increase NMDA receptor expression on occurs if an opiate antagonist such as naloxone is adminis- some neurons. The decrease in receptors for the major in- tered to precipitate withdrawal (illustrating dependence). The de- to glutamatergic projections to the LC from the nucleus crease in GABAA receptor function is possibly due in part paragigantocellularis of the medulla. Lesions of the paragi- to decreased GABAA-1 subunit expression in the striatum, gantocellularis, or glutamate receptor antagonists admin- cortex, and hippocampus (46). Conversely, chronic ethanol istered locally in the LC, attenuate withdrawal-induced appears to increase the number and function of NMDA increases in LC firing rates by approximately 50%. During withdrawal, glutamate release is in- regulated cAMP pathway also may mediate this effect, as creased for up to 36 hours in the NAc, hippocampus, and long-term use of opiates causes up-regulation of the cAMP striatum (48). Overall, there is increasing evidence to sug- pathway in the paragigantocellularis and its major afferents. In these animals two of the major CREB iso- Motivational Aspects of Dependence forms, and , were disrupted.

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Anxiolytic effects of 5-HT1 antagonists for antidepressant activity by blockade of central substance P in animals discount tadora 20mg with mastercard boyfriend erectile dysfunction young. Anxiolytic action of a neurokinin 1 receptor antagonist ioral pharmacology 20 mg tadora with visa erectile dysfunction doctor austin. Tachykinin NK3 Natl Acad Sci USA 1998;95(24):14476–14481. Neuropharmacol- Natl Acad Sci USA 1998;95(26):15153–15154. Psychopharmacology: the fourth generation of progress. Clinical pharmacokinetics and phar- Press, 1995:75–85. Glutamate as a neurotransmitter in the brain: cokinet 1999;36(4):277–287. The putative AMPA receptor antago- of reduction in NMDA receptor glycine affinity in mice carrying nist, LY326325, produces anxiolytic-like effects without altering targeted point mutations in the glycine binding site. Antagonism of non-NMDA re- pharmacological characterization of ( )-2–aminobicyclo- ceptors in the dorsal periaqueductal grey induces anxiolytic ef- 93. Psychopharmacology 1997;132: lective, and orally active group 2 metabotropic glutamate recep- 14–18. Role of corticotropin-releasing J Med Chem 1997;40:528–537. Behav Brain Res 1999;100: effect profile of LY354740: a potent, highly selective, orally 207–215. Hormonal polypeptides of the upper intes- Pharmacol Exp Ther 1998;284:651–660. Distribution of cholecys- anti-anxiety, anti-addictive effects of LY 354740, a selective tokinin-like immunoreactivity in the nervous system. Co-exis- group II glutamate metabotropic receptors agonist in animal tence with classical neurotransmitters and other neuropeptides. Distribution of cholecys- tropic glutamate receptor agonist prevents lactate-induced tokinin-like peptides in the human brain. J Neurochem 1982; panic-like response in panic-prone rats. The selective mGlu2/3 receptor receptors: implications for behavioral actions. Brain Res 1986; agonist LY354740 attenuates morphine-withdrawal-induced activation of locus coeruleus neurons and behavioral signs of 362:175–179. MDL 100,458 and the human brain and gastric cholecystokinin receptor: structure, MDL 102,288: two potent and selective glycine receptor antag- functional expression and chromosomal localization. Eur J Pharmacol 1995; Biophys Res Commun 1992;189:296–303. Novel structure having antagonist controlled study of a CCKB receptor antagonist, CI-988, in actions at both the glycine site of the N-methyl-D-aspartate patients with generalized anxiety disorder. J Clin Psychopharma- receptor and neuronal voltage-sensitive sodium channels: bio- col 1995;15:428–434. A placebo-con- J Pharmacol Exp Ther 2000;292:215–227. A characterization of anxiolytic-like Biol Psychiatry 1995;37:462–466. Lack of efficacy of a cholecystokinin-B antagonist L-701,324. Increased knowledge of the neural mechanisms and ology and neural circuits underlying fear and anxiety states neurotransmitters involved in extinction may offer novel and the potential for badly needed advances in the diagnosis, therapeutic approaches. If we can discover pharmacologic pathophysiology, and treatment of anxiety disorders. There Kessler and Greenberg chapter on the economic burden of is evidence of extinction being mediated by -aminobutyric anxiety and stress disorders. This suggests the possibility of aug- that anxiety and stress disorders are the most commonly menting extinction-based psychotherapy with GABA ago- occurring of all mental disorders. Indeed the combined occur- orders is critically important to progress in understanding rence of high lifetime prevalence with an early age at onset etiology and improving treatment. Merikangas and Pine review the evidence that the major The chapter by Stein and Lang reviews in detail the subtypes of the anxiety disorders aggregate in families. How- course of anxiety and stress disorders over the lifetime. One ever, the magnitude of heritability is relatively moderate, point they make that is especially important to emphasize indicating a strong environmental contribution to etiology. The presence of an anxiety disorder in childhood anxiety disorders have not been fruitful. Future studies or adolescence is a predictor of the persistence into adult- should determine if components of anxiety syndromes are hood of not only anxiety disorders but other psychiatric controlled by specific genes.

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