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By G. Gorn. Butler University. 2019.

The four methods (59) most widely signed to QTLs on mouse chromosomes 1 discount zantac 300mg with amex, 4 cheap 300mg zantac with visa, and 11. The used are (a) linkage analysis: the inheritance pattern of phe- locus on chromosome 11 accounted for 12% of the genetic notypes and genotypes are elucidated in pedigrees; (b) allele variability in withdrawal liability and was near the genes for sharing methods: affected relatives are compared to detect the 2, 1, and 6 subunits of GABAA receptors. Further- excess genotype sharing; (c) association (case-control) stud- more, a 2 subunit polymorphism has now been found to ies: unrelated affected and unaffected individuals are com- be genetically correlated with alcohol withdrawal severity in pared; (d) analysis of inbred, transgenic, and gene-knockout mice (65). QTLs for alcohol-induced hypothermia, alcohol animals (principally mice and rats). An alternative approach is to employ an endopheno- ships between different phenotypes indicate that the same type as a trait specific marker, e. On Serotonin is involved in behavioral inhibition and is a target chronic exposure to alcohol they show less evidence of toler- for the pharmacologic treatment of alcoholism. These mice also work harder to self-administer cocaine serotonin reuptake inhibitors play a limited role in modify- and show an increased locomotor response, behaving as if ing craving for alcohol and also modify other comorbid already sensitized to the drug (69). The dopamine-related genes that have been knocked out Pathologically low levels of serotonin may contribute to in mice are the DRD4 dopamine receptor, which is located impulsivity and ASPD; for example, a group of criminal, at the site of one of the alcohol QTLs, the D1 and D2 alcoholic Finns was shown to have low cerebrospinal fluid dopamine receptors, the dopamine transporter, and (CSF) 5-hydroxyindolacetic acid (5-HIAA), the lowest lev- VMAT2 (the vesicular transporter). The DRD4 knockout els being found in those who had committed impulsive mice appear to be supersensitive to ethanol, cocaine, and crimes (75). These are the alcoholics who would be most amphetamine (70). Mice lacking the D2 receptor consume likely to have a serotonin gene variant affecting function. VMAT2 knockout mice have a pronounced supersensitivity to cocaine, amphet- Serotonin Transporter amine, and ethanol (72). The availability of brainstem serotonin transporter, mea- For morphine preference, three loci identified on murine sured by (I-123) -CIT and single photon emission com- chromosomes 1, 6, and 10 are apparently responsible for puted tomography, has been found to be significantly re- nearly 85% of the genetic variance in this trait (73). The duced in alcoholics, and correlated with ratings of opioid receptor gene is located at the site of the largest depression and anxiety during withdrawal (76). A functional QTL, and this QTL also affects consumption of alcohol polymorphism, 5-HTTLPR, in the serotonin transporter and cocaine (73). Several association analyses result is a large genomic region of interest rather than a have shown that the s-allele, which reduces transcriptional gene. There may be functional compensation in knockout efficiency, is increased in French alcoholics (79), severely mice during development. Mice and humans may not share affected German alcoholics (80), and early-onset, violent the same functional variants at the same allele; for example, Finnish alcoholics with ASPD (81). However, neither link- the ALDH2-2 allele is not even present in all human popu- age nor association for the s-allele was found in a family- lations and is not found in mice. However, QTL analyses in mice are useful ciation study of alcoholics with withdrawal seizures was also for the identification of candidate genes and gene regions. Population stratification may be a problem GENETICS OF REWARD NEUROCIRCUITS, with these association studies as allele frequencies have been AND NEUROCIRCUITS REGULATING shown to vary in European-American, African-American, IMPULSE CONTROL and Japanese populations (85). Candidate Gene Approach: Case-Control Serotonin-Metabolizing Enzymes Association Studies A tryptophan hydroxylase (TPH) intron variant that affects A logical approach to understanding vulnerability to alcohol splicing is associated with reduced 5-HIAA and suicidality addiction is to look directly for variants in genes involved in impulsive alcoholics (86,87). Of particular interest is the reward pathway, incorporating sero- Serotonin Receptors toninergic, GABAergic, dopaminergic, opioid, and gluta- Several serotonin receptors are known to be abundant in matergic neurotransmission, and the largely serotoninergic the NAC: 5-HT1B, 5-HT2C, 5-HT3, 5-HT4, and 5-HT6. Genes for neurotransmitter me- There are as yet few published studies in which these seroto- tabolizing enzymes, transporters, and receptors are good nin receptors have been genotyped in humans. Because of the complexity of causation of alco- Studies in rats suggest that activation of 5-HT1B recep- Chapter 99: Molecular and Cellular Genetics of Alcohol Addiction 1419 tors in the NAC may be inhibitory on the behavioral effects transcriptionally significant promoter polymorphisms offer of elevated mesolimbic dopamine transmission (88) by promising tools for understanding the roles of DRD2 (101) primarily modulating the activity of glutamatergic hip- and DAT (102) in alcoholism. In a large sib-pair linkage analysis Opioid Receptors of Finnish alcoholic criminal offenders, significant evidence of linkage and association of antisocial alcoholism to Three endogenous opioid receptors ( , , and ) are the HTR1B G861C was found, and this was also observed in targets of the major opioid peptides ( -endorphin, enke- a Southwest American Indian tribe, suggesting that a locus phalins, and dynorphins, respectively). The rewarding prop- predisposing to antisocial alcoholism may be linked to erties of - and -receptor ligands are brought about by HTR1B at 6q13-15 (90). Activation Activation of 5-HT receptors inhibits DA release in of receptors is dysphoric. However, the functional Cys23Ser polymor- plicate the opioid system, particularly the opioid receptor, phism does not appear to be associated with alcohol depen- in both initial sensitivity or response to alcohol, and in the dence (92). Subjects at high 5-HT receptors may be involved in several facets of risk for alcoholism have been shown to have lower basal 3 alcohol-seeking behavior, alcohol intoxication, and addic- plasma -endorphin levels but a more pronounced release tion (93); however, at the present time there are no pub- after exposure to ethanol (103). Some studies have found lished studies on the role of 5-HT variants in alcoholics. How- ever, association and sib-pair linkage analyses of Asn40Asp, GABA Receptors a opioid receptor polymorphism, in 100 U. The power to detect a small to moderate effect of OPRM1 varia- A GABA receptor exists as a number of subtypes that are tion on alcohol dependence (105). Findings were also nega- A composed of combinations of at least 14 different subunits. Several studies have found associations between GABAA 6 and alcohol depen- NMDA Receptors dence (84,95) and antisocial alcoholism (96). Differences At the present time there are no published studies on the in allele frequencies between alcoholics and controls have role of NMDA variants in alcoholism. Such studies would been found in GABAA 3 but not in a GABAA 1 (97).

However buy 150 mg zantac overnight delivery, ACR has far greater sensitivity than PCR for the detection of low levels of proteinuria and thus lends itself to detection and identification of CKD best zantac 150 mg. When the clinical and cost-effectiveness evidence is all taken into account, considerable uncertainty remains about the choice of ACR or PCR. Clinical opinion was divided among stakeholder organisations and within the GDG, but given the considerations above, the GDG made a consensus recommendation that ACR should be the test of choice to identify proteinuria and possible chronic kidney disease. The GDG however also noted that there will often be good clinical reasons for subsequently using PCR to quantify and monitor significant levels of proteinuria. The GDG noted that an ACR of ≥30 mg/mmol, or PCR ≥50 mg/mmol in association with haematuria or an ACR ≥70 mg/mmol, or PCR ≥100 mg/mmol in the absence of haematuria were considered indications for referral to nephrology (see section 6. It was agreed that the finding of levels of ACR <70 mg/mmol, or PCR <100 mg/mmol should be confirmed using an early morning urine sample. R12 To detect and identify proteinuria, use urine albumin:creatinine ratio (ACR) in preference, as it has greater sensitivity than protein:creatinine ratio (PCR) for low levels of proteinuria. For quantification and monitoring of proteinuria, PCR can be used as an alternative. ACR is the recommended method for people with diabetes. R13 For the initial detection of proteinuria, if the ACR is 30 mg/mmol or more (this is approximately equivalent to PCR 50 mg/mmol or more, or a urinary protein excretion 0. If the initial ACR is 70 mg/mmol or more, or the PCR 100 mg/mmol or more, a repeat sample need not be tested. Measurement of total protein in urine is a traditional, inexpensive and well established test for kidney injury. A vast body of nephrological literature is predicated on 24-hour urinary total protein. Significant proteinuria is an independent risk factor for both progression of CKD and cardiovascular disease. Monitoring of urinary proteinuria is both part of the routine evaluation of those at risk of CKD and is an important method of assessing progression and response to therapy. Proteins normally excreted in the urine include albumin, low molecular weight immunoglobulin (filtered plasma proteins), and secreted tubular proteins. The upper limit of normal is approximately 150 mg/24 h, equivalent to a protein:creatinine ratio (PCR) of 15 mg/mmol (given an average daily urine creatinine excretion of 10 mmol), but the cut off for abnormal varies from laboratory to laboratory. By contrast, urinary albumin measurement provides a quantitative, relatively standardised measurement of excretion of the single most important protein in most nephropathies. The normal mean value for urine albumin is 10 mg/day, microalbuminuria is defined as 30–300 mg/day or an albumin:creatinine ratio (ACR) of >2. Macroalbuminuria is a urinary albumin greater than 300 mg/day (ACR >30 mg/mmol). Proteinuria displays considerable biological variability, and may be increased by urinary tract infection (UTI), upright posture, exercise, fever, and heart failure as well as by kidney disease. Biological variation of both measures is high, with lower variation generally being reported for an albumin:creatinine ratio (ACR) on an early morning urine (EMU) compared to PCR (e. There is a high correlation between total protein and albuminuria at high levels of protein excretion (so-called nephrotic range proteinuria, PCR >300 mg/mmol) but at low levels correlation is poor. This is because urine protein measurement in the normal range and at low levels is both imprecise and relatively non- specific. Albumin as a proportion of total protein is highly variable at normal and moderately increased levels of proteinuria. The Welsh Renal NSF has defined proteinuria as a PCR of ≥100 mg/mmol, approximately equivalent to an excretion rate of 1000 mg/24 h. It has been accepted for many years that total protein measurement is insufficiently sensitive to detect the onset of diabetic nephropathy and that urine albumin must be used for this purpose. This is enshrined in many clinical practice guidelines including those for type 1 and 2 diabetes produced by NICE. There is also evidence that urine albumin is a more sensitive test to enable detection of glomerular disease associated with some other systemic diseases (e. The diabetic nephropathy literature and the classification of diabetic nephropathy is based upon urine albumin excretion (commonly expressed as an ACR measurement) and the 41 Chronic kidney disease recent Kidney Disease Improving Global Outcomes (KDIGO) classification of CKD is clear in that it requires urine albumin measurement to facilitate diagnosis of stage 1 and 2 CKD. There is strong evidence from epidemiological studies linking urinary albumin excretion to cardiovascular mortality and kidney disease progression in people with diabetes and to cardiovascular and non-cardiovascular mortality in those without diabetes. The NKF-KDOQI guidelines therefore recommend urinary albumin measurement in preference to total protein when detecting and monitoring proteinuria. Conversely, the UK CKD guidelines and CARI guidelines have recommended urine PCR for non-diabetic kidney disease, with ACR being reserved for patients with diabetes. Increasingly the management of CKD is being undertaken by general practitioners and other non-nephrologists. Also, where the National Vascular Screening Programme identifies people with conditions such as hypertension, diabetes and impaired GFR an ACR will be recommended. Furthermore, the Quality and Outcomes framework now includes proteinuria in the CKD indicators.

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A transgene consist- ing of a full-length huntingtin cDNA driven by the CMV A MODEL OF POLYGLUTAMINE promoter resulted in a line of mice with a rather different PATHOGENESIS phenotype generic 150mg zantac with amex, characterized by early weight gain and hyperac- tivity followed later by hypoactivity generic zantac 150 mg on line. These mice have both A model for HD pathogenesis is depicted in Figure 125. Several of the steps are speculative, and, as has been evident Perhaps the most promising mouse model of HD in- in this summary, the data supporting the model are at times volves the use of YAC constructs, so the transgene consists conflicting. Here we highlight areas of uncertainty: of the entire human HD gene, including the human HD Evidence for pathogenetically significant proteolytic promotor and all introns, with an expanded repeat. The finding that mice develop neurologic signs, electrophysiologic abnormal- nuclear inclusions can be labeled for N-terminal epitopes, ities, and a shortened life span (92). A single founder with but not for internal or C-terminal epitopes, is consistent a long repeat had striking evidence of selective striatal neuro- with proteolytic cleavage, but it could also result from mask- degeneration and nuclear localization of N-terminal epi- ing of epitopes. In addition, details of the cleavage, includ- topes of huntingtin in striatal neurons. If additional lines ing whether it is processive or endoproteolytic and where can be generated, this model may be the closest to the in the cell it may occur, are uncertain. The figure shows human disease of any model yet generated. It seems ingtin gene, thus avoiding the confounding factor of the likely that the mutant protein adopts an abnormal confir- presence of the human transgene. So far, these mice have mation and that this is a necessary step in pathogenesis. There is evidence of translocation of copy may represent a downstream event, an epiphenome- huntingtin into the nucleus in striatal neurons. Thus, these non, or even a protective reaction, and therefore they may mice may model early aspects of HD pathogenesis and could not be directly tied to pathogenesis. Our hypothesis is that provide a useful model for studying the early features of the mutant huntingtin adopts an abnormal confirmation, lead- disease. An example of such protein is CREB binding pro- containing exon 1of huntingtin with an expanded gluta- tein, an important transcriptional regulator; sequestration mine repeat under the control of the tet-off system was of this and similar proteins could have marked effects on inserted so that the timing of transgene expression could neuronal function and survival. With the transgene on, mice events also remains unclear. In our model, the location of developed neurologic signs and neuropathologic changes in- huntingtin in the nucleus leads to altered gene transcription. Remarkably, when the expres- However, huntingtin could act also within the cytoplasm sion of huntingtin was turned off, these abnormalities par- to interfere with proteins that could otherwise be imported tially reversed. This surprising result suggests that the brain into the nucleus. Furthermore, huntingtin may interact may have more restorative and plastic ability than previously with cytoplasmic molecules, including microtubules or mi- appreciated, and that if the pathologic changes of HD could crotubule motors, caspase adaptors, and other proteins, to be halted, substantial repair would perhaps be possible. We propose that HD pathogenesis begins with altered conformation of the protein con- taining the expanded polygluta- mine repeat. Proteolysis generates a fragment that leads to toxicity through several pathways. Nuclear importation may lead to altered gene transcription with a detri- mental effect on cell survival. Inclu- sions also form in the nucleus but may not be a major cause of cell death. Huntingtin fragments may interfere with mitochondrial en- ergy metabolism, either directly, or more likely indirectly, perhaps by altered gene transcription. Micro- aggregation of the fragment may lead to caspase activation and the consequent initiation of cell death pathways. Fragments maybe trans- ported into neurites, interfering with cytoskeletal function. Toxicity may also be mediated by the full- length huntingtin protein with the expanded repeat. As discussed in the text, many of the steps remain speculative. THERAPY Recent biochemical, cell, and animal studies are beginning to suggest approaches for development of rational therapeu- tics (Fig. As described earlier, current therapeutics for HD are limited to symptomatic treatments, so any inter- vention that can stop or slow disease progression would be a major advance. The first generation of agents designed to slow the pro- gression or delay the onset of HD has emerged from neuro- toxicologic models of HD. Coenzyme Q is a mitochondrial cofactor, and remacemide is a glutamate-receptor antagonist, and both drugs have efficacy in neurotoxicologic mouse models. The CARE-HD Study is the first multicenter HD drug trial and involves 340 patients treated for 30 months under the sponsorship of the Huntington Study Group. Neurotoxico- logic models have also led to smaller trials of other agents, including vitamin E, idebenone, and lamotrigine.

Reversible labeling of the 3 count for their synergistic interaction in cAMP accumula- H2 receptor was achieved using [ H]tiotidine or discount 300mg zantac amex, more relia- 125 tion cheap 300mg zantac amex. By screening cDNA or genomic libraries with homolo- gous probes, the intronless gene encoding the H2 receptor HistamineH3 Receptor was first identified in dogs (34) and, subsequently, in other species including humans (1). The H2 receptor is organized The H3 receptor was initially detected as an autoreceptor like other receptors positively coupled to adenylyl cyclase: controlling histamine synthesis and release in brain. There- it displays a short third intracellular loop and a long C- after, it was shown to inhibit presynaptically the release of terminal cytoplasmic tail. Hence H receptor mine (2), then [3H]N -methylhistamine, a less selective ag- 2 stimulation can trigger intracellular signals either opposite onist, was also proposed (19), as well as, more recently, or similar to those evoked by H receptor stimulation. Paral- [125I]iodophenpropit and [125I]iodoproxyfan, two antago- 1 lel observations were made for a variety of biological re- nists (41). The regulation of agonist binding by guanylnucleotides Helmut Haas and colleagues showed that, in hippocam- (39), and the sensitivity of several H3-receptor–mediated Chapter 14: Histamine 183 responses to pertussis toxin (42,43), suggested that the H3 Interaction with NMDA Receptors receptor was G /Gi o protein coupled, a suggestion confirmed Histamine potentiates NMDA-evoked currents in acutely by the cloning of the corresponding human (44) and rodent dissociated and cultured hippocampal and cortical neurons, (45) cDNAs. The H3 receptor gene contains two introns an effect that could not be ascribed to activation of the in its coding sequence and several splice variants H3L and known histamine receptors (17,18), but rather of a novel H3S differing by a stretch of 30 amino acids in the third recognition site on NMDA receptors containing the sub- intracellular loop, were identified (45). It facilitates the NMDA-induced Significant differences in the pharmacology of the depolarization of projection neurons in cortical slices (54) human and rodent H3 receptor (47) could be assigned to and phase shifts the circadian clock by a direct potentiation differences in only two amino acid residues in the third TM of NMDA currents in the suprachiasmatic nucleus (55). In various cell lines, stimulation of the H3 receptor, Histamine, presumably acting through NMDA receptors, like that of other G -protein–coupledi receptors, inhibits facilitates the induction of long-term potentiation and adenylate cyclase (44) or phospholipase C (42) and activates causes long-lasting increases of excitability in the CA1 re- phospholipase A2 (48a). On neurons, the H3 receptor mediates presynaptic inhi- The histamine-induced modulation of NMDA responses bitions of release of several neurotransmitters, including his- is higher under slightly acidic conditions (56), which occur tamine itself (2,39), norepinephrine, serotonin, dopamine, during hypoxia or epileptiform activity. This may lead to glutamate, GABA, and tachykinins (40), presumably by in- enhancement of neurotransmission or histamine-mediated hibiting voltage-dependent calcium channels (39,43). This response was originally attributed to blockade of the inhibitory effects of endogenous hista- HISTAMINERGIC NEURON ACTIVITY AND mine and was therefore used in many studies, such as behav- THEIR CONTROL ioral studies, to delineate the functions of histaminergic Electrophysiologic Properties neurons. However, these drugs were shown to act, in fact, as inverse agonists, and the native H receptor in brain dis- Cortically projecting histaminergic neurons share with other 3 play high constitutive activity including in vivo (48a). They fire spontaneously 3 monkey brain shows it highly concentrated in the neostria- slowly and regularly, and their action potentials are of long duration (26). Among the pacing events that may contribute tum, the nucleus accumbens, the cingulate and infralimbic to their spontaneous firing, tuberomammillary neurons ex- cortices, the bed nucleus of the stria terminalis, and the hibit a tetrodotoxin-sensitive persistent Na current (58), substantia nigra pars lateralis. In contrast, its density is rela- 2 aCa current probably of the low-threshold type (59), tively low in the hypothalamus (including the tuberomam- 2 and multiple high-voltage–activated Ca currents (43). In millary nucleus), which contains the highest density of hista- addition, they exhibit inward rectification attributed to an minergic axons (and perikarya), a finding indicating that Ih current that may increase whole-cell conductance and most H3 receptors are not autoreceptors. In agreement with may decrease the efficacy of synaptic inputs during periods this concept, intrastriatal kainate strongly decreases H3 of prolonged hyperpolarization , that is, when histaminergic binding sites in the forebrain (as well as in the substantia neurons fall silent (60). In the human brain, the high densities of H3 receptors found in the striatum and globus pallidus (29) Modulation of HistamineSynthesis and were lower in patients with Huntington disease, a finding Release In Vitro suggesting that the H3 receptor is also located on striatoni- The autoreceptor-regulated modulation of histamine syn- gral projection neurons of the direct and indirect pathways thesis in, and release from, brain neurons is well docu- (52). Consistent with the proposal that most H3 receptors mented (2). It was initially evidenced in brain slices or syn- are not autoreceptors, a strong expression of H3-receptor aptosomes after labeling the endogenous pool of histamine mRNAs was observed not only within the tuberomammil- using the [3H]histamine precursor. Exogenous histamine lary nucleus, but also in various regions of the rat (44) and decreases the release and formation of [3H]histamine in- guinea pig (45) brain, including the cerebral cortex, the duced by depolarization, and analysis of these responses led basal ganglia, and the thalamus. The auto- 184 Neuropsychopharmacology: The Fifth Generation of Progress regulation was found in various brain regions known to active phase (2). In mouse cerebral cortex, striatum, and contain histamine nerve endings, a finding suggesting that hypothalamus, telemethylhistamine levels are doubled at the all terminals are endowed with H3 autoreceptors. Histamine release from the posterior hypothalamus (39), and somatodendritic H3 the anterior hypothalamus of freely moving rats, evaluated autoreceptors inhibit the firing of tuberomammillary neu- by in vivo microdialysis, gradually increases in the second rons (26) by modulating high-voltage–activated calcium half of the light period and is maintained at a maximal level channels (43). Such state-related changes are Galanin, a putative cotransmitter of a subpopulation of also found in single-unit extracellular recordings performed histaminergic neurons, regulates histamine release only in in the ventrolateral posterior hypothalamus of freely moving regions known to contain efferents of this subpopulation, cats. Neurons with properties consistent with those of hista- that is, in hypothalamus and hippocampus but not in cere- minergic neurons exhibited a circadian rhythm of their fir- bral cortex or striatum (61). In brain slices, galanin also ing rate, falling silent during deep slow-wave or paradoxical hyperpolarizes and decreases the firing rate of tuberomam- sleep (2). An important determinant of this circadian millary neurons (26). Other putative cotransmitters of histaminergic in the hypothalamus of conscious rats (68). Histaminergic neurons failed to affect [3H]histamine release from slices of neurons are a target for leptin in its control of feeding is rat cerebral cortex (62). An enhancement of histamine turnover was ob- postsynaptic potentials are mediated by GABAA receptors served after intracerebroventricular infusion of leptin (70). To what extent these Changes in the metabolism and release of histamine ob- receptors play an autoinhibitory role is unclear. A subpopu- served in vivo after occlusion of the middle cerebral artery lation of histaminergic neurons contains GABA (5), but the in rats suggest that the histaminergic activity is also en- tuberomammillary nucleus also receives dense GABAergic hanced by cerebral ischemia (71).

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Moreover purchase zantac 300 mg on line, based on genetic manipulations generic 300mg zantac with amex, transporter. CREB has been implicated in both invertebrate and verte- 6. Altered brain serotonin brate models of synaptic plasticity and long-term memory homeostasis and locomotor insensitivity to 3,4-methylenedioxy- (80–82,95). Moreover, changes in striatal synaptic physiol- methamphetamine ('Ecstasy')in serotonin transporter-deficient mice. At the systems level, dorsal re- norepinephrine transporter are supersensitive to psychostimu- gions of striatum appear to be involved in the learning and lants. Cocaine self- particularly in response to external cues. Ventral striatal administration in dopamine-transporter knockout mice [see com- ments] [published erratum appears in Nat Neurosci 1998;1(4): areas are involved in acting on the motivational significance 330]. Opioids excite dopamine neurons by regions may contribute to drug use through consolidation hyperpolarization of local interneurons. J Neurosci 1992;12: of drug-taking and -seeking behaviors. Destruction of dopa- mine in the nucleus accumbens selectively attenuates cocaine but of genes transiently induced by addictive drugs, the products not heroin self-administration in rats. Psychopharmacology (Berl) of which produce stable remodeling of synapses. Heroin and cocaine intravenous self-administration in rats: mediation by separate CONCLUSION neural systems. Disruption of cocaine and heroin self-administration following kainic acid lesions of All of the initial molecular targets of drugs of abuse have the nucleus accumbens. Pharmacol Biochem Behav 1985;23: been characterized and cloned. Blockade of nucleus accum- zation, and most important, compulsive drug use, and late bens opiate receptors attenuates intravenous heroin reward in the rat. Molecular genetic analysis of the role of GABAergic has been made in identifying large numbers of molecular systems in the behavioral and cellular actions of alcohol. Behav changes initiated by drugs of abuse, but coherent biological Genet 1996;26:313–323. Ethanol enhances 1378 Neuropsychopharmacology: The Fifth Generation of Progress the release of dopamine and serotonin in the nucleus accumbens 38. Alcohol Clin Exp Res 1992;16: phine tolerance on the paw-pressure and tail-shock vocalization 781–785. GABAA receptor antagonism in the ex- pensatory responding. Psychopharmacology (Berl) 1999;145: tended amygdala decreases ethanol self-administration in rats. The phasic reward signal of primate dopamine neu- 17. Naltrexone in the treatment of alco- Res Rev 1993;18:247–291. Addictive drugs as reinforcers: multiple partial ac- 20. Molecular and cellular basis of addic- Trends Pharmacol Sci 1997;18:54–59. Reduction of mor- sumption in null mutant mice lacking 5-HT1B serotonin recep- phine abstinence in mice with a mutation in the gene encoding tors. Genetic analysis of drug addiction: mine lesions on the locomotor stimulant action of nicotine in the role of cAMP response element binding protein. Alteration of GABAA nucleus accumbens and similarity to those of addictive drugs [see receptor alpha 1-subunit mRNA in mouse brain following con- comments]. Ethanol and neurotransmit- tors containing the beta2 subunit are involved in the reinforcing ter interactions—from molecular to integrative effects. Ethanol withdrawal is associated with nicotinic receptor subunit in nicotine-elicited locomotion, dem- onstrated by in vivo antisense oligonucleotide infusion. Neurore- increased extracellular glutamate in the rat striatum. Cocaine addiction: psychology and neurophysiology linergic and opioid receptor mechanisms in nicotine- induced [published erratum appears in Science 1991;253:494]. Drug abuse: hedonic homeostatic dysreg- Neuropsychiatry Clin Neurosci 1997;9:482–497.

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The alpha-2a noradrenergic agonist zantac 150 mg amex, and beta-adrenoceptor activation buy 150mg zantac. Locus coeruleus activation in- adult rhesus monkeys. Psychopharmacology (Berl) 1998;136: duces perforant path-evoked population spike potentiation in 8–14. Locus coeruleus potentiation methyl-para-tyrosine (AMPT) in drug-free depressed patients. Lesions to terminals of noradrenergic chemical effects of catecholamine depletion on antidepressant- locus coeruleus neurones do not inhibit opiate withdrawal be- induced remission of depression. Venlafaxine: a novel lesion of noradrenergic neurons of the locus ceruleus does not antidepressant that has a dual mechanism of action. Depression alter either naloxone-precipitated or spontaneous opiate with- 1996;4:48–56. Neurotransmitter re- the amygdala on naloxone-precipitated opiate withdrawal in the ceptor and transporter binding profile of antidepressants and rat. Reboxetine: a phar- opiate withdrawal behaviors on microinfusion of a protein ki- macologically potent, selective, and specific norepinephrine nase A inhibitor versus activator into the locus coeruleus or reuptake inhibitor. Local opioid withdrawal in rat single pressant therapy. Advancing from the ventral substrates for anxiety and fear: clinical associations based on preclinical research. Psychophar- striatum to the extended amygdala: implications for neuropsychiatry macology: the fourth generation of progress. New York: New York Academy of Sciences, Press, 1995:387–397. Beta-adrenergic antagonists attenuate withdrawal anxiety in cocaine- and morphine-dependent rats. Relative sensitivity to neurons in the monkey are selectively activated by attended naloxone of multiple indices of opiate withdrawal: a quantitative stimuli in a vigilance task. Potential significance for attention-deficit hyperactiv- tory afferent input to the locus coeruleus impairs retention in ity disorder. We have restricted our scope to a limited number of neuropsychopharmacology. Indeed, the vast majority of regulatory mechanisms that have been elucidated by de- clinically relevant neuropsychiatric drugs either bind di- tailed study of the some of the most extensively character- rectly to specific GPCRs (e. First, we survey classic studies describing the or function indirectly via GPCRs by influencing the amount general properties of the physiologic and pharmacologic reg- of available native agonist (e. Regulation of GPCRs is thought focus on specific mechanisms of receptor regulation. A number of pathologic states are associated with of receptor phosphorylation in mediating rapid desensitiza- disturbances in the number or functional activity of certain tion of GPCRs. In addition, many clinically important drugs mediating regulated endocytosis of certain GPCRs, and dis- influence the physiologic regulation of GPCRs (6). To- cuss how this endocytic mechanism can promote rapid de- gether, these observations suggest that mechanisms of sensitization and resensitization of receptor-mediated signal GPCR regulation may be of fundamental importance to transduction. In this section, we also highlight the close neuropsychiatric disorders and to the actions of clinically interdependence between mechanisms of GPCR phosphor- relevant drugs. Finally, we discuss the functions regulation has motivated an enormous amount of study into of both phosphorylation and endocytic membrane traffick- underlying molecular mechanisms of regulation. Progress ing in mediating longer-term regulation of the number of in this area has been facilitated enormously by molecular GPCRs present in cells, focusing on recent studies into and cell biological approaches applied to a variety of experi- mechanisms that control down-regulation of receptors via mental model systems. Our understanding remains at an proteolytic degradation in lysosomes. Nevertheless, great progress has been made in elucidating certain mechanisms of GPCR regula- GENERAL PROCESSES OF GPCR tion, to the extent that it is possible to begin to discern REGULATION Rapid Desensitization and Resensitization Mark von Zastrow: Department of Psychiatry, Department of Cellular and Molecular Pharmacology, and Program in Cell Biology, University of It has been known for many years that multiple mechanisms California, San Francisco, California. Early studies, 60 Neuropsychopharmacology: The Fifth Generation of Progress which preceded the elucidation of any of the biochemical tization and is mediated, at least in part, by regulation of machinery involved, distinguished general processes of re- the receptor itself. A process of rapid desensitization was so ceptor regulation according to differences in kinetics and named because it occurs within seconds to minutes after reversibility. This is well illustrated by classic studies of the agonist-induced activation. Rapid desensitization of the 2-adrenergic receptor (B2AR), reviewed in detail elsewhere B2AR can be reversed within several minutes after removal (2–4).