Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P08908 (5-HT1A)
 5,574 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The augmentation of serotonin (5-HT) neurotransmission attenuates alcohol consumption, whereas depletion enhances use. A number of serotonin-specific pharmacological probes appear to be effective in reducing the voluntary consumption of alcohol. The 5-HT1A receptor agonist buspirone is an anxiolytic which has been shown to diminish the desire to consume alcohol in anxious alcoholic patients. Thus, serotonin may represent a common denominator for a spectrum of behavioural disorders including anxiety and alcoholism. Novel serotonin drugs, such as the azapirones, may usefully supplement conventional treatment strategies for substance abuse.
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PMID:Anxiety and alcoholism: a serotonin link. 184 Jul 61

Recent literature has addressed a frequent comorbidity between alcoholism and anxiety/depression. These disorders have been interdigitated with the brain amines serotonin (5-HT) and norepinephrine. We investigated 51 dually diagnosed patients (generalized anxiety disorder with depressive features plus alcohol abuse/dependency) under a randomized, double-blind, placebo-controlled trial employing the 5-HT1A compound buspirone. Buspirone was superior to placebo as an anxiolytic. It was well tolerated and reduced the number of days patients desired alcohol. At the final study dose, the buspirone metabolite 1-pyrimidinylpiperazine (1-PP) was significantly related to improvement in anxiety, global depressive symptoms, and number of days not using alcohol. Analysis using the Hamilton Rating Scale for Depression and its retardation cluster revealed significant improvement secondary to anxiolysis. Thus, buspirone (especially via its 1-PP metabolite) may be an effective treatment strategy in the anxious or mixed anxious-depressive patient with comorbid alcoholism when other conventional anxiolytics may be contraindicated.
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PMID:The association of buspirone and its metabolite 1-pyrimidinylpiperazine in the remission of comorbid anxiety with depressive features and alcohol dependency. 192 64

The serotonin system has long been thought to play a role at several steps in the cycle of alcohol abuse. Initial motivation may be triggered by anxiety, which may exhibit a serotonergic component (5-HT1A receptor). Alcohol can potentiate the opening of 5-HT3 receptor ion channels, and agents which elevate serotonergic tone, including serotonergic agonists, uptake inhibitors and releasers, have shown promise in assisting with recovery from alcoholism. In this review, recent advances in serotonin receptor research are presented, with a special emphasis on the impact and interpretation of molecular biological data. Genetic and pharmacological concepts of receptor subtypes are reviewed and related to a new classification system for the 14 currently recognized subtypes of serotonin receptors. The current and likely future impact on drug design of the molecular approach to serotonin receptors is discussed. Finally, the question of why there are so many serotonin receptor subtypes is examined, along with possible roles of multiple G protein and second messenger pathways, and their effect on conserved domains of these receptor proteins.
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PMID:Molecular pharmacology of serotonin receptors. 751 66

Serotonergic neurotransmission represents a complex mechanism involving pre- and post-synaptic events and distinct 5-HT receptor subtypes. Serotonin (5-HT) receptors have been classified into several categories, and they are termed as 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6 and 5-HT7 type receptors. 5-HT1 receptors have been further subdivided into 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E and 5-HT1F. 5-HT2 receptors have been divided into 5-HT2A, 5-HT2B and 5-HT2C receptors. All 5-HT2 receptor subtypes are linked to the multifunctional phosphoinositide (PI) signalling system. 5-HT3 receptors are considered ion-gated receptors and are also linked to the PI signalling system by an unknown mechanism. The 5-HT2A receptor subtype is the most widely studied of the 5-HT receptors in psychiatric disorders (for example, suicide, depression and schizophrenia) as well as in relation to the mechanism of action of antidepressant drugs. The roles of 5-HT2C and 5-HT3 receptors in psychiatric disorders are less clear. These 5-HT receptors also play an important role in alcoholism. It has been shown that 5-HT2A, 5-HT2C and 5-HT3 antagonists cause attenuation of alcohol intake in animals and humans. However, the exact mechanisms are unknown. The recent cloning of the cDNAs for 5-HT2A, 5-HT2C and 5-HT3 receptors provides the opportunity to explore the molecular mechanisms responsible for the alterations in these receptors during illness as well as pharmacotherapy. This review article will focus on the current research into the pharmacological properties, molecular biology, and clinical correlates of 5-HT2A, 5-HT2C and 5-HT3 receptors.
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PMID:Phosphoinositide system-linked serotonin receptor subtypes and their pharmacological properties and clinical correlates. 778 83

The effect of buspirone, a drug with mainly 5-HT1A-agonist activity, on voluntary ethanol intake was tested in a rat model of alcoholism. In this model the treatment consists of an injection of ethanol (2.0 g/kg) or saline once a week, preceded by a 24 h choice between water and ethanol (10% w/v). This weekly injection of ethanol reduces voluntary ethanol intake in male rats. Maximal inhibition is seen after 5-6 weeks. At this maximal inhibition buspirone or saline was injected prior to the voluntary 24 h intake of ethanol in both the ethanol- and saline-injected groups. The tested doses were 5 mg/kg (week 5) and 20 mg/kg (week 6). There was no reduction in ethanol intake in the buspirone-injected groups when compared with their corresponding controls. A second experiment with buspirone was performed during the evaluation period following treatment with ethanol. This treatment consisted of a choice between water and ethanol (10%, w/v) for 1 day each week, followed by an injection of ethanol 2.0 g/kg) and lasted for 52 weeks. During the evaluation period the rats had a continuous choice between ethanol and water for 37 weeks and no injections were given. In this situation, with a longer exposure to ethanol, a dose of 20 mg/kg of buspirone in week 90 reduced ethanol intake by approximately 40%, when compared with controls. The effect of this buspirone dose lasted at least a week. This indicates that the long-term exposure to ethanol in the second experiment induces changes that affect the serotonergic transmission, and that this changed neural system is involved in the regulation of voluntary ethanol intake.
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PMID:Buspirone as an inhibitor of voluntary ethanol intake in male rats. 873 10

The present series of experiments was conducted to investigate whether the previously reported ethanol intake reducing effects of the 5-HT1A receptor agonist ipsapirone could be based on possible stimulus similarities between both compounds. Rats were trained to discriminate ethanol (12.5% w/v, 1000 mg/kg, IP) from saline in a two-lever food-reinforced drug discrimination (DD) procedure. Discrimination criterion was reached after a mean number of training sessions of 42. In subsequent generalization sessions, a dose-response curve was established for ethanol (125-1000 mg/kg, IP, ED50 value: 355 mg/kg). In additional cross-generalization tests with ipsapirone (1-30 mg/kg, IP), stimulus substitution for the ethanol cue was not noted (maximal degree of generalization: 33%, at 10 and 30 mg/kg). To confirm the DD findings that ipsapirone does not substitute for ethanol, an alternative cross-familiarization conditioned taste aversion paradigm (CF-CTA) was utilized. In rats, 1000 mg/kg IP ethanol was used as the reference drug producing a conditioned taste aversion (CTA). It was found that preexposure to ethanol (500-1500 mg/kg, IP) dose-dependently attenuates the CTA produced by this same drug. Full familiarization was noted with 1000 and 1500 mg/kg. In contrast with this, ipsapirone (1-30 mg/kg, IP) failed to abolish ethanol-induced CTA, suggesting again that the ipsapirone stimulus complex is dissimilar to that produced by ethanol. Because the present findings indicate that, in rats, ipsapirone does not substitute for ethanol, it is suggested that the reported ethanol intake-reducing effects of ipsapirone in animal models of alcoholism are not due to simple stimulus substitution.
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PMID:Ethanol intake-reducing effects of ipsapirone in rats are not due to simple stimulus substitution. 880 94

The neurotransmitter serotonin (5-HT) has long been implicated in the etiology of aberrant consumption of alcohol. Several compounds thought to possess a potential therapeutic value to counteract drinking have high affinities for 5-HT1A and 5-HT2A receptors in the brain. For example, amperozide and FG5865 significantly reduce the volitional intake of alcohol, without altering food intake, both in rats genetically predisposed or chemically induced to drink alcohol. The present study was undertaken in the alcohol-preferring (P) rat to determine whether an amperozide like drug. FG5938 (1-[4-(p-fluorophenyl)butyl]-4-(6-methyl-2-pyridinyl)-piperazine fumarate). exerts an action on the volitional drinking of alcohol as well as on the intakes of food and water. In 11 male P rats, the pattern of preference for different concentrations of alcohol was determined by an 11-day test for water vs. 3 to 30% alcohol solutions. After maximally preferred alcohol concentrations, i.e., 9 to 15% had stabilized for 4 days, saline or FG5938 was injected subcutaneously at 1600 and 2200 h in a dose of 2.5, 5.0, or 10.0 mg/kg over 4 consecutive days. Following treatment, preference testing for the same concentrations of alcohol was continued for 5 additional days. FG5938 caused a significant suppression in alcohol drinking in terms of both absolute g/kg and proportion to total fluid intake. During its administration, FG5938 also enhanced the ingestion of food and water of the P animals significantly, with the largest intake occurring on the initial day, while body weights increased. After FG5938 injections, food and water intakes returned to predrug levels. The saline control vehicle had no significant effect on the intakes of alcohol, food, or water of the P rats. Overall, these results show that FG5938 acts to attenuate alcohol preference while simultaneously increasing the ingestion of food paradoxically. To our knowledge, this is the first known drug to possess this unique property. Finally, these findings support the view that a compound having affinities to both 5-HT1A and 5-HT2A receptors may be useful as a therapeutic agent in the treatment of alcoholism.
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PMID:The mixed 5-HT 1A/2A receptor drug FG5938 suppresses alcohol drinking while enhancing feeding in P rats. 888 50

Both 5-HT1A and 5-HT2A receptors have been implicated in modulating ethanol self-administration. A novel serotonergic compound, FG 5974, with combined 5-HT1A agonist/5-HT2A antagonist activities, has shown effects in decreasing ethanol consumption in two-bottle choice paradigms. In the present study, the effect of this compound on operant responding for ethanol (as well as water and a saccharin solution) was compared to compounds possessing the separate neuropharmacological effects of this drug (the 5-HT1A agonist, 8-OH-DPAT, and the 5-HT2A antagonist, amperozide). While all three serotonergic compounds decreased operant responding for ethanol, only FG 5974 had no effect on water and saccharin responding. These results suggest that combined 5HT1A agonist/5-HT2A antagonist activity provides a more selective effect on ethanol reinforcement than either neuropharmacological action alone. Therefore, further analysis of mixed serotonergic compounds in general, and FG 5974 in particular, is warranted as they offer potential treatments for alcoholism.
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PMID:Effects of amperozide, 8-OH-DPAT, and FG 5974 on operant responding for ethanol. 963 53

The serotonin (5-hydroxytryptamine: 5-HT) system has been thought to play an important role in several steps of alcohol craving. A number of studies, including our own, have reported that alcohol dependence is associated with dysfunction of 5-HT transmission. Pharmacological and clinical studies have shown that the 5-HT transporter (5-HTT) and the 5-HT1A receptor appear to be candidate loci for the aetiology of alcohol dependence. We have analysed the presence of different 5-HTT and 5-HT1A variants in 104 alcohol-dependent patients and 38 controls for a possible association with alcohol dependence. In alcohol-dependent patients, we found a high frequency of the S allele of 5-HTTLPR (45.5% vs. 29%, chi2 = 6.33, p = 0.0081). No other significant differences were observed between the two populations for other polymorphisms. These results provide, for the first time, preliminary evidence that alcohol abuse disorders are associated with a genetic variant for 5-HT transmission. It might be possible to use this detection of the "S" allele as a clinical tool for pathology diagnosis and to advise recovering alcoholics and it could represent an aid to the prevention of relapse. Therapeutic actions could be envisaged to use this genotyping to help select the best therapeutic strategy.
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PMID:Does the short variant of the serotonin transporter linked polymorphic region constitute a marker of alcohol dependence? 1006 77

This review discusses efforts to develop rodent models for the study of neurobiological mechanisms underlying chronic alcohol drinking, alcoholism, and abnormal alcohol-seeking behavior. Selective breeding has produced stable lines of rats that reliably exhibit high and (for comparison purposes) low voluntary alcohol consumption. In addition, animal models of chronic ethanol self-administration have been developed in rodents, who do not have a genetic predisposition for high alcohol-seeking behavior, to explore environmental influences in ethanol drinking and the effects of physical dependence on alcohol self-administration. The selectively bred high-preference animals reliably self-administer ethanol by free-choice drinking and operantly respond for oral ethanol in amounts that produce pharmacologically meaningful blood alcohol concentrations (50 to 200 mg% and higher). In addition, the alcohol-preferring rats will self-administer ethanol by intragastric infusion. With chronic free-choice drinking, the high alcohol-preferring rats develop tolerance to the high-dose effects of ethanol and show signs of physical dependence after the withdrawal of alcohol. Compared with nonpreferring animals, the alcohol-preferring rats are less sensitive to the sedative-hypnotic effects of ethanol and develop tolerance more quickly to high-dose ethanol. Nonselected common stock rats can be trained to chronically self-administer ethanol following its initial presentation in a palatable sucrose or saccharin solution, and the gradual replacement of the sucrose or saccharin with ethanol (the sucrose/saccharin-fade technique). Moreover, rats that are trained in this manner and then made dependent by ethanol-vapor inhalation or liquid diet increase their ethanol self-administration during the withdrawal period. Both the selectively bred rats and common-stock rats demonstrate "relapse" and an alcohol deprivation effect following 2 or more weeks of abstinence. Systemic administration of agents that (1) increase synaptic levels of serotonin (5-HT) or dopamine (DA); (2) activate 5-HT1A, 5-HT2, D2, D3, or GABA(A) receptors; or (3) block opioid and 5-HT3 receptors decrease ethanol intake in most animal models. Neurochemical, neuroanatomical, and neuropharmacological studies indicate innate differences exist between the high alcohol-consuming and low alcohol-consuming rodents in various CNS limbic structures. In addition, reduced mesolimbic DA and 5-HT function have been observed during alcohol withdrawal in common stock rats. Depending on the animal model under study, abnormalities in the mesolimbic dopamine pathway, and/or the serotonin, opioid, and GABA systems that regulate this pathway may underlie vulnerability to the abnormal alcohol-seeking behavior in the genetic animal models.
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PMID:Animal models of alcoholism: neurobiology of high alcohol-drinking behavior in rodents. 1034 15


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