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 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.
Alcohol 1999 Feb
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

Buspirone, a 5-HT1A agonist, has been shown to decrease the intake of ethanol when given as a single dose to rats with a psychological dependence induced according to our rat model of alcoholism. The present experiment evaluates the effects different treatments with buspirone have on voluntary ethanol intake in these psychologically dependent rats. As a first treatment, buspirone was given once daily for 23 days at the dose of 20 mg/kg/day. Ethanol was withheld except for the first and the last day of the treatment. On the first day, the buspirone injection decreased ethanol intake from the pretreatment value (1.94+/-0.18 g/kg/day), down to 1.36+/-0.18 g/kg (p < 0.01, n = 12). The rats were again given a choice between water and 10% ethanol after the last injection of buspirone. During the following 24 hr period, the ethanol intake was increased to 3.56+/-0.24 g/kg/day (p < 0.001 vs. the pretreatment intake, n = 12). A loss of correlation with the pretreatment intake of ethanol indicated an altered regulation of ethanol intake for approximately 3 more weeks. Fifteen weeks after the start of the first treatment, buspirone (20 mg/kg) was re-tested as a single dose, with no effect on ethanol intake. Twenty-two weeks after the start of the first treatment, a 1-week treatment with 20 mg/kg/day of buspirone was started. During this treatment, the rats had a continuous choice between 10% ethanol and water. There was, as in the first re-test, no effect on ethanol intake on the first day of the treatment. However, on the last 2 days of the treatment, the ethanol intake was increased to 2.86+/-0.28 g/kg and to 2.89+/-0.26 g/kg respectively (p < 0.05, n = 10 on both days, compared with the pretreatment intake of 1.78+/-0.36 g/kg). Thus, an acute dose of buspirone can decrease voluntary ethanol intake in psychologically dependent rats, but long-lasting changes in the effect of buspirone seem to develop during a 3-week treatment period.
Alcohol Clin Exp Res 1999 May
PMID:Acute and long term effects of buspirone treatments on voluntary ethanol intake in a rat model of alcoholism. 1037 1

It is becoming increasingly clear that environmental stimuli play a critical role in the maintenance of drug taking behaviour. This has led to investigations into the neural mechanisms by which environmental stimuli can come to control behaviour using paradigms such as conditioned reinforcement. The majority of this work has involved the use of food-paired conditioned stimulus rodent paradigms. Relatively few studies have attempted to investigate the neuropharmacology of behaviour maintained by presentation of a stimulus paired with ethanol drinking. Several lines of research support an important role for brain serotonin (5-HT) neurotransmitter systems in the control of alcohol drinking behaviour. The aim of the present study was, initially, to establish a procedure in which rats respond for an ethanol-paired conditioned stimulus, and second, to study the effects of a range of serotonergic compounds previously shown to be effective in reducing oral ethanol self-administration, on responding for this conditioned stimulus. Results showed that the 5-HT releaser d-fenfluramine, the selective serotonin reuptake inhibitor fluoxetine, the 5-HT1A receptor agonist 8-hydroxy-2[di-n-propylamino]tetralin, the partial 5-HT1A receptor agonist buspirone, and the 5-HT1B/5-HT2C receptor agonist 1-(3-trifluoromethylphenyl)piperazine, but not the 5-HT2A/5-HT2C receptor agonist 1-(2,5-dimethoxy-4-iodophenylaminopropane)-2, selectively reduced responding on a lever leading to presentation of an ethanol paired conditioned stimulus. In addition the non-specific D1/D2 dopamine receptor antagonist haloperidol was active in this paradigm. Results are consistent with involvement of the dopaminergic and 5-HT systems, in particular activation of 5-HT1A and 5-HT1B receptor subtypes, in mediation of the conditioned or secondary reinforcing properties of ethanol.
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PMID:Manipulation of operant responding for an ethanol-paired conditioned stimulus in the rat by pharmacological alteration of the serotonergic system. 1119 50

Although several serotonin (5-HT) receptor subtypes influence ethanol consumption, the motivational mechanisms underlying these changes remain unclear. The present experiments characterized the rewarding, aversive and stimulant effects of ethanol in combination with a specific 5-HT1A receptor antagonist (pindobind-5HT1A). In a place conditioning study, adult male Swiss-Webster mice received 6 parings of a distinctive tactile stimulus with either 2 g/kg ethanol, 2.5 mg/kg pindobind-5HT1A, or both drugs in combination. Ethanol-conditioned preference for the tactile cue was enhanced in mice also receiving pindobind-5HT1A, which did not produce cue preference in the absence of ethanol. In a taste conditioning study, Swiss-Webster mice received 4 trials consisting of access to a distinctive NaCl flavor followed by either 4 g/kg ethanol, 2.5 mg/kg pindobind-5HT1A, or both drugs. As expected, ethanol produced avoidance of the flavor. Pindobind-5HT1A did not reduce or enhance ethanol-conditioned flavor aversion. In a study characterizing locomotor activity, 2 g/kg ethanol produced stimulation, which was enhanced after 10 daily treatments. Locomotor sensitization was not altered by co-treatment with pindobind-5HT1A. Overall, the present results show specific effects of 5-HT1A blockade on ethanol reward.
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PMID:5-HT1A receptor blockade and the motivational profile of ethanol. 1207 58

Heterozygous brain-derived neurotrophic factor (BDNF) (+/-) mice display abnormalities in central serotonergic neurotransmission, develop decrements in serotonergic innervation of the forebrain, and exhibit enhanced intermale aggressiveness. As disturbances of serotonin neurotransmission are implicated in alcohol abuse and aggression, we have examined in BDNF (+/-) mice alcohol drinking behavior, as well as central 5-hydroxytryptamine (5-HT)1A receptor function at the level of 5-HT1A receptor-G protein interaction. BDNF (+/-) mice displayed increased ethanol intake in a two-bottle choice procedure. There was no difference in the preference ratio for non-alcoholic tastants (i.e. quinine or saccharin) between genotypes. In the brains of alcohol-naive mice, we measured [35S]GTP gamma S binding stimulated by the 5-HT1A receptor agonist (+/-)-8-hydroxy-2-dipropyl-aminotetralin hydrobromide (8-OH-DPAT; 1 microM). In BDNF (+/-) versus wild-type (WT) mice, 5-HT1A receptor-stimulated [35S]GTP gamma S binding was significantly attenuated in the median raphe nucleus. There was a decrease in (+/-)8-OH-DPAT-stimulated [35S]GTP gamma S binding in the dorsal raphe, which did not reach statistical significance. In the hippocampus, 5-HT1A receptor-stimulated [35S]GTP gamma S binding was significantly attenuated in BDNF (+/-) mice. 5-HT1A receptor-stimulated [35S]GTP gamma S binding was attenuated in the anterior cingulate cortex and lateral septum, although these reductions did not reach statistical significance. 5-HT1A receptor number was not different between genotypes in any area of brain examined, suggesting that 5-HT1A receptor function, specifically the capacity of the 5-HT1A receptor to activate G proteins, is attenuated in BDNF (+/-) mice.
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PMID:Ethanol consumption and serotonin-1A (5-HT1A) receptor function in heterozygous BDNF (+/-) mice. 1275 73

Previously, this laboratory showed that in utero and in vitro ethanol exposure significantly reduces developing serotonin (5-HT) neurons and that treatment with a 5-HT1A agonist such as buspirone or ipsapirone prevents the ethanol-associated loss. The present study investigated whether ethanol decreases fetal rhombencephalic neurons, including 5-HT neurons, by causing apoptosis. We also investigated whether ipsapirone prevents the ethanol-associated deficit of fetal rhombencephalic neurons by reducing apoptosis. The results of these studies strongly suggest that the ethanol-associated reduction in fetal rhombencephalic neurons that accompanies both in utero and in vitro exposure to physiological concentrations of ethanol is associated with increased apoptosis in these neurons. A physiological concentration of ethanol (i.e., 50 mM) increases apoptosis in fetal rhombencephalic neurons and decreases the number 5-HT neurons. It also appears that the 5-HT1A agonist ipsapirone provides neuroprotection to these neurons by reducing apoptosis. Another mechanism by which ethanol-associated apoptosis can be blocked is by including serum proteins in the media at a concentration of 1% or higher; this concentration of serum proteins is high in comparison to the protein concentration in cerebrospinal fluid.
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PMID:The serotonin-1A agonist ipsapirone prevents ethanol-associated death of total rhombencephalic neurons and prevents the reduction of fetal serotonin neurons. 1515 72

We evaluated cortisol response to buspirone in extended abstinent alcoholic patients to determine 5-HT1A receptor sensitivity in alcoholism. Alcoholic patients were inpatients with an extended abstinent period of at least 3 months. Alcoholics had a significantly lower cortisol level than did the normal controls from 60 min through to 150 min after administration of 30 mg buspirone. Our results show that cortisol response to buspirone was significantly decreased in alcoholic patients compared to normal controls, reflecting decreased 5-HT1A receptor sensitivity.
Alcohol Alcohol
PMID:Cortisol response to buspirone in extended abstinent alcoholics. 1520 58

Repeated withdrawals from chronic ethanol induce a persistent adaptive change. Further, stress substitutes for the initial two withdrawals of a multiple-withdrawal protocol to sensitize rats to withdrawal-induced anxiety-like behavior ('anxiety'). Therefore, it was tested whether the persistent adaptation induced by multiple-withdrawal exposures allows stress to elicit anxiety after a period of abstinence. Social interaction was used to assess the degree of anxiety induced by 45 min of restraint stress 3, 7, or 14 days after rats were exposed to multiple withdrawals from a chronic 4.5% ethanol diet. Restraint stress reduced social interaction (ie anxiety-like behavior) at 3, but not at 7 or 14 days, after the multiple withdrawals. No anxiety response was observed in animals that received multiple withdrawals without stress or in animals that received stress when exposed only to control liquid diet. Drugs (ie a CRF1-receptor antagonist, a benzodiazepine receptor antagonist, and a 5-HT1A-receptor agonist) previously demonstrated to block the cumulative adaptation, when administered during repeated withdrawals, prevented stress-induced anxiety-like behavior during abstinence. Additionally, these drugs applied prior to stress in the rats previously exposed to the repeated withdrawal protocol, likewise, minimized stress-induced anxiety. The anxiety following stress during abstinence from previous chronic ethanol exposure is indicative of an interaction of stress with the persistent adaptive change caused by repeated withdrawals. Stress eliciting anxiety-like behavior during abstinence from previous ethanol exposures in rats is consistent with stress inducing anxiety during recovery (sobriety) in the alcoholic, a circumstance that can facilitate craving and relapse.
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PMID:Prior multiple ethanol withdrawals enhance stress-induced anxiety-like behavior: inhibition by CRF1- and benzodiazepine-receptor antagonists and a 5-HT1a-receptor agonist. 1572 14

This chapter reviews findings, mainly obtained from the selectively bred alcohol-preferring (P) line of rats, on (a) the development of alcohol drinking during the peri-adolescent period, (b) neurobiological factors that may contribute to adolescent drinking, (c) interventions to prevent alcohol drinking during adolescence, and (d) some long-lasting consequences of adolescent alcohol drinking. The findings indicate that P rats readily initiate alcohol drinking during the early post-weaning, adolescent and peri-adolescent periods of development. The early age-of-onset of alcohol drinking in the P compared to the NP line is associated with (a) higher densities of serotonin-1A (5-HT1A) receptors in cerebral cortical and hippocampal regions; (b) lower densities of dopamine (DA) D2 receptors in the ventral tegmental area (VTA); (c) higher functional activity in several limbic, cortical and hippocampal regions; and (d) sensitivity to the low-dose stimulating effect of ethanol. Conditioned taste aversion (CTA) training during adolescence produces long-term effects on preventing high alcohol drinking behavior of P rats. Alcohol drinking during peri-adolescence by P rats produces long-lasting effects that increase the acquisition of ethanol self-administration in adulthood, and, in addition, increase craving-like behavior and the potential for alcohol relapse. With suitable animal models, a better understanding of the mechanisms underlying adolescent alcohol drinking and its long-range consequences can be attained.
Recent Dev Alcohol 2005
PMID:Adolescent alcohol drinking and its long-range consequences. Studies with animal models. 1578 63


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