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)

Inconsistencies in the effects of alcohol on aggression in rodent models suggest that this effect is mediated through some other factor that is differentially involved in the various tests. The patterning of alcohol enhancement of aggression suggests that this may be most apparent in tests in which defensiveness or anxiety act to reduce aggression. Thus, an understanding of the relationship between alcohol and aggression may also involve determination of alcohol effects on anxiety. New ethoexperimental models of anxiety in rodents involve the measurement of a range of defensive behaviors to approaching, contacting predators, or to situations associated with (absent) predators. A Fear/Defense Test Battery, measuring the former, showed little, and inconsistent, response to traditional (benzodiazepine) or nontraditional (5-HT1A agonist) anxiolytics. However, an Anxiety/Defense Test Battery, measuring the latter, produced an "anxiolytic profile" of changes seen consistently to both traditional and nontraditional anxiolytics, but not to nonanxiolytic drugs. Alcohol (0.6 and 1.2 g/kg) altered the four behaviors of the "anxiolytic profile" in a manner consistent with the effects of diazepam (2.0 and 4.0 mg/kg), indicating that it is also anxiolytic. The consistency of alcohol and diazepam effects on anxiety provide a possible mechanism for their somewhat similar effects on aggression. However, alcohol at nonsedative doses, but not diazepam, additionally enhances defensive attack. Although defensive attack is behaviorally and neurally different from offensive aggression, the two are not separated in analyses of human "aggression," suggesting that alcohol effects in the latter may also be mediated by changes in defensive attack.
J Stud Alcohol Suppl 1993 Sep
PMID:Alcohol and anxiety: effects on offensive and defensive aggression. 841 Sep 68

A two-bottle, free-choice paradigm was used to investigate the influence of the serotonergic (5-HT) system on ethanol intake in genetically heterogeneous Wistar rats. Systemic administration of the 5-HT1A agonist ipsapirone (1.25-5.0 mg/kg) caused a dose-dependent decrease in ethanol preference and intake, while the 5-HT2 antagonist ritanserin (1.25-5.0 mg/kg) and the 5-HT3 antagonists ondansetron (0.01-1.0 mg/kg) and granisetron (0.5-1.0 mg/kg) failed to alter ethanol consumption. The effect of ipsapirone treatment on ethanol intake was more pronounced in high-preferring animals than in low-preferring. A closer look at the microstructure of the rat's drinking behaviour by means of a microcomputer-controlled data acquisition system showed that ipsapirone treatment caused a significant decrease in the number of licks recorded at the ethanol-containing bottle and a decrease in the time spent at this bottle. Furthermore, ipsapirone treatment caused a significant increase in the number of breaks in licking behaviour recorded at this bottle. The drinking behaviour at the water-containing bottle was not affected by the ipsapirone treatment. Neither was the rat's eating behaviour altered by this treatment. These findings support the hypothesis that the 5-HT system is involved in the regulation of ethanol intake, with special emphasis on the involvement of the 5-HT1A receptor subtype, and may indicate that central reward-mediating mechanisms are influenced.
Alcohol
PMID:Involvement of the serotonergic system in ethanol intake in the rat. 850 91

Wistar rats can develop a high preference for 3% alcohol after a period of forced alcohol exposure and 2 days of alcohol withdrawal. If these rats are selected at a medium (> or = 60%) and a high (> or = 85%) level of alcohol preference, it is possible to study the effects of various compounds on alcohol intake and alcohol preference in rats with two different levels of alcohol preference. With this procedure, it was demonstrated that the benzodiazepine chlordiazepoxide can reduce alcohol preference at doses > or = 10.0 mg/kg in the high alcohol preference group, by increasing the water consumption without affecting alcohol drinking. Chlordiazepoxide had no effects in the medium alcohol preference group. The 5-HT uptake inhibitors fluoxetine and citalopram reduced alcohol intake and alcohol preference in both the medium and the high alcohol preference groups by means of a reduction in consummatory behaviour. Both drugs clearly affected total fluid intake and body weight gain. The 5-HT1A agent buspirone reduced alcohol intake and alcohol preference in the group of medium alcohol preferring rats at doses between 0.0025 and 0.63 mg/kg. The drug did not change water drinking so that total fluid consumption diminished. At doses > or = 2.5 mg/kg buspirone, there was an increased alcohol consumption. Buspirone was without important effects on the high alcohol preferring rats. The 5-HT3 antagonist ondansetron reduced alcohol intake in both the medium and high alcohol preferring rats at doses between 0.01 and 0.16 mg/kg. The drug had no effects on alcohol preference and water consumption. At some doses, there was a reduction in total fluid intake. The 5-HT2/1C antagonist ritanserin reduced alcohol intake and alcohol preference at doses between 0.04 and 2.50, and 0.16 and 10.0 mg/kg in the medium and high alcohol preferring rats, respectively. Together with the decrease in alcohol consumption there was an increase in water drinking, leaving total fluid intake unaffected. The activity of ritanserin was less pronounced in the high as compared to the medium alcohol preference group. These results indicate that various serotonergic agents can affect alcohol intake and alcohol preference by different mechanisms of action.
Alcohol Alcohol 1993 Mar
PMID:Effects of various serotonergic agents on alcohol intake and alcohol preference in Wistar rats selected at two different levels of alcohol preference. 851 86

Behavioral effects induced by 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; i.e., lower lip retraction, flat body posture, and forepaw treading) were examined in rats during ethanol withdrawal following a 2-week period of access to a liquid diet containing 9% (v/v) ethanol. After an 18 h withdrawal period, tolerance to 8-OH-DPAT-induced flat body posture and, conversely, sensitization to the effects of 8-OH-DPAT on lower lip retraction were observed in the 9% ethanol group as compared to control rats fed an isocaloric diet. In contrast, 8-OH-DPAT-induced forepaw treading in the 9% ethanol group was not significantly different in comparison to control rats. Plasma corticosterone levels were significantly higher in the ethanol-exposed group than in control animals, an effect which was not additive with the increase in corticosterone levels normally observed after the administration of low doses of 8-OH-DPAT. Altered flat body posture and lower lip retraction responses to a submaximal dose of 8-OH-DPAT (2.5 mg/kg i.p.) were still observed as late as 3 days after withdrawal of the 9% ethanol liquid diet, but were no longer apparent at 7 days. Interestingly, prominent ethanol withdrawal signs such as tremor and rigidity, while occurring on the first day, were completely absent on the third day. Taken together, these results indicate that chronic ethanol exposure differentially alters sensitivity to several pharmacological effects of the 5-HT1A receptor ligand 8-OH-DPAT. They further support the involvement of 5-HT (5-hydroxytryptamine, serotonin) systems in alcohol abuse and therapeutic interventions using 5-HT1A ligands.
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PMID:Modification of behavioral effects of 8-hydroxy-2-(di-n-propylamino)tetralin following chronic ethanol consumption in the rat: evidence for the involvement of 5-HT1A receptors in ethanol dependence. 852 4

The expression of central 5-HT1A and 5-HT1B receptors was studied in several brain areas of rats subjected to a 2-week period of chronic alcoholization, followed by 18 h withdrawal. Quantitative autoradiography indicated that the ethanol treatment provoked an increase (approximately +30%) in the labeling by [3H]8-hydroxy-2-(di-n-propylamino)tetralin ([3H]8-OH-DPAT) and [3H]N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexane carboxamide ([3H]WAY-100635) of 5-HT1A autoreceptors in the dorsal raphe nucleus, accompanied by a concomitant decrease in the labeling of postsynaptic 5-HT1A receptors in the hippocampus (approximately -20%), anterior (approximately -30%) and posterior (approximately -32%) cortices. These changes were associated with a tendency toward an increase and decrease in 5-HT1A mRNA levels in the anterior raphe area and hippocampus, respectively, suggesting that the changes observed are due to modifications in 5-HT1A receptor protein synthesis. The autoradiographic labeling of 5-HT1B receptors by serotonin-O-carboxymethylglycyl[125I]iodotyrosinamide ([125I]GTI) was found to increase (+55%) in the globus pallidus of alcoholized rats. Interestingly, a significant increase (+57%) in 5-HT1B receptor mRNA levels was observed in the striatum, which contains cell bodies of neurons projecting into the globus pallidus. These data suggest that altered sensitivity of chronically alcoholized rats to 5-HT1A and 5-HT1B receptor ligands may result from alcohol-induced changes in the transcription of the genes encoding these receptors.
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PMID:Chronic alcoholization alters the expression of 5-HT1A and 5-HT1B receptor subtypes in rat brain. 852 5

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.
Alcohol Alcohol 1996 Mar
PMID:Buspirone as an inhibitor of voluntary ethanol intake in male rats. 873 10

Previous work in this laboratory demonstrated that in utero ethanol exposure is associated with abnormal development of the serotonergic system. Specific abnormalities included deficiencies of serotonin (5-HT) and its metabolites, and cortical 5-HT reuptake sites. The concentration of 5-HT1A receptors was also altered. The serotonin deficit was detected in the fetal ethanol-exposed brain, at an age when 5-HT would normally function as an essential trophic factor. Thus, it was hypothesized that the early 5-HT ethanol-associated deficit of an essential trophic factor (e.g. 5-HT) could contribute to subsequent developmental abnormalities in serotonergic neurons. In the present investigation we used quantitative autoradiography (QAR) to more fully characterize the developmental abnormalities in 5-HT reuptake sites in developing offspring of ethanol-fed rats. In addition, we attempted to overcome the potential negative impact of the ethanol-associated deficit of fetal 5-HT, by administering a 5-HT1A agonist, buspirone, to pregnant rats. These investigations demonstrated that postnatal (PN) 19 and/or 35 day ethanol-exposed offspring had a significant decrease in [3H]citalopram binding to 5-HT reuptake sites in the frontal cortex, parietal cortex, lateral hypothalamus, substantia nigra, medial septum, and striatum. In contrast, [3H]citalopram binding was increased in the dorsal raphe on PN5 and in the median raphe on PN19. No significant ethanol-associated changes were detected in the hippocampus CA3 region or in the amygdala. When [3H]citalopram binding was compared in the offspring of saline- and buspirone-treated dams, it appeared that maternal treatment with buspirone prevented or reversed most of the ethanol-associated developmental abnormalities in 5-HT reuptake sites. Buspirone prevented the decline in binding of [3H]citalopram in the frontal cortex, lateral hypothalamus, substantia nigra and medial septum. Similarly, buspirone treatment prevented the ethanol-associated increase in binding in the dorsal and median raphe. Additional experiments are needed to elucidate the impact of maternal buspirone treatment on the development of other neurotransmitter systems in offspring.
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PMID:Protective effects of maternal buspirone treatment on serotonin reuptake sites in ethanol-exposed offspring. 873 26

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

Amperozide (FG5606), a 5-HT2 receptor antagonist, is well known to suppress alcohol consumption in different rat models of drinking. The present study compared the efficacy of three drugs, FG5974, FG5893, and amperozide, which have differential affinities for 5-HT1A and 5-HT2A receptors, on alcohol drinking in the genetic alcohol-preferring (P) rat. After preference for alcohol vs. water was determined over 10 days when concentrations of alcohol were increased from 3% to 30%, the maximal concentration of alcohol preferred by each animal was selected for drug testing. A 4-day predrug preference test was followed by SC injection of the saline control vehicle or doses of 1.0 and 2.5 mg/kg FG5974, FG5893, or amperozide given at 1600 and 2200 h for 4 days. Alcohol preference testing concluded with a final 4-day interval. A total daily dose of 5.0 mg/kg FG5974 reduced absolute g/kg intake of alcohol and proportional intakes of the P rats significantly; the lower dose of FG5974 also reduced alcohol drinking significantly following treatment. The mixed 5-HT1A agonist/5-HT2A antagonist, FG5893, which suppresses drinking in cyanamide-treated rats, was without effect on alcohol ingested by the P rats. However, amperozide caused a dose-dependent decline in both absolute intakes and proportion of alcohol that was more intense than that of FG5974. The control vehicle failed to alter alcohol drinking and, like the FG compounds, did not affect food intake or body weight. Although the inhibition of alcohol drinking by amperozide corresponds precisely with previous findings, the effect of FG5974 contrasts to results obtained with a structurally analogous drug FG5893. Thus, the genetic strain of rat as well as the nature of the chemical characteristics of a 5-HT agonist/antagonist will determine the differential efficacy of a drug in influencing the volitional drinking of alcohol.
Alcohol
PMID:Differential efficacy of serotonergic drugs FG5974, FG5893, and amperozide in reducing alcohol drinking in P rats. 883 30

(+/-)3,4-Methylenedioxymethamphetamine (MDMA) releases dopamine and serotonin in vivo and stimulates locomotor activity. Previous work demonstrated that MDMA-stimulated dopamine release could be reduced by the selective 5-HT2A receptor antagonist [R-(+)-a- (2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinem ethanol] (MDL 100,907). In the present study MDL 100,907 significantly reduced MDMA-stimulated locomotion without affecting basal levels of locomotion. Other agents with 5-HT2A antagonist activity (ritanserin, clozapine, MDL 28,133A, or methiothepin), as well as agents that block 5-HT1A-(propranolol), D2-(haloperidol), or D1 receptors (SCH 23390) also reduced MDMA-stimulated locomotion. Intraventricularly administered 5,7-dihydroxytryptamine decreased regional 5-HT levels and attenuated MDMA-stimulated locomotion. These data support the conclusion that serotonin released onto 5-HT2A receptors contributes to MDMA-stimulated locomotion and suggest that MDMA-stimulated locomotion may be useful as an in vivo behavioral measure of 5-HT2A antagonism. The data also support previous reports of contributions of 5-HT1A, D1 and D2 receptors to MDMA-stimulated locomotion. A preliminary time-course analysis indicating time-dependent contributions of different receptors to MDMA-stimulated locomotion suggests the potential utility of this model for characterizing potential atypical antipsychotic compounds.
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PMID:Effects of the selective 5-HT2A receptor antagonist MDL 100,907 on MDMA-induced locomotor stimulation in rats. 884 Mar 47


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