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 relationship between impulsivity and drug abuse is poorly understood despite evidence that impulsive behaviour both predicts, and is a consequence of, drug use. Moreover, although there are clear individual differences in the propensity to addiction, this relationship has not been investigated with respect to impulsive behaviour. We tested whether early environmental experience would influence behavioural measures of impulsivity, and further, whether this experience would alter impulsive choice following ethanol intoxication. Thirty-six male, Long-Evans rats were reared in either isolated (1 rat/cage), standard (2 rats/cage), or enriched (group housed with toys) conditions. After a 3-month rearing period, animals were tested in two operant tasks measuring either motor (go/no-go) or cognitive (delay-to-reinforcement) impulsivity. Rats were then re-tested following 0, 0.3, 0.6, 0.9, and 1.2 g/kg ethanol. Forebrain 5-HT1A binding was assessed post-mortem using in vitro receptor autoradiography with the agonist [3H]8-OH-DPAT (3H-8-hydroxy-2-[di-n-propylamino]tetralin). Rearing condition did not influence baseline motor impulsivity, but isolation rearing led to decreased baseline cognitive impulsivity. Ethanol did not affect motor impulsivity, but dose-dependently increased impulsive choice in the delay-to-reinforcement task. Enriched rats were more impulsive overall, and isolation-reared rats only showed a shift in impulsive behaviour after 1.2 g/kg. Isolation rearing decreased, and enrichment rearing increased 5-HT1A binding in the frontal pole of the cortex following experience in the delay-to-reinforcement task. Isolation-reared rats also showed a significant decrease in 5-HT1A binding in the dentate gyrus of the ventral hippocampus following experience in the delay-to-reinforcement relative to the go/no-go task. These data indicate that differential rearing has a significant influence on cognitive impulsivity, and that altered serotonergic function may underlie these differences.
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PMID:Early environmental experience alters baseline and ethanol-induced cognitive impulsivity: relationship to forebrain 5-HT1A receptor binding. 1581 84

Previous work with Sprague-Dawley (SD) rats indicated that subjecting these rats to multiple episodes of ethanol diet could provoke anxiety-like responses. Because alcohol-preferring P rats have been reported to have neurochemical alterations in many systems shown to modulate anxiety-like responses, P rats were compared to SD rats. Rats were subjected to one or three cycles of 5 days' exposure to 4.5% or 7% ethanol diet to assess anxiety-like behavior. The social interaction test was conducted 5 h after ethanol was removed. Other groups of P and SD rats were injected with flumazenil (5 mg/kg), a benzodiazepine (BZD) receptor antagonist, CP-154,526 (10 mg/kg), CRF1 receptor antagonist, SB243,213, a 5-HT2C receptor inverse agonist, or vehicle during the 1st and 2nd withdrawals but not the third. After a single 5-day cycle of ethanol exposure, SD rats did not exhibit a change in social interaction, but P rats exhibited a decrease after exposure to the 7% ethanol. Both strains of rats exhibited anxiety-like behavior following three cycles of exposure to ethanol and the concentration of ethanol in the diet did not influence the response. It was confirmed that flumazenil, CP-154,523, and SB243,213 had prophylactic effects on anxiety-like behavior in the SD rats. Neither flumazenil nor SB243,213 was as effective in the P rats, while the CRF1 receptor antagonist completely counteracted the reduced social interaction in repeatedly withdrawn P rats. A small study showed that buspirone, a 5-HT1A agonist, also had prophylactic effects in P rats. These findings show that alcohol-preferring P rats exhibit anxiety-like behavior more readily following exposure to ethanol-containing diets and that this behavior is counteracted more readily by pretreatment with a CRF1 receptor antagonist than with BZD or 5-HT2C receptor antagonists.
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PMID:Pharmacological modulation of repeated ethanol withdrawal-induced anxiety-like behavior differs in alcohol-preferring P and Sprague-Dawley rats. 1589 69

Previously, this laboratory demonstrated that developing serotonin (5-HT) neurons and other fetal rhombencephalic neurons are reduced by in vivo and in vitro exposure to ethanol, effects that are related to ethanol's augmentation of apoptosis. We also found that 5-HT1A agonists diminished the ethanol-associated reduction of 5-HT neurons and other fetal rhombencephalic neurons by attenuating the pro-apoptotic effects of ethanol. Presently, we investigated the hypothesis that the protective/anti-apoptotic effects of a 5-HT1A agonist on fetal rhombencephalic neurons are mediated by activation of the phosphatidylinositol 3' kinase (PI-3K) and/or the mitogen-activated protein kinase kinase (MAPKK) pathway. Apoptotic and non-apoptotic fetal rhombencephalic neurons were quantitated in primary cultures that were treated with 50 mM ethanol and with 100 nM of a 5-HT1A agonist such as 8-OH-DPAT [8-hydroxy 2-(di-n-propylamino)tetralin], ipsapirone, or buspirone. Analysis of neurons stained with Hoechst 33342 demonstrated the anti-apoptotic effects of 5-HT1A agonists and implicated the involvement of the PI-3K pathway and possibly the MAPKK pathway with the protective effects of these drugs. The protective effects were blocked by a 5-HT1A antagonist (WAY 100635), an inhibitor of PI-3K (LY294002), and an inhibitor of MAPKK (PD98059). Western blot analyses showed that ethanol treatment reduces basal pAkt levels. These analyses also provide support for the involvement of the PI-3K pathway; ipsapirone stimulated the phosphorylation of Akt in control and ethanol-treated neurons, and these effects were antagonized by LY294002.
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PMID:Signaling pathways involved with serotonin1A agonist-mediated neuroprotection against ethanol-induced apoptosis of fetal rhombencephalic neurons. 1608 Nov 65

Evidence suggests that 5-hydroxytriptamine-1B (5-HT1B) receptors play a role in modifying ethanol's reinforcing effects and voluntary intake, and that 5-HT1B receptors within the ventral tegmental area (VTA) are involved in regulation of mesolimbic dopaminergic neuronal activity. Since increased mesolimbic dopaminergic transmission has been implicated in ethanol's reinforcing properties, this study was designed to assess the involvement of VTA 5-HT1B receptors in mediating the stimulatory effects of ethanol on VTA dopaminergic neurons. Dual-probe microdialysis was performed in freely moving adult Sprague-Dawley rats with one probe within the VTA and the other within the ipsilateral nucleus accumbens (NACC). Dopamine (DA) levels in dialysates from both areas, as the index of the activity of mesolimbic DA neurons, were measured simultaneously. The results showed that intraperitoneal injection of ethanol at the doses of 1 and 2 g/kg increased extracellular DA concentrations in both the VTA and the NACC, suggesting increased DA neuronal activity. These ethanol-induced increases of the DA release in the VTA and the NACC were significantly attenuated by intra-tegmental infusion of SB 216641 (a 5-HT(1B) receptor antagonist), but not BRL 15572 (a 5-HT(1D/1A) receptor antagonist) or WAY 100635 (a 5-HT1A receptor antagonist). Administration of ethanol at the same doses did not significantly alter extracellular levels of GABA in the VTA. The results also showed that intra-tegmental infusion of CP 94253, a 5-HT1B receptor agonist, significantly prolonged the effects of ethanol on NACC DA. The results suggest that blockade and activation of VTA 5-HT1B receptors attenuates and potentiates the neurochemical effects of ethanol, respectively, and support the suggestion that VTA 5-HT(1B) receptors may be involved in part in mediating the activating effects of ethanol on mesolimbic DA neurons.
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PMID:Involvement of 5-HT1B receptors within the ventral tegmental area in ethanol-induced increases in mesolimbic dopaminergic transmission. 1621 43

This study utilized a novelty-induced suppression of feeding task to examine anxiety-like behaviour and the anxiolytic effects of the 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), in rats prenatally exposed to ethanol. Adult offspring from ethanol exposed (E), pair-fed control (PF) and ad libitum-fed control (C) dams were habituated to a novel palatable food for 21 days and measures of baseline feeding obtained. On day 22 (d 22), animals received either 8-OH-DPAT (0.06 mg/kg) or vehicle (0.9% NaCl) and feeding behaviour in the home cage or a novel cage was observed. Factor analyses revealed that feeding behaviour on d 21 (habituation) and d 22 (test day) are reflective of two different affective states, and that the single factor that emerged for novel cage testing on d 22 likely reflects the anxiety evoked by the novel test condition. Analyses of variance on the variables loading significantly onto the factors support the suggestion that the novel environment is anxiogenic for both females and males, and that 8-OH-DPAT acts as an anxiolytic. However, although both females and males showed alterations in behaviours (latency, amount, duration of feeding) reflective of anxiety, 8-OH-DPAT had anxiolytic effects primarily in females. Importantly, prenatal ethanol exposure altered several aspects of behavior in this task. Both E females and males consumed less than their control counterparts on d 21, suggesting a possible delay or deficit in response habituation. During home cage testing on d 22, overall feeding rate was slower in E than in C females, and E males consumed less than PF and C males. In addition, a smaller percentage of E than PF and C females fed in the novel environment, and latency to feed was significantly increased in E compared to control females. These findings indicate that prenatal ethanol exposure results in increased anxiety-like behaviour in adulthood, and that prenatal ethanol-induced hyponeophagia may be, at least in part, mediated by the 5-HT1A receptor. This study is one of the first to demonstrate specific increases in anxiety-like behaviour in animals prenatally exposed to ethanol, and further supports the utility of the novelty-induced suppression of feeding task in assessing anxiety and the effectiveness of anxiolytic agents.
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PMID:Prenatal ethanol exposure: sex differences in anxiety and anxiolytic response to a 5-HT1A agonist. 1635 22

It has been shown that ethanol produces a complex interoceptive cue in rodents with distinct GABAergic, glutamatergic, and serotonergic (5-hydroxytryptamine, 5-HT) components. The present study aimed to examine the contribution of the 5-HT system originating in the dorsal raphe nucleus (DRN) to the discriminative stimulus effects of ethanol in male Wistar rats. Therefore, selective lesions of 5-HT neurons in the DRN were induced by microinfusions of 5,7-dihydroxytryptamine. The DRN- and sham-lesioned rats were trained to discriminate ethanol (1.0 g/kg) from saline in a standard two-lever drug discrimination procedure. Acquisition of ethanol discrimination and discrimination performance after consumption of lower doses of ethanol did not differ between the groups. In substitution tests, diazepam (0.5-2.5 mg/kg), a nonselective benzodiazepine receptor agonist, partially generalized from the ethanol cue in both groups. In contrast, m-chlorophenylpiperazine (0.1-0.9 mg/kg), a mixed 5-HT(1B/2C) receptor agonist, did not mimic the ethanol cue. The drug decreased response rates in both groups, but this effect was more evident in the sham-lesioned group. A 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propyloamino)-tetraline (0.05-0.4 mg/kg), did not produce significant increase in ethanol-appropriate responding in either group. These results may indicate that 5-HT neurons of the DRN are not critically involved in ethanol discrimination in the rat.
Alcohol 2005 Jun
PMID:Effects of 5,7-dihydroxytryptamine lesion of the dorsal raphe nucleus on ethanol discrimination in the rat. 1639 44

The 5HT1A receptor is one of at least 14 different receptors for serotonin which has a role in moderating several brain functions and may be involved in the aetiology of several psychiatric disorders. The C(-1019)G 5-HT1A promoter polymorphism was reported to be associated with major depression, depression-related personality traits and suicidal behavior in various samples. The G(-1019) allele carriers are prone to depressive personality traits and suicidal behavior, because serotonergic neurotransmission is reduced. The aim of this study is to replicate previous findings in a sample of 185 Alcohol-dependent individuals. Personality traits were evaluated using the NEO FFI and TCI. History of suicidal behavior was assessed by a standardized semistructured interview (SSAGA). No significant differences across C(-1019)G 5-HT1A genotype groups were found for TCI temperament and character traits and for NEO FFI personality scales. No association was detected between this genetic variant and history of suicide attempts. These results neither support a role of C(-1019)G 5-HT1A promoter polymorphism in the disposition of personality traits like harm avoidance or neuroticism, nor confirm previous research reporting an involvement of the G allele in suicidal behavior in alcoholics. Significant associations, however, were detected between Babor's Type B with number of suicide attempts in history, high neuroticism and harm avoidance scores in alcoholics.
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PMID:The C(-1019)G 5-HT1A promoter polymorphism and personality traits: no evidence for significant association in alcoholic patients. 1650 34

We have evaluated in C57BL/6J mice the effect of maternal separation and post-weaning social isolation on ethanol intake, and on serotonin1A (5-HT1A) receptor function at the level of receptor-G protein interaction in the hippocampus and dorsal raphe nucleus. From postnatal days 2-14, litters were separated from the mother for 15 min (Handled) or for 180 min (Maternal separation). After weaning, pups were housed in pairs or in social isolation. At 2 months of age, ethanol intake and preference in mice were assessed using the two-bottle choice paradigm. Maternal separation increased ethanol preference in female mice that were subsequently housed in isolation. By contrast, post-weaning isolation increased ethanol preference and consumption in male mice regardless of pre-weaning rearing conditions. The increased ethanol preference and intake were limited to a 5% (v/v) concentration of ethanol. Our data suggest that adolescent mice are susceptible to the effects of post-weaning social isolation as shown by increased ethanol preference and consumption. Using quantitative autoradiography, 5-HT1A receptor number and function were determined by the binding of [3H]WAY-100635, and by [35S]GTPgammaS binding stimulated by the 5-HT1A receptor agonist 8-OH-DPAT, respectively. The binding experiments were done at approximately 3 months after the end of the two-bottle choice test in an attempt to minimize direct effects of ethanol drinking on 5-HT1A receptor function and number. 5-HT1A receptor-stimulated [35S]GTPgammaS binding in the dorsal raphe nucleus was increased in animals reared after weaning in isolation vs. in pairs, regardless of gender or pre-weaning rearing conditions. Our data suggest that there are long-term neurochemical consequences of social isolation of adolescent mice, specifically increased 5-HT1A receptor function in the dorsal raphe nucleus.
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PMID:Effect of early rearing conditions on alcohol drinking and 5-HT1A receptor function in C57BL/6J mice. 1713 28

An elevated plus maze (EPM) test was used to determine if the 5-HT1A, GABAA, and benzodiazepine receptors play a role in the anxiolytic-like effects of a 50% EtOH extract of Cinnamomum cassia (C. cassia) in mice. A single treatment with C. cassia (750 mg/kg, p.o.) significantly increased the number of entries into and the time spent in the open arms of the EPM compared with the controls. A repeated treatment with C. cassia (100 mg/kg, 5 days, p.o.) significantly increased the time spent in the open arms of the EPM. Moreover, WAY 100635, (+)-bicuculline, and flumazenil blocked the effect of C. cassia. However, there were no changes in the locomotor activity and horizontal wire test observed in any group compared with the controls. Taken together, these results show that C. cassia has no adverse effects, such as myorelaxant effects, and might be an effective anxiolytic agent by regulating the serotonergic and GABAergic system.
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PMID:Involvement of 5-HT1A and GABAA receptors in the anxiolytic-like effects of Cinnamomum cassia in mice. 1751 74

Heightened impulsivity and differential sensitivity to a drug's behavioral effects are traits that, individually, have been associated with chronic drug use and dependence. Here, we used an animal model to test whether individual differences in cocaine-induced activity are predictive of impulsive choice behavior. Adult, male Sprague-Dawley rats were given cocaine (10mg/kg, i.p.) and classified into low or high cocaine responders (LCRs or HCRs, respectively) based on their locomotor response in an open-field arena. Rats were then trained in a delay-discounting task that offers a choice between immediately delivered, but smaller reinforcements, or larger reinforcements that are delivered after a delay. We also examined the effects of amphetamine (AMPH; 0.3-1.0mg/kg) and the 5-HT1A agonist 8-OH-DPAT (0.3-1.0mg/kg) on delay-discounting. Lastly, all rats were retested in the open-field to determine if phenotypes were stable. We observed baseline differences in choice behavior between the groups, with HCRs behaving more impulsively (i.e., choosing the small reinforcement) compared to LCRs. AMPH decreased choice of the large reinforcement in LCRs, but did not alter choice in HCRs. Impulsive choice was increased in both phenotypes following 8-OH-DPAT, with LCRs exhibiting changes across a wider range of delays. When cocaine-induced open-field behavior was retested, responses in LCRs were similar whereas HCRs showed evidence of tolerance. Our results suggest that differential sensitivity to cocaine-induced locomotion is predictive of impulsivity and the potential neurobiological differences in LCRs and HCRs may provide insight into mechanisms contributing to vulnerability for chronic drug use and/or dependence.
Drug Alcohol Depend 2008 Nov 01
PMID:Disparate cocaine-induced locomotion as a predictor of choice behavior in rats trained in a delay-discounting task. 1853 7


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