Alcohol Intake After Serotonin Transporter Inactivation in Mice (original) (raw)

Reappraisal of the serotonin 5-HT1B receptor gene in alcoholism: of mice and men

Brain Research Bulletin, 2002

Because pharmacological and genetic data supported the idea that serotonin receptors of the 5-HT 1B type can play a modulatory role in alcohol consumption in both human and rodents, the 5-HT 1B receptor gene is considered as a candidate gene for alcohol dependence. However, contradictory results have been reported as a positive association between alcohol dependence, and either the 861C or the 861G allele of the G861C polymorphism of the 5-HT 1B receptor gene can be found in the literature. Further investigations in a population of 136 male alcoholics compared with 72 male control subjects demonstrated that none of these alleles was actually associated with alcohol dependence. In addition, in contrast with previous results of the literature, ethanol intake under free choice conditions (i.e., ethanol solution vs. water) was found to be similar in 5-HT 1B ؊/؊ knock mice and paired wild-type controls. The 5-HT 1B receptor gene may thus not be a key component in the genetic background underlying alcohol dependence in human and alcohol preference in rodents, although these results should be considered as preliminary according to the small size of our sample.

Neural serotonergic circuits for controlling long-term voluntary alcohol consumption in mice

Molecular Psychiatry

Alcohol-use-disorders are chronic relapsing illnesses, often co-morbid with anxiety. We have previously shown using the “drinking-in-the-dark” model in mice that the stimulation of the serotonin receptor 1A (5-HT1A) reduces ethanol binge-drinking behaviour and withdrawal-induced anxiety. The 5-HT1A receptor is located either on Raphe neurons as autoreceptors, or on target neurons as heteroreceptors. By combining a pharmacological approach with biased agonists targeting the 5-HT1A auto- or heteroreceptor and a chemogenetic approach (DREADDs), here we identified that ethanol-binge drinking behaviour is dependent on 5-HT1A autoreceptors and 5-HT neuronal function, with a transition from DRN-dependent regulation of short-term (6 weeks) ethanol intake, to MRN-dependent regulation after longer ethanol exposure (12 weeks). We further identified a serotonergic microcircuit (5-HTMRN→DG) originating from the MRN and projecting to the dentate gyrus (DG) of the hippocampus, that is specifically...

Serotonin 5-HT3 antagonists fail to affect ethanol self-administration of rats

Alcohol, 1994

Serotonin 5-HT~ antagonists fail to affect ethanol self-administration of rats. ALCOHOL 11(5) [389][390][391][392][393][394][395] 1994.-Five Long-Evans hooded rats were trained to lever press according to fixed-ratio 5 reinforcement schedules for 0.06 mi dipper deliveries of 8aTe w/v ethanol during daily (M-F) 0.5-h experimental sessions. After ethanol self-administration was established, doses of the serotonin 5-HT3 antagonists, ondansetron (0,03-3.0 mg/kg), granisetron (0.01-1.0 mg/kg), and SC-51296 (0.1-10.0 mg/kg) were administered prior to ethanol sessions to determine their effects on ethanol self-administration. None of the doses of the antagonists had significant effects on numbers of obtained ethanol deliveries. Subsequently, each antagonist (ondansetron, 0.1 mg/kg; granisetron, 0.3 mg/kg; SC-51296, 0.1 mg/kg) was administered b.i.d, for five consecutive daily sessions. During none of these chronic tests with the 5-HT3 antagonists were there significant main effects of drug administration. Overall, these results do not support the hypothesis that the serotonin 5-HT3 antagonists would have robust therapeutic efficacy in the treatment of alcoholism.

Role of 5-hydroxytryptamine 1B (5-HT1B) receptors in the regulation of ethanol intake in rodents

Journal of Psychopharmacology, 2012

Evidence indicates that the serotonergic system is important in mediating dependence on and craving for alcohol. Among serotonin receptors, 5-hydroxytryptamine 1B (5-HT1B) receptors have been associated with drug abuse including alcohol. In this review, the neurocircuitry involving 5-HT1B receptors in central reward brain regions related to alcohol intake are discussed in detail. Emphasis has been placed on the pharmacological manipulations of 5-HT1B receptor-mediated alcohol intake. Furthermore, 5-HT1B auto- and hetero-receptors regulate alcohol intake through the regulatory mechanism involving release of 5-HT, gamma-aminobutyric acid (GABA), dopamine, and glutamate is evaluated. Thus, interactions between 5-HT1B receptors and these neurotransmitter systems are suggested to modulate alcohol-drinking behavior. This review on the role of 5-HT1B receptors in neurotransmitter release and consequent alcohol intake provides important information about the potential therapeutic role of 5-...

Availability of the serotonin transporter in patients with alcohol dependence

World Journal of Biological Psychiatry, 2011

Objectives. Evidence has suggested that the serotonin transporter (SERT) plays a role in the pathogenesis of alcohol dependence, anxiety and depression and that polymorphisms of the serotonin-transporter-linked promoter region (5-HTTLPR) may infl uence the SERT. This study evaluated the differences in SERT availability between healthy controls and alcoholic patients and the impact of 5-HTTLPR polymorphisms on SERT availability. Methods. Eleven healthy controls and 28 alcoholic patients were recruited. SERT availability was measured in vivo with single photon emission computed tomography and 123 I-labelled 2-((2-((dimethyl-amino)methyl)phenyl)thio)-5-iodophenylamine in the midbrain, thalamus and striatum. Each subject was genotyped for the 5-HTTLPR polymorphism. Results. Compared to healthy controls, there was a signifi cantly lower availability of SERT in the midbrain among patients with pure alcohol dependence (pure ALC). Of patients with anxiety, depression and alcohol dependence (ANX/DEPALC), the carriers of one L A allele showed a signifi cantly higher availability of SERT in the striatum compared to non-L A carriers. After Bonferroni correction, these signifi cances vanished. There were no signifi cant differences in SERT availability between controls and ANX/DEP ALC. Conclusions. The results suggest that pure alcoholics may have lower SERT availability in the midbrain; the 5HTTLPR polymorphism may infl uence SERT availability in ANX/DEP ALC. These fi ndings may serve as a springboard for future large-scale studies.

The serotonin-2 receptor modulator, (-)-trans-PAT, decreases voluntary ethanol consumption in rats

European Journal of Pharmacology, 2013

Serotonin (5-HT) 5-HT 2C receptor agonists have shown promise as novel alcoholism pharmacotherapies, but developing selective agonists has been problematic. Female Sprague Dawley rats were given ethanol in a palatable gel vehicle during operant sessions. 5-HT 2C receptor modulators (Ro60-0175, SB242,084, and (−)-trans-PAT) were administered before operant sessions. As a control for the effects of 5-HT 2C receptor agonism on caloric intake, drugs were also tested using non-ethanol containing gelatin. Ro60-0175, a 5-HT 2 family receptor agonist, decreased both ethanol and vehicle responding while (−)-trans-PAT, a 5-HT 2C receptor agonist with 5-HT 2A-2B receptor inverse agonist activity, selectively reduced only ethanol responding. The effect of 5-HT 2C receptor agonists on self-administration after reinstatement of ethanol after a three week deprivation was also determined. (−)-trans-PAT eliminated increases in ethanol intake following ethanol deprivation whereas Ro60-0175 had no effect. These results emphasize the need for caloric controls and further support the idea that selective modulation of 5-HT 2 family receptors is a potential pharmacotherapeutic approach in the treatment of alcoholism.

Serotonergic Neuroplasticity in Alcohol Addiction

Brain Plasticity, 2016

Alcohol addiction is a debilitating disorder producing maladaptive changes in the brain, leading drinkers to become more sensitive to stress and anxiety. These changes are key factors contributing to alcohol craving and maintaining a persistent vulnerability to relapse. Serotonin (5-Hydroxytryptamine, 5-HT) is a monoamine neurotransmitter widely expressed in the central nervous system where it plays an important role in the regulation of mood. The serotonin system has been extensively implicated in the regulation of stress and anxiety, as well as the reinforcing properties of all of the major classes of drugs of abuse, including alcohol. Dysregulation within the 5-HT system has been postulated to underlie the negative mood states associated with alcohol use disorders. This review will describe the serotonergic (5-HTergic) neuroplastic changes observed in animal models throughout the alcohol addiction cycle, from prenatal to adulthood exposure. The first section will focus on alcohol-induced 5-HTergic neuroadaptations in offspring prenatally exposed to alcohol and the consequences on the regulation of stress/anxiety. The second section will compare alterations in 5-HT signalling induced by acute or chronic alcohol exposure during adulthood and following alcohol withdrawal, highlighting the impact on the regulation of stress/anxiety signalling pathways. The third section will outline 5-HTergic neuroadaptations observed in various genetically-selected ethanol preferring rat lines. Finally, we will discuss the pharmacological manipulation of the 5-HTergic system on ethanol-and anxiety/stress-related behaviours demonstrated by clinical trials, with an emphasis on current and potential treatments.