Genomic screen for QTLs underlying alcohol consumption in the P and NP rat lines

Selective breeding for voluntary alcohol consumption was utilized to establish the alcohol-preferring (P) and alcohol-nonpreferring (NP) rat lines. Inbreeding was initiated after 30 generations of selection and, after 19 generations of inbreeding, 384 F₂ intercross progeny were created to identify quantitative trait loci (QTLs) influencing alcohol consumption. We had reported previously a QTL on Chromosome (Chr) 4; additional markers genotyped on Chr 4 have increased the maximum lod score from 8.6 to 9.2. This QTL acts in an additive fashion and continues to account for approximately 11% of the phenotypic variability. The 95% confidence interval is 12.5 cM and includes the candidate gene, neuropeptide Y. Subsequent to the identification of the QTL on Chr 4, a genome scan was completed to identify additional QTLs influencing alcohol consumption. A lod score of 2.5 was obtained on Chr 3, syntenic to a region previously reported for alcohol preference in mice. Analysis of Chr 8 produced a lod score of 2.2 near the dopamine D2 and serotonin 1b receptors, which have been previously reported as candidate genes for alcohol preference. Evidence for linkage to alcohol consumption was not found on any other chromosome. It therefore appears likely that, in addition to the QTL on Chr 4, multiple loci of small to moderate effect, such as those on Chrs 3 and 8, underlie the difference in alcohol consumption in the P/NP lines. Received: 15 September 1998 / Accepted: 8 October 1998     

Relaxin-3 Receptor (RXFP3) Signalling Mediates Stress-Related Alcohol Preference in Mice

Stressful life events are causally linked with alcohol use disorders (AUDs), providing support for a hypothesis that alcohol consumption is aimed at stress reduction. We have previously shown that expression of relaxin-3 mRNA in rat brain correlates with alcohol intake and that central antagonism of relaxin-3 receptors (RXFP3) prevents stress-induced reinstatement of alcohol-seeking. Therefore the objectives of these studies were to investigate the impact of Rxfp3 gene deletion in C57BL/6J mice on baseline and stress-related alcohol consumption. Male wild-type (WT) and Rxfp3 knockout (KO) (C57/B6J^{RXFP3TM1/DGen}) littermate mice were tested for baseline saccharin and alcohol consumption and preference over water in a continuous access two-bottle free-choice paradigm. Another cohort of mice was subjected to repeated restraint followed by swim stress to examine stress-related alcohol preference. Hepatic alcohol and aldehyde dehydrogenase activity was assessed in mice following chronic alcohol intake and in naive controls. WT and Rxfp3 KO mice had similar baseline saccharin and alcohol preference, and hepatic alcohol processing. However, Rxfp3 KO mice displayed a stress-induced reduction in alcohol preference that was not observed in WT littermates. Notably, this phenotype, once established, persisted for at least six weeks after cessation of stress exposure. These findings suggest that in mice, relaxin-3/RXFP3 signalling is involved in maintaining high alcohol preference during and after stress, but does not appear to strongly regulate the primary reinforcing effects of alcohol.     

Hyperactive hypothalamus,motivated and non‐distractible chronic overeating in ADAR2 transgenic mice

ADAR2 transgenic mice misexpressing the RNA editing enzyme ADAR2 (Adenosine Deaminase that act on RNA) show characteristics of overeating and experience adult onset obesity. Behavioral patterns and brain changes related to a possible addictive overeating in these transgenic mice were explored as transgenic mice display chronic hyperphagia. ADAR2 transgenic mice were assessed in their food preference and motivation to overeat in a competing reward environment with ad lib access to a running wheel and food. Metabolic activity of brain and peripheral tissue were assessed with [¹⁸F] fluorodeoxyglucose positron emission tomography (FDG‐PET) and RNA expression of feeding related genes, ADAR2, dopamine and opiate receptors from the hypothalamus and striatum were examined. The results indicate that ADAR2 transgenic mice exhibit, (1) a food preference for diets with higher fat content, (2) significantly increased food intake that is non‐distractible in a competing reward environment, (3) significantly increased messenger RNA (mRNA) expressions of ADAR2, serotonin 2C receptor (5HT_2CR), D1, D2 and mu opioid receptors and no change in corticotropin‐releasing hormone mRNAs and significantly reduced ADAR2 protein expression in the hypothalamus, (4) significantly increased D1 receptor and altered bioamines with no change in ADAR2, mu opioid and D2 receptor mRNA expression in the striatum and (5) significantly greater glucose metabolism in the hypothalamus, brain stem, right hippocampus, left and right mid brain regions and suprascapular peripheral tissue than controls. These results suggest that highly motivated and goal‐oriented overeating behaviors of ADAR2 transgenic mice are associated with altered feeding, reward‐related mRNAs and hyperactive brain mesolimbic region .     

Three-generation investigation on serotonin content in rat immune cells long after beta-endorphin exposure in late pregnancy.

Female rats were treated with beta-endorphin on the 19th day of pregnancy. Serotonin content of immune cells (peritoneal lymphocytes, monocyte-macrophage-granulocyte group (mo-gran), mast cells, blood lymphocytes, granulocytes and monocytes, thymus lymphocytes) were studied in the mothers (P-generation four weeks after delivery), in the male offspring (F1) generation (at seven weeks), in the female offspring (four weeks after their own delivery) and in their offspring (F2 generation, at seven weeks). P-mother cells' serotonin content was not influenced by endorphin treatment, while F1 generation's mo-gran and blood lymphocyte serotonin content was reduced (in contrast, histamine content of mo-gran increased). Four weeks after delivery, an increase in serotonin content was observed in the F1 generation in the peritoneal lymphocytes and mast cells as well as in blood lymphocytes. In contrast, serotonin content was reduced in blood granulocytes and monocytes. In the F2 (grandson) generation, a reduction in mast cell serotonin content and sensitization of blood and thymic lymphocytes to repeated endorphin treatment was provoked. The significant changes were more expressed in the F2 generation compared to F1, also appearing earlier. The results unequivocally suggest that the increase in endorphin levels during late pregnancy can cause permanent changes in the F1 and F2 generations, which means that the imprinting effect can be transgenerationally transmitted.     

Dopamine D2R DNA transfer in dopamine D2 receptor-deficient mice: effects on ethanol drinking

Dopamine (DA) signals are transmitted via specific receptors including the D2 receptors (D2R). Previous studies have shown that D2R upregulation in the nucleus accumbens (NAc) attenuated alcohol consumption. We hypothesized that upregulation of D2R in the NAc would significantly influence alcohol drinking. We tested this hypothesis by determining the effect that D2R upregulation has on alcohol intake in genetically altered mice lacking D2Rs. After a steady baseline of drinking behavior was established for all mice, a null vector or a genetically modified adenoviral vector containing the rat D2R cDNA was infused into the NAc of wild-type (Drd2+/+), heterozygous (Drd2+/-), and receptor-deficient mice (Drd2-/-). Ethanol intake and preference were then determined using the two-bottle choice paradigm. Our results indicated that Drd2+/+ mice treated with the D2R vector significantly attenuated (58 %) their ethanol intake as well as reduced preference. Drd2+/- and mutant mice showed a similar attenuation, although the change was not as marked (12 %) and did not last as long. In contrast, Drd2-/- mice treated with the D2R vector displayed a temporary but significant increase (46 %) in ethanol intake and preference (consumption). These results supported the notion that the D2R plays an important role in alcohol consumption in mice and suggest that a key threshold range of D2R levels is associated with elevated alcohol consumption. Significant deviations in D2R levels from this range could impact alcohol consumption, and could help to explain possible individual variations in alcohol response, metabolism, sensitivity and consumption.     

Role of Serotonin via 5-HT2B Receptors in the Reinforcing Effects of MDMA in Mice

The amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) reverses dopamine and serotonin transporters to produce efflux of dopamine and serotonin, respectively, in regions of the brain that have been implicated in reward. However, the role of serotonin/dopamine interactions in the behavioral effects of MDMA remains unclear. We previously showed that MDMA-induced locomotion, serotonin and dopamine release are 5-HT_2B receptor-dependent. The aim of the present study was to determine the contribution of serotonin and 5-HT_2B receptors to the reinforcing properties of MDMA.We show here that 5-HT_2B ^−/− mice do not exhibit behavioral sensitization or conditioned place preference following MDMA (10 mg/kg) injections. In addition, MDMA-induced reinstatement of conditioned place preference after extinction and locomotor sensitization development are each abolished by a 5-HT_2B receptor antagonist (RS127445) in wild type mice. Accordingly, MDMA-induced dopamine D1 receptor-dependent phosphorylation of extracellular regulated kinase in nucleus accumbens is abolished in mice lacking functional 5-HT_2B receptors. Nevertheless, high doses (30 mg/kg) of MDMA induce dopamine-dependent but serotonin and 5-HT_2B receptor-independent behavioral effects.These results underpin the importance of 5-HT_2B receptors in the reinforcing properties of MDMA and illustrate the importance of dose-dependent effects of MDMA on serotonin/dopamine interactions.     

Brain Serotonin Signaling Does Not Determine Sexual Preference in Male Mice

It was reported recently that male mice lacking brain serotonin (5-HT) lose their preference for females (Liu et al., 2011, Nature, 472, 95–100), suggesting a role for 5-HT signaling in sexual preference. Regulation of sex preference by 5-HT lies outside of the well established roles in this behavior established for the vomeronasal organ (VNO) and the main olfactory epithelium (MOE). Presently, mice with a null mutation in the gene for tryptophan hydroxylase 2 (TPH2), which are depleted of brain 5-HT, were tested for sexual preference. When presented with inanimate (urine scents from male or estrous female) or animate (male or female mouse in estrus) sexual stimuli, TPH2-/- males show a clear preference for female over male stimuli. When a TPH2-/- male is offered the simultaneous choice between an estrous female and a male mouse, no sexual preference is expressed. However, when confounding behaviors that are seen among 3 mice in the same cage are controlled, TPH2-/- mice, like their TPH2+/+ counterparts, express a clear preference for female mice. Female TPH2-/- mice are preferred by males over TPH2+/+ females but this does not lead to increased pregnancy success. In fact, if one or both partners in a mating pair are TPH2-/- in genotype, pregnancy success rates are significantly decreased. Finally, expression of the VNO-specific cation channel TRPC2 and of CNGA2 in the MOE of TPH2-/- mice is normal, consistent with behavioral findings that sexual preference of TPH2-/- males for females is intact. In conclusion, 5-HT signaling in brain does not determine sexual preference in male mice. The use of pharmacological agents that are non-selective for the 5-HT neuronal system and that have serious adverse effects may have contributed historically to the stance that 5-HT regulates sexual behavior, including sex partner preference.     

Change in certain forms of aggressive behavior and the concentration of monoamines in the brain during selection of wild rats for taming

Norway rats have been selected during 20 generations by the absence of aggressive reaction to man (tamed rats). From 7 up to 20th generations of selection, different forms of aggressive behaviour (reaction to glove, intermale, shock-induced aggression and predatory aggression) were studied, and the level of noradrenaline, serotonin and its metabolite 5-hydroxyindoleacetic acid was determined in the brain. In the absence of aggressive reaction to glove in tamed rats, the shock-induced aggression considerably decreased while the predatory aggressiveness (mouse-killing behaviour) and intermale aggressiveness did not change. Beginning from 15-16th generation of selection, a higher level of the 5-hydroxyindoleacetic acid in the hypothalamus was established, in the 20th generation an increased content of serotonin was revealed in the hypothalamus and the midbrain. In some generations of selection an increased level of noradrenaline in the hypothalamus in comparison to wild rats was observed. A conclusion is made that the selection of animals by taming unequally influences different kinds of aggressiveness and is accompanied by inherited consolidated reorganization of the monoamine brain systems.     

Brain serotonin deficiency leads to social communication deficits in mice

A deficit in brain serotonin is thought to be associated with deteriorated stress coping behaviour, affective disorders and exaggerated violence. We challenged this hypothesis in mice with a brain-specific serotonin depletion caused by a tryptophan hydroxylase 2 (TPH2) deficiency. We tested TPH2-deficient (Tph2^−/–) animals in two social situations. As juveniles, Tph2^−/− mice displayed reduced social contacts, whereas ultrasonic vocalizations (USVs) were unchanged within same-sex same-genotype pairings. Interestingly, juvenile females vocalized more than males across genotypes. Sexually naive adult males were exposed to fresh male or female urine, followed by an interaction with a conspecific, and re-exposed to urine. Although Tph2^−/− mice showed normal sexual preference, they were hyper-aggressive towards their interaction partners and did not vocalize in response to sexual cues. These results highlight that central serotonin is essential for prosocial behaviour, especially USV production in adulthood, but not for sexual preference.     

Increased ethanol intake and preference in cyclin D2 knockout mice

Inhibitory effects of passive ethanol exposure on brain neurogenesis have been extensively documented in animal models. In contrast, a role of brain neurogenesis in ethanol self-administration has not been addressed, as yet. The aim of this study was to assess intake of, and preference for, ethanol solutions [2-16% (v/v)] in a mouse model of adult neurogenesis deficiency based on permanent knockout (KO) of cyclin D2 (Ccnd2). Wild type (WT) and Ccnd2 KO mice did not differ in 2% and 4% ethanol intake. The KO group consumed significantly more ethanol in g/kg when offered with 8% or 16% ethanol as compared with the WT controls. The WT and KO mice did not differ in 2% ethanol preference, but the KO group showed a significantly higher preference for 4-16% ethanol. Animal and human studies have suggested that the low level of response to the sedative/hypnotic effects of alcohol is genetically associated with enhanced alcohol consumption. However, in this study, there were no between-genotype differences in ethanol-induced loss of righting reflex. Previous reports have also suggested that high ethanol intake is genetically associated with the avidity for sweets and better acceptance of bitter solutions. However, the KO and WT mice consumed similar amounts of saccharin solutions and the KOs consumed less quinine (i.e. bitter) solutions as compared with the WTs. In conclusion, these results may indicate that Ccnd2 and, possibly, brain neurogenesis are involved in central regulation of ethanol intake in mice.     

Antidepressant Treatment Outcome Depends on the Quality of the Living Environment: A Pre-Clinical Investigation in Mice

Antidepressants represent the standard treatment for major depression. However, their efficacy is variable and incomplete. A growing number of studies suggest that the environment plays a major role in determining the efficacy of these drugs, specifically of selective serotonin reuptake inhibitors (SSRI). A recent hypothesis posits that the increase in serotonin levels induced by SSRI may not affect mood per se, but enhances neural plasticity and, consequently, renders the individual more susceptible to the influence of the environment. Thus, SSRI administration in a favorable environment would lead to a reduction of symptoms, while in a stressful environment might lead to a worse prognosis. To test this hypothesis, we treated C57BL/6 adult male mice with chronic fluoxetine while exposing them to either (i) an enriched environment, after exposure to a chronic stress period aimed at inducing a depression-like phenotype, or (ii) a stressful environment. Anhedonia, brain BDNF and circulating corticosterone levels, considered endophenotypes of depression, were investigated. Mice treated with fluoxetine in an enriched condition improved their depression-like phenotype compared to controls, displaying higher saccharin preference, higher brain BDNF levels and reduced corticosterone levels. By contrast, when chronic fluoxetine administration occurred in a stressful condition, mice showed a more distinct worsening of the depression-like profile, displaying a faster decrease of saccharin preference, lower brain BDNF levels and increased corticosterone levels. Our findings suggest that the effect of SSRI on depression-like phenotypes in mice is not determined by the drug per se but is induced by the drug and driven by the environment. These findings may be helpful to explain variable effects of SSRI found in clinical practice and to device strategies aimed at enhancing their efficacy by means of controlling environmental conditions.     

Genetics of gene expression characterizes response to selective breeding for alcohol preference

Numerous selective breeding experiments have been performed with rodents, in an attempt to understand the genetic basis for innate differences in preference for alcohol consumption. Quantitative trait locus (QTL) analysis has been used to determine regions of the genome that are associated with the behavioral difference in alcohol preference/consumption. Recent work suggests that differences in gene expression represent a major genetic basis for complex traits. Therefore, the QTLs are likely to harbor regulatory regions (eQTLs) for the differentially expressed genes that are associated with the trait. In this study, we examined brain gene expression differences over generations of selection of the third replicate lines of high and low alcohol‐preferring (HAP3 and LAP3) mice, and determined regions of the genome that control the expression of these differentially expressed genes (_deeQTLs). We also determined eQTL regions (_rveQTLs) for genes that showed a decrease in variance of expression levels over the course of selection. We postulated that _deeQTLs that overlap with _rveQTLs, and also with phenotypic QTLs, represent genomic regions that are affected by the process of selection. These overlapping regions controlled the expression of candidate genes (that displayed differential expression and reduced variance of expression) for the predisposition to differences in alcohol consumption by the HAP3/LAP3 mice.     

Serotonin content in different sections of the brain, liver, intestines and blood of rats predisposed and not predisposed to alcohol consumption

Experiments were made with white random-bred rats (males) exposed to ethanol. The content of serotonin measured by spectrofluorometry was higher in the hypothalamus, brain stem and intestine, and was lower in the thalamus, striatum liver and blood in the animals predisposed to voluntary alcohol consumption and with lateral position duration 62 +/- 18 min as compared with the animals not predisposed to alcohol consumption and with lateral position duration 196 +/- 23 min, the dose of ethanol being 4.5 g/kg i. p. Thirty minutes after ethanol administration in a dose of 2.5 g/kg i. p. to the alcohol-predisposed rats there was a lowering of the serotonin content in the hypothalamus and an increase in the thalamus, brain stem, liver and blood. Meanwhile in the rats not predisposed to alcohol consumption, the serotonin content rose in the hypothalamus, brain stem, liver, intestine and blood and fell in the thalamus and striatum. It is assumed that the serotoninergic system of the brain may play a role in the formation of "positive" or "negative" attitudes to ethanol in the population of white random-bred rats.     

Interstrain differences in the serotonin and 5-hydroxyindoleacetic acid levels in the postnatal ontogeny of C57BL/6J and BALB/cLac strain mice

The content of serotonin and 5-hydroxy-indole-acetic acid (5-HIAA) was determined in the brain stem and hemispheres in 1 and 3 months old C57BL/6J and BALB/cLac mice. The characteristic dynamics of serotonin and its metabolite content related to the age was found in different brain regions and proved to be similar in both the strains, but the rate of serotonin system development in C57BL/6J mice was higher than in BALB/c Lac mice. An intensive catabolism of serotonin, possibly, related to the reaction to new environment was noted in the newborn animals. Sex differences in the rate of serotonin system maturation and serotonin and 5-HIAA content were shown for 12--16 days old mice: 12 days old males were characterized by more intensive metabolism than females while 16 days old males had less serotonin than females.     

The involvement of brain 5-HT(1A)-receptors in genetically determined aggressive behavior

The hypothesis was tested that one of the critical mechanisms underlying genetically determined aggressiveness involves brain serotonin 5-HT(1A)-receptors. The expression of 5-HT(1A)-receptor mRNA in brain structures and functional correlate for 5-HT(1A)-receptors identified as 8-OH-DPAT-induced hypothermia were studied in Norway rats bred over the course of 59 generations for the low and high affective (defensive) aggressiveness with respect to man and in highly aggressive (offensive) MAO A-knockout mice (Tg8 strain). Considerable differences between the aggressive and the nonaggressive animals were shown. Agonist of 5-HT(1A)-receptor 8-OH-DPAT (0.5 mg/kg for rats and 2.0 mg/kg for mice, i.p.) produced a distinct hypothermic reaction in nonaggressive rats and mice and did not affect significantly the body temperature in aggressive animals. In aggressive rats, a significant reduction of the expression of 5-HT(1A)-receptor mRNA was found in the midbrain. In Tg8 mice, 5-HT(1A)-receptor mRNA level was increased in the frontal cortex and amygdala and not changed in the hypothalamus and the midbrain. The results provide support for the idea that brain 5-HT(1A)-receptors contribute to the genetically determined individual differences in aggressiveness.     

Modeling the periodically-changing predictable response to mutagen exposure in CBA/LacY mice in a successive inbred generations]

A hypothesis on the genetic determination of periodic fluctuations of the sensitivity to the mutagen thioTEPA in successive inbred generations of mice has been earlier put forward. This study was the initial stage of testing this hypothesis. The mouse strain CBA/LacY was divided into two substrains, which differed in the rate of generation change. As a result, two colonies of isogenic mice differing by 10-12 generations with respect to the inbred age were obtained. Both the rate and range of variations in the mutagen sensitivity (four generations per period of the cycle and 20-40% of cells with chromosome aberrations after the standard dose of 2.5 mg/kg of thioTEPA, respectively) in 19 generations of the "fast" substrain agreed with earlier data. The response of the "slow" substrain corresponded to the expected response of the "fast" substrain after the given number of generations. In the mice of generations F142 and F146 that lived simultaneously and differed in thioTEPA sensitivity, the effects of the carcinogen benzo[a]pyrene (BaP) were significantly different. The levels of these effects corresponded to the levels of the responses to thioTEPA. The data obtained agree with the hypothesis tested.     

Antibodies to catecholamines and serotonin during alcoholic intoxication in animals with different predispositions to the development of experimental alcoholism

Experiments on C57Bl/6, CBA and DBA/2 mice characterized by different preferences for ethanol have shown that during chronic administration of alcohol to animals with natural ethanol motivation (strain C57Bl/6) the level of antibodies to catecholamines and serotonin was increased on the 3rd month of ethanol intoxication, with the voluntary alcohol consumption in mice decreased by this time. On the contrary in mice rejecting alcohol (strains DBA/2, CBA) no antibodies to catecholamines and serotonin have been found.     

Mice Genetically Depleted of Brain Serotonin Display Social Impairments,Communication Deficits and Repetitive Behaviors: Possible Relevance to Autism

Autism is a complex neurodevelopmental disorder characterized by impaired reciprocal social interaction, communication deficits and repetitive behaviors. A very large number of genes have been linked to autism, many of which encode proteins involved in the development and function of synaptic circuitry. However, the manner in which these mutated genes might participate, either individually or together, to cause autism is not understood. One factor known to exert extremely broad influence on brain development and network formation, and which has been linked to autism, is the neurotransmitter serotonin. Unfortunately, very little is known about how alterations in serotonin neuronal function might contribute to autism. To test the hypothesis that serotonin dysfunction can contribute to the core symptoms of autism, we analyzed mice lacking brain serotonin (via a null mutation in the gene for tryptophan hydroxylase 2 (TPH2)) for behaviors that are relevant to this disorder. Mice lacking brain serotonin (TPH2−/−) showed substantial deficits in numerous validated tests of social interaction and communication. These mice also display highly repetitive and compulsive behaviors. Newborn TPH2−/− mutant mice show delays in the expression of key developmental milestones and their diminished preference for maternal scents over the scent of an unrelated female is a forerunner of more severe socialization deficits that emerge in weanlings and persist into adulthood. Taken together, these results indicate that a hypo-serotonin condition can lead to behavioral traits that are highly characteristic of autism. Our findings should stimulate new studies that focus on determining how brain hyposerotonemia during critical neurodevelopmental periods can alter the maturation of synaptic circuits known to be mis-wired in autism and how prevention of such deficits might prevent this disorder.     

On the role of brain serotonin system in the pathway from gene to behaviour

This paper concentrates on involvement of protein elements in the brain neurotransmitter serotonin system (key enzymes in serotonin metabolism and 5-HT(1A) receptors) in the genetic control of behaviour. The data were obtained using Norway rats selected for more that 50 generations for lack of aggressive response and for aggressive behaviour towards humans (fear-induced aggression), inbred mouse strains, and MAO A knockout mice. The review provides converging line of evidence that: 1) brain serotonin contributes to critical mechanism underlying genetically defined individual differences in aggressiveness, and 2) genes encoding pivotal enzymes in serotonin metabolism (tryptophan hydroxylase, MAO A) and 5-HT(1A) receptors belong to a group of genes that modulate aggressive behaviour.     

Cannabinoid-serotonin interactions in alcohol-preferring vs. alcohol-avoiding mice

Because cannabinoid and serotonin (5-HT) systems have been proposed to play an important role in drug craving, we investigated whether cannabinoid 1 (CB1) and 5-HT(1A) receptor ligands could affect voluntary alcohol intake in two mouse strains, C57BL/6 J and DBA/2 J, with marked differences in native alcohol preference. When offered progressively (3-10% ethanol) in drinking water, in a free-choice procedure, alcohol intake was markedly lower (approximately 70%) in DBA/2 J than in C57BL/6 J mice. In DBA/2 J mice, chronic treatment with the cannabinoid receptor agonist WIN 55,212-2 increased alcohol intake. WIN 55,212-2 effect was prevented by concomitant, chronic CB1 receptor blockade by rimonabant or chronic 5-HT(1A) receptor stimulation by 8-hydroxy-2-(di-n-propylamino)-tetralin, which, on their own, did not affect alcohol intake. In C57BL/6 J mice, chronic treatment with WIN 55,212-2 had no effect but chronic CB1 receptor blockade or chronic 5-HT(1A) receptor stimulation significantly decreased alcohol intake. Parallel autoradiographic investigations showed that chronic treatment with WIN 55,212-2 significantly decreased 5-HT(1A)-mediated [35S]guanosine triphosphate-gamma-S binding in the hippocampus of both mouse strains. Conversely, chronic rimonabant increased this binding in C57BL/6 J mice. These results show that cannabinoid neurotransmission can exert a permissive control on alcohol intake, possibly through CB1-5-HT(1A) interactions. However, the differences between C57BL/6 J and DBA/2 J mice indicate that such modulations of alcohol intake are under genetic control.