The inhibitory effects of the novel calcium antagonist Goe 5438 on calcium-dependent processes of excitation and contraction of single cardiomyocytes

Summary The calcium-antagonistic properties of the novel compound Goe 5438 have been studied in single cardiomyocytes from embryonic (chicken) and adult (guinea-pig) ventricles, in part in comparison with the inhibitory effects of the 1,4-dihydropyridine calcium antagonist nimodipine. Both substances block spontaneous action potentials and contractions of embryonic heart cells at about 0.1 mol/l. In collagenase-dispersed ventricular cardiomyocytes of guinea-pigs, stereospecific inhibition of the slow calcium current (I _ca ) by Goe 5438 was observed at 10 mol/l by means of voltage-clamp experiments. The (+)-enantiomer of Goe 5438 elicited a stronger inhibition of the slow inward current than the (–)-enantiomer. The frequency dependence of the inhibitory effect of Goe 5438 as well as that of nimodipine could be shown to be negligible in measurements of I _Ca and contractions, whereas the inhibitory influence of verapamil, verified in the same experimental arrangement, exhibited a distinct frequency dependence. With respect to a possible potential dependence of the inhibitory effect of Goe 5438 and nimodipine, it could be shown that a hyperpolarization during the course of application of either calcium antagonist produced recovery of the calcium-dependent excitation neither in adult nor in embryonic cells. In adult cardiomyocytes, the dependence of I _Ca on the membrane potential was not altered by Goe 5438. It is concluded that the mode of action of Goe 5438 resembles that of 1,4-dihydropyridine calcium antagonists.Supported by the Austrian Science Research Fund, grant No. 4662A preliminary report of some findings has been presented at the 28th Spring Meeting of Deutsche Gesellschaft für Pharmakologie und Toxikologie, Mainz 1987 (Wagner and Koidl 1987) Send offprint requests to B. Koidl     

Naloxone attenuates voluntary ethanol intake in rats selectively bred for high ethanol preference

The effect of naloxone on voluntary ethanol intake was examined in rats which were selectively bred for oral ethanol preference (High Alcohol Drinking or HAD line). Rats of the HAD line were treated with naloxone in doses of 0.05-18.0 mg/kg b.wt. before access to water alone or to a free-choice between a 10% (v/v) ethanol solution and water. Naloxone suppressed water intake when water was presented as the sole source of fluid. In contrast, naloxone produced a dose-dependent decrease in ethanol consumption, without altering water intake, when rats were given a free-choice between the ethanol solution and water. Selective suppression of ethanol consumption by naloxone was not attributable to changes in blood ethanol concentrations or ethanol elimination rates following naloxone treatment. It appears that although naloxone may attenuate the positively reinforcing properties of both ethanol and water, ethanol drinking is a subset of consummatory behaviors that is particularly sensitive to opioid receptor blockade. The results suggest that activation of the endogenous opioid system may be an important mechanism which serves to maintain continued ethanol drinking.     

Nicotine-induced behavioral disinhibition and ethanol preference correlate after repeated nicotine treatment

This study investigated the effects of repeated daily nicotine (0.35 mg/kg; 15 days) treatment on behavioral inhibition and locomotor activity in the elevated plus-maze and on voluntary ethanol consumption. When challenged with nicotine before the test, rats pretreated with repeated nicotine spent more time on and made more entries onto the open arms of an elevated plus-maze than did vehicle-pretreated animals. The ethanol preference and intake, measured during 3 h after a nicotine injection, was also higher in the nicotine-pretreated animals. In ethanol consumption experiments, there was a positive correlation between the % time and % entries made onto open arms vs. the ethanol preference and intake. However, no correlation between the total number of entries made in the elevated plus-maze and the measures of ethanol consumption was observed. These findings suggest that the ability of repeated nicotine administration to increase ethanol consumption is related to development of a nicotine-induced reduction of inhibitory control rather than development of locomotor sensitization.     

Effect of nociceptin on alcohol intake in alcohol-preferring rats

The present study investigated the effect of nociceptin (NC), the endogenous ligand of the opioid-like orphan receptor ORL1, on ethanol intake in genetically selected Marchigian Sardinian alcohol-preferring (msP) rats. Acute intracerebroventricular (ICV) injection of 250 or 500 ng/rat of NC, just before access to 10% ethanol (offered 2 h/day), significantly increased ethanol intake. Subchronic (7 days) ICV injection of 500 ng/rat of NC, given just before access to 10% ethanol (for 30 min/day), resulted in a progressive decrease in ethanol consumption. After the end of NC treatment, rats progressively recovered their usual ethanol intake. When NC, 500 or 1000 ng/rat, was tested versus the effect of ethanol in the place conditioning paradigm, NC significantly reduced the increase in time spent in the ethanol-paired compartment after conditioning. This finding suggests that NC reduces the rewarding properties of ethanol in msP rats; thus, they may respond to the acute NC administration by increasing their ethanol intake in an attempt to achieve the usual reinforcing effect of ethanol, whereas subchronic NC treatment may result in extinction of ethanol drinking. The results of the present study suggest that the brain NC mechanisms may represent an interesting target of pharmacological interventions for the treatment of alcoholism. Received: 11 August 1998/Final version: 15 October 1998     

Administration of leu-enkephalin impairs the acquisition of preference for ethanol

The effects of subcutaneous administration of leuenkephalin (LEU-E) (10, 100 and 300 µg/kg) and LEU-E (100 µg/kg) plus naloxone (2.5 mg/kg) on ethanol preference and fluid intake have been investigated in rats. Under our procedural conditions, rats develop ethanol preference through forced ethanol drinking (conditioning session). Preconditioning administration of LEU-E induced a reduction of later ethanol preference. Post-conditioning administration of LEU-E (10 and 100 µg/kg) also attenuated the development of ethanol preference. NX antagonized the effects of LEU-E on ethanol preference and fluid consumption in the two experimental procedures used, indicating an involvement of opioid receptors in the LEU-E-induced impairment of the acquisition of ethanol preference.Supported by a PFPI fellowship from the MEC     

Inhibition of nitric oxide formation reduces voluntary ethanol consumption in the rat

Brain nitric oxide is involved in the mechanisms that regulate ingestive behaviour. To test whether this compound plays a role in alcohol preference, we studied the effects of different doses ofN ^G-nitro-L-arginine (L-NO arg), an inhibitor of nitric oxide synthase (NOS), on voluntary consumption of ethanol and on blood alcohol levels produced by a single intraperitoneal dose of alcohol in the rat. L-NO arg produced a significant and dose-dependent reduction of ethanol intake (P<0.001) without influencing total fluid consumption or feeding behaviour. L-NO arg did not influence the kinetics of alcohol. Our data show that inhibition of nitric oxide formation accompanies reduction of ethanol intake and suggest a possible role for nitric oxide in ethanol self-administration.     

Hydrophobic properties of novel dihydronaphthyridine calcium antagonists and biological activity in porcine isolated cardiac and vascular smooth muscle

Summary Dihydronaphthyridine calcium antagonists are structurally related to the well known dihydropyridines and act in a similar manner. In order to establish the vascular selectivity of these compounds contractile force was evaluated in porcine isolated ventricular trabeculae and right coronary arteries. The dihydropyridine derivatives nisoldipine and nitrendipine as well as the structurally different compounds gallopamil and flunarizine were included for comparison purpose.All compounds studied exhibited dose-dependent negative inotropic and vasodilator activities. The negative inotropic potency of all dihydronaphthyridines, especially of the highly lipophilic bulky ester-variated derivatives (Goe 5584-A, Goe 5806-A) was comparable to that of flunarizine but was considerably less pronounced than that of nisoldipine, nitrendipine or gallopamil. By contrast, half-maximal vasodilator responses of the dihydronaphthyridines studied in coronary arteries being in the nanomolar concentration range were comparable to the dihydropyridines nisoldipine and nitrendipine, whereas the activity of gallopamil and flunarizine was less marked. On the other side the dihydronaphthyridines, especially the more hydrophilic 3-ethylester-4-(2-cyanophenyl) derivative Goe 5606, exerted an obvious biphasic concentration-response behaviour in coronary arteries leading to a high affinity relaxant process in subnanomolar concentrations, whereas the low affinity response could be observed at rather high concentrations (mostly > 1 µM). Mainly due to their relative uneffectiveness in cardiac muscle, vascular selectivity of the dihydronaphthyridines was considerably higher than that of the structurally related dihydropyridines nisoldipine resp. nitrendipine increasing in the following order: nitrendipine < nisoldipine < Goe 5606 < Goe 5438< Goe 5584-A < Goe 5806-A. By contrast, gallopamil exerted a slight cardiac preference, whereas the vascular selectivity of flunarizine was also pronounced. Negative inotropic potency of the dihydronaphthyridines decreased with increasing lipophilicity. However, an inverse relationship was found regarding the vasodilator activity of these compounds.Thus, modulation of the molecular structure, thereby affecting the physicochemical properties, may improve the vascular selectivity of the dihydronaphthyridines studied, when compared to dihydropyridine calcium antagonists.Parts of the results of this paper were presented on the spring meeting of the German Society of Pharmacology and Toxicology in Mainz 1989 (Werner et al. 1989) Send offprint requests to G. Werner at the above address     

A single injection of the kappa opioid antagonist norbinaltorphimine increases ethanol consumption in rats

Rationale Kappa opioid receptor (KOR) agonists interfere with the reinforcing effects of drugs of abuse. KOR agonists decrease heroin, cocaine, and ethanol self-administration, and block heroin and cocaine conditioned place preference (CPP) in rats. However, KOR agonists also produce emesis and dysphoria, making it difficult to determine if their effects on self-administration are due to an action on reward mechanisms or are secondary to the drug's direct aversive effects. Assuming that endogenous KOR ligands modulate circuits involved in drug and alcohol reward, selective KOR antagonists can be used to clarify these issues. If KOR antagonists increase drug self-administration then it is likely that endogenous KOR agonists directly modulate drug intake. Objectives To determine the effects of nor-BNI, the highly selective KOR antagonist, on ethanol consumption and CPP. Methods Thirty-eight male Lewis rats were given free access to ethanol until stable self-administration was achieved. Animals were then administered a single injection of nor-BNI (10 mg kg⁻¹) while ethanol intake was monitored. Results A single injection of nor-BNI induces a long-lasting increase in ethanol consumption, but does not induce a CPP. A high/low split revealed that this effect was primarily due to an increase in drinking in nor-BNI-treated high drinkers, which drank significantly more than saline-treated high drinkers and also drank significantly more when compared to their own pretreatment baseline. Conclusions Blocking the KOR system increases ethanol self-administration, suggesting that the decrease in self-administration seen with KOR agonists is due to a direct modulation of reward circuitry.     

Varenicline and cytisine: two nicotinic acetylcholine receptor ligands reduce ethanol intake in University of Chile bibulous rats

Rationale

Neuronal nicotinic acetylcholine receptors (nAChRs) are pharmacological targets that have recently been implicated in the reinforcing effects of many drugs of abuse, including ethanol. Varenicline and cytisine are nAChR partial agonists in clinical use as smoking cessation aids. However, their efficacies to reduce alcohol consumption have not been fully studied.

Objectives

This study aims to compare the effects of varenicline and cytisine on ethanol consumption by rats bred for many generations as high ethanol drinkers (UChB).

Results

Repeated dosing (0.5 or 1.0 mg/kg/day?i.p.) of varenicline or cytisine, for three consecutive days, to male UChB rats pre-exposed to 10 % (v/v) ethanol and water 24 h/day for 4 weeks, significantly reduced alcohol intake and preference of ethanol over water during 1- and 24-h ethanol access periods. This effect was specific for ethanol intake and was not observed for 0.2 % saccharin or water consumption. Varenicline appears to be more effective than cytisine, probably due to its more favorable pharmacokinetic and pharmacodynamic properties. Long-term use of both nAChRs ligands for more than 8–10 days induced tolerance to their effects on ethanol consumption.

Conclusions

This preclinical study in UChB rats demonstrated that both varenicline and cytisine reduce alcohol intake, with varenicline producing a greater and longer-lasting reduction than cytisine. However, dose adjustment will have to be considered as a possible way to counter tolerance arising after continued use.     

Stimulation of voluntary ethanol intake by cannabinoid receptor agonists in ethanol-preferring sP rats

RATIONALE: Recent studies have shown that the cannabinoid CB1 receptor antagonist, SR 141716, is capable of reducing voluntary ethanol intake in rodents, suggesting the involvement of the CB1 receptor in the neural circuitry mediating the positive reinforcing properties of ethanol. OBJECTIVES: The present study extended to the agonists the investigation on the pharmacological manipulation of ethanol intake by cannabinoid agents. METHODS: Selectively bred, Sardinian alcohol-preferring (sP) rats were offered ethanol and water under the two-bottle free choice procedure with unlimited access for 24 h/day. RESULTS: The acute administration of WIN 55,212-2 (0.5-2 mg/kg; IP) and CP 55,940 (3-30 microg/kg; IP) induced a significant, dose-dependent increase in ethanol intake. Conversely, water consumption and intake of regular food and a highly palatable sucrose solution were not affected by treatment with WIN 55,212-2 and CP 55,940. The stimulatory effect of WIN 55,212-2 and CP 55,940 on ethanol intake was completely prevented by administration of SR 141716 (0.3 mg/kg; IP) and the opioid receptor antagonist, naloxone (0.1 mg/kg; IP). CONCLUSIONS: Administration of WIN 55,212-2 and CP 55,940 promoted voluntary ethanol intake in sP rats. This effect was mediated by stimulation of the cannabinoid CB1 receptor and required the activation of the endogenous opioid system. The results of the present study add further support to the hypothesis that the cannabinoid CB1 receptor is part of the neural substrate regulating ethanol intake. These results are also discussed in terms of WIN 55,212-2 and CP 55,940 administration possibly fixing to a higher level the hedonic set-point mechanism regulating ethanol drinking behavior in sP rats.     

Reduction of voluntary ethanol consumption in alcohol-preferring Alko alcohol (AA) rats by desoxypeganine and galanthamine

The effects of desoxypeganine, an alkaloid from Peganum harmala L., and of galanthamine, an alkaloid from Galanthus nivalis L., on voluntary ethanol consumption were investigated in female Alko alcohol (AA) rats. Desoxypeganine-HCl reduced ethanol intake and ethanol preference dose-dependently at a dose range between 10 and 30 mg/kg body weight when given by gavage. Subcutaneous and intraperitoneal applications of desoxypeganine lead to even more pronounced decreases of ethanol intake and ethanol preference. The effects of desoxypeganine and galanthamine seem to be additive. A combination of both substances in doses, which were ineffective when administered alone, caused a significant decrease of ethanol preference. To exclude habituation to desoxypeganine treatment, the substance was given once daily over a period of 16 days. No decreases of the desoxypeganine effects on ethanol intake, total fluid intake, and ethanol preference were observed. This attenuation of ethanol preference combined with unchanged total fluid intake and food consumption represents a promising activity especially because no acquirement of tolerance after repeated administration was observed.     

Rewarding effects of ethanol and cocaine in µ opioid receptor-deficient mice

To investigate the role of mu opioid receptors in the reinforcing effects of psychotropic drugs, the voluntary ethanol intake and ethanol- and cocaine-induced conditioned place preference in mu opioid receptor-deficient mice and their wild-type counterpartners was tested. Moreover, dopamine D1 and D2 receptor binding was measured. It was found that ethanol intake was significantly lower in deficient mice. Conditioned place preference in wild-type animals was induced with 5.0 mg/kg cocaine and this dose was ineffective in the knockouts. In this group conditioned place preference occurred after injection of 10.0 mg/kg cocaine. Cocaine induced a similar increase in locomotor activity in both groups of mice. There was no difference in dopamine D1 receptor binding, whereas dopamine D2 receptor binding was significantly lower in the hippocampus of deficient animals. This suggests that interaction between opioid systems and dopaminergic systems may account for the differences in responding to the drugs.     

Effect of acute and chronic conditions of over-crowding on free choice ethanol intake in rats

Male albino rats of Wistar strain were exposed to overcrowding stress in two different groups for a period of seven days. One group of rats was kept under stress for six hours per day (acute stressed group) and the other group rats was kept under stress continuously (chronic stressed group). The effect of these acute and chronic stresses on voluntary alcohol (2% w/v) intake was monitored during the 7 days of stress exposure, and ethanol preference and total ethanol intake in terms of g/kg body weight were also studied. A significant increase in ethanol preference and ethanol intake was observed in one-day and 7 days chronic stressed group. No significant increase in ethanol intake was observed in acute stress. Thus a short lasting stressor may not increase ethanol-drinking behavior, whereas when animals were exposed to more intense stressor continuously for 7 days, an increase in voluntary drinking behavior may be seen.     

Repeated cycles of chronic intermittent ethanol exposure in mice increases voluntary ethanol drinking and ethanol concentrations in the nucleus accumbens

Rationale  This study examined the relationship between voluntary ethanol consumption and ethanol concentrations measured in the nucleus accumbens of ethanol dependent and nondependent C57BL/6J mice. Materials and methods  Mice were offered ethanol in a two-bottle choice; limited access paradigm and consummatory behavior was monitored with lickometers. After baseline intake stabilized, mice received chronic intermittent ethanol (EtOH group) or air (CTL group) exposure by inhalation (16 h/day for 4 days) and then resumed drinking. Brain ethanol levels during voluntary drinking were measured by microdialysis procedures and compared to brain ethanol concentrations produced during chronic intermittent ethanol vapor exposure. Results  Voluntary ethanol consumption progressively increased over repeated cycles of chronic intermittent ethanol exposure but remained unchanged in CTL mice. Analysis of lick patterns indicated EtOH mice consumed ethanol at a faster rate compared to CTL mice. The greater and faster rate of ethanol intake in EtOH mice produced higher peak brain ethanol concentrations compared to CTL mice, and these levels were similar to levels produced during chronic intermittent ethanol exposure. Conclusions  These results show that in this model of dependence and relapse drinking, dependent mice exhibit enhanced voluntary ethanol consumption relative to nondependent controls, which consequently produces blood and brain ethanol concentrations similar to those experienced during chronic intermittent ethanol exposure.     

Gamma-Vinyl GABA Decreases Voluntary Alcohol Consumption in Alcohol-Preferring AA Rats

The effect of a GABA transaminase inhibitor, gamma-vinyl GABA, on the voluntary alcohol consumption of alcohol-preferring AA rats produced by selective breeding for high alcohol preference, was studied. The rats were first trained to voluntarily drink 10% (v/v) ethanol solution until their ethanol consumption stabilized. Gamma-vinyl GABA (100, 200 or 500 mg/kg) was then injected intraperitoneally in three groups of rats, with saline-injected animals serving as a control group. The rats continued to have a free choice between 10% ethanol and plain tap water for five days after the injection, and their ethanol, water and food consumptions were measured daily. Gamma-vinyl GABA decreased ethanol consumption by the rats in a dose-dependent way. The consumption remained significantly decreased for three days in the two groups receiving the highest doses, with only a small concomitant tendency to decreased food intake. The results suggest that an increase in brain GABA concentration decreases alcohol drinking, possibly through potentiation of the pharmacological action of ethanol.     

Free-choice responding for ethanol versus water in alcohol preferring (P) and unselected Wistar rats is differentially modified by naloxone,bromocriptine, and methysergide

The role of opioids, dopamine and serotonin in ethanol (EtOH) reward and preference was investigated in non-deprived, Alcohol-Preferring (P), and genetically heterogenous Wistar rats. Operant responding for ethanol was initiated using sweet-solution substitution procedures. The rats were then trained in 30-min daily sessiosn to respond for ethanol (10% v/v) versus water under a two-lever, free-choice contingency. All testing was conducted in the absence of water and food deprivation or addition of sweeteners to the ethanol drinking solution. Rats of both strains developed stable preferences in responding for ethanol over water and consumed ethanol at quantities sufficient to produce pharmacologically relevant mean blood alcohol concentrations (P-Rats: 98±19.6 mg%; unselected Wistars: 41.7±8.5 mg%). InP-rats, systemic naloxone (NAL; 0.125, 0.25 and 0.5 mg/kg) pretreatments resulted in a dose-dependent suppression in responding for both ethanol and water, but did not alter ethanol preference (expressed as percent ethanol of total intake). In contrast, bromocriptine (BRO; 1.0, 2.0 and 4.0 mg/kg) produced a significant, dose-dependent shift in preference from ethanol toward water by inhibiting responding for ethanol while enhancing water consumption. Inunselected Wistar rats, NAL and BRO treatments produced changes in ethanol preference patterns similar to those observed in P-rats. However, compared to P-rats, these changes were smaller and not consistently dose dependent. No changes in ethanol preference and water or ethanol intake were observed with methysergide (MET; 2.5, 5.0, 10.0 mg/kg) in either strain of rat. Together, the results suggest a possible involvement of dopaminergic mechanisms in the reinforcing properties of ethanol. In contrast, the response decrements observed with naloxone may reflect a more general depression in consummatory behavior.This is publication number 5768 BCR from the Research Institute of Scripps Clinic, La Jolla, California     

Temporal studies of the inhibition of voluntary ethanol intake in the rat induced by intermittent ethanol treatment and some long term neurochemical consequences.

Male rats were injected with ethanol (groups 3 and 5; 2.0 g/kg i.p.) or saline (groups 2 and 4) once a week for 52 weeks. The rats had access to ethanol as a voluntary choice for 24 h either once 6 days after the injection (groups 2 and 3) or twice 3 and 6 days after the injection (groups 4 and 5). At the beginning of the treatment ethanol injections inhibited voluntary ethanol intake if tested 6 days later (groups 3 and 5), but a tolerance developed to this inhibition. During tolerance development the rats in group 5 also drank less ethanol on day 3 than on day 6. No corresponding behaviour was seen in group 4. Thus part of the tolerance was a gradual reduction of the duration of inhibition. During the evaluation period (25 weeks) after the treatment, ethanol exposure (20 weeks) consisted of a continuous choice between ethanol and water. Of different ethanol concentrations both ethanol-injected groups (3 and 5) took the same voluntary dose of ethanol independent of the offered concentration. After 5 weeks without ethanol all rats were killed and a number of neurochemical variables were determined. Compared with almost unexposed rats (group 1) changes were seen in inositol phospholipid breakdown, muscarinic binding sites in hippocampus, noradrenaline concentrations in frontal cortex, hippocampus and hypothalamus, dopamine concentration in frontal cortex and 5-hydroxytryptamine concentration in hypothalamus. In most cases the largest changes were seen in group 5. None of the variables had a constant relation to ethanol intake in the total population. However, significant correlations were found in some of the groups.     

An investigation of the mechanisms of action of 5-hydroxytryptamine in the suppression of ethanol intake

The effect of blockade of 5-hydroxytryptamine and norepinephrine uptake on voluntary ethanol consumption in rats was investigated. It was demonstrated that attenuation of ethanol intake occurred only as a result of treatment with specific 5-hydroxytryptamine uptake inhibitors. These results suggest that increasing the availability of central 5-hydroxytryptamine may in some way interfere with the positive reinforcing properties of ethanol. The second phase was designed to determine whether the attenuation of ethanol intake following blockade of 5-hydroxytryptamine uptake may be due to increased post-synaptic activity. Ethanol-preferring animals were pretreated with methergoline, a postsynaptic receptor blocker, followed by treatment with zimelidine, a 5-hydroxytryptamine uptake inhibitor. The results indicate that treatment with methergoline did not alter the zimelidineduced attenuation of ethanol intake. Based on these results it is suggested that blockade of 5-hydroxytryptamine uptake produces an attenuation of ethanol intake but not as a result of increased post-synaptic activity.     

Dopamine D3 Receptor Is Necessary for Ethanol Consumption: An Approach with Buspirone

Mesolimbic dopamine (DA) controls drug- and alcohol-seeking behavior, but the role of specific DA receptor subtypes is unclear. We tested the hypothesis that D₃R gene deletion or the D₃R pharmacological blockade inhibits ethanol preference in mice. D₃R-deficient mice (D₃R^−/−) and their wild-type (WT) littermates, treated or not with the D₃R antagonists SB277011A and U99194A, were tested in a long-term free choice ethanol-drinking (two-bottle choice) and in a binge-like ethanol-drinking paradigm (drinking in the dark, DID). The selectivity of the D₃R antagonists was further assessed by molecular modeling. Ethanol intake was negligible in D₃R^−/− and robust in WT both in the two-bottle choice and DID paradigms. Treatment with D₃R antagonists inhibited ethanol intake in WT but was ineffective in D₃R^−/− mice. Ethanol intake increased the expression of RACK1 and brain-derived neurotrophic factor (BDNF) in both WT and D₃R^−/−; in WT there was also a robust overexpression of D₃R. Thus, increased expression of D₃R associated with activation of RACK1/BDNF seems to operate as a reinforcing mechanism in voluntary ethanol intake. Indeed, blockade of the BDNF pathway by the TrkB selective antagonist ANA-12 reversed chronic stable ethanol intake and strongly decreased the striatal expression of D₃R. Finally, we evaluated buspirone, an approved drug for anxiety disorders endowed with D₃R antagonist activity (confirmed by molecular modeling analysis), that resulted effective in inhibiting ethanol intake. Thus, DA signaling via D₃R is essential for ethanol-related reward and consumption and may represent a novel therapeutic target for weaning.