Effects of subunit selective nACh receptors on operant ethanol self-administration and relapse-like ethanol-drinking behavior

Rationale and objectives  The sensitivity to ethanol central effects is partially determined by the subunit composition of brain nicotinic acetylcholine receptors (nAChRs). Thus, the effects of intraventral tegmental area (VTA) administration of the nicotinic subunit-specific antagonist, α-conotoxin MII (αCtxMII, α₃β₂*, β₃*, α₆*), were compared to those of systemic mecamylamine (MEC, an allosteric negative modulator of the nAChR), dihydro-β-erythroidine (DHβE, α₄β₂*), and methyllycaconitine (MLA, α₇*) to elucidate involvement of different subunits of nAChRs in operant ethanol self-administration and relapse-like activation of ethanol consumption after ethanol deprivation in rats. Methods  The effects of drugs were studied in rats trained for operant oral self-administration of ethanol (FR = 1). For ethanol deprivation, trained animals were subjected to a period of alcohol deprivation for 10 days. αCtxMII was given directly into the VTA through implanted permanent intracranial cannulae, whereas MEC, DHβE, and MLA were administered systemically. Results  αCtxMII reduced operant ethanol self-administration and blocked the deprivation-induced relapse-like ethanol consumption. MEC reduced operant ethanol self-administration and inhibited the deprivation-induced increase in alcohol consumption. DHβE did not alter ethanol self-administration in the lower-dose range but inhibited ethanol intake at a higher dose (4 mg/kg), although this effect might have been nonspecific. MLA failed to block self-administration of ethanol and relapse-like drinking after deprivation. Conclusions  Our results indicate that nAChRs are involved in the modulation of operant alcohol self-administration and relapse-like alcohol drinking behavior in rats. Our observations support the working hypothesis that systemically active selective ligands for nAChR α₃β₂*, β₃, and/or α₆* receptor subunits might be of therapeutic value for the treatment of alcoholism.     

Effect of ganaxolone and THIP on operant and limited-access ethanol self-administration

Recent evidence suggests that GABA(A) receptor ligands may regulate ethanol intake via effects at both synaptic and extrasynaptic receptors. For example, the endogenous neurosteroid, allopregnanolone (ALLO) has a similar pharmacological profile as ethanol, and it alters ethanol intake in rodent models. Additionally, recent evidence suggests that δ-subunit-containing extrasynaptic GABA(A) receptors may confer high sensitivity to both ethanol and neurosteroids. The purpose of the present study was to determine the effects of ganaxolone (GAN; an ALLO analog) and gaboxadol (THIP; a GABA(A) receptor agonist with selectivity for the extrasynaptic δ-subunit) on ethanol intake, drinking patterns, and bout characteristics in operant and limited-access self-administration procedures. In separate studies, the effects of GAN (0-10 mg/kg) and THIP (2-16 mg/kg) were tested in C57BL/6J male mice provided with 2-h access to a two-bottle choice of water or 10% ethanol or trained to respond for 30 min of access to 10% ethanol. GAN had no overall significant effect on operant ethanol self-administration, but tended to decrease the latency to consume the first bout. In the limited-access procedure, GAN dose-dependently decreased ethanol intake. THIP dose-dependently decreased ethanol intake in both paradigms, altering both the consummatory and appetitive processes of operant self-administration as well as shifting the drinking patterns in both procedures. These results add to literature suggesting time-dependent effects of neurosteroids to promote the onset, and to subsequently decrease, ethanol drinking behavior, and they support a role for extrasynaptic GABA(A) receptor activation in ethanol reinforcement.     

The induction of oral ethanol self-administration by contingent ethanol delivery

The necessity of delivering a highly reinforcing stimulus (20% sucrose) contingent upon ethanol consumption in order to induce ethanol self-administration in free-feeding rats was investigated. Rats water deprived for 12-16 h were placed in an environment in which ethanol drinking resulted in the presentation of ethanol. This procedure was successful in inducing and maintaining ethanol self-administration over concentrations of 5-20% (v/v). Compared to a group of rats initially reinforced for drinking ethanol with sucrose presentation, contingent ethanol delivery resulted in greater ethanol self-administration behavior. When 20% ethanol was available the group trained with ethanol had average intake of 0.91 g/kg, whereas the group trained with sucrose had a mean intake of 0.69 g/kg in a 30-min session. The results suggest that ethanol's reinforcing properties are sufficient to establish ethanol self-administration within the context of the inducing environment.     

The effects of microinjection of d-amphetamine into the n. accumbens during the late maintenance phase of an ethanol consumption bout.

The microinjection of d-amphetamine into the n. accumbens of rats, prior to the start of an operant ethanol self-administration session, increases operant behavior and the amounts of ethanol presented as the reinforcer. Although this effect could result by blocking termination processes regulating a consummatory bout, it could also be a result of enhancing the stimulus control regulating the maintenance of a drinking bout. To explore this issue, rats were trained to self-administer 10% ethanol in an operant situation. Following establishment of stable behavior, they were surgically instrumented so that the n. accumbens could be microinjected with d-amphetamine during a drinking bout, without having to handle the animal. The microinjection of d-amphetamine in the rats self-administering ethanol at the late phase of the drinking bout resulted in a prolonged bout and increased self-administration. During extinction testing, a reinstatement of responding was found following the amphetamine microinjection. The data suggest the most likely action of the amphetamine microinjection was to alter stimulus control factors, which normally regulate the maintenance of drinking, thereby prolonging the bout and increasing intake.     

Inhibition of orexin-1/hypocretin-1 receptors inhibits yohimbine-induced reinstatement of ethanol and sucrose seeking in Long–Evans rats

RATIONALE: Previous studies have shown that orexin-1/hypocretin-1 receptors play a role in self-administration and cue-induced reinstatement of food, drug, and ethanol seeking. In the current study, we examined the role of orexin-1/hypocretin-1 receptors in operant self-administration of ethanol and sucrose and in yohimbine-induced reinstatement of ethanol and sucrose seeking. MATERIALS AND METHODS: Rats were trained to self-administer either 10% ethanol or 5% sucrose (30 min/day). The orexin-1 receptor antagonist SB334867 (0, 5, 10, 15, 20 mg/kg, i.p.) was administered 30 min before the operant self-administration sessions. After these experiments, the operant self-administration behaviors were extinguished in both the ethanol and sucrose-trained rats. Upon reaching extinction criteria, SB334867 (0, 5, 10 mg/kg, i.p.) was administered 30 min before yohimbine (0 or 2 mg/kg, i.p.). In a separate experiment, the effect of SB334867 (0, 15, or 20 mg/kg, i.p.) on general locomotor activity was determined using the open-field test. RESULTS: The orexin-1 receptor antagonist, SB334867 (10, 15 and 20 mg/kg) decreased operant self-administration of 10% ethanol but not 5% sucrose self-administration. Furthermore, SB334867 (5 and 10 mg/kg) significantly decreased yohimbine-induced reinstatement of both ethanol and sucrose seeking. SB334867 did not significantly affect locomotor activity measured using the open-field test. CONCLUSIONS: The results suggest that inhibition of OX-1/Hcrt-1 receptors modulates operant ethanol self-administration and also plays a significant role in yohimbine-induced reinstatement of both ethanol and sucrose seeking in rats.     

Erucine suppresses ethanol intake and preference in alcohol-preferring Fawn-Hooded rats

Aim： Brucine （BRU） extracted from the seeds of Strychnos nux-vomica L is glycine receptor antagonist. We hypothesize that BRU may modify alcohol consumption by acting at glycine receptors, and evaluated the pharmacodynamic profiles and adverse effects of BRU in rat models of alcohol abuse. Methods： Alcohol-preferring Fawn-Hooded （FH/Wjd） rats were administered BRU （10, 20 or 30 mg/kg, sc）. The effects of BRU on alcohol consumption were examined in ethanol 2-bottle-choice drinking paradigm, ethanol/sucrose operant self-administration paradigm and 5-d ethanol deprivation test. In addition, open field test was used to assess the general locomotor activity of FH/Wjd rats, and conditioned place preference （CPP） was conducted to assess conditioned reinforcing effect. Results： In ethanol 2-bottle-choice drinking paradigm, treatment with BRU for 10 consecutive days dose-dependently decreased the ethanol intake associated with a compensatory increase of water intake, but unchanged the daily total fluid intake and body weight. In ethanol/sucrose operant self-administration paradigms, BRU （30 mg/kg） administered before each testing session significantly decreased the number of lever presses for ethanol and the ethanol intake, without affecting the number of sucrose （10%） responses, total sucrose intake, and the number of lever presses for water. Acute treatment with BRU （30 mg/kg） completely suppressed the deprivation-induced elevation of ethanol consumption. Treatment with BRU （10, 20, and 30 mg/kg） did not alter locomotion of FH/Wjd rats, nor did it produce place preference or aversion. Conclusion： BRU selectively decreases ethanol consumption with minimal adverse effects. Therefore, BRU may represent a new pharmacotherapy for alcoholism.     

Dopamine D3 receptor knockout mice and the motivational effects of ethanol

Dopamine D3 receptors have been implicated in the behavioral effects of abused drugs including ethanol. The present experiments characterized the acquisition of ethanol-induced place conditioning and ethanol self-administration in D3 knockout (D3 KO) mice compared with C57BL/6J (C57) mice. For place conditioning, D3 KO and C57 mice received six pairings of a tactile stimulus with ethanol (3 g/kg i.p.). D3 KO mice showed higher basal locomotor activity levels in comparison with the C57 mice during conditioning. Ethanol produced similar magnitudes of conditioned place preference in both genotypes. In a two-bottle drinking procedure, mice of each genotype received 24 h access to water and either 3% or 10% v/v ethanol. No difference was noted between D3 KO and C57 mice in either consumption or preference. In an operant self-administration procedure using 23 h sessions, D3 KO and C57 mice received access to 10% v/v ethanol on an FR4 schedule of reinforcement, food on an FR1 schedule of reinforcement and water from a sipper tube. D3 KO and C57 mice had similar response rates of ethanol and food as well as similar water intakes. Overall, these results indicate that elimination of D3 receptor function has little influence on ethanol reward or intake.     

Operant, oral alcoholic beer self-administration by C57BL/6J mice: effect of BHF177, a positive allosteric modulator of GABAB receptors

Rationale

With its high palatability, near-beer has been successfully used in rats as a vehicle to induce ethanol oral self-administration.

Objectives

The study aimed to develop an operant model of oral alcoholic beer self-administration promoting a stable intake of pharmacologically relevant amounts of ethanol in free-feeding C57BL/6J mice. It also aimed to assess the model's predictive validity by evaluating the influence of baclofen, a GABA_B agonist, and BHF177, a GABA_B positive allosteric modulator, on alcoholic beer self-administration.

Methods

Mice were trained to self-administer, under a fixed ratio three schedule of reinforcement, 10?μl of beer containing increasing ethanol concentrations (0–18% v/v) in daily 30-min sessions. The effects on motor coordination (rotarod), locomotor activity (open field, automated cages) and anxiety-like behavior (elevated plus maze, EPM) were examined. Baclofen (1.25–5?mg/kg, intraperitoneal, i.p.) and BHF177 (3.75–30?mg/kg, i.p.) were used to see the effects on 9% alcoholic beer and near-beer self-administration.

Results

Near-beer stably maintained operant oral self-administration in mice. Adding ethanol to near-beer reduced the number of active lever presses, while the corresponding amount of ethanol self-administration increased (0.8–1.0?g/kg/session). Motor impairment was observed when more than 1.3?g/kg/session of ethanol was self-administered with beer and slight but consistent hyperlocomotion with more than 0.9–1.0?g/kg/session. BHF177 (15?mg/kg) preferentially reduced 9% alcoholic beer self-administration, while the higher dose (30?mg/kg)—like baclofen 5?mg/kg—also reduced near-beer self-administration.

Conclusions

The operant model of oral alcoholic beer self-administration in C57BL/6J mice should prove useful for studying ethanol-reinforced behaviors and to identify candidate compounds for the pharmacological management of alcohol addiction.     

The mGluR5 antagonist MPEP decreases operant ethanol self-administration during maintenance and after repeated alcohol deprivations in alcohol-preferring (P) rats

Rationale Recent research indicates that blockade of mGluR5 modifies the reinforcing properties of ethanol.Objectives The present studies examined the effects of mGluR5 receptor blockade in a genetic model of high ethanol intake, the alcohol-preferring (P) rat, on the maintenance of operant ethanol self-administration. In addition, we determined the effect of 2-methyl-6-(phenylethyl)-pyridine (MPEP) on the repeated alcohol deprivation effect.Methods Twelve male (P) rats were trained in experimental sessions to self-administer 10% w/v ethanol via a sucrose-fading procedure. After the establishment of operant ethanol self-administration, subjects were treated with various metabotropic glutamate receptor (mGluR) subtype antagonists immediately prior to experimental sessions: the mGluR5 antagonist MPEP (1, 3, and 10 mg/kg); the mGluR2–3 antagonist LY-341495 (1, 3, and 10 mg/kg); and the mGluR1 antagonist CPCCOEt (1, 3, and 10 mg/kg). After determining the role of mGluR5 in the maintenance of operant ethanol self-administration, we examined the role of this receptor in relapse following repeated periods of alcohol deprivation by depriving subjects of ethanol exposure for three 2-week deprivation periods.Results The mGluR5 antagonist MPEP dose-dependently decreased operant ethanol self-administration. In addition, rats that received saline immediately prior to repeated alcohol deprivation sessions self-administered ethanol at increasing levels that were above those achieved in the last operant-conditioning session prior to the initial 2-week deprivation period. This repeated alcohol deprivation effect was prevented in subjects pretreated with MPEP (10 mg/kg).Conclusions These findings suggest that mGluR5 receptors may modulate both the maintenance of operant ethanol self-administration and abstinence-induced increases in ethanol intake.     

Reinstatement of ethanol and sucrose seeking by the neurosteroid allopregnanolone in C57BL/6 mice

Rationale  Recent work in our laboratory documented that the “sipper” method of operant ethanol self-administration produced high ethanol intake and blood ethanol concentrations as well as the typical extinction “burst” in responding under nonreinforced conditions in male C57BL/6 mice. However, the neurochemical basis for reinstatement of responding following extinction has not been examined in mice with this model. Objectives  Based on findings that the GABAergic neurosteroid allopregnanolone (ALLO) significantly increased the consummatory phase of ethanol self-administration, the present study determined the effect of ALLO on the reinstatement of extinguished ethanol-seeking behavior and compared this effect to the reinstatement of responding for sucrose reward. Materials and methods  Separate groups of male C57BL/6 mice were trained to lever press for access to a 10% ethanol (10E) or a 5% sucrose (5S) solution. A single response requirement of 16 presses (RR16) on an active lever resulted in 30 min of continuous access to the 10E or 5S solution. After the animals responded on the RR16 schedule for 14 weeks, mice were exposed to 30 min extinction sessions where responding had no scheduled consequence. Once responding stabilized below the preextinction baseline, mice received an intraperitoneal injection of ALLO (0, 3.2, 5.6, 10, or 17 mg/kg) 15 min prior to the extinction session in a within-subjects design. Results  ALLO produced a dose-dependent increase in responding under nonreinforced conditions in both the 10E and 5S groups. Additional work documented the ability of a conditioned cue light or a compound cue (light+lever retraction) to reinstate nonreinforced responding on the previously active lever. Conclusions  These findings definitively show that conditioned cues and priming with ALLO are potent stimuli for reinstating both ethanol- and sucrose-seeking behavior in C57BL/6 mice.     

Lack of operant ethanol self-administration in dopamine D2 receptor knockout mice

RATIONALE: Dopamine D2 receptors are postulated to play an important role in modulating the reinforcing effects of abused drugs including ethanol. OBJECTIVES: This experiment examined operant ethanol self-administration in dopamine D2 receptor knockout (KO) mice and wild-type (WT) mice using a continuous access procedure. METHODS: Adult male KO and WT mice were trained in 30-min sessions to perform a lever press response for access to 10% v/v ethanol. After training, the mice were placed in test chambers on a continuous (23 h/day) basis with access to food (one lever press, i.e., FR1), 10% v/v ethanol (four lever presses, i.e., FR4), and water from a sipper tube (phase 1). After 30 consecutive sessions, response patterns were determined for 0, 5, 10, 20 and 30% v/v ethanol (phase 2). Saccharin (0.2% w/v) was subsequently added to the ethanol mixture and responding was examined for 0, 5, 10 and 20% ethanol (phase 3). RESULTS: During phase 1, WT mice displayed higher ethanol-lever responding compared to KO mice. Food lever responding and water intake was the same in both genotypes. During phase 2, WT mice displayed concentration-dependent ethanol lever responding, whereas KO mice responded at low rates regardless of ethanol concentration. WT mice also responded more for food compared to KO mice. Each genotype showed similar water intakes except at the 20% ethanol concentration, where WT mice had lower intakes. During phase 3, WT mice continued to show higher responding for all concentrations including saccharin alone. WT mice also continued to respond more for food compared to KO mice, but drank less water. In each phase, WT mice displayed episodic (bout) responding on the ethanol lever. KO mice did not respond for ethanol in bouts. CONCLUSIONS: Reduced responding in the KO mice for several reinforcers including ethanol indicates a more general role for dopamine D2 receptors in motivated responding rather than a specific role in ethanol reinforcement.     

Effect of the cannabinoid CB1 receptor antagonist SR-141716A on ethanol self-administration and ethanol-seeking behaviour in rats

Rationale It has been suggested that endocannabinoid mechanisms are involved in the control of ethanol consumption. Objectives The aims of the present study were (1) to evaluate the role of the endocannabinoid system in the control of operant ethanol self-administration and in the reinstatement of ethanol seeking, when induced by stress or conditioned stimuli and (2) to offer new insights on the specificity of such a role. Methods Rats were administered intraperitoneally with the selective cannabinoid CB₁ receptor antagonist, SR-141716A, 30 min before operant self-administration or reinstatement sessions. Two schedules of reinforcement, the fixed-ratio 1 (FR1) and the progressive ratio (PR), were used to study 10% (w/v) alcohol and 5.0% sucrose self-administration. NaCl (2% w/v) intake in sodium-depleted rats was studied only under the FR1 program. Results Treatment with SR-141716A (0.3–3.0 mg/kg) significantly attenuated FR1 alcohol self-administration and lowered the break point for ethanol under PR. SR-141716A also markedly inhibited the reinstatement of alcohol seeking elicited by presentation of cues predictive of drug availability. Conversely, the cannabinoid antagonist did not prevent the reinstatement of alcohol seeking induced by foot-shock stress. Lever pressing for sucrose under FR1 and PR schedules was also significantly decreased by SR-141716A treatment, whereas the drug modestly and only at the highest dose decreased 2% NaCl self-administration. Conclusions Results emphasize that endocannabinoid mechanisms play a major role in the control of ethanol self-administration and in the reinstatement of conditioned ethanol seeking. However, these effects extend to the control of operant behaviours motivated by natural rewards (i.e. sucrose). On the other hand, SR-141716A only weakly reduces NaCl self-administration in sodium-depleted rats, in which salt intake is largely controlled by homeostatic mechanisms. Overall, these observations demonstrate that the inhibition of operant behaviour following blockade of CB₁ receptors by SR-141716A is linked to a reduction of reward-related responding and is not related to drug-induced motor deficits.     

Reduction of oral ethanol self-administration in rats by monoamine oxidase inhibitors.

Evidence for a role of dopamine and serotonin in the control of ethanol intake in animals suggests that monoamine oxidase (MAO) inhibitors, which increase the synaptic availability of serotonin and dopamine by blocking their metabolism, might have efficacy in the treatment of alcohol dependence. The aim of the present study was, therefore, to evaluate several MAO inhibitors for their capacity to affect ethanol self-administration in rats trained to self-administer ethanol (10% v/v) orally in a free-choice two-lever operant task. The nonselective and irreversible MAO inhibitors, phenelzine (3-10 mg/kg), tranylcypromine (1-3 mg/kg), and nialamide (30 mg/kg), decreased rates of responding maintained by ethanol reinforcement. The reversible MAO-A inhibitor, befloxatone (0.3-3 mg/kg), and the irreversible MAO-A inhibitor, clorgyline (10-30 mg/kg), also reduced ethanol self-administration. However, befloxatone-induced effects leveled off at a 50% decrease. The irreversible MAO-B inhibitors, pargyline (30 mg/kg) and l-deprenyl (3-10 mg/kg) also decreased responding maintained by ethanol reinforcement; these results are consistent with previous findings that both drugs decreased ethanol intake in mice. In conclusion, the present results showing that several MAO inhibitors decreased ethanol self-administration in rats are consistent with previous findings that synaptic levels of serotonin and dopamine play a critical role in the control of ethanol self-administration.     

The nicotinic acetylcholine receptor antagonist mecamylamine prevents escalation of cocaine self-administration in rats with extended daily access

Rationale Escalation from moderate to excessive drug intake is a hallmark of human addiction that can be modeled in rats by giving them longer daily access time to self-administer cocaine. Nicotine and cocaine are commonly coabused drugs in humans and recent work in animals suggests that activation of nicotinic acetylcholine receptors (nAChR) can increase cocaine self-administration. Objectives Determine the role of nAChR in the escalation of cocaine self-administration. Methods Control rats self-administered cocaine (0.75 mg/kg/infusion) for either 1 or 6 h per day. Experimental groups had the nAChR antagonist mecamylamine (MEC) added to the cocaine solution for 5 days after the transition from short (1 h per day) to long access (6 h per day) for cocaine self-administration. After 5 days, MEC was removed from the cocaine solution. Results Control rats and rats that received a low dose of MEC (7 μg/infusion) with cocaine increased their average hourly intake over 5 days of 6 h per day cocaine access. Rats that received a higher dose of MEC (70 μg/infusion) did not increase their intake of cocaine during 6 h access but continued to self-administer cocaine. When MEC was removed, this group showed an escalation in cocaine self-administration. MEC did not alter cocaine intake in a group that had continuous 1 h access. Conclusions Antagonism of nAChRs during the initial exposure to extended cocaine self-administration access time prevented escalation of, but did not eliminate, drug intake. These findings indicate that MEC-sensitive nAChRs are critical for determining cocaine intake as a function of longer access time.     

Neuropeptide Y administration into the third ventricle does not increase sucrose or ethanol self-administration but does affect the cortical EEG and increases food intake

RATIONALE: Several studies have provided indirect evidence that neuropeptide Y (NPY) may play a role in the regulation of ethanol consumption. However, the direct effects of central NPY administration on ethanol drinking are unclear. OBJECTIVE: This study examined the effects of NPY on ethanol, sucrose, and food consumption as well as its concomitant effects on the cortical EEG. METHODS: Wistar rats were implanted with cortical recording electrodes and a cannula in the third ventricle after using a sucrose substitution procedure to establish ethanol self-administration. NPY (0-15 microg/3.0 microl) was infused into the third ventricle prior to drinking sessions, when 10% ethanol (10E), 2% sucrose (2S), 0.5% sucrose (0.5S), or food were available. Behavior and cortical EEG were monitored during the sessions. RESULTS: NPY had no effect on the intake of 10E, 2S, or 0.5S, but NPY (15 microg/3.0 microl) significantly increased food intake. Under baseline drinking conditions, EEG power in the 6-8 Hz range was significantly greater when 2S was consumed compared to 10E. NPY decreased power in the 8-16 Hz range, decreased peak frequency in the 6-8 Hz range, and increased peak frequency in the 32-50 Hz range when 10E or 2S was available. CONCLUSIONS: These data suggest that NPY administration into the third ventricle preferentially regulates feeding compared to ethanol or sucrose drinking. In addition, since NPY significantly altered the cortical EEG in the absence of effects on ethanol and sucrose consumption, these data may indicate that NPY's cortical EEG effects are more related to its sedative or anxiolytic properties, rather than any effect on consumption.     

Kappa-opioid receptor modulation of accumbal dopamine concentration during operant ethanol self-administration

Our study examined ethanol self-administration and accumbal dopamine concentration during kappa-opioid receptor (KOPr) blockade. Long-Evans rats were trained to respond for 20 min of access to 10% ethanol (with sucrose) over 7 days. Rats were injected s.c. with the long-acting KOPr antagonist, nor-binaltorphimine (NOR-BNI; 0 or 20 mg/kg) 15-20 h prior to testing. Microdialysis revealed a transient elevation in dopamine concentration within 5 min of ethanol access in controls. NOR-BNI-treated rats did not exhibit this response, but showed a latent increase in dopamine concentration at the end of the access period. The rise in dopamine levels correlated positively with dialysate ethanol concentration but not in controls. NOR-BNI did not alter dopamine levels in rats self-administering 10% sucrose. The transient dopamine response during ethanol acquisition in controls is consistent with previous results that were attributed to ethanol stimulus cues. The altered dopamine response to NOR-BNI during ethanol drinking suggests that KOPr blockade temporarily uncovered a pharmacological stimulation of dopamine release by ethanol. Despite these neurochemical changes, NOR-BNI did not alter operant responding or ethanol intake, suggesting that the KOPr is not involved in ethanol-reinforced behavior under the limited conditions we studied.     

Ivermectin reduces alcohol intake and preference in mice

The high rate of therapeutic failure in the management of alcohol use disorders (AUDs) underscores the urgent need for novel and effective strategies that can deter ethanol consumption. Recent findings from our group showed that ivermectin (IVM), a broad-spectrum anthelmintic with high tolerability and optimal safety profile in humans and animals, antagonized ethanol-mediated inhibition of P2X4 receptors (P2X4Rs) expressed in Xenopus oocytes. This finding prompted us to hypothesize that IVM may reduce alcohol consumption; thus, in the present study we investigated the effects of this agent on several models of alcohol self-administration in male and female C57BL/6 mice. Overall, IVM (1.25-10 mg/kg, intraperitoneal) significantly reduced 24-h alcohol consumption and intermittent limited access (4-h) binge drinking, and operant alcohol self-administration (1-h). The effects on alcohol intake were dose-dependent with the significant reduction in intake at 9 h after administration corresponding to peak IVM concentrations (C(max)) in the brain. IVM also produced a significant reduction in 24-h saccharin consumption, but did not alter operant sucrose self-administration. Taken together, the findings indicate that IVM reduces alcohol intake across several different models of self-administration and suggest that IVM may be useful in the treatment of AUDs.     

Milk consumption during adolescence decreases alcohol drinking in adulthood

Early onset of alcohol consumption increases the risk for the development of dependence. Whether adolescent consumption of other highly palatable solutions may also affect alcohol drinking in adulthood is not known. The purpose of this study was to determine the effects of adolescent consumption of four solutions: water, sucrose, sucrose-milk and milk on ethanol drinking in adult rats. Rats had limited access to one of the four solutions from day PND 29 to PND 51 and were subsequently trained to consume ethanol (E) using a sucrose (S) fade-out procedure. Adolescent consumption of sucrose and sucrose-milk solutions increased intake of 2.5% E when it was combined with 10% S but it had no effect on the drinking of 10% E alone. Adolescent consumption of milk and sucrose-milk significantly decreased the intake of 10% E when it was combined with 10% S, and milk significantly reduced 10% E consumption alone and when it was combined with 5% S. Adolescent exposure to the sucrose-milk and sucrose solutions was also found to increase sucrose and sucrose-milk consumption. Our findings suggest adolescent exposure to sucrose increases, whereas, exposure to milk reduces ethanol consumption in adult rats. Our results may provide a new theoretical approach to the early prevention of alcoholism.     

Nonselective suppression of operant ethanol and sucrose self-administration by the mGluR7 positive allosteric modulator AMN082

Emerging evidence indicates that specific metabotropic glutamate receptors (mGluRs) modulate ethanol self-administration. In general, inhibition of glutamate transmission through blockade of postsynaptic mGluRs, or activation of presynaptic mGluRs, inhibits ethanol self-administration. The goal of this preclinical study was to further characterize mGluR regulation of ethanol self-administration by examining effects of AMN082, an allosteric positive modulator of presynaptic mGluR7 activity. Separate groups of C57BL/6J male mice were trained to self-administer ethanol or sucrose on a fixed-ratio 4 schedule of reinforcement during 1 h sessions. On test days, mice were pretreated with AMN082 (0, 1.0, 3.0, 5.6, or 10 mg/kg) 30 min prior to self-administration sessions. Functional specificity and activity was examined by testing the effects of AMN082 (0-10 mg/kg) on open-field locomotor activity and HPA axis function as measured by plasma corticosterone levels. AMN082 (10 mg/kg) produced a significant reduction in ethanol and sucrose reinforced responding, and inhibited locomotor activity. Plasma corticosterone levels were significantly increased following AMN082 (5.6 and 10 mg/kg) suggesting a dose-dependent dissociation between the behavioral and hormonal effects of the compound. These data suggest that activation of mGluR7 by AMNO82 produces nonspecific reductions in motivated behavior that are associated with negative effects on motor activity.     

5-HT(3A) receptor subunit is required for 5-HT3 antagonist-induced reductions in alcohol drinking.

The ionotropic serotonin subtype-3 (5-HT3) receptor has emerged as a potential therapeutic target in the treatment of alcohol abuse and alcoholism because selective pharmacological antagonists reduce alcohol consumption in preclinical and clinical models. 5-HT binds to the extracellular N-terminus of the 5-HT(3A) receptor subunit but receptor activation is also enhanced by distinct allosteric sites, which indicates the presence of other receptor subunits. It is not known if specific molecular subunits of the 5-HT3 receptor modulate alcohol drinking. To address this issue, we characterized acute locomotor response to alcohol and alcohol consumption in a two-bottle home-cage procedure by congenic C57BL/6J mice with a targeted deletion of the 5-HT(3A) receptor subunit gene. 5-HT(3A)-null mice did not differ from wild-type littermate controls on measures of spontaneous locomotor activity, habituation to a novel environment, or locomotor response to ethanol (0, 0.5, 1, or 2 g/kg). Moreover, null mice did not differ from controls on measures of ethanol (2-10%) intake and preference during or after a two-bottle home-cage sucrose fading procedure. Systemic administration of the 5-HT3 antagonist LY-278,584 (0-10 mg/kg) decreased intake of both sweetened (2% sucrose+10% ethanol) and unsweetened (10% ethanol) ethanol in wild-type mice only. These findings indicate that reduction of alcohol drinking produced by 5-HT3 antagonism is dependent on the presence of 5-HT(3A)-containing receptors.