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Approximately 30% of current drinkers in the United States drink excessively, and are referred to as problem/hazardous drinkers. These individuals, who may not meet criteria for alcohol abuse or dependence, comprise binge, heavy drinkers, or both. Given their high prevalence, interventions that reduce the risk of binge and heavy drinking have important public health implications. Impulsivity has been repeatedly associated with excessive drinking in the clinical literature. As impulsivity is correlated with, and may play a critical role in, the initiation and maintenance of excessive drinking, this behavior may be an important target for therapeutic intervention. Hence, a better understanding of pharmacological treatments capable of attenuating excessive drinking and impulsivity may markedly improve clinical outcomes. The high-alcohol-preferring (HAP) mice represent a strong rodent model to study the relationship between impulsivity and excessive alcohol drinking, as recent evidence indicates they consume high levels of alcohol throughout their active cycle and are innately impulsive. Using this model, the present study demonstrates that the triple monoamine uptake inhibitors (TUIs) amitifadine and DOV 102, 677 effectively attenuate binge drinking, heavy drinking assessed via a 24-hour free-choice assay, and impulsivity measured by the delay discounting procedure. In contrast, 3-PBC, a GABA-A α1 preferring ligand with mixed agonist-antagonist properties, attenuates excessive drinking without affecting impulsivity. These findings suggest that in HAP mice, monoamine pathways may predominate as a common mechanism underlying impulsivity and excessive drinking, while the GABAergic system may be more salient in regulating excessive drinking. We further propose that TUIs such as amitifadine and DOV 102, 677 may be used to treat the co-occurrence of impulsivity and excessive drinking.

Background Concurrent inhibitors of dopamine, norepinephrine and serotonin uptake have been proposed as novel antidepressants. Given the high comorbidity between alcoholism and depression, we evaluated the activity of DOV 102,677 (DOV) on alcohol-maintained responding and performance in the forced swim test (FST), a model of antidepressant (AD) activity, using alcohol-preferring (P) rats.

In the present study, in vitro and in vivo studies were conducted to determine the relationship between innate substance P (SP) levels and alcohol-motivated behavior in alcohol-preferring (P) and nonpreferring (NP) rat lines. In Experiment 1, in situ hybridization and quantitative autoradiography were used to detect and measure SP mRNA levels in discrete brain loci of the P and NP rats. The results indicated significantly lower SP mRNA levels in the central nucleus of the amygdala (CeA) of P compared with those of NP rats. Experiment 2 evaluated the effects of SP, microinfused into the CeA, on alcohol (10%, v/v) and sucrose (2%, w/v) motivated responding in the P rat. The results revealed that, when infused into the CeA (1–8 μg), SP reduced alcohol responding by 48–85% of control levels, with no effects on sucrose responding. Neuroanatomical control infusions (1–8 μg) into the caudate putamen (CPu) also failed to significantly alter alcohol- or sucrose-motivated behaviors. Given the selective reductions on alcohol (compared to sucrose) responding by direct intracranial infusion of SP, the data suggest that deficits in SP signaling within the CeA (an anxiety regulating locus) are inversely associated with alcohol-motivated behaviors. Activation of SP receptors in the CeA may reduce anxiety-like behavior in the P rat and contribute to reductions on alcohol responding. The SP system may be a suitable target for the development of drugs to reduce alcohol-drinking behavior in humans. Synapse 63:972–981, 2009. © 2009 Wiley-Liss, Inc.

The bed nucleus of the stria terminalis (BNST) has been reported to release increased levels of extracellular dopamine (DA) following the systemic administration of abused drugs in outbred rats. This study examined the BNST as a novel locus for supporting operant responding for brain stimulation reward (BSR) in rats bred for alcohol preference while determining any potentiating effects of ethanol (EtOH) (0.125–1.25 g/kg, i.p.) and amphetamine (0.25–1.60 mg/kg, i.p.) on BSR within the BNST. Also examined was the capability of D1 receptor blockade to attenuate any observed potentiation. Following surgical implantation, alcohol-preferring (P) and nonpreferring (NP) rats responded to a range of descending frequencies (300–20 Hz) as evaluated by a rate-frequency paradigm. The results revealed that the BNST was capable of supporting BSR in P but not NP rats. Also, amphetamine pretreatment produced a significant leftward shift in the rate-frequency function in P rats with significant reductions observed in three other measures of reward threshold, while EtOH only lowered the minimum frequency needed to produce responding. The effects of systemic amphetamine were successfully attenuated by the unilateral infusion of the D1 receptor antagonist SCH 23390 (5.0 μg) into the contralateral nucleus accumbens. The results suggest the BNST is capable of supporting BSR performance in P, but not NP rats, possibly due to increased sensitivity to the electrical stimulation-induced DA release of BSR in the innately DA “deficient” limbic system of P rats. Synapse 61:912–924, 2007. © 2007 Wiley-Liss, Inc.

Background Previous research has implicated the alpha5-containing GABAA receptors of the hippocampus in the reinforcing properties of alcohol. In the present study, a selective GABAA alpha5 benzodiazepine inverse agonist (e.g., RY 023) was used in a series of in vivo and in vitro studies to determine the significance of the alpha5-receptor in the neurobehavioral actions of alcohol. Methods In experiment one, systemic injections of RY 023 (1 to 10 mg/kg IP) dose-dependently reduced ethanol-maintained responding by 52% to 86% of controls, whereas bilateral hippocampal infusions (0.3 to 20 microg) reduced responding by 66% to 84% of controls. Saccharin responding was reduced only with the highest intraperitoneal (e.g., 10 mg) and microinjected (e.g., 20 microg) doses. In experiment two, RY 023 (3.0 to 15 mg/kg IP) reversed the motor-impairing effects of a moderate dose of alcohol (0.75 g/kg) on an oscillating bar task in the absence of intrinsic effects. In the open field, RY 023 (3.0 to 7.5 mg/kg) produced intrinsic effects alone but attenuated the suppression of the 1.25 g/kg ethanol dose. Because the diazepam-insensitive receptors (e.g., alpha4 and alpha6) have been suggested to play a role in alcohol motor impairing and sedative actions, experiment three compared the efficacy of RY 023 with Ro 15-4513 and two prototypical benzodiazepine antagonists (e.g., flumazenil and ZK 93426) across the alpha4beta3gamma2-, alpha5beta3gamma2-, and alpha6beta3gamma2-receptor subtypes in Xenopus oocytes. Results RY 023 produced classic inverse agonism at all receptor subtypes, whereas Ro15-4513 and the two antagonists displayed a neutral or agonistic profile at the diazepam-insensitive receptors. Conclusions Overall, the results extend our previous findings by demonstrating that an alpha5-subtype ligand is capable of attenuating not only the rewarding action of alcohol but also its motor impairing and sedative effects. We propose that these actions are mediated in part by the alpha5-receptors of the hippocampus. The hippocampal alpha5-receptors could represent novel targets in understanding the neuromechanisms regulating the neurobehavioral actions of alcohol in humans.

Background: This study examined the associations among selective breeding for alcohol preference, intake of sweet solutions, and responding for brain stimulation reward (BSR), a nonoral reinforcer, in alcohol-preferring high–alcohol-drinking (HAD)-1 and nonpreferring low–alcohol-drinking (LAD)-1 rats. Methods: Adult male HAD-1 and LAD-1 rats were trained to lever press for medial forebrain bundle stimulation. Current intensity was varied in separate sessions to generate a rate/intensity function. To further examine BSR responding, the animals responded for stimulation at 100 Hz and at a fixed current intensity on an FR1 schedule. In subsequent sessions, the schedule was increased to FR6 and then to FR12. To examine responding for the sucrose solution, we trained a separate group of HAD-1/LAD-1 rats to bar press for sucrose on an FR1 schedule. Similar to the BSR experiment, in following sessions, the schedule was increased to an FR6 and then to an FR12 schedule. Results: No significant differences were observed between the two rat lines across a range of current intensities. As the reinforcement schedule increased, HAD-1 rats exhibited a dramatic decrease in BSR responding, whereas the LAD-1 rats displayed a more protracted reduction. In contrast to BSR, marked elevations in responding were observed for sucrose as the schedule increased. However, in HAD-1 rats, response rates were similar on the FR6 and FR12 schedules, whereas LAD-1 rats showed a reduction in response rates from the FR6 to FR12 schedule. Furthermore, HAD-1 rats exhibited significantly more responses compared with LAD-1 rats across the three reinforcement schedules. An analysis of the response profile for the three reinforcement schedules suggested that few if any postreinforcement pauses were exhibited when the reinforcer was BSR compared with sucrose in both lines. Conclusion: Medial forebrain bundle BSR is a powerful reinforcer in both HAD-1 and LAD-1 lines. However, BSR responding was not associated with selective breeding for alcohol preference. In contrast, selective breeding for alcohol preference was associated with sucrose consumption, especially as the amount of work increased. The lack of correspondence between BSR and sweet taste rewards in HAD-1 and LAD-1 lines may suggest important differences yet an overlapping brain reward mechanism in the control of motivated behaviors in these selected lines.

The effects of two widely abused drugs, ethanol and cocaine, were examined alone and in combination on intracranial reward processes. In agreement with previous research, higher doses of both cocaine and ethanol alone produced facilitation of behavior maintained by brain stimulation reward. Low intraperitoneal doses of ethanol and cocaine, which alone did not affect performance, were found to reduce stimulation reward threshold and modestly increase response rate. The enhancement of brain stimulation reward by the combination of ethanol and cocaine suggests that both drugs may produce their rewarding effects through common neuronal substrates and that they may potentiate the abuse of each other.

Previous work in our laboratory demonstrated that Ro15-4513, a partial inverse benzodiazepine agonist, decreases self-administration of ethanol (ETOH) in rats maintained on a two-bottle regmine of a saccharin ethanol solution (ES) and water over a 35-day consumption period. The present study extended the consumption period to 60 days and examined the effects of Ro15-4513 (2.5 mg/kg), flumazenil (Ro15-1788) (8.0 mg/kg), and Ro15-4513 in combination with Ro15-1788 on the time course of ETOH self-administration. High initial intake of ES observed during the first 4 weeks declined significantly over subsequent weeks. Ro15-4513 pretreatment, however, resulted in significant reduction of ES, while significantly preventing the "normal" reduction of consumption as was observed under control conditions. The antagonistic actions of Ro15-4513 were blocked/attenuated by the benzodiazepine receptor antagonist, Ro15-1788, independent of whether consumption of the ES was low or high. Both Ro15-4513 and Ro15-1788 affected water intake differentially compared with vehicle-injected controls. The results suggest that GABA-benzodiazepine mechanisms may be important in altering chronic ETOH drinking patterns depending upon experience with ETOH, tolerance, or learning.

The unit outlines four basic protocols designed to systematically evaluate the capacity of potential pharmacotherapeutic agents to effectively treat alcohol addiction and dependence in rats. Also included are procedures designed to study the neural mechanisms regulating alcohol-seeking behaviors.

Nalmefene, the 6-methylene derivative of naltrexone, was examined after subcutaneous (s.c.) (0.0001 to 8.0 mg/kg) and oral (10 to 80.0 mg/kg) administration in ethanol (EtOH)-preferring rats whose responding (i.e., lever pressing) was maintained by the presentation of EtOH. Naltrexone (0.01 to 40 mg/kg) was used as a reference opioid antagonist. EtOH (10% v/v) and saccharin (0.025 to 0.1% w/v) solutions were concurrently available for 1 hr each day under a two-lever, fixed-ratio schedule in which four responses on one lever produced the EtOH solution and four responses on the other lever produced the saccharin solution. When basal response rates for saccharin were 10% that of EtOH, all routes of nalmefene administration reduced control levels of responding maintained by EtOH by 38 to 84%. When basal response rates for saccharin-maintained responding were 60% or 82% that of EtOH, only lower s.c. naltrexone (e.g., 0.01 to 0.025 mg/kg) and nalmefene (e.g., 0.01 to 0.10 mg/kg) doses produced a selective dose-dependent suppression of EtOH-maintained responding. Higher nalmefene (0.25 to 8.0 mg/kg) and naltrexone (1.0 to 20.0 mg/kg) doses failed to produce a dose-dependent suppression on EtOH or saccharin maintained responding. Both antagonists suppressed responding maintained by EtOH primarily during the initial 10-min period, with little additional suppression occurring across the remainder of the 60-min period. Subcutaneous nalmefene was 3200- to 6400-fold more potent than oral nalmefene, suggesting bioavailability was optimized using the s.c. route. Nalmefene (0.5 mg/kg, s.c.) treatment for 10 consecutive days produced mild tolerance development, whose effects dissipated by day 8. Naltrexone (10 to 40 mg/kg) and nalmefene (1.5 to 3.0 mg/kg), given 8 to 24 hr before the test session, reduced control levels of responding maintained by EtOH by 82%. Thus, immediate opioid receptor occupancy was not required to observe antagonism. These data demonstrate that, under a variety of experimental conditions, nalmefene is an effective antagonist of responding maintained by EtOH and lend support to clinical reports that nalmefene may function as an alternative pharmacotherapy to naltrexone to reduce EtOH-motivated behavior and prevent relapse.