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This study was designed to replicate and extend a previous report that the increase in performance of an attentional set-shifting task (ASST) in rhesus monkeys predicted their future alcohol drinking status as a heavy drinker (HD) or non-heavy drinker (NHD). A cohort of 6 young adult male monkeys was trained and tested under the same ASST and then underwent a alcohol self-administration protocol that maintained open-access (22 hours/day) choice of alcohol or water 7 days/week for approximately 6 months. The average improvement in performance in the ASST, as measured by a performance index, was replicated in the cohort of 6 monkeys when compared to the increase in the task performance in a previous cohort of 9 male monkeys. The alcohol self-administration protocol was then used to determine the drinking status (HD: n = 4 or NHD: n = 2) of the replicate cohort, which was accurately predicted by the performance on the ASST. Finally, individuals from both cohorts could be combined based on future drinking status of HD (n = 8) or NHD (n = 7), and the association with pre-alcohol ASST performance remained. Specifically, monkeys that had lower rates of PI improvement were more likely to become HDs. To our knowledge, this is the first study to replicate that deficits in the set-shifting performance can predict chronic heavy alcohol drinking in primates., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Sardinian alcohol-preferring (sP) rats have been selectively bred, over almost 40 years, for high alcohol preference and consumption. sP rats have served as an animal model for more than 120 published studies. With very few exceptions, however, these studies have always employed male sP rats, and little is known about alcohol-related behaviors in female sP rats. The present study was designed to fill, at least in part, this gap. Accordingly, alcohol self-administration under the fixed ratio 4 schedule of reinforcement was compared among male, intact female, and ovariectomized female sP rats. Additionally, it was investigated whether i) estrous cycle influenced alcohol self-administration, and ii) alcohol self-administration in the three sP rat groups differed in sensitivity to pharmacological manipulation. Lever-responding for alcohol was steadily higher in male than intact and ovariectomized female sP rats; conversely, because of large sex differences in rat body weight, estimated amount of self-administered alcohol (in g/kg) did not differ among the three sP rat groups or occasionally was higher in intact female than male and ovariectomized female sP rats. Blood alcohol levels derived from self-administered alcohol i) did not differ among the three sP rat groups and ii) were positively correlated with the number of lever-responses for alcohol and the estimated amount of self-administered alcohol. Treatment with the opioid receptor antagonist, naloxone (0, 0.3, 1, and 3 mg/kg, i.p. [intraperitoneally]), and the positive allosteric modulator of the GABA B receptor, GS39783 (0, 25, 50, and 100 mg/kg, i.g. [intragastrically]), reduced alcohol self-administration with comparable potency and efficacy in the three sP rat groups. The impact of the estrous cycle on alcohol self-administration was relatively modest, limited to a tendency toward a reduction in the number of lever-responses for alcohol and the estimated amount of self-administered alcohol in estrus and metestrus. Together, these results provide the first characterization of alcohol-seeking and -taking behavior in female sP rats., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Positive allosteric modulators (PAMs) of the GABA B receptor constitute a class of pharmacological agents gaining increasing attention in the alcohol research field because of their ability to suppress several alcohol-related behaviors in rodents. CMPPE is a novel GABA B PAM, still limitedly characterized in vivo. It was therefore of interest to test its ability to affect operant, oral self-administration of alcohol and cue-induced reinstatement of alcohol seeking in alcohol-preferring rats. To this end, female Sardinian alcohol-preferring (sP) rats were trained to lever-respond for alcohol (15% v/v) under the fixed ratio (FR) 5 (FR5) schedule of reinforcement. Once lever-responding had stabilized, rats were exposed to test sessions (under the FR5 [Experiment 1] and progressive ratio [PR; Experiment 2] schedules of reinforcement) preceded by treatment with CMPPE (0, 2.5, 5, and 10 mg/kg; intraperitoneally [i.p.]). In Experiment 3, once lever-responding had stabilized, rats underwent an extinction responding phase and then a single reinstatement session during which lever-responding was resumed by the non-contingent presentation of a complex of alcohol-associated cues; CMPPE (0, 2.5, 5, and 10 mg/kg; i.p.) was administered before the reinstatement session. Selectivity of CMPPE action was assessed by evaluating the effect of CMPPE (0, 2.5, 5, and 10 mg/kg; i.p.) on self-administration of a chocolate solution in male Wistar rats (Experiment 4). In Experiments 1 and 2, treatment with 5 and 10 mg/kg CMPPE reduced lever-responding and breakpoint for alcohol. In Experiment 3, treatment with 5 and 10 mg/kg CMPPE suppressed reinstatement of alcohol seeking. In Experiment 4, no dose of CMPPE affected lever-responding for the chocolate solution. These results extend to CMPPE the ability of all previously tested GABA B PAMs to affect alcohol-motivated behaviors in rodents and confirm that these effects are a shared feature of the entire class of GABA B PAMs. This conclusion is of relevance in view of the forthcoming transition of GABA B PAMs to clinical testing., (Copyright © 2018 Elsevier Inc. All rights reserved.)

We have shown that dysregulation of the dynorphin/kappa-opioid receptor (DYN/KOR) system contributes to escalated alcohol self-administration in alcohol dependence and that KOR antagonists with extended durations of action selectively reduce escalated alcohol consumption in alcohol-dependent animals. As KOR antagonism has gained widespread attention as a potential therapeutic target to treat alcoholism and multiple neuropsychiatric disorders, we tested the effect of zyklophin (a short-acting KOR antagonist) on escalated alcohol self-administration in rats made alcohol-dependent using intermittent alcohol vapor exposure. Following dependence induction, zyklophin was infused centrally prior to alcohol self-administration sessions and locomotor activity tests during acute withdrawal. Zyklophin did not impact alcohol self-administration or locomotor activity in either exposure condition. To investigate the neurobiological basis of this atypical effect for a KOR antagonist, we utilized a κ-, μ-, and δ-opioid receptor agonist-stimulated GTPyS coupling assay to examine the opioid receptor specificity of zyklophin in the rat brain and mouse brain. In rats, zyklophin did not affect U50488-, DAMGO-, or DADLE-stimulated GTPyS coupling, whereas the prototypical KOR antagonist nor-binaltorphimine (norBNI) attenuated U50488-induced stimulation in the rat brain tissue at concentrations that did not impact μ- and δ-receptor function. To reconcile the discrepancy between the present rat data and published mouse data, comparable GTPyS assays were conducted using mouse brain tissue; zyklophin effects were consistent with KOR antagonism in mice. Moreover, at higher concentrations, zyklophin exhibited agonist properties in rat and mouse brains. These results identify species differences in zyklophin efficacy that, given the rising interest in the development of short-duration KOR antagonists, should provide valuable information for therapeutic development efforts., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The dried roots of Salvia miltiorrhiza are highly valued in Chinese folk medicine for use in the prevention and treatment of a series of ailments. Previous studies have demonstrated that administration of standardized extracts of S. miltiorrhiza selectively reduced excessive alcohol drinking and relapse-like drinking in selectively bred Sardinian alcohol-preferring (sP) rats. The present study was designed to extend these findings on the "anti-alcohol" properties of S. miltiorrhiza extracts to operant procedures of oral alcohol self-administration. Two independent groups of sP rats were trained to lever-respond on an FR4 schedule of reinforcement for alcohol (15%, v/v) or sucrose (1-3%, w/v) in daily 30 min sessions. Once responding had stabilized, rats were tested under the fixed ratio 4 (FR4) schedule of reinforcement (index of alcohol reinforcing properties) and the progressive ratio (PR) schedule of reinforcement (index of alcohol motivational properties). Treatment with S. miltiorrhiza extract (0, 50, 100, and 200 mg/kg, intragastrically [i.g.]) markedly reduced lever responding for alcohol, amount of self-administered alcohol, and breakpoint for alcohol (defined as the lowest response requirement not achieved in the PR experiment). No dose of S. miltiorrhiza extract altered any parameter of sucrose self-administration. These results a) demonstrate that treatment with S. miltiorrhiza extract selectively reduced the reinforcing and motivational properties of alcohol in sP rats and b) extend to operant procedures of alcohol self-administration previous data on the "anti-alcohol" effects of S. miltiorrhiza extracts. These data strengthen the notion that novel pharmacological approaches for treatment of alcohol use disorders may stem from natural substances., (Copyright © 2014 Elsevier Inc. All rights reserved.)