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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. [ABSTRACT FROM AUTHOR]

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 GABAB 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. [ABSTRACT FROM AUTHOR]

Positive allosteric modulators (PAMs) of the GABAB 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 GABAB 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 GABAB PAMs to affect alcohol-motivated behaviors in rodents and confirm that these effects are a shared feature of the entire class of GABAB PAMs. This conclusion is of relevance in view of the forthcoming transition of GABAB PAMs to clinical testing. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: The central amygdala (CeA) is uniquely situated to function as an interface between stress- and addiction-related processes. This brain region has long been attributed an important role in aversive (e.g., fear) conditioning, as well as the negative emotional states that define alcohol dependence and withdrawal. The CeA is the major output region of the amygdala and receives complex inputs from other amygdaloid nuclei as well as regions that integrate sensory information from the external environment (e.g., thalamus, cortex). The CeA is functionally and anatomically divided into lateral and medial subdivisions that themselves are interconnected and populated by inhibitory interneurons and projections neurons. Neuropeptides are highly expressed in the CeA, particularly in the lateral subdivision, and the role of many of these peptides in regulating anxiety- and alcohol-related behaviors has been localized to the CeA. This review focuses on two of these peptides, corticotropin-releasing factor (CRF) and neuropeptide Y (NPY), that exhibit a high degree of neuroanatomical overlap (e.g., in CeA) and largely opposite behavioral profiles (e.g., in regulating anxiety- and alcohol-related behavior). CRF and NPY systems in the CeA appear to be recruited and/or up-regulated during the transition to alcohol dependence. These and other neuropeptides may converge on GABA synapses in CeA to control projection neurons and downstream effector regions, thereby translating negative affective states into anxiety-like behavior and excessive alcohol consumption. [Copyright &y& Elsevier]

Abstract: Preclinical and clinical evidence suggest an association between alcoholism and the primary regulator of extracellular dopamine concentrations, the dopamine transporter (DAT). However, the nature of this association is unclear. We determined if 10 days of voluntary alcohol self-administration followed by withdrawal could directly alter DAT function, or if genetically mediated changes in DAT function and/or availability could influence vulnerability to alcohol abuse. Heterozygous (DAT+/−) and homozygous mutant (DAT−/−) and wild-type (DAT+/+) mice were allowed to consume 5% alcohol in a schedule-induced polydipsia (SIP) task. In vivo fixed potential amperometry in anesthetized mice was used to (1) identify functional characteristics of mesoaccumbens dopamine neurons related to genotype, including dopamine autoreceptor (DAR) sensitivity, DAT efficiency, and DAT capacity, (2) determine if any of these characteristics correlated with alcohol drinking observed in DAT+/+ and DAT+/− animals, and (3) determine if SIP-alcohol self-administration altered DAR sensitivity, DAT efficiency, and DAT capacity by comparing these characteristics in wild-type (DAT+/+) mice that were SIP-alcohol naïve, with those that had undergone SIP-alcohol testing. DAT−/− mice consumed significantly less alcohol during testing and this behavioral difference was related to significant differences in DAR sensitivity, DAT efficiency, and DAT capacity. These functional characteristics were correlated to varying degrees with g/kg alcohol consumption in DAT+/+ and DAT+/− mice. DAR sensitivity was consistently reduced and DAT efficiency was enhanced in SIP-alcohol–experienced DAT+/+ mice when compared with naïve animals. These results indicate that DAR sensitivity is reduced by SIP-alcohol consumption and that DAT efficiency is modified by genotype and SIP-alcohol exposure. DAT capacity appeared to be strictly associated with SIP-alcohol consumption. [Copyright &y& Elsevier]

Abstract: Clinical evidence often points to stress as a cause or an antecedent to the development of drinking problems. Yet, animal models of alcohol drinking have yielded inconsistent evidence for a direct contribution of stress, and many studies have shown that stress suppresses alcohol consumption. The aim of the present study was to examine alcohol reward in animals exposed to repeated, mild social stress, and to determine whether alcohol drinking changes as a function of the temporal parameters of alcohol access relative to the stressor. Male Long-Evans rats, trained to self-administer a 6% (wt/vol) alcohol solution using a sucrose-fading procedure, were exposed to five brief (5min) episodes of contact with an aggressive male. Full contact with the resident was limited to a single episode of defeat, whereas the following four encounters occurred with the subjects behind a protective wire mesh cage. Alcohol self-administration was measured 1 week prior to stress (baseline), on each day of stress exposure, and 1 week following stress. Separate groups of animals were randomly assigned to self-administer alcohol immediately prior, immediately following, or 2h following defeat stress. Stress preferentially increased alcohol drinking on stress-exposure days, and further elevated the amount consumed 1 week following stress. Temporal parameters of alcohol access relative to the stressor were found to be important. Average alcohol consumption was greatest for animals drinking 2h postdefeat, whereas animals drinking immediately prior to or following the stressor did not show a significant increase in alcohol consumption. Results suggest that mild social defeat stress is sufficient to elicit increases in alcohol consumption in nonpreferring strains of rodents, provided alcohol access occurs at an optimal time interval after the social defeat experience. [Copyright &y& Elsevier]

Abstract: We have recently shown that the alcohol self-administration context can reinstate extinguished responding for alcohol when that extinction occurs in a different context [Burattini, C., Gill, T. M., Aicardi, G., & Janak, P. H. (2006)]. The ethanol self-administration context as a reinstatement cue: acute effects of naltrexone. Neuroscience, in press; Zironi, I., Burattini, C., Aicardi, G., & Janak, P. H. (2006). Context is a trigger for relapse to alcohol. Behav Brain Res 167, 150–155). Here, we test whether the C57BL/6 mice will also show context-induced reinstatement for alcohol, and whether presentation of an alcohol-associated cue will alter the observed responding. Male C57BL/6 mice were trained to lever press on a fixed ratio-3 schedule for a 10% ethanol solution in a context made distinctive using visual, tactile, and olfactory stimuli. Each ethanol delivery was paired with a compound tone-light stimulus. After training, extinction sessions were given in a distinct context, comprised of different visual, tactile, and olfactory stimuli; the compound cue and the alcohol were not available during these sessions. In Experiment 1, after response extinction, subjects were tested by placement into both the alcohol self-administration context and, on a subsequent test, by response-contingent presentation of the cue following placement into the alcohol self-administration context. In Experiment 2, after response extinction, subjects were tested in both of these conditions, with the addition of a test of the effects of response-contingent presentation of the cue in the extinction context. The results indicate that the alcohol self-administration context produces a mild increase in responding at the alcohol lever, and that presentation of the alcohol-associated cue in the alcohol context, but not the extinction context, strongly increases responding on the alcohol lever. These findings suggest that the power of an alcohol-associated cue can be modulated by the context. The observed effects of alcohol contexts and cues on alcohol-seeking behavior in the C57BL/6 mouse suggest that this reinstatement model may be useful for understanding the neurobiological and genetic mechanisms of relapse triggered by conditioned environmental stimuli. [Copyright &y& Elsevier]

Abstract: Recent studies have demonstrated that treatment with the γ-aminobutyric acid (GABAB) receptor agonist, baclofen, reduces alcohol intake in selectively bred Sardinian alcohol-preferring rats tested under the homecage two-bottle “alcohol versus water” choice regimen. This study was designed to investigate whether baclofen also reduces alcohol-reinforcing effects in Sardinian alcohol-preferring rats. To this aim, sP rats were trained to lever press for oral alcohol (15%, vol/vol) or sucrose (0.3%, wt/vol; included as alternative reinforcer to evaluate the specificity of baclofen effect on alcohol reinforcement) under a fixed ratio schedule of 4. Once steady levels of alcohol or sucrose self-administration behavior were established, the effects of acutely administered baclofen (0, 1.7, and 3mg/kg, intraperitoneal [ip]) and naloxone (0, 1, and 3mg/kg, ip; included as reference compound) on alcohol- or sucrose-reinforced responding were evaluated. Baclofen administration dose dependently, although not specifically, reduced alcohol-reinforced responding to an extent comparable to that of naloxone. Baclofen also produced a dose-dependent and specific delay in the onset of alcohol-reinforced responding, suggesting that it suppressed the rats'' motivation to start drinking alcohol. These data are discussed in terms of adding further support to the hypothesized involvement of the GABAB receptor in the neural system mediating alcohol reinforcement. These data are also in agreement with the results of recent preliminary clinical studies suggesting that baclofen may have therapeutic efficacy in the treatment of alcohol dependence. [Copyright &y& Elsevier]