Neural correlates of cocaine-induced conditioned place preference in the posterior cerebellar cortex.

Introduction: Addictive drugs are potent neuropharmacological agents capable of inducing long-lasting changes in learning and memory neurocircuitry. With repeated use, contexts and cues associated with consumption can acquire motivational and reinforcing properties of abused drugs, triggering drug craving and relapse. Neuroplasticity underlying drug-induced memories takes place in prefrontal-limbic-striatal networks. Recent evidence suggests that the cerebellum is also involved in the circuitry responsible for drug-induced conditioning. In rodents, preference for cocaine-associated olfactory cues has been shown to correlate with increased activity at the apical part of the granular cell layer in the posterior vermis (lobules VIII and IX). It is important to determine if the cerebellum's role in drug conditioning is a general phenomenon or is limited to a particular sensory modality. Methods: The present study evaluated the role of the posterior cerebellum (lobules VIII and IX), together with the medial prefrontal cortex (mPFC), ventral tegmental area (VTA), and nucleus accumbens (NAc) using a cocaine-induced conditioned place preference procedure with tactile cues. Cocaine CPP was tested using ascending (3, 6, 12, and 24 mg/kg) doses of cocaine in mice. Results: Compared to control groups (Unpaired and Saline animals), Paired mice were able to show a preference for the cues associated with cocaine. Increased activation (cFos expression) of the posterior cerebellum was found in cocaine CPP groups and showed a positive correlation with CPP levels. Such increases in cFos activity in the posterior cerebellum significantly correlated with cFos expression in the mPFC. Discussion: Our data suggest that the dorsal region of the cerebellum could be an important part of the network that mediates cocaine-conditioned behavior.

Effects of naltrexone on alcohol, sucrose, and saccharin binge-like drinking in C57BL/6J mice: a study with a multiple bottle choice procedure.

Chronic alcohol (ethyl alcohol, EtOH) binging has been associated with long-term neural adaptations that lead to the development of addiction. Many of the neurobiological features of EtOH abuse are shared with other forms of binging, like pathological feeding. The drinking-in-the-dark (DID) paradigm has been used extensively to study the neurobiology of EtOH binge-like drinking due to its ability to promote high intakes relevant to human behavior. DID can also generate high consumption of other tastants, but this procedure has not been fully adapted to study forms of binging behavior that are not alcohol-driven. In the present study, we used a modified version of DID that uses multiple bottle availability to promote even higher levels of EtOH drinking in male C57BL/6J mice and allows a thorough investigation of tastant preferences. We assessed whether administration of systemic naltrexone could reduce binging on EtOH, sucrose, and saccharin separately as well as in combination. Our multiple bottle DID procedure resulted in heightened levels of consumption compared with previously reported data using this task. We found that administration of the opioid receptor antagonist naltrexone reduced intakes of preferred, highly concentrated EtOH, sucrose, and saccharin. We also report that naltrexone was able to reduce overall intakes when animals were allowed to self-administer EtOH, sucrose, or saccharin in combination. Our modified DID procedure provides a novel approach to study binging behavior that extends beyond EtOH to other tastants (i.e. sucrose and artificial sweeteners), and has implications for the study of the neuropharmacology of binge drinking.

Alcohol Binge Drinking and Anxiety-Like Behavior in Socialized Versus Isolated C57BL/6J Mice.

BACKGROUND: Binge alcohol drinking has been characterized as a key feature of alcoholism. The drinking-in-the-dark (DID) preclinical model, a procedure that promotes high levels of ethanol (EtOH) intake in short periods of time, has been extensively used to investigate neuropharmacological and genetic determinants of binge-like EtOH consumption. Using DID methodology, alcohol-preferring strains of mice such as C57BL/6J (B6) mice consume enough EtOH to achieve blood concentrations (≥1.0 mg/ml) associated with behavioral intoxication (i.e., motor incoordination). DID procedures typically involve the use of socially isolated animals (single-housed prior to and during the experiment). Previous research indicates that stress associated with social isolation can induce anxiety-like behavior and promote increases in EtOH intake. The present study investigates the role of housing conditions in anxiety-like behavior and binge-like EtOH intake using a DID procedure. METHODS: Male and female B6 mice were isolated or pair-housed for a period of 6 weeks prior to evaluation of anxiety-like (elevated plus maze, light and dark box, open field) and drinking (water, 10% sucrose, 10 to 30% EtOH) behavior. In order to measure intake, a variation of the standard DID procedure using a removable, transparent, and perforated plastic barrier strip (designed to temporarily divide the cage in 2) was introduced. This allowed for individual intake records (2-hour test) of isolated and socially housed animals. RESULTS: Increased anxiety-like behavior and reduced sucrose consumption were found in isolated mice. The effects of housing conditions on EtOH intake were sex- and concentration-dependent. In male mice, isolation increased 20 and 30% EtOH intake. In females, however, an increased intake of EtOH (30%) was found in socialized animals. No effects of housing or sex were found at EtOH 10%. CONCLUSIONS: Together with previous literature, the present study suggests that social isolation can promote anxiety-associated behavior and produce sex-dependent changes in binge-like EtOH consumption.