Heightened Exploratory Behavior Following Chronic Excessive Ethanol Drinking: Mediation by Neurotensin Receptor Type 2 in the Anterior Paraventricular Thalamus

• Published in: Alcoholism, clinical and experimental research Vol. 44; no. 9; pp. 1747 - 1759
• Main Authors: Pandey, Surya, Barson, Jessica R.
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.09.2020
• Subjects: Abstinence; Acute Abstinence; Adaptation; Alcohol use; Alcoholism; Dark Box; Drinking behavior; Elevated Plus Maze; Ethanol; Exploratory behavior; Gene expression; Individual Differences; JMV‐431; Light; Neurotensin; Thalamus; Dark Box; Elevated Plus Maze; JMV-431; Individual Differences; Acute Abstinence; Light
• ISSN: 0145-6008; 1530-0277
• DOI: 10.1111/acer.14406

Background Chronic, excessive alcohol drinkers, even without dependence, can exhibit changes in behavior and neurochemical systems. Identifying these changes and their relationship with one another could provide novel avenues for the prevention and treatment of alcohol use disorder. We recently demonstrated, in rats, that neurotensin (NTS) in the paraventricular thalamus (PVT) regulates excessive ethanol (EtOH) drinking. Here, we investigate the effects of chronic EtOH drinking on the PVT‐NTS system and its contribution to EtOH‐induced behavioral changes. Methods We gave adult male Long‐Evans rats 20% EtOH under the intermittent access 2‐bottle‐choice paradigm or maintained them on chow and water for up to 11 weeks. Prior to EtOH exposure and following several weeks of access, during acute abstinence, we tested these groups for multiple behaviors. In the 12th week, during acute abstinence, we examined gene expression and peptide levels of NTS and its receptors in the anterior and posterior subregions of the PVT. Finally, in chronic EtOH drinkers, during acute abstinence, we microinjected the NTS receptor type 2 (NTS2R) agonist, JMV‐431, in the anterior PVT (aPVT) and examined subsequent EtOH intake and behavior. Results Following chronic intermittent EtOH access, rats were classified by cluster analysis as high or low EtOH drinkers. High EtOH drinkers spent more time in the light chamber of a light–dark box and open arms of an elevated plus maze and entered fewer familiar holes in a hole‐board apparatus. These differences were absent prior to EtOH exposure but were detectable as early as 4 weeks into drinking. Time in the light chamber following chronic drinking also predicted level of subsequent drinking. High EtOH drinkers also showed elevated protein levels of NTS2R in the aPVT, and pharmacological stimulation of aPVT NTS2R in low drinkers mimicked the increased time spent in the light chamber that was observed in high drinkers. Conclusions Our findings suggest that chronic, excessive, but not lower level, EtOH drinking induces heightened or flexible exploratory behavior, which predicts future EtOH drinking and is partly mediated by elevated NTS2R signaling in the aPVT. These EtOH‐induced alterations represent adaptations that could perpetuate excessive drinking and lead to the development of EtOH dependence. Early detection of neurochemical and behavioral changes induced by excessive alcohol drinking can be useful in the prevention and treatment of alcohol use disorder. Using a rodent model, excessive alcohol drinkers were found to exhibit heightened exploratory behavior as early as four weeks into drinking and to have elevated levels of the neurotensin receptor type 2 in the anterior paraventricular thalamus, which were directly related to the exploratory behavior. Similar features may characterize vulnerable human alcohol drinkers.