PRINCIPAL INVESTIGATOR: BESHEER, JOYCE
GRANT NUMBER: R01 AA019682-04S1
ABSTRACT: The present application requests an administrative supplement to R01 AA019682 (PI – Joyce Besheer). The goal of this supplement is directly in line with the goals of CRAN in that the proposed experiments will broaden the scope and increase the impact of the parent award by examining the compounding effects of an additional substance in an existing animal model. The parent award is focused on examining the effects of chronic stress hormone exposure (corticosterone, CORT) on sensitivity to the interoceptive effects of alcohol, and the functional consequence of neuroadaptations in nucleus accumbens mGluR5. Therefore, the goal of this administrative supplement is to examine the effects of CORT exposure on sensitivity to an alcohol+nicotine interoceptive cue, and determine the functional involvement of mGluR5. This topic is highly relevant not only because the incidence of smoking and drinking is highly prevalent, but also because individuals tend not only to drink more during/after experiencing stressful episodes, but also smoke more as well. Consequently, there is need to better understand the behavioral and neurobiological mechanisms that may contribute to these stress induced and maladaptive increases in the co-abuse of alcohol drinking and cigarette smoking. One such behavioral mechanism relates to interoceptive (subjective) drug cues, which can be measured using standard drug discrimination methods in rodents. Interoceptive drug cues can serve as potent modulators of drug-taking, seeking and relapse and as a result, it is important to consider potential changes to interoceptive drug cues during stressful episodes as possible contributors to escalated drug intake. For example, if an individual is sensitive to the subjective/interoceptive cues induced by smoking and drinking (together), and those cues are blunted during/after experiencing a stressful episode (i.e., trauma, stressful life events), then the likelihood of heightened smoking and drinking may be increased. Indeed, as we have shown during the funding period of the parent award, following a period of prolonged and heightened elevations in the stress hormone CORT, animals show decreased sensitivity to the interoceptive effects of alcohol (both experimenter and selfadministered). To broaden the scope and increase the impact of the parent award, Aim 1 of the present supplement will extend these studies to examine how sensitivity to an alcohol+nicotine cue will be affected by the same CORT exposure and also how subsequent sensitivity to each drug alone is altered. Experiments in the parent award have also determined that mGluR5 expression in the nucleus accumbens is dramatically impacted by CORT exposure, suggesting that reduced sensitivity to alcohol following CORT exposure may be related to neuroadaptations in the nucleus accumbens. Indeed, pharmacological activation of mGluR5 by systemic injection and targeted site-specific injections in the nucleus accumbens restores sensitivity to alcohol. Therefore, Aim 2 will extend those findings to examine the effects of mGluR5 activation on sensitivity to an alcohol+nicotine compound stimulus. Restoring sensitivity to the interoceptive effects of a drug or drug mixture can have therapeutic implications given the importance of interoceptive effects to drug taking and these findings will be highly relevant to co-abuse of nicotine and alcohol during stressful episodes. Lastly, Aim 3 will target the functional involvement of mGluR5 in the nucleus accumbens. We will determine whether pharmacological activation of mGluR5 in this brain region will restore sensitivity to the alcohol+nicotine compound. Together, the studies in this proposal have the potential to move the field forward by providing insight into how chronic glucocorticoid elevations can influence sensitivity to the interoceptive effects of an alcohol+nicotine compound cue via a novel mGluR5-related mechanism.