The role of nucleus accumbens connections in alcohol and naltrexone actions revealed by manganese-enhanced MRI

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Hyytiä P1, Dudek M1, Canals S2, Sommer WH3

1Department of Pharmacology, University of Helsinki, Helsinki, Finland
2Instituto de Neurociencias, Consejo Superior de Investigaciones Científicas & Universidad Miguel Hernández, Sant Joan d’Alacant, Spain
3Institute for Psychopharmacology, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany

Opioid antagonists have been shown to suppress alcohol self-administration and alcohol seeking in various experimental models. In human alcoholics, opioid antagonism with naltrexone and nalmefene reduce alcohol consumption, craving, and relapse. The neurobiological mechanisms underlying the regulation of alcohol-related behaviours by opioid antagonists are not completely understood. However, there is evidence to suggest that the effects of opioid antagonists could be mediated partly through an interaction with the mesolimbic dopamine system. In the present experiments, we used manganese-enhanced magnetic resonance imaging (MEMRI) for characterizing the role of nucleus accumbens connections in the regulation of alcohol drinking and the suppression thereof by the nonselective opioid antagonist naltrexone. Following long-term free-choice drinking of alcohol and water, AA (Alko Alcohol) rats received injections of MnCl2 into the nucleus accumbens for activity-dependent tracing of accumbal connections. The global T1-weighted scans acquired immediately after the MnCl2 injections were contrasted with those acquired 24 hours later. This comparison revealed a clearly defined ipsilateral continuum through the ventral pallidum, bed nucleus of the stria terminalis, globus pallidus, and lateral hypothalamus to the substantia nigra and ventral tegmental area. Compared with the water-drinking rats, alcohol drinking increased signal intensity along this continuum without affecting intensity in the substantia nigra or VTA, whereas abstinent rats with a history of alcohol drinking exhibited slightly decreased intensity. In contrast, a single naltrexone administration clearly suppressed alcohol-induced signal increase along this forebrain-midbrain tract. Because there were no differences between the experimental groups in the amount of injected MnCl2, the observed differences in manganese accumulation cannot be explained by passive diffusion from the injection site, but were rather produced by differences in neural activity. These findings suggest a role for the accumbal connections in alcohol reinforcement and mediation of naltrexone’s suppressive effects on alcohol drinking through their deactivation. Furthermore, mapping the effects of pharmacological agents in discrete anatomical pathways could be a useful translational tool for developing and evaluating pharmacotherapies for alcohol use disorders.