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Ethanol-seeking behavior is expressed directly through an extended amygdala to midbrain neural circuit.

ABSTRACT: Abstinent alcohol-dependent individuals experience an enduring sensitivity to cue-induced craving and relapse to drinking. There is considerable evidence indicating that structures within the midbrain and extended amygdala are involved in this process. Individually, the ventral tegmental area (VTA) and the bed nucleus of the stria terminalis (BNST) have been shown to modulate cue-induced ethanol-seeking behavior. It is hypothesized that cue-induced seeking is communicated through a direct projection from the BNST to VTA. In the current experiments, an intersectional viral strategy was used in DBA/2J mice to selectively target and inhibit BNST projections to the VTA during a test of ethanol conditioned place preference (CPP). Inhibitory designer receptors exclusively activated by designer drugs (hM4Di DREADDs) were expressed in VTA-projecting BNST (BNST-VTA) cells by infusing a retrograde herpes-simplex virus encoding cre recombinase (HSV-Cre) into VTA and a cre-inducible adeno-associated virus encoding hM4Di (AAV-DIO-hM4Di) into BNST. Before testing the expression of preference, clozapine-N-oxide (CNO) was peripherally administered to activate hM4Di receptors and selectively inhibit these cells. Ethanol CPP expression was blocked by CNO-mediated inhibition of BNST-VTA cells. A follow-up study revealed this effect was specific to CNO activation of hM4Di as saline- and CNO-treated mice infused with a control vector (HSV-GFP) in place of HSV-Cre showed significant CPP. These findings establish a role for a direct BNST input to VTA in cue-induced ethanol-seeking behavior.

SUBMITTER: Pina MM

PROVIDER: S-EPMC5214453 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Ethanol-seeking behavior is expressed directly through an extended amygdala to midbrain neural circuit.

Pina Melanie M MM Cunningham Christopher L CL

Neurobiology of learning and memory 20161117

Abstinent alcohol-dependent individuals experience an enduring sensitivity to cue-induced craving and relapse to drinking. There is considerable evidence indicating that structures within the midbrain and extended amygdala are involved in this process. Individually, the ventral tegmental area (VTA) and the bed nucleus of the stria terminalis (BNST) have been shown to modulate cue-induced ethanol-seeking behavior. It is hypothesized that cue-induced seeking is communicated through a direct projec ...[more]

PMID: 27866960

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Project description:Withdrawal anxiety following chronic ethanol exposure is often associated with relapse in recovering alcoholics. It is likely that brain regions regulating anxiety-like behaviors adapt during chronic ethanol exposure to ultimately regulate such behaviors. The central amygdala contains numerous neurotransmitter systems that have been implicated in the regulation of anxiety-like behavior, including corticotropin releasing factor (CRF) and NMDA-type glutamate receptors. Chronic ethanol exposure causes functional adaptations in both CRF and NMDA receptors that are likely to regulate anxiety-like behaviors expressed during withdrawal. However, the molecular mechanisms governing these adaptations remain unexplored. We therefore evaluated these neurotransmitter systems in Sprague-Dawley rats during chronic ingestion of an ethanol-containing liquid diet. Quantitative real-time reverse transcription-PCR demonstrated that preproCRF mRNA was significantly upregulated by chronic ethanol exposure, whereas mRNA expression of CRF binding protein did not change. There were also no significant changes observed in any of the NMDA subunit mRNAs, although there was a trend toward greater NR2A mRNA expression during chronic ethanol exposure. Using Western blotting analysis we measured NMDA receptor subunit protein expression. Chronic ethanol exposure did not affect protein levels of the NR1 and NR2B subunits. Like the mRNA measures, chronic ethanol exposure did influence NR2A protein levels but the effects were modest. Our results demonstrate that NMDA receptor subunit mRNA and protein expressions are not strongly influenced by exposure to chronic ethanol. This suggests that the functional NMDA receptor adaptations identified in previous studies [Roberto, M., Schweitzer, P., Madamba, S. G., Stouffer, D. G., Parsons, L. H., & Siggins, G. R. (2004). Acute and chronic ethanol exposure alter glutamatergic transmission in rat central amygdala: an in vitro and in vivo analysis. J Neurosci 24, 1594-1603] are likely to be mediated by post-translational events. In contrast, enhanced levels of CRF during/after chronic ethanol exposure are likely to be mediated by increased levels of prepro CRF mRNA. Together, our findings suggest that adaptations to chronic ethanol exposure by proanxiety factors expressed in the central nucleus appear to be mediated by distinct cellular and molecular mechanisms.

Dataset Information

Ethanol-seeking behavior is expressed directly through an extended amygdala to midbrain neural circuit.

Publications

Ethanol-seeking behavior is expressed directly through an extended amygdala to midbrain neural circuit.

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