Abstracts - Speakers

First Annual Waggoner Center Advance - March 22, 2013

Robert O. Messing, MD

Vice Provost for Biomedical Sciences

Drinking Despite Aversive Consequences: Circuits and Receptors

The compulsion to drink in excess is a key feature of alcoholism that has been difficult to model in animals. The nucleus accumbens core (NAc) is of particular interest for the study of compulsive drinking, since it plays an essential role in initiation of motivated behavior. The NAc receives inputs from insula and medial prefrontal (mPFC) cortex that are hypothesized to mediate compulsive drinking in humans, although nearly nothing is known about the actual molecular and circuit mechanisms involved. To study compulsive behavior, we examined quinine-resistant drinking in rats as a model of drinking “despite adverse consequences”. Coincident with the development of quinine-resistant alcohol drinking, rats showed an unusual NMDA receptor current that is active at hyperpolarized potentials under NAc inputs from the insula and mPFC. RNA interference indicated that these currents are mediated by NR2C subunits, which are normally not present in adult animals. Using optogenetic techniques, we found that inhibition of NAc inputs from the insula or the mPFC reduced quinine-resistant alcohol intake, as did inhibition of NMDA receptors or knockdown of NR2C subunits within the NAc. None of these manipulations altered intake when alcohol was not paired with an aversive consequence, suggesting that compulsive intake specifically recruits cortical circuitry. Thus, our findings identify a novel mechanism by which long-term ethanol consumption leads to the expression of NMDARs under cortical inputs to the NAc that are active at hyperpolarized potentials, contain NR2C subunits, and promote compulsive drinking. These results suggest inhibitory NMDAR modulators as potential treatments for compulsive intake of alcohol.