Mesolimbic Nociceptin Signaling and Cocaine Reward Suppression

Addiction is a pressing public health concern that impacts millions of people in the U.S, causing a sizable burden on the health care system and thousands of unnecessary deaths, 1 in 5 of which are due to psychostimulant abuse, such as cocaine. However, the mechanisms that control response to cocaine are not clearly defined, and there is a pressing need to understand these mechanisms. The current study will explore the possibility that the neuropeptide, NOF/Q (aka: nociceptin), is a potent cocaine reward suppressor that acts in mesolimbic terminal regions of the nucleus accumbens (NAc). Preliminary data strongly support that NOF/Q signaling in NAc blocks cocaine reward, and that NOF/Q can act directly upon DAergic terminals within NAc. However, the mechanisms and circuitry that mediate NOF/Q reward suppression in NAc are completely undefined, nor is it known whether there is basal NOF/Q tone in NAc that constitutively sets sensitivity to rewarding substances. The proposed exploratory studies will leverage a variety of cutting-edge viral and genetic tools to fully characterize NOF/Q tone and effects on reward in NAc, as well as the NOF/Q circuitry innervating NAc and that likely serve as an endogenous reward suppression system. Studies in Aim 1 will provide an in-depth analysis of cocaine reward suppression by NOF/Q in male and female mice, and leverage optogenetics in PNOCCre mice to determine whether endogenous NOF/Q signaling is sufficient to suppress cocaine reward. Studies in Aim 2 will leverage NOPRfl/fl mice to test whether NOF/Q signaling on DAergic mesolimbic terminals is required for cocaine suppression by NOF/Q. In addition, Aim 2 studies will use PNOCCre mice to retrogradely trace NOF/Q afferents in NAc, to the likely source of endogenous NOF/Q. Taken together, these studies will provide a fundamental understanding of the potential for NOF/Q signaling as powerful suppressant of cocaine reward, and will shed light on an intrinsic mechanism that sets reward tone. Importantly, the findings will lay the necessary groundwork for future work aimed at understanding the mechanisms and specific circuits that mediate NOF/Q reward suppression.