Hypocretin Receptor 1 Regulation of Dopamine Neurotransmission and Motivated Behavior

Abstract

Hypocretin- (also known as orexin) containing neurons of the lateral hypothalamus project widely throughout the brain and are implicated in a range of behaviors via signaling at hypocretin receptor 1 (HCRTr1) and hypocretin receptor 2. These neurons send a moderate, but influential, projection to the dopaminergic ventral tegmental area which—as part of the mesolimbic dopamine system—is highly implicated in motivated behavior and substance abuse. In this chapter, we will explore the contribution of HCRTr1 to dopamine neurotransmission and its consequential importance to addiction-related processes. Following, we review evidence for HCRTr1 involvement in supporting drug-associated behavior across behavioral models of addiction. We then discuss HCRTr1 regulation of ventral tegmental dopamine neuron activity and its impact on dopamine neurotransmission in the nucleus accumbens, and address hypocretin-dopamine interactions and their effects in females. Finally, we propose that HCRTr1 regulation of dopamine release influences behavioral responses to drug-associated cues.