Hypocretin / Orexin Receptor 1 Knockdown in GABA or Dopamine Neurons in the Ventral Tegmental Area Differentially Impact Mesolimbic Dopamine and Motivation for Cocaine.

The hypocretins/orexins (HCRT) have been demonstrated to influence motivation for cocaine through actions on dopamine (DA) transmission. Pharmacological or genetic disruption of the hypocretin receptor 1 (Hcrtr1) reduces cocaine self-administration, blocks reinstatement of cocaine seeking, and decreases conditioned place preference for cocaine. These effects are likely mediated through actions in the ventral tegmental area (VTA) and resulting alterations in DA transmission. For example, HCRT drives VTA DA neuron activity and enhances the effects of cocaine on DA transmission, while disrupting Hcrtr1 attenuates DA responses to cocaine. These findings have led to the perspective that HCRT exerts its effects through Hcrtr1 actions in VTA DA neurons. However, this assumption is complicated by the observation that Hcrtr1 are present on both DA and GABA neurons in the VTA and HCRT drives the activity of both neuronal populations. To address this issue, we selectively knocked down Hcrtr1 on either DA or GABA neurons in the VTA and examined alterations in DA transmission and cocaine self-administration in female and male rats. We found that Hcrtr1 knockdown in DA neurons decreased DA responses to cocaine, increased days to acquire cocaine self-administration, and reduced motivation for cocaine. Although, Hcrtr1 knockdown in GABA neurons enhanced DA responses to cocaine, this manipulation did not affect cocaine self-administration. These observations indicate that while Hcrtr1 on DA versus GABA neurons exert opposing effects on DA transmission, only Hcrtr1 on DA neurons affected acquisition or motivation for cocaine - suggesting a complex interplay between DA transmission and behavior.