Hypocretin receptor 1 knockdown in the ventral tegmental area attenuates mesolimbic dopamine signaling and reduces motivation for cocaine

The hypocretin receptor 1 (HCRTr1) is a critical participant in the regulation of motivated behavior and dopamine (DA) signaling, likely through actions on the VTA. However, while hypocretin signaling appears to influence some degree of VTA activity, its ongoing neuromodulatory role remains somewhat unknown. To further examine the involvement of VTA-HCRTr1 in regulating reward and reinforcement processing, we develop a viral technique to induce long-term knockdown of HCRTr1 expression in the VTA, and measure effects on motivated behavior, DA neurotransmission, and cell activity in the nucleus accumbens (NAc). We determine that viral knockdown induces sustained downregulation of HCRTr1 specifically in VTA, without producing toxicity, and without altering the expression of proteins important for DA synthesis and transport. HCRTr1 knockdown also delays the acquisition of cocaine self-administration, and reduces the motivation to pursue cocaine reinforcers, without affecting arousal. Additionally, we observe that HCRTr1 knockdown dramatically reduces baseline dopamine release, and attenuates the effects of cocaine on DA uptake. We then targeted HCRTr1 in only dopamine-producing cells of the VTA, and determined that such knockdown reduces DA release under low doses of cocaine, while impairing the inhibition of DA uptake inhibition of high dose of cocaine, and changes the firing pattern of cells in the NAc. Together this research helps establish viral knockdown as an important experimental technique, and provides critical information for understanding how the hypocretin system regulates addictive processes.Ph.D., Neuroscience -- Drexel University, 201