The hypocretin system has been shown to impact the neural processes that support cocaine use via actions on hypocretin receptor 1 in the ventral tegmental area. Consequently, hypocretin receptors are posited to be a potentially valuable target for the treatment of cocaine addiction. To date, however, hypocretin-based treatment approaches have been met with limited efficacy largely due to lack of neuron-specificity of hypocretin receptor 1 manipulations. This poses a significant hurdle for understanding the therapeutic potential of hypocretin-based treatments since hypocretin receptor 1 are present on both dopamine and GABA neurons in the ventral tegmental area. To circumvent this limitation, I will use combinatorial viral approaches to selectively knockdown hypocretin receptor 1 in dopamine or GABA neurons of the ventral tegmental area, thereby allowing for selective examination of hypocretin manipulations on cocaine abuse. I will apply techniques such as ex-vivo fast-scan cyclic voltammetry and western blotting to query the effect of cell type-specific hypocretin receptor 1 knockdown on dopamine dynamics in the nucleus accumbens at baseline and in response to cocaine. Further, I will investigate the influence of hypocretin receptor 1 manipulations on dopamine dynamics across key phases of cocaine abuse using fast-scan cyclic voltammetry in self-administering rats. The proposed studies will afford the opportunity, for the first time, to uncover cell type-specific and real-time influences of hypocretin across acquisition, maintenance, extinction, and reinstatement of cocaine self-administration. Together, these findings will provide a more comprehensive understanding of hypocretin modulation of dopamine neurotransmission during cocaine self-administration and uncover potential targets for future development of treatment strategies for cocaine use disorder.
The hypocretin/orexin system has been shown to impact the neural processes that support cocaine use and as such, is posited to be a valuable target for the treatment of cocaine addiction. Despite this evidence, hypocretin-based treatment approaches used in preclinical research display limited efficacy largely due to lack of specificity of tools which preclude examination of neuron-specific influences of hypocretin. In the proposed research, I will utilize viral strategies combined with behavioral and neurochemical approaches to assess the extent to which cell type-specific manipulations of the hypocretin system modulate dopaminergic and behavioral responses to cocaine, which will enable future development of more effective temporally- and molecularly-targeted treatment approaches for cocaine use disorder.
