The role of Hypocretin Receptor 1 in the Ventral Tegmental Area in Modulating Motivated Behavior and Dopamine Neurotransmission

Drexel University, Philadelphia PA

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Abstract

? DESCRIPTION (provided by applicant): The Hypocretin-1 (HCRTr1) receptor may play a substantial role in drug addiction. Previous research suggests that this receptor is capable of modulating reward-seeking behavior through actions on the brain's reward circuitry. However, most of this research utilizes acute, non-specific manipulations to HCRT signaling. Consequently, little is known about the long-term, modulatory role of HCRTr1 in specific brain regions, including reward-associated areas such as the Ventral Tegmental area (VTA). It is also unclear how this relationship affects the activity of brain regions that receive significant input from the VTA, such as the Nucleus Accumbens (NAc), or how this impacts behavior. We investigate these issues by using an adeno-associated virus to selectively reduce HCRTr1 expression in the VTA, and measuring the effects on reward circuit function. We measure these effects using a variety of neuroscience techniques. First, we assess the effects on the acquisition and maintenance of cocaine self administration behavior. Next, we characterize the effects on dopamine (DA) neurotransmission in the NAc. We assess presynaptic DA release and uptake using Fast Scan Cyclic Voltammetry. Next, we characterize the effects on the firing of medium spiny neurons (critical for modulating motivated behavior) in NAc, using multiunit electrophysiology. Finally, we assess the effects on DA synthesis and trafficking proteins, using western blotting. This research elucidates the long-term modulatory role of HCRTr1 in the VTA, and may provide critical data for guiding the development of future HCRTr1-based therapeutic treatments.