Date of Award

2016

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience

College

College of Graduate Studies

First Advisor

Arthur Riegel

Second Advisor

Peter Kalivas

Third Advisor

Joseph B. Blumer

Fourth Advisor

Prakash Kara

Fifth Advisor

Howard Becker

Sixth Advisor

David Lovinger

Abstract

Reward learning involves burst firing of midbrain dopamine neurons in the Ventral Tegmental Area (VTA). The resulting dopamine release from VTA terminals instructs regions like the prefrontal cortex (PFC) about rewards and reward-related cues. Glutamatergic PFC neurons initiate motivated behaviors via innervation of the nucleus accumbens. Chronic use of drugs of abuse such as cocaine disrupts this natural reward pathway, leading to enduring cellular adaptations in dopaminergic signaling that contribute to relapse vulnerability. However, how dopamine modulates activity in this circuitry is not known. We posit that dopamine release from VTA terminals gates intrinsic inhibition in the PFC via a dopamine D1 receptor mediated reduction in potassium channel function. By blocking dopamine reuptake in the cortex, cocaine elevates dopamine signaling at these receptors, increasing D1 receptor activation and the subsequent activation of intracellular signaling cascades. We propose that disruptions in these mechanisms following chronic cocaine use contribute to addiction pathology, resulting in long–lasting reductions in intrinsic inhibition that contribute to drug-seeking in response to cues. We test this hypothesis using the extinction–reinstatement rodent model of cocaine addiction. This in vivo protocol resembles the human condition, in that exposure to drug-associated cues induces drug-seeking behavior. In combination with in situ electrophysiology, chemogenetics, optogenetics, and retrograde tracing, we show that activation of VTA terminals reduces intrinsic inhibition in accumbens core-projecting prelimbic (PL) PFC cells. Operant cocaine self-administration renders PL cells hypersensitive to depolarization via elevated D1 receptor signaling, resulting in calcium store dependent desensitization of inhibitory Kv7 potassium channels and an enduring reduction in intrinsic inhibition. The deficit in Kv7 function and intrinsic inhibition is overcome by pharmacological stabilization of Kv7 channels with retigabine, which when microinjected into the PL reduces cue-induced reinstatement of cocaine-seeking. These studies underscore the significance of dopamine modulation of intrinsic inhibition in accumbens-projecting PL neurons as a mediator of relapse to drug seeking, and offer Kv7 as a potential novel drug target for cocaine addiction.

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