Source: Dissertation Abstracts International, Volume: 78-07(E), Section: B.

Adviser: Jane Rebecca Taylor.

The successful prevention of relapse is the gold standard outcome when treating substance use disorders. Often, a trigger for relapse is exposure to environmental stimuli, or cues, which are associated with drug use, such as the smell of cigarette smoke. These cues create a strong desire to seek and use drugs, which leads to relapse. The midbrain dopamine (DA) system encodes these cues, which can be predictive of both natural rewards (e.g., food) as well as drugs of abuse. Specifically, upon cue presentation, DA neurons in the ventral tegmental area (VTA) transition from tonic-like firing (3-8Hz) to bursting (>14 Hz) which produces large, subsecond increases in phasic DA signaling in the nucleus accumbens core (NAc). Phasic DA signaling is defined as a large (>10nM) and transient (~1s) change in DA concentration in contrast to the background or tonic levels of dopamine, which change at a much slower time scale (minutes). Thus, phasic DA signaling events are thought to capture ongoing changes in the environment, such as the indication of the availability of food or drug. Functionally, phasic NAc core signaling, especially upon activation of D1 receptors, is critical for the ability of cues to drive food and drug-seeking behaviors. However, prior to my dissertation, the specific VTA receptor mechanisms underlying phasic DA signaling and permitting drug cues to drive relapse was unknown. Using a combination of in vivo fast-scan cyclic voltammetry and behavioral pharmacology, my dissertation work determined the critical VTA receptor mechanisms mediating (1) phasic DA signaling in the NAc, (2) cue-induced drug-relapse, and (3) cue-induced food-relapse as well as defined the distinct receptor types that mediate relapse to these two different types of reward.

In Chapter 1, I provide a broad overview of dopamine signaling and its role in driving both reward and cue driven behavior. In Chapter 2, I probed the VTA receptor mechanism underlying phasic DA signaling in the NAc core. My hypothesis was informed by work suggesting that the VTA receives strong excitatory cholinergic inputs from the hindbrain as well as glutamatergic inputs from a variety of forebrain structures. In agreement with my hypothesis, using Sprague-Dawley rats under urethane anesthesia, blocking either the two different types of acetylcholine receptors (AChRs), the VTA ionotropic nicotinic AChRs (nAChRs) or the VTA metabotropic muscarinic AChRs (mAChRs), produced potent decreases in phasic DA signaling in the NAc. Critically, I identified the nAChR subtype, the alpha6beta2* nAChR (where the asterisk indicated the presence of other subunits) as the putative VTA nAChR which drives phasic DA release. Additionally, blockade of VTA glutamate receptors, specifically the NMDA receptor (NMDAR) produced strong decreases in phasic DA signaling in the NAc. These multiple excitatory receptor types are required for phasic DA signaling in the NAc, an essential part of the brain circuits involved in the VTA's encoding of reward cues. In Chapter 3, in collaboration with Dr. Wojciech Solecki and Dr. Eric Nunes, we blocked VTA nAChRs, mAChRs, or NMDARs in cue-induced cocaine or cue-induced sucrose-seeking paradigms, a measure of cue-dependent relapse behavior. We found that both VTA nAChRs and mAChRs were critical in driving cue-induced cocaine-seeking, but not VTA NMDARs. Moreover, we found that only VTA mAChRs, and not VTA nAChRs nor NMDARs, drove cue-induced food-seeking. Critically, these data suggest VTA nAChRs preferentially mediate cue-driven behaviors when the cue is paired with drug, but not food.

In Chapter 4, I demonstrated that blockade of VTA nAChRs decreased the reinforcing value of drug-paired cues, using a conditioned reinforcement task. Work from Dr. Jane Taylor's lab which supports my findings is discussed in the context of our results. In Chapter 5, limitations, future directions, and clinical implications of my dissertation work are discussed. The present work is of strong clinical importance as they point to potential nAChR-centered therapeutic approaches which can limit craving and relapse specifically induced by drug-paired cues, while preserving natural-reward paired cues role in regulating behavior.