Dopamine (DA) signaling has received considerable attention for its role in reward-related processes, including the motivation to seek drugs and relapse in response to drug-associated cues (1-4). Destruction of DA cells in the ventral tegmental area (VTA), or DA terminals in regions such as the nucleus accumbens, disrupts drug self-administration (5-6) and administration of DA receptor antagonists attenuates the ability of drug-associated stimuli to promote reinstatement (7). In human addicts, striatal DA release in response to drug-associated stimuli is associated with increased drug craving and future relapse (8,9). Though DA has been generally implicated in drug taking and relapse, DA systems have thus far not been manipulated with the temporal precision and cell-type specificity required to isolate their role in specific aspects of those behaviors. Optogenetic tools have been applied to target DA neurons in transgenic mice, demonstrating that DA signaling supports behavioral conditioning and facilitates instrumental responding for food (20-21). More recently, a Th:Cre transgenic ratline was developed that allows for the selective targeting of DA neurons with optogenetic methods (22-23) in more complex behavioral paradigms optimized for use in rats. In this proposal, I will utilize Th:Cre rats, incorporating in vivo optogenetics and electrophysiology in combination with sophisticated behavioral analyses, to probe the causal contribution of DA signaling to different aspects of instrumental cocaine intake and relapse in response to Pavlovian cocaine stimuli. First, in Aim 1 I propose to test the sufficiency of VTA DA neuron activation to modulate cocaine self-administration and cocaine cue-induced reinstatement. Second, in Aim 2 I propose to test the necessity of DA signaling, via inhibition of VTA DA neurons, for cocaine intake and reinstatement. Additionally, the VTA contains a heterogeneous mixture of not only DA neurons, but also a substantial fraction of non-DA neurons that contribute to motivational processing (11-19), but little is known about how different populations of neurons in the VTA encode drug-related behaviors. Thus, in Aim 3 I propose to characterize the firing patterns optogenetically-identified VTA DA neurons (16) during self-administration and reinstatement.
Addiction, which is characterized by compulsive drug seeking and a high probability of relapse, is a major public health problem in the United States. The goal of this project is to examine the causal contribution of brain dopamine systems to cocaine intake and relapse, with the hope of identifying therapeutic targets that will foster the development of addiction treatments.