David J. Barker, BS, MS - US grants

DESCRIPTION (provided by applicant): The development of effective behavioral or pharmacological treatments for cocaine dependence relies on increasing our understanding of the behavioral and neural correlates of drug-seeking. Positive and negative affective states both have a reported role in the initiation of drug use (Newcomb & Felix-Ortiz 1992), bingeing behavior (Barker et al., 2010; Maier et al., 2010), withdrawal (Covington & Miczek 2003; Barros & Miczek 1996; Mutschler & Miczek 1998a; Mutschler & Miczek 1998b), or relapse (Hodgins et al., 1995). Still, studies investigating the neurobiological correlates of affect and the role affect plays in drug dependence are limited. Over the last fifteen years, the hypothesis that the affective states of rats can be reliably indexed through ultrasonic vocalizations (USVs) has received much support; 50-kHz USVs and 22-kHz USVs are consistently reported to be correlated with indices of positive and negative affective states, respectively, in adult rats in a variety of experimental paradigms. Incorporating USVs with self-administration behavior would therefore allow for a more comprehensive animal model of addiction. Preliminary results from our lab (Barker et al., 2010) suggest that doses of cocaine that prevent drug 'satiety' produce a higher ratio of negative affective USVs while those that allow animals to reach their preferred blood concentration produce a higher ratio of positive affective USVs. Research examining the neurochemistry of USV production has suggested that two separate but overlapping systems modulate 22- and 50-kHz USVs, respectively. The first of these systems-the mesolimbic dopamine system-has a purported role in the modulation of 50-kHz USVs. On the other hand, 22-kHz USVs are thought to be modulated by a second, cholinergic circuit originating in the laterodorsal tegmental nucleus (Brudzynski, 2008). One key region of overlap between these systems is the nucleus accumbens. Appropriately, eletrophysiological and neurochemical evidence has also implicated the NAcc in processing appetitive and aversive outcomes (e.g. Wheeler et al., 2008) as well as facilitating approach and avoidance behaviors (e.g. Rada & Hoebel, 2001; Hoebel, Avena, & Rada, 2007) To further investigate the neural substrates of affective processing during self-administration, as well as the role that affect plays in the reinstatement of drug-seeking behavior, we will record ultrasonic vocalizations, and the firing of NAcc core and medial shell neurons during a zero dose saline condition, two self-administered cocaine doses, and tests of reinstatement. PUBLIC HEALTH RELEVANCE: The proposed research is in line with NIDA's strategies for the prevention of drug use and prevention of escalated intake in current substance users. Specifically, the project serves to inform our understanding of the neurobiological substrates of affect and provide insight into the role affect may play in influencing the brain circuitry involved in the initiation of drug use, bingeing, withdrawal, and relapse.

Project Summary/Abstract Drug addiction is a complex neurological disorder which produces aberrant function in limbic circuits and limbic-associated structures. One specific portion of the basal forebrain?the lateral preoptic area?serves as an important relay between limbic structures and the lateral habenula, a region that has been implicated in addiction and depression. Under the primary mentorship of Drs. Marisela Morales and Geoffrey Schoenbaum, the present Pathway to Independence award will allow me to obtain training in electron microscopy and in vivo calcium imaging in order to elucidate the role of the preopto-habenular projection in the processing of rewarding and aversive stimuli, and eventually the role that this circuitry plays in cocaine addiction. In the mentored phase of this grant, I will use a combination of viral tracers and immuno-electron microscopy in order to determine the targets of the lateral preoptic area glutamatergic and GABAergic axons that establish synapses on lateral habenula neurons and to determine how individual differences in postsynaptic receptors contribute to individual differences in the processing of rewarding and aversive stimuli. Subsequently, fiber photometry calcium imaging will be used in order to determine how the terminals of lateral preoptic glutamatergic and GABAergic neurons in the lateral habenula process rewarding or aversive outcomes and their associated cues. In the independent phase, I will combine these cutting-edge techniques with my prior training in order to simultaneously record the axon terminals of lateral preoptic neurons in the lateral habenula using fiber photometry and the responses of the postsynaptic cells in the lateral habenula using single-unit electrophysiological recordings in order to establish a role for the preopto-habenular pathway in cocaine self-administration, punishment-imposed abstinence, and cued reinstatement. In summary, the research proposed in this Pathway to Independence Award will elucidate the ultrastructural architecture and functional mechanisms of a novel circuit that participates in cocaine self-administration while simultaneously providing me with the tools to establish an independent research program capable of producing high impact studies that bridge anatomical data with cutting-edge techniques for examining circuit function.