Pathway-Specific Modulation of Motivation and Mood in Cocaine Addiction

Ut Southwestern Medical Center, Dallas TX

Investigators

Abstract

? DESCRIPTION (provided by applicant): Cocaine addiction is a chronic relapsing disorder with deleterious health consequences. Cocaine addicts often suffer from other psychological disorders, such as depression, which can complicate treatment efforts. Currently there are no effective pharmacological therapies for cocaine addiction, and existing rehabilitation programs in the United States have low success rates. Part of the issue is an incomplete understanding of the neural mechanisms underlying the dysregulations in behavior and mood accompanying drug addiction. The objective of the proposed research is to determine which pathways in the brain are responsible for the severe alterations in motivation and mood due to cocaine use. The nucleus accumbens is a key region in the brain's reward circuit that has been shown to be involved in both positive and negative affective states. The accumbens projects to several other brain regions such as the ventral tegmental area and the ventral pallidum, and these pathways are believed to regulate different aspects of motivation and mood. Specifically, the projection from the accumbens to the ventral tegmental area (known as the direct pathway) is involved in the initial rewarding effects of drugs and responses to pleasurable stimuli. The projection to the ventral pallidum (known as the indirect pathway) is involved in mediating drug seeking after chronic drug use as well as responses to stressful stimuli. Therefore the hypotheses to be tested in the proposal are that driving activity in the direct pathway will promote drug-taking and positive mood, whereas driving activity in the indirect pathway will have the opposite effect. Unti recent technological advances it has been very difficult to specifically manipulate each pathway separately to thoroughly examine their respective contributions. The proposed study will make use of novel optogenetic techniques to selectively activate the direct and indirect pathways in rats trained to self-administer cocaine to test their respective roles in addiction and mood. Mood will be assessed using the forced swim test and sucrose preference test, well-established procedures to detect despair-like and anhedonic behavior in rodents, respectively. Finally, to further understand these pathways on a physiological level the proposed research will make use of immunohistological and electrophysiological techniques to analyze neural tissue after optogenetic stimulation. The results from these studies will provide critical insight into the neurl pathways responsible for addiction-related alterations in motivation and mood. Furthermore, these findings could lead to innovative treatment options targeting individual circuit mechanisms.