Investigations into the Role of Orexin (Hypocretin) and Dynorphin in Drug Seeking, Reinforcement, and Withdrawal

Abstract

Psychostimulant dependence remains a major health and economic problem, leading to premature death and costing $181 billion annually in health care, crime, and lost productivity costs. Currently, no pharmacotherapies are available to effectively treat psychostimulant dependence. Psychostimulants cause changes in neural circuits involved in reward and affect, but addiction neurocircuitry is incompletely understood and new targets for therapeutic intervention are needed. Lateral hypothalamic orexins (hypocretins) have been shown to have functional roles in arousal, reward processing, attention, motivation, and impulsivity. The opioid peptide dynorphin, co-localized with orexin, has critical roles in producing negative affective emotion states through interactions with, among others, stress circuitry. Orexin-dynorphin neurons project to neural substrates governing positive and negative motivated behavior, including the bed nucleus of the stria terminalis (BNST), amygdala, locus coeruleus and ventral tegmental area (VTA). Orexin and dynorphin modulate post-synaptic membrane activity through opposing signaling mechanisms; while orexins bind to predominantly excitatory orexin-1 and -2 G-protein coupled receptors, dynorphins bind to predominantly inhibitory G-protein coupled kappa opioid receptors (KORs). Multiple psychopathologies, including anxiety and substance abuse disorders, are characterized in part by alterations in orexin-dynorphin signaling. While these peptides have been shown to co-localize within single presynaptic vesicles and exert opposing effects on post-synaptic membrane potentials, the utility of producing oppositely-behaving peptides and the implications on psychopathologies remains unknown. The present studies were conducted to explore the role of orexin and dynorphin activity in cocaine’s rewarding effects as well as the negative effects of withdrawal. To accomplish this, we measured 1. Effects of orexin and cocaine administration on impulsive behaviors that increase the likelihood of psychostimulant addiction, using 5-choice serial reaction time task in concert with systemic and site directed pharmacology. 2. Effects of orexin and dynorphin on motivation for cocaine administration and intracranial self-stimulation. Using immunohistochemistry, ultrasonic vocalizations, and fast scan cyclic voltammetry we explored possible dopaminergic mechanisms of orexin and dynorphin contributions to reward. Lastly 3. Effects of orexin, dynorphin and chronic cocaine on withdrawal-induced anhedonia using intracranial self-stimulation, elevated plus maze, and correlations with immunohistochemistry and plasma corticosterone levels to explore further mechanisms. The results of this dissertation support our hypothesis that orexin receptor activity contributes to cocaine-induced impulsivity, motivation to self-administer cocaine and the reinforcing effects of psychostimulants. Dynorphin activity contributes to anhedonia and anxiety seen during drug abstinence after chronic exposure. Orexin and dynorphin exert these effects, in part, by modulating activity of dopaminergic neurons projecting from the ventral tegmental area to the nucleus accumbens.