Neural mechanisms of anxiety during opiate withdrawal:role of the ventral tegmental area and extended amygdala.

Abstract

Exposure to addictive drugs alters neural circuits involved in reward and motivation, executive control, habit formation, learning and memory, and negative affect, and all except the last are known to depend on changes in the mesolimbic dopamine system. Negative affective symptoms of withdrawal are common to all drugs of abuse and negatively reinforce drug taking behavior. Using potentiation of the acoustic startle reflex as a measure of anxiety during withdrawal from acute morphine exposure, the experiments detailed in this thesis tested the hypothesis that µ-opioid receptor-mediated activation of VTA dopaminergic neurons is responsible for triggering negative emotional symptoms of withdrawal via recruitment of the extended amygdala. These experiments demonstrate the emergence of a negative affective state that occurs during withdrawal from direct infusion of morphine into the ventral tegmental area (VTA), the origin of the mesolimbic dopamine system. Potentiation of startle during withdrawal from systemic morphine exposure requires a decrease in ì-opioid receptor stimulation in the VTA and can be relieved by systemic or intra-nucleus accumbens administration of a dopamine receptor agonist. Investigation of mechanisms downstream of dopaminergic signaling found a role for type 2 corticotropin-releasing factor receptors following the very first, but not subsequent, opiate exposures. Together these results suggest that transient activation of the VTA mesolimbic dopamine system triggers the expression of anxiety during opiate withdrawal, possibly via direct recruitment of the extended amygdala. This conclusion provides unique insight into the neural mechanisms responsible for negative reinforcement of drug taking during the earliest stages of dependence.