Mesoaccumbens dopamine signaling alteration underlies behavioral transition from tolerance to sensitization to morphine rewarding properties during morphine withdrawal.

Although the firing activity of dopamine (DA) neurons in the ventral tegmental area (VTA) and the behavioral response to morphine rewarding properties alter as opiate withdrawal, little is known about the dynamic changes in DA signal pathway from the VTA to the nucleus accumbens (NAc) during prolonged withdrawal, and whether the changes are indicative of vulnerability to relapse of drug abuse. Here we report that morphine spontaneously withdrawn (SW) rats are incapable of responding to small dose of morphine-induced conditioned place preference (CPP) from 24h-SW to 30d-SW, but recover response at 45d-SW. Interestingly, mesoaccumbens DA signaling, including the firing of DA neurons in the VTA, contents of DA and its metabolic ratio, and the membrane level of dopamine D1 receptor in the NAc elicited by morphine challenge, display a similar pattern of time-dependent changes during morphine withdrawal. Moreover, blockade of D1 receptor abolishes this behavioral transition. In addition, a strong correlation was found between % change in CPP score and membrane D1 receptor level induced by morphine challenge. These results indicate a time-dependent behavioral switch from tolerance to sensitization during the prolonged withdrawal, which could offer a window for therapeutic intervention via manipulations of D1 receptors.