Mu-Opioid Receptors involvment in Cocaine addiction



Journal Title

Journal ISSN

Volume Title



The nucleus accumbens (NAc) receives dopaminergic input from the ventral tegmental area (VTA) and is intricately involved in the reinforcing properties of cocaine. Mu-opioid receptors (MOR) are highly expressed in the NAc and act to modulate glutamatergic and dopaminergic input in response to various stimuli. Chronic cocaine self-administration may modulate MOR expression and mediate increased craving and relapse that characterizes cocaine addiction. Chapter 3 determined MOR regulation by cocaine administration. Both contingent and non-contingent cocaine administration decrease MOR specifically in the core while delta opioid receptors (DOR) were not altered by chronic cocaine. Cocaine self-administration mediated down-regulation of MOR was ?-endorphin dependent since blockade of ?-endorphin prevented MOR phosphorylation, down-regulation, and endocytosis. Chapter 4 determined whether opioid receptor stimulation was sufficient to reinstate drug-seeking behaviors in extinguished animals. Both MOR and DOR specific agonists (DAMGO and DPDPE, respectively) induced cocaine seeking as did the endogenous opioids, ?-endorphin and endogenously released enkephalins. Blockade of MOR decreased cocaine-primed reinstatement, indicating MOR involvement in drug-primed reinstatement. Chapter 5 identified long-term neuroadaptations possibly involved in high craving and relapse rates typically seen in humans and modeled in animals. MOR expression increased with withdrawal time indicating a potential correlate of time-dependent increases in cocaine seeking in withdrawal. To determine whether the up-regulation of MOR translated into enhanced cocaine-seeking behavior, MOR stimulated locomotor activity and cocaine-seeking/reinstatement was assessed. Locomotor behavior in response to intra-NAc DAMGO infusions did not change after long-term withdrawal, however there were age variables that may have contributed to the negative data. When drug-seeking was assessed at 6 w withdrawal, animals had increased drug-seeking behavior compared to 1 w withdrawal animals, an effect that was potentiated by intra-NAc ?-endorphin. DAMGO increased relapse to cocaine-seeking at 6 w withdrawal with no effect at 1 w withdrawal. ?-endorphin primed reinstatement was similar in both groups however the effect was only significant in the 6 w withdrawal group. These findings indicate NAc MOR is regulated by cocaine self-administration and withdrawal and stimulation of MOR results in drug craving and relapse behaviors. Results further indicate a potential target in the treatment of cocaine addiction.