Nucleus Accumbens Mu-Opioid Receptor Involvement in Cocaine Addiction
Simmons, Diana Lynn
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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.