Reduced psychostimulant effects on dopamine dynamics in the nucleus accumbens of μ-opioid receptor knockout mice

Abstract

Dopamine neurotransmission in the nucleus accumbens plays a pivotal role in the reinforcing properties of drugs of abuse. Two interacting processes regulate nucleus accumbens dopamine overflow: release of dopamine from presynaptic terminals and the subsequent reuptake by dopamine transporters. Opioid neurotransmission, primarily through μ-opioid receptors has also been strongly implicated in drug reward. We have previously shown that mice lacking the μ-opioid receptor display decreased cocaine self-administration. In addition, we found decreased impulse activity of midbrain dopaminergic neurons and an increased GABAergic input to these neurons in μ-opioid receptor knockout mice. In the present study we investigated whether these changes in dopaminergic cell bodies are accompanied by altered dopamine dynamics at the terminal level. To that aim, we measured nucleus accumbens dopamine overflow using fast scan cyclic voltammetry. Our data demonstrate that in μ-opioid receptor knockout mice 1) the reuptake of dopamine in the nucleus accumbens is slower, and 2) the relative effect of cocaine and amphetamine on the reuptake of dopamine is smaller compared with wild type mice. These data provide a mechanism for the decreased reinforcing properties of cocaine observed in μ-opioid receptor knockout mice.