Vulnerability for cocaine dependence / Involvement of µ-opioid receptors

Drug dependence is a major health issue worldwide, which is characterised by its persistence and high rates of relapse. Individual differences exist in the vulnerability for drug dependence after first exposure to drugs of abuse like cocaine. A likely risk factor for drug dependence is the sensitivity to the positive reinforcing effects of drugs of abuse. The studies described in this thesis reveal an important role of µ-opioid receptors in the sensitivity to cocaine reinforcement. Knockout mice, that lack the gene encoding the µ-opioid receptor, were impaired in cocaine self-administration, suggesting that they are less sensitive to the reinforcing effects of cocaine. In contrast, both acute and chronic cocaine-induced locomotor activity were not subjective to changes in absence of µ-opioid receptors. Therefore, µ-opioid receptors appear to have an important and specific role in modulating cocaine reinforcement. Further studies described in this thesis provide insight into the mechanism of µ-opioid receptor mediated modulation of cocaine reinforcement. Cocaine self-administration was associated with pro-opiomelanocortin (POMC) expression in the arcuate nucleus, suggesting that POMC and POMC-derived peptides, like the µ-opioid receptor selective peptide â-endorphin, might contribute to cocaine reinforcement. In absence of µ-opioid receptors, increased GABAergic inhibitory input onto dopamine neurons in the ventral tegmental area was observed. It is proposed that regulation of GABAergic neurotransmission in the VTA contributes to µ-opioid receptor mediated modulation of cocaine reinforcement. Considering the important role of µ-opioid receptors in cocaine reinforcement, variations in µ- opioid receptors might contribute to vulnerability for cocaine dependence. Future studies, both preclinical and clinical, should confirm that variations in µ-opioid receptors indeed contribute to the risk for cocaine dependence. This knowledge may lead to improved strategies in prevention and treatment of drug dependence