The Role of Mu Opioid Receptors in the Behavioral Effects of Cocaine

Abstract

Animal models have proven to be useful tools for modeling human neurochemical and behavioral responses to drugs of abuse, including cocaine. Cocaine is a psychomotor stimulant that facilitates monoaminergic neurotransmission by binding to transporters and inhibiting the reuptake of dopamine, serotonin and norepinephrine into presynaptic neurons. Many of the behavioral effects of cocaine, including its locomotor-activating and reinforcing properties, have been attributed to the ability of cocaine to enhance dopaminergic activity. In addition to its direct effects on monoamine neurotransmitters, cocaine impacts other neurotransmitter systems including the endogenous opioid system. The effects of selectively antagonizing mu opioid receptors on cocaine-induced behaviors were evaluated during this research. This research also evaluated the effect of selectively antagonizing dopamine D1 or D2 receptors on cocaine-induced mu opioid receptor occupancy by endogenous opioid ligands. This research furthered our understanding of how the endogenous opioid and dopaminergic systems interact to mediate cocaine-induced behaviors. Although data support the role of mu opioid receptors in modulating cocaine-mediated locomotion and reward, the location of the mu opioid receptors involved has not been established. An evaluation of the effects of a selective mu opioid receptor antagonist administered directly into specific brain regions on cocaine-induced behaviors is important for understanding how the endogenous opioid and dopaminergic systems interact to mediate cocaine-induced behaviors. The studies outlined herein sought to determine the contribution of mu opioid receptors in specific regions of the mesocorticolimbic system to the rewarding and locomotor-activating effects of cocaine in the rat. In addition, to further understand the role of mu opioid receptors in cocaine reward, neuronal activation was studied via cFos activation following the expression of cocaine-induced place preference. Results of the research outlined herein demonstrate the importance of mu opioid receptors in cocaine-induced reward and activity, and demonstrate the anatomical selectivity of mu receptors within the nucleus accumbens, VTA and caudate putamen in this regard. These data suggest that cocaine causes the release of endogenous opioid peptides and that these peptides contribute to the rewarding and locomotor-stimulating effects of cocaine. Further, these data also suggest that opioid peptides are released in the nucleus accumbens shell during the expression of cocaine place preferences and that mu opioid receptors in this region are critical for the manifestation of this behavior. Although data demonstrate that extracellular levels of endogenous opioid peptides are increased following cocaine administration, the time- and dose-dependent occupancy of mu opioid receptors within specific brain regions had not been established in previous studies. The present research sought to determine the time- and dose-dependent occupancy of mu opioid receptors, measured indirectly by displacement of 3H-DAMGO binding, within specific brain regions. 3H-DAMGO binding was measured by in vitro autoradiography. In addition, the contribution of dopamine D1 and D2 receptors in cocaine-induced 3H-DAMGO displacement was evaluated. Results demonstrate that cocaine administration caused a dose- and time-dependent displacement of 3H-DAMGO binding to mu opioid receptors within the nucleus accumbens core and shell. This displacement was attenuated by pretreatment with a selective D2 dopamine receptor antagonist, demonstrating that cocaine, acting via D2 dopamine receptors, can cause the release of an endogenous opioid peptide that binds to mu opioid receptors within the nucleus accumbens core and shell. Previous studies have demonstrated that chronic administration of non-selective mu opioid receptor antagonists has profound effects on mu opioid receptor density and signaling. The research presented herein sought to determine whether chronic treatment with the selective mu opioid receptor antagonist, CTAP, would increase mu opioid receptor density and agonist-stimulated G-protein activation. In addition, this research sought to determine whether chronic CTAP administration would sensitize animals to the locomotor stimulating effects of cocaine. Results outlined herein demonstrate that chronic CTAP treatment sensitized animals to the locomotor effects of cocaine and that this sensitization occurred in conjunction with an increase in mu opioid receptor density within the nucleus accumbens core and shell.