Involvement of dopaminergic receptor signaling in the effects of glutamatergic receptor antagonists on conditioned place aversion induced by naloxone in single-dose morphine-treated rats

A better understanding of the neurochemical mechanisms mediating the aversive consequences of drug withdrawal is important for understanding drug addiction. We previously demonstrated that the inhibitory effect of glutamate receptor antagonists on the conditioned place aversion (CPA) induced by naloxone-precipitated withdrawal after a single morphine exposure could be blocked by dopamine receptor antagonists. Thus, a glutamatergic-dopaminergic interaction may participate in this phenomenon. The current study was undertaken to further characterize this interaction by employing both D ₁ (SCH 23390) and D ₂ (raclopride and eticlopride) dopamine receptor antagonists. The influence of these antagonists on the attenuation of CPA by MK-801 (NMDA receptor antagonist), GYKI 52466 (AMPA receptor antagonist), and MCPG (metabotropic glutamate receptor antagonist) was determined in rats receiving a single dose of morphine. The dopamine antagonists showed either a significant reversal or a tendency to reverse the effects of MK-801 on CPA. The effect of GYKI 52466 was also attenuated by the blockade of either D ₁ or D ₂ receptors. The effect of MCPG, however, was only blocked by D ₂ antagonists and not by the D ₁ antagonist SCH 23390. These results add evidence to the hypothesis that a glutamatergic-dopaminergic interaction may be involved in the CPA induced by naloxone-precipitated withdrawal following a single morphine exposure and suggest that both D ₁ and D ₂ dopamine receptor signaling mechanisms play a role in mediating the aversive aspects of acute dependence.