Dopaminergic and Glutamatergic Mechanisms Mediate the Induction of FOS-Like Protein by Cocaethylene

Abstract

Cocaethylene is a psychoactive metabolite formed during the combined consumption of cocaine and ethanol. As this metabolite has many properties in common with cocaine, it is conceivable that cocaethylene administration may induce the activity of nuclear transcription factors that regulate the expression of late-response genes. Therefore, the temporal induction of FOS-like protein in rat brain was examined following IP administration of 60 μmol/kg cocaethylene. Immunoreactivity for the protein was detectable at 1 h in striatal neurons and had virtually disappeared 6 h after drug treatment. Administration of specific dopaminergic (SCH-23390; 0.5 mg/kg) and glutamatergic (MK-801; 1 mg/kg) receptor antagonists prior to cocaethylene indicated a significant role for dopamine (D1) and N-methyl-d-aspartate receptor subtypes in mediating the nuclear induction of the aforementioned transcription factor protein. In contrast, no significant effects on FOS-like protein in discrete neurons of the caudate putamen were found when spiradoline (U-62066), a kappa opioid-receptor agonist, was administered either IP (10 mg/kg) or directly (50 nmol) into the brain parenchyma. In addition, we uncovered a differential sensitivity of Long-Evans rats to the behavioral effects of cocaethylene, with the psychoactive metabolite producing significantly less behavioral activity (e.g., locomotion, rearing, and continuous sniffing) than that produced by cocaine (molar equivalent of 60 μmol/kg cocaethylene). These findings indicate both common and disparate effects of cocaethylene and its parent compound, cocaine, on receptor pathways that regulate target alterations in gene expression and drug-induced motor behavior.