Repeated eticlopride administration increases dopamine D-2 receptor expression and restores behavioral flexibility disrupted by methamphetamine exposure to male rats

Repeated methamphetamine exposure impairs reversal learning in laboratory animals and downregulates dopamine D2 receptor expression. In the present study, we tested the possibility that repeated exposure to the dopamine D-2 antagonist, eticlopride, would increase D-2 receptor expression, improve behavioral flexibility and restore behavioral flexibility that was disrupted by exposure to methamphetamine in rats. Male Sprague-Dawley rats received repeated daily pretreatment with the dopamine D-2 antagonist, eticlopride (0.0 or 0.3 mg/kg/day, 14 days). Three days after the last treatment, whole brain (minus olfactory bulbs and cerebellum) dopamine D2 receptor expression was measured using flow cytometry in one group and reversal learning performance was measured in another group. Reversal learning was also measured in other groups prior to and after metham-phetamine exposure (0.0 or 2.0 mg/kg, 4 injections, 2 h apart, 1 day) followed by repeated eticlopride (0.0 or 0.3 mg/kg, 14 days) treatment. Eticlopride treatment increased D2 receptor expression and improved reversal learning performance. Methamphetamine impaired reversal learning performance and eticlopride treatment reversed the deficit. These results suggest that repeated administration of eticlopride can restore behavioral flexibility and that upregulation of D-2 receptors might be an effective adjunct to treatment of methamphetamine misuse.