PREVENTION AND REVERSAL OF DOPAMINE-RECEPTOR SUPERSENSITIVITY BY CYCLO(LEUCYL-GLYCYL) (CLG) - BIPHASIC DOSE-RESPONSE CURVES

Chronic administration (21 days) of haloperidol (HAL) (IP, 1.0 mg/kg/d ay) induced a behavioral supersensitivity (stereotypic sniffing) to do pamine (DA) agonists (apomorphine) and upregulation (increased B-max f or sulpiride-inhibitable [H-3]spiroperidol binding) of striatal and li mbic D-2 DA receptors (DAr). Coadministration of cyclo(leucyl-glycyl) (CLG; 8mg/kg, SC; every third day, every other day, but not every day) with HAL attenuated the behavioral supersensitivity. D-2-DAr binding assays showed 1) that CLG-induced changes in B-max parallel these beha vioral changes and 2) that the biphasic CLG dose-response curve may in volve CLG failure at high cumulative doses to lower B-max. CLG also re versed an already established D-2 DAr supersensitivity/upregulation (i .e., when CLG was injected daily for four days after the withdrawal of HAL). CLG alone did not alter behavior or binding. CLG's ability to b oth prevent and reverse D-2 DAr upregulation/supersensitivity in anima l models suggests that CLG may be useful, within a therapeutic window, in clinical disorders that are thought to involve upregulated DAr (e. g., tardive dyskinesia, L-DOPA-induced dyskinesias, and schizophrenia) .