Prevention and reversal of dopamine receptor supersensitivity by cyclo(leucyl-glycyl) (CLG): Biphasic dose-response curves

Abstract

Chronic administration (21 days) of haloperidol (HAL) (IP, 1.0 mg/kg/day) induced a behavioral supersensitivity (stereotypic sniffing) to dopamine (DA) agonists (apomorphine) and upregulation (increased B max for sulpiride-inhibitable [ 3H]spiroperidol binding) of striatal and limbic 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 behavioral changes and 2) that the biphasic CLG dose-response curve may involve CLG failure at high cumulative doses to lower B max. CLG also reversed an already established D 2 DAr supersensitivity/upregulation (i.e., when CLG was injected daily for four days after the withdrawal or HAL). CLG alone did not alter behavior or binding. CLG's ability to both prevent and reverse D 2 DAr upregulation/supersensitivity in animal 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).