Effects of prolyl-leucyl-glycinamide and cyclo(leucyl-glycine) on the supersensitivity of dopamine receptors in brain induced by chronic administration of haloperidol to rats

Abstract

The effects of melanotropin release-inhibiting factor, a tripeptide (Pro-Leu-Gly-NH 2) derived from the hypothalamus, and its enzymatically stable analog, cyclo(Leu-Gly) on the supersensitivity of dopamine receptors in brain induced by chronic administration of haloperidol to male Sprague-Dawley rats was determined. Oral administration of haloperidol (1.5 mg/kg per day) for 21 days induced supersensitivity of dopamine receptors as shown by enhanced locomotor activity in response to apomorphine, and an increase in the number of binding sites for [ 3H]spiroperidol in the striatum. Subcutaneous administration of Pro-Leu-Gly-NH 2 or cyclo(Leu-Gly) in doses of 2 mg/kg per day, given prior to the injection of haloperidol, inhibited both the enhanced response to apormorphine as well as the increase in the number of binding sites for [ 3H]spiroperidol in the striatum. Chronic administration of either of the peptides alone did not modify either the apomorphine-induced response or the binding of [ 3H]spiroperidol in the striatum. These studies suggest that the hypothalamic peptide, Pro-Leu-Gly-NH 2 and its long-acting analog, cyclo (Leu-Gly) can prevent the development of both behavioral and biochemical supersensitivity of dopamine receptors in brain induced by neuroleptic drugs and that these peptides may be useful in preventing the development of neuroleptic-induced tardive dyskinesia.