Modulatory effects of PLG and its peptidomimetics on haloperidol-induced catalepsy in rats

A behavioral model of dopaminergic function in the rat was used to ex ami ne the anticataleptic effects of L-prolyl-L-leucyl-glycinamide (PLG) and peptidomimetic analogs of PLG. Administration of 1 mg/kg PLG intraperitoneally significantly attenuated haloperidol (1 mg/kg)-induced catalepsy (as measured by the standard horizontal bar test), whereas doses of 0.1 and 10 mg/kg PLG did not. Eight synthetic PLG peptidomimetics (C alpha, alpha-dialkylated glycyl residues with lactam bridge constraint [1-4] and without [5-8]) were tested in the same manner (at a dose of 1 mu g/kg) and categorized according to their activity, i.e. very active (5), moderately active (2, 3, 4, and 6), and inactive (1, 7, and 8). The catalepsy-reversal action of the diethylglycine-substituted peptidomimetic 5 was examined further and found to exhibit a U-shaped dose-response effect with an optimal dose of 1 mu g/kg. The similarity between the effects of PLC and the synthetic peptidomimetics suggests a common mechanism of action. Finally, the synthetic peptidomimetics examined here, particularly peptidomimetic 5, were more effective than PLG in attenuating haloperidol-induced catalepsy. (C) 1999 Elsevier Science Inc. All rights reserved.