ANXIOLYTIC ACTIVITY OF NPY RECEPTOR AGONISTS IN THE CONFLICT TEST

This investigation examined receptor subtype specificity and possible modulation by GABAa receptor ligands of NPY-induced behavioral respons es to stressful stimuli. First, a series of NFY receptor agonists were examined for their potential effects on punished responding in a conf lict test modified for incremental shock. NPY, peptide YY (PYY) and NP Y Y-1 receptor agonists [Leu(31), Pro(34)]-NPY and [Gly(6), Glu(26), L ys(29), Pro(34)]-NPY produced increases in punished responding in the conflict test. No significant effects on unpunished responding were no ted. The pattern of responding was similar to that observed with the b enzodiazepine agonist chlordiazepoxide. Neither pancreatic peptide (PP ) nor the Y-2 agonists NPY13-36 or [Glu(2,32),Ala(6),Dpr(27),Lys(28)]- NPY significantly altered punished or unpunished responding. Of signif icance, the atypical Y-1 agonist [Cys(7,21),Pro(34)]- NPY produced neg ligible effects on punished responding, consistent with the presence o f a subclass of YI receptors. Second, the anxiolytic effects of NPY we re subjected to treatments that block actions at the GABAa receptor co mplex. The increase in punished responding produced by NPY was not alt ered by administration of the benzodiazepine antagonist flumazenil and only partially blocked by the picrotoxinin receptor ligand isopropylb icyclophosphate (10 and 15 mu g/kg). These findings further support th e hypothesis that the pharmacologic substrates for the anxiolytic-like actions of NPY may be mediated by the Y-1 receptor subtype and sugges t that these actions are independent of either the benzodiazepine or p icrotoxinin binding sites of the GABA/benzodiazepine receptor complex.