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 responses to stressful stimuli. First, a series of NFY receptor agonists were examined for their potential effects on punished responding in a conflict test modified for incremental shock. NPY, peptide YY (PYY) and NPY Y-1 receptor agonists [Leu(31), Pro(34)]-NPY and [Gly(6), Glu(26), Lys(29), Pro(34)]-NPY produced increases in punished responding in the conflict test. No significant effects on unpunished responding were noted. The pattern of responding was similar to that observed with the benzodiazepine 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 significance, the atypical Y-1 agonist [Cys(7,21),Pro(34)]- NPY produced negligible effects on punished responding, consistent with the presence of a subclass of YI receptors. Second, the anxiolytic effects of NPY were subjected to treatments that block actions at the GABAa receptor complex. The increase in punished responding produced by NPY was not altered by administration of the benzodiazepine antagonist flumazenil and only partially blocked by the picrotoxinin receptor ligand isopropylbicyclophosphate (10 and 15 mu g/kg). These findings further support the hypothesis that the pharmacologic substrates for the anxiolytic-like actions of NPY may be mediated by the Y-1 receptor subtype and suggest that these actions are independent of either the benzodiazepine or picrotoxinin binding sites of the GABA/benzodiazepine receptor complex.