In vivo intrinsic efficacy of the 5-HT1A receptor antagonists NAD-299, WAY-100,635 and (S)-(-)-UH-301 at rat brain monoamine receptors

The receptor-mediated control of brain monoamine synthesis was used to exam ine the in vivo intrinsic efficacy of the 5-HT1A receptor antagonists NAD-2 99, S(-)-UH-301 and WAY-100,635. The rate of monoamine synthesis was estima ted by measuring the accumulation of DOPA and 5-HTP in the ventral neostria tum and the ventral hippocampus in rats pretreated with an inhibitor of cer ebral aromatic L-amino acid decarboxylase. S(-)-UH-301 (2.0-32.0 mu mol kg( -1)), but not WAY-100,635 (0.08-1.2 mu mol kg(-1)), produced a decreased 5- HTP accumulation in the neostriatum and in the hippocampus. The administrat ion of NAD-299 (0.75-12.0 mu mol kg(-1)) resulted in a slight increase in n eostriatal, but not hippocampal, 5-HTP acccumulation. Neostriatal DOPA accu mulation was decreased by S(-)-UH-301, whereas treatment with WAY-100,635 r esulted in an increase. NAD-299 did not affect neostriatal DOPA levels. The re were no effects by any of these agents on DOPA levels in the ventral hip pocampus. It is concluded that S(-)-UH-301, but not WAY-100,635 or NAD-299, displays intrinsic efficacy at brain 5-HT1A and DA D-2/3 receptors, wherea s WAY-100,635 behaves as a DA D-2/3 receptor antagonist. By this comparison , NAD-299 appears to be the most selective and specific 5-HT1A receptor ant agonist. (C) 1999 Elsevier Science B.V./ECNP. All rights reserved.