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 examine the in vivo intrinsic efficacy of the 5-HT1A receptor antagonists NAD-299, S(-)-UH-301 and WAY-100,635. The rate of monoamine synthesis was estimated by measuring the accumulation of DOPA and 5-HTP in the ventral neostriatum and the ventral hippocampus in rats pretreated with an inhibitor of cerebral 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 administration of NAD-299 (0.75-12.0 mu mol kg(-1)) resulted in a slight increase in neostriatal, but not hippocampal, 5-HTP acccumulation. Neostriatal DOPA accumulation was decreased by S(-)-UH-301, whereas treatment with WAY-100,635 resulted in an increase. NAD-299 did not affect neostriatal DOPA levels. There were no effects by any of these agents on DOPA levels in the ventral hippocampus. 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, whereas 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 antagonist. (C) 1999 Elsevier Science B.V./ECNP. All rights reserved.