DELAYED-EFFECTS OF SPIPERONE ON SEROTONIN(1A) RECEPTORS IN THE DORSALHIPPOCAMPUS OF RATS

The effects of 5-HT1A antagonists spiperone, methiothepin and BMY 7378 on [H-3]-8-OH-DPAT binding were determined in vitro and ex vivo in ra t hippocampus CA3 membrane preparations, and ex vivo in tissue section s of CA1 and CA3 subfields using quantitative autoradiography. In CA3 membranes from rats sacrificed 1 h or 24 h after administration of 5 m g/kg i.p. spiperone or methiothepin, no decrease in [H-3]-8-OH-DPAT B( max) values approached statistical significance. Autoradiograms from i dentically treated rats showed significant increases in K(d) values in both CA1 and CA3 hippocampal subfields 24 h but not 1 h after adminis tration of the drugs, while no changes were observed in the dorsal rap he at either time. In vitro co-incubation of membranes with spiperone (200 or 500 nM) or methiothepin (500 nM) resulted in significant decre ases in both affinity and B(max) values. In contrast, co-incubation wi th BMY 7378 (5 nM) increased only K(d) values. GTP(gamma)S produced a concentration-dependent inhibition of specific [H-3]8-OH-DPAT binding. At 0.1 mM of GTP(gamma)S, K(d) values were increased three-fold and B (max) values were significantly decreased. When membranes were co-incu bated with GTP(gamma)S and spiperone or BMY 7378, K(d) values increase d further. Moreover, the effects of spiperone and GTP(gamma)S on B(max ) values were additive. It is concluded that BMY 7378 acts as a compet itive antagonist at hippocampal post-synaptic 5-HT1A receptors, wherea s spiperone and methiothepin exert their delayed antagonistic effects at these receptors through a non-competitive mechanism of action, poss ibly affecting the coupling of the receptors to their G(i/o) proteins.