Different effects on the responses of functional pre- and postsynaptic 5-HT 1A receptors by repeated treatment of rats with the 5-HT 1A receptor agonist 8-OH-DPAT

Abstract

The effects of repeated treatment of rats with 8-hydroxy-2-(di- n-propylamino)tetralin (8-OH-DPAT), 1.0 mg/kg, subcutaneously, twice daily for 7 days, on the stimulation of post- and presynaptic 5-HT 1A receptors were examined. The postsynaptic responses, hypothermia and inhibition of the cage-leaving response, evoked by 0.05 mg/kg 8-OH-DPAT, were measured 48 hr after the final injection. Another postsynaptic response, the 5-HT syndrome (flat body posture and forepaw treading) was observed after the third injection of 8-OH-DPAT (1.0 mg/kg s.c.). One presynaptic response examined was the 8-OH-DPAT-induced decrease in the concentration of 5-hydroxyindoleacetic acid (5-HIAA), that indicates a decrease in turnover of 5-HT, due to stimulation of 5-HT receptors on the cell bodies and measured as the ratio of 5-HIAA to 5-HT in the hippocampus, hypothalamus and medulla oblongata. Another presynaptic response was the 8-OH-DPAT-induced decrease in the accumulation of 5-hydroxytryptophan (5-HTP) in the hippocampus and hypothalamus, after inhibition of l-aromatic amino acid decarboxylase by 3-hydroxybenzylhydrazine (NSD 1015), that is due to stimulation of autoreceptors on the 5-HT cell bodies. The kinetic properties of 5-HT 1A receptors in the cerebral cortex and hippocampus, hippocampus alone, hypothalamus and medulla oblongata were determined with [ 3H]8-OH-DPAT. It was found that the postsynaptic effects were markedly attenuated after the treatment, the hypothermic effect already after a single dose. The strength of the 5-HT syndrome was almost abolished, when measured one day after the third injection, and still markedly decreased 1 but not 2 weeks after this injection. In contrast to these changes, no attenuation of the decrease in the turnover of 5-HT or the accumulation of 5-HTP was found in any of the regions examined. The kinetic parameters of the 5-HT 1A receptors ( B max and K D ) were also unchanged in all the regions analyzed. These findings, which are contradictory to some previous observations, indicate that pre- and postsynaptic 5-HT 1A receptor responses are mediated by different signal systems and that some of them, possibly G i proteins coupled to adenylate cyclase, may be quite sensitive to repeated stimulation.