Antidepressant-like action of 8-OH-DPAT, a 5-HT1A agonist, in the learned helplessness paradigm: evidence for a postsynaptic mechanism.

In animal models of depression, the 5-HT1A agonists, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), buspirone, gepirone and ipsapirone administered i.p. have been shown to mimic the behavioural effects of antidepressants. For instance, in the present study, using the learned helplessness paradigm, 8-OH-DPAT dose-dependently reversed helpless behaviour. To assess the possible role of pre- or postsynaptic 5-HT1A receptors in this effect, the ability of 8-OH-DPAT to reduce helpless behaviour was investigated following (1) i.p. administration (0.125 or 0.25 mg/kg/day) in rats whose ascending 5-HT neurons were partially destroyed by previous 5,7-dihydroxytryptamine (5,7-DHT) injection (5 micrograms free base in 0.6 microliter) into the raphe nuclei or (2) after local microinjection (0.1 or 1.0 microgram in 0.5 microliter) into the raphe nuclei or into the septum. The reversal of helpless behaviour by 8-OH-DPAT (i.p.) was still observed in 5,7-DHT-treated rats with telencephalic 5-HT uptake reduced by 50-75% depending on the region. 8-OH-DPAT microinjected into the raphe nuclei did not reverse helpless behaviour; in contrast, 8-OH-DPAT microinjected into the septum reversed helpless behaviour. These results suggest that the ability of 8-OH-DPAT to reverse helpless behaviour probably involved the stimulation of postsynaptic rather than presynaptic 5-HT1A receptors.