Activation of post-synaptic 5-HT(1A) receptors in the dorsal hippocampus prevents learned helplessness development

Activation of post-synaptic 5-HT(1A) receptors in the dorsal hippocampus is proposed to mediate stress adaptation. Chronic social stress and high corticosteroid levels would impair this coping mechanism, predisposing animals to learned helplessness. To test the hypothesis that increasing serotonin levels in the dorsal hippocampus would attenuate the development of learned helplessness, rats received inescapable foot-shock (pre-test session) and were tested in a shuttle box 24-h later. Pre-stressed animals showed impairment of escape responses. This effect was prevented by chronic (21 days) treatment with imipramine (15 mg/kg). Similar results were obtained when the animals received bilateral intra-hippocampal injections, immediately after pre-test, of zimelidine (100 nmol/0.5 microl), a serotonin reuptake blocker, or 8-OH-DPAT (10 nmol), a 5-HT(1A) receptor agonist. The zimelidine effect was prevented by pre-treatment with WAY-100635 (30 nmol), a 5-HT(1A) receptor antagonist. These data suggest that facilitation of serotonergic neurotransmission in the dorsal hippocampus mediates adaptation to severe inescapable stress, probably through the activation of post-synaptic 5-HT(1A) receptors.