Neuroanatomical basis for the antidepressant-like effects of the 5-HT1A receptor agonists 8-OH-DPAT and ipsapirone in the rat forced swimming test

In the rat forced swimming test, systemic application of the serotonin 1A (5-HT(1A)) receptor agonist 8-OH-DPAT reduced immobility (ID(50) 0.17-1.37mg/kg, depending on route of application and application schedule). Intracerebroventricular (i.c.v.) or local application into the dorsal raphe nucleus (DRN), a brain area rich in presynaptic 5-HT(1A) receptors, resulted in a parallel shift of the dose-response curve to the left (ID(50) 5.1 and 3.9µg/rat, respectively). Systemic application of the 5-HT(1A) receptor partial agonist ipsapirone resulted in a U-shaped dose-response curve (maximal effect about 30% immobility reduction at 3-10mg/kg). Local application of ipsapirone in the DRN reduced immobility (maximal effect 40% at 60µg/rat). However, 8-OH-DPAT and ipsapirone were still effective after depletion of brain 5-HT by means of 5,7-DHT (150µg, i.c.v.) or pCPA (either 2 x 150mg/kg or 2 x 350mg/kg, i.p.) Additionally, in non-lesioned rats: (1) the putative (postsynaptic) 5-HT(1A) antagonist NAN-190, but not spiperone, haloperidol, prazosin or 1-PP, was able to block the anti-immobility effects of 8-OH-DPAT in a behaviorally specific manner; (2) local application of 8-OH-DPAT and ipsapirone in the lateral septum (a brain area rich in postsynaptic 5-HT(1A) receptors) reduced immobility (8-OH-DPAT: ID(50) 11.4µg/rat; ipsapirone; maximal effect at 30µg/rat 38%); and (3) pretreatment with ipsapirone resulted in an attenuation of the effect of 8-OH-DPAT when both compounds were administered either systemically or in the lateral septum but not when both compounds were microinjected into the DRN. It is hypothesized that the anti-immobility effects of 5-HT(1A) receptor agonists are mediated by pre- and postsynaptic 5-HT(1A) receptors and that they closely reflect the intrinsic activity of these compounds at these receptors.