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-HT1A) receptor agonist 8-OH-DPAT reduced immobility (ID50 0.17- 1.37 mg/kg, depending on route of application and application schedule ). Intracerebroventricular (i.c.v.) or local application into the dors al raphe nucleus (DRN), a brain area rich in presynaptic 5-HT1A recept ors, resulted in a parallel shift of the dose-response curve to the le ft (ID50 5.1 and 3.9 mu g/rat, respectively). Systemic application of the 5-HT1A receptor partial agonist ipsapirone resulted in a U-shaped dose-response curve (maximal effect about 30% immobility reduction at 3-10 mg/kg). Local application of ipsapirone in the DRN reduced immobi lity (maximal effect 40% at 60 mu g/rat). However, 8-OH-DPAT and ipsap irone were still effective after depletion of brain 5-HT by means of 5 ,7-DHT (150 mu g, i.c.v.) or pCPA (either 2 X 150 mg/kg or 2 x 350 mg/ kg, i.p.) Additionally, in non-lesioned rats: (1) the putative (postsy naptic) 5-HT1A antagonist NAN-190, but not spiperone, haloperidol, pra zosin or 1-PP, was able to block the anti-immobility effects of 8-OH-D PAT in a behaviorally specific manner; (2) local application of 8-OH-D PAT and ipsapirone in the lateral septum (a brain area rich in postsyn aptic 5-HT1A receptors) reduced immobility (8-OH-DPAT: ID50 11.4 mu g/ rat; ipsapirone: maximal effect at 30 mug/rat 38%); and (3) pretreatme nt with ipsapirone resulted in an attenuation of the effect of 8-OH-DP AT when both compounds were administered either systemically or in the lateral septum but not when both compounds were microinjected into th e DRN. It is hypothesized that the anti-immobility effects of 5-HT1A r eceptor agonists are mediated by pre- and postsynaptic 5-HT1A receptor s and that they closely reflect the intrinsic activity of these compou nds at these receptors.