MEDIATION OF THE ANTIDEPRESSANT-LIKE EFFECT OF 8-OH-DPAT IN MICE BY POSTSYNAPTIC 5-HT1A RECEPTORS

1 The 5-hydroxytryptamine (5-HT)1A agonist 8-hydroxy-2-(dipropylamino)tetralin (8-OH-DPAT) has been evaluated in a mouse model for detecting potential antidepressants (Porsolt test). The effects of various receptor antagonists, lesions of brain monoaminergic neurones and chronic drug treatments on this 8-OH-DPAT-induced response have also been determined. 2 8-OH-DPAT (0.3-10.0 mg kg-1, s.c.) dose-dependently increased the mobility of mice in the Porsolt test. Other selective 5-HT1A receptor ligands (0.3-30 mg kg-1, s.c.) either mimicked the 8-OH-DPAT response (ipsapirone, at 10 and 30 mg kg-1, s.c.) or were inactive (buspirone and gepirone). However, each of these compounds (less-than-or-equal-to 100 mg kg-1, p.o.) inhibited the response to 8-OH-DPAT (3 mg kg-1, s.c.) when given concurrently. 3 The putative 5-HT1A antagonists, spiroxatrine (1-30 mg kg-1, p.o.), (+/-)-pindolol (30 mg kg-1, p.o.) and methiothepin (3- 10 mg kg-1, p.o.), each attenuated the 8-OH-DPAT (3 mg kg-1, s.c.)-induced increase in mobility. 4 The dopamine D1 receptor antagonist, SCH 23390 (3-10 mg kg-1, p.o.), weakly reversed the 8-OH-DPAT response. Antagonists at 5-HT1C/5-HT2 receptors (ketanserin; 0.1-3.0 mg kg-1, p.o.), 5-HT3 receptors (ondansetron; 0.03-10 mg kg-1, p.o.), alpha1-adrenoceptors (prazosin, 1-3 mg kg-1, p.o.), alpha2-adrenoceptors (idazoxan; 3-30 mg kg-1, p.o.), beta1-adrenoceptors (metoprolol; 1-30 mg kg-1, p.o.), beta2-adrenoceptors (ICI 118,551; 1-30 mg kg-1, p.o.), dopamine D2 receptors (sulpiride; 10-300 mg kg-1, p.o.) and opiate receptors (naloxone; 3-100 mg kg-1, p. o.) had no effect on the 8-OH-DPAT response. 5 Selective destruction of 5-HT neurones with 5,7-dihydroxytryptamine or inhibition of 5-HT synthesis with p-chlorophenylalanine did not change the 8-OH-DPAT response in the Porsolt test. This response was also unaltered by pretreatment with the noradrenergic neurotoxin, DSP-4. 6 Administration of 8-OH-DPAT (3 mg kg-1, s.c.) twice-daily for 10 days attenuated the hypothermia, but not the increased mobility, induced by 8-OH-DPAT (3 mg kg-1, s.c.). Similarly, repeated administration of amitriptyline (3-30 mg kg-1), desipramine (3-30 mg kg-1) or dothiepin (10-100 mg kg-1) also attenuated the former, but not the latter, response. 7 We conclude that 8-OH-DPAT produces an antidepressant-like effect in the Porsolt test which is mediated via postsynaptic 5-HT1A receptors.