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Mediation of the antidepressant‐like effect of 8‐OH‐DPAT in mice by postsynaptic 5‐HT 1A receptors
Author(s) -
Luscombe Graham P.,
Martin Keith F.,
Hutchins Lisa J.,
Gosden Jane,
Heal David J.
Publication year - 1993
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1993.tb12859.x
Subject(s) - postsynaptic potential , antidepressant , 5 ht receptor , 8 oh dpat , mediation , receptor , serotonin , neuroscience , endocrinology , chemistry , pharmacology , medicine , biology , hippocampus , political science , law
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‐HT 1A 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 (≤ 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‐HT 1A 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 D 1 receptor antagonist, SCH 23390 (3–10 mg kg −1 , p.o.), weakly reversed the 8‐OH‐DPAT response. Antagonists at 5‐HT 1C /5‐HT 2 receptors (ketanserin; 0.1–3.0 mg kg −1 , p.o.), 5‐HT 3 receptors (ondansetron; 0.03–10 mg kg −1 , p.o.), α 1 ‐adrenoceptors (prazosin; 1–3 mg kg −1 , p.o.), α 2 ‐adrenoceptors (idazoxan; 3–30 mg kg −1 , p.o.), β 1 ‐adrenoceptors (metoprolol; 1–30 mg kg −1 , p.o.), β 2 ‐adrenoceptors (ICI 118,551; 1–30 mg kg −1 , p.o.), dopamine D 2 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‐HT 1A receptors.