INTERACTIONS BETWEEN DARODIPINE OR ISRADIPINE AND THE 5-HT(1)A RECEPTOR AGONIST 8-OHDPAT IN RAT-BRAIN

Isradipine and darodipine are dihydropyridine calcium antagonists that affect the serotonergic pathways with a peculiar profile of effects b ecause, at low dose (0.08 and 0.3 mg/kg, respectively) they facilitate , but at high dose (1.60 and 5.0 mg/kg, respec- tively) they inhibit t he serotonergic neurotransmission. To investigate the mechanisms of th ese effects, the selective 5-HT(1)A receptor agonist 8-OHDPAT was inje cted SC to rats pretreated IP with isradipine (0.04-1.60 mg/kg) or dar odipine (0.3-5.0 mg/kg). By stimulating presynaptic 5-HT(1)A autorecep tor, 8-OHDPAT induced signs of inhibition of the serotonergic neutrans mission (i.e., decrease of the 5-HIIA/5-HT ratio), but it also produce d behavioral effects by stimulating postsynaptic 5-HT(1)A receptors (i .e., forepaw treadings). A low dose of isradipine (0.08 mg/kg) or daro dipine (0.3 mg/kg) antagonized the presynaptic, but enhanced the posts ynaptic effects of 8-OHDPAT, suggesting relief of the autoreceptor-med iated inhibition of the 5-HT release. Thus, the amine released could s timulate postsynaptic receptors, adding its action to that of 8-OHDPAT . A high dose of isradipine (1.60 mg/kg) or darodipine (5.0 mg/kg) lef t unchanged, or also enhanced, the signs of inhibition of serotonergic neurotransmission displayed by 8-OHDPAT, reducing but not suppressing the increase in the behavioral response to the stimulation of postsyn aptic 5-HT(1)A receptors. It was speculated that the effects of isradi pine and darodipine on serotonergic pathways of rat brain could be due to changes in the back-regulation of the neurotransmission, mediated by 5-HT(1)A autoreceptors. This mechanism of action could be extended to other dihydropyridine calcium antagonists, because blockade of L-ty pe VSCC by these compounds appears to be involved in their effects on brain 5-HT turnover. (C) 1997 Elsevier Science Inc.