Interactions between darodipine or isradipine and the 5-HT1A 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 because, at low dose (0.08 and 0.3 mg/kg, respectively) they facilitate, but at high dose (1.60 and 5.0 mg/kg, respectively) they inhibit the serotonergic neurotransmission. To investigate the mechanisms of these effects, the selective 5-HT1A receptor agonist 8-OHDPAT was injected S.C. to rats pretreated I.P. with isradipine (0.04-1.60 mg/kg) or darodipine (0.3-5.0 mg/kg). By stimulating presynaptic 5-HT1A autoreceptor, 8-OHDPAT induced signs of inhibition of the serotonergic neutransmission (i.e., decrease of the 5-HIIA/5-HT ratio), but it also produced behavioral effects by stimulating postsynaptic 5-HT1A receptors (i.e., forepaw treadings). A low dose of isradipine (0.08 mg/kg) or darodipine (0.3 mg/kg) antagonized the presynaptic, but enhanced the postsynaptic effects of 8-OHDPAT, suggesting relief of the autoreceptor-mediated inhibition of the 5-HT release. Thus, the amine released could stimulate 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) left 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 postsynaptic 5-HT1A receptors. It was speculated that the effects of isradipine and darodipine on scrotonergic pathways of rat brain could be due to changes in the back-regulation of the neurotransmission, mediated by 5-HT1A autoreceptors. This mechanism of action could be extended to other dihydropyridine calcium antagonists, because blockade of L-type VSCC by these compounds appears to be involved in their effects on brain 5-HT turnover.
Gaggi
R
R
Department of Pharmacology, University of Bologna, Italy.
D'Allolio
R
R
Santangelo
M
M
Roncada
P
P
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000187:drug effects*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D017275:Isradipine / Q000494:pharmacology*; D008297:Male; D009543:Nifedipine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*
D002121:Calcium Channel Blockers; D017366:Serotonin Receptor Agonists; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D009543:Nifedipine; C034600:darodipine; D017275:Isradipine