Effects of isradipine and darodipine on serotonergic system of the rat brain.
Isradipine and darodipine are dihydropyridine calcium antagonists that easily pass into the brain, showing high affinity for cerebral L-type voltage-sensitive calcium channel (VSCC). These drugs were IP administered to rats to study their effects on serotonergic systems of discrete brain areas. Isradipine (0.05-5.0 mg/kg) and darodipine (0.3-20 mg/kg) increased the 5-HIAA/5-HT ratio, mostly enhancing the metabolite (5-HIAA) content in various brain areas, suggesting that serotonin (5-HT) turnover was increased. This increase appeared to depend on facilitation of serotonergic neurotransmission, because low doses of isradipine (< 0.075 mg/kg) or darodipine (< 0.6 mg/kg) enhanced the number of head twitches induced by L-5-hydroxytryptophan (L-5-HTP). However, higher doses of isradipine (1.5 mg/kg) or darodipine (5 mg/kg) also appeared to stimulate a negative feedback mechanism, which predominated over the facilitation when the serotonergic neurotransmission was strongly activated. Thus, higher drug doses decreased both the serotonin turnover and the number of head twitches on rats treated with L-5-HTP. It was speculated that the observed effects were due to brain VSCC blockade, although the studied compounds showed a peculiar profile of properties when compared to other previously studied calcium antagonists. Moreover, it was concluded that darodipine appeared to be more effective and selective than isradipine regarding the effects on brain serotonergic systems.
Gaggi
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R
Department of Pharmacology, University of Bologna, Italy.
Dall'Olio
R
R
Roncada
P
P
Gianni
A M
AM
D006916:5-Hydroxytryptophan / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D017275:Isradipine / Q000494:pharmacology*; D008297:Male; D009543:Nifedipine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects
D002121:Calcium Channel Blockers; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D006916:5-Hydroxytryptophan; D009543:Nifedipine; C034600:darodipine; D017275:Isradipine