The effects of Ca2+ antagonists and hydralazine on central 5-hydroxytryptamine biochemistry and function in rats and mice

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Abstract
1 The effects of calcium antagonists on behaviour mediated by 5-hydroxytryptamine (5-HT) have been studied in rats and mice together with an investigation of the effects of these drugs on 5-HT synthesis in rat brain and endogenous 5-HT release from brain slices. 2 Administration of felodipine (35 mg kg−1 i.p.) to rats pretreated with tranylcypromine (20 mg kg−1, i.p.) resulted in the animals displaying the complete 5-HT-mediated behavioural syndrome (including head weaving, reciprocal forepaw treading and hind limb abduction) 75 min later. No evidence was obtained for the rate of 5-HT synthesis in brain regions differing between control and felodipine-treated rats. 3 Pretreatment with felodipine (10 or 35 mg kg−1) enhanced the 5-HT-mediated behavioural syndrome induced by injection of tranylcypromine and l-tryptophan. The rate of 5-HT accumulation in the brain was similar in both groups. Administration of Bay K 8644 (1 mg kg−1, i.p.) did not prevent the enhanced behaviour induced by felodipine (10 mg kg−1). 4 The 5-HT behavioural syndrome induced by injection of the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) was unaltered by either acute injection of felodipine (35 mg kg−1) or administration of felodipine twice daily for 3 days. 5 Felodipine (10 μm), verapamil (10 μm) and Bay K 8644 (10 μm) did not alter either basal release of endogenous 5-HT from slices prepared from frontal cortex or hind brain, or release following addition of K+ at a concentration of 20 mm, or 35 mm. 6 Verapamil (25 mg kg−1, i.p.), nicardipine (25 mg kg−1, i.p.) and nifedipine (20 mg kg−1, i.p.) all markedly inhibited the 5-HT2 receptor-mediated head twitch response in mice produced by injection of 5-methoxy-N,N-dimethyl-tryptamine (5-MeODMT). Felodipine had the same effect with an ED50 of 2.6 mg kg−1. Bay K 8644 did not reverse this effect. Both verapamil (IC50:2.5 μm) and nicardipine (IC50:8 μm) were 5-HT2 antagonists as indicated by inhibition of [3H]-ketanserin binding in mouse frontal cortex. However felodipine and nifedipine antagonized 5-HT2 receptor binding only in the millimolar range. 7 Hydralazine (5 mg kg−1, i.p.) induced the 5-HT behavioural syndrome in tranylcypromine pretreated rats, enhanced the tranylcypromine/l-tryptophan behavioural syndrome, inhibited 5-MeODMT-induced head twitch behaviour in mice and was not a 5-HT2 receptor antagonist. 8 These data indicate that at a high dose, Ca2+ antagonists produce complex changes in 5-HT function in rodents which are similar to those produced by lithium administration. The data with hydralazine suggest that the effects seen are not related to an action at Ca2+ channels.