THE CONDITIONS OF CA-2+ ENTRY VIA L-TYPE CHANNELS FOR INDUCTION OF SEROTONIN RELEASE FROM RABBIT HIPPOCAMPUS

The L-type voltage-sensitive calcium channel (VSCC) agonists of the dihydropyridine (DHP) type, Bay K 8644 and (+)-202-791, concentration dependently enhanced the K+ (26.2 mM)-induced 5-HT release from slices of rabbit hippocampus prelabelled with [H-3]5-HT when the slices were treated with the monoamine oxidase (MAO) inhibitor, pargyline. The DHP agonists were ineffective on K+ (26.2 mM)-induced release in the absence of pargyline. However, when omega-conotoxin GVIA pretreatment of the slices irreversibly blocked N-type VSCCs, (+)-202-791 markedly enhanced the release of 5-HT evoked by 26.2 mM K+. Thus, at this rather strong stimulus intensity either an increase in the (preferentially cytoplasmic) transmitter pool or blockade of N-type VSCCs was necessary in order to unmask agonist-activated L-type VSCCs. Reduction of the depolarization intensity from 26.2 to 17.2 mM K+, given for 8 min, strongly intensified the stimulatory effects of L-type VSCC agonists irrespective of the use of pargyline under these conditions. The concentration-response curve of (+)-202-791 was 'competitively' shifted to the right by the enantiomer, (-)-202-791, with a pA2 value of 8.6. In conclusion, N- and L-type VSCCs seem to differ in their relation to the cellular machinery for 5-HT release, the latter getting markedly operative when a weak and sustained depolarization is applied or when N-type VSCCs are blocked or when the cytoplasmic transmitter pool is expanded by inhibition of MAO.