INVOLVEMENT OF N-TYPE AND P Q-TYPE BUT NOT L-TYPE OR T-TYPE VOLTAGE-GATED CALCIUM CHANNELS IN ISCHEMIA-INDUCED STRIATAL DOPAMINE RELEASE IN-VITRO/

Calcium influx and transmitter efflux are central events in the neurop athological cascade that occurs during and following cerebral ischaemi a. This study explored the role of voltage-gated calcium channels (VGC Cs) in ischaemia-induced striatal dopamine (DA) release in vitro. Slic es (350 mu m thickness) of rat neostriatum were superfused (400 ml/h) with an artificial cerebrospinal fluid (aCSF) at 34 degrees C and subj ected to episodes of 'ischaemia' by reduction of the glucose concentra tion from 4 to 2 mM and gassing with 95% N-2/5% CO2. DA release was mo nitored with fast cyclic voltammetry at implanted carbon fibre microel ectrodes. The time to onset, time to peak, rate and magnitude of DA re lease were measured. Non-selective blockade of VGCCs with a high conce ntration of Ni2+ (2.5 mM), markedly delayed (P < 0.01) and slowed (P < 0.05) DA release but preferential blockade of T-type VGCCs with a low er concentration (200 mu M) had no effect. DA release was also unaffec ted by selective antagonism of L-type VGCCs with nimodipine and nicard ipine (10 mu M each). Selective blockade of N-type VGCCs with omega-co notoxin GVIA (100 nM) delayed DA release (P < 0.05) but did not affect its rate or magnitude. Blockade of P- and possibly Q-type VGCCs with omega-agatoxin IVA (up to 200 nM) both delayed (P < 0.05) and slowed ( P < 0.05) DA release. Preferential blockade of P- type VGCCs with neom ycin (500 mu M) also delayed (P < 0.05) and slowed (P < 0.05) DA relea se. These findings suggest that N-, P- and possibly Q- but not L- or T -type VGCCs mediate ischaemia-induced DA release. Although it is not p ossible to say, on the basis of these results, that the effects are di rectly upon the dopamine terminals, these calcium channels nevertheles s constitute promising targets for therapeutic intervention.