SODIUM-CHANNEL BLOCKADE UNMASKS 2 TEMPORALLY DISTINCT MECHANISMS OF STRIATAL DOPAMINE RELEASE DURING HYPOXIA HYPOGLYCAEMIA IN-VITRO/

Massive striatal dopamine release during cerebral ischaemia has been i mplicated in the resulting neuronal damage. Sodium influx is an early event in the biochemical cascade during ischaemia and blockade of sodi um channels may increase resistance to ischaemia by reducing energy de mand involved in compensation for sodium and potassium fluxes. In this study, we have determined the effects of opening and blockade of volt age-gated sodium channels on hypoxia/hypoglycaemia-induced dopamine re lease. Slices of rat caudate nucleus were maintained in a slice chambe r superfused by an oxygenated artificial cerebrospinal fluid containin g 4 mM glucose. Ischaemia (hypoxia/hypoglycaemia) was mimicked by a sw itch to a deoxygenated artificial cerebrospinal fluid containing 2 mM glucose and dopamine release was measured using fast cyclic voltammetr y. In drug-free (control) slices, there was a 2-3 min delay after the onset of hypoxia/hypoglycaemia followed by a rapid dopamine release ev ent which was associated with anoxic depolarization. In slices treated with the Na+ channel opener, veratridine (1 mu M), the time to onset of dopamine release was shortened (101+/-20 s, compared with 171+/-8 s in controls, P<0.05). Conversely, phenytoin (100 mu M), lignocaine (2 00 mu M) and the highly selective sodium channel blocker, tetrodotoxin (1 mu M) markedly delayed and slowed dopamine release vs paired contr ols. In the majority of cases, dopamine release was biphasic after sod ium channel blockade: a slow phase preceded a more rapid dopamine rele ase event. The latter was associated with anoxic depolarization. Neith er the fast nor the slow release events were affected by pretreatment with the selective dopamine uptake blocker GBR12935 (0.2 mu M), sugges ting that uptake carrier reversal did not contribute to these events. In conclusion, sodium channel antagonism delays and slows hypoxia/hypo glycaemia-induced dopamine release in vitro. Furthermore, sodium chann el blockade delays anoxic depolarization and its associated neurotrans mitter release, revealing an earlier dopamine release event that does not result from reversal of the uptake carrier. (C) 1997 IBRO. Publish ed by Elsevier Science Ltd.