OVERFLOW OF NORADRENALINE AND DOPAMINE IN FRONTAL-CORTEX AFTER [N-(2-CHLOROETHYL)-N-ETHYL-2-BROMOBENZYLAMINE] (DSP-4) TREATMENT - IN-VIVO MICRODIALYSIS STUDY IN ANESTHETIZED RATS

The changes in the extracellular concentration of endogenous noradrena line and dopamine in the frontal cortex following pretreatment with no radrenergic neurotoxin DSP-4 [N-(2-chloroethyl)-N-ethyl-2-bromobenzyla mine] were studied by in vivo microdialysis in rats anaesthetized with chloral hydrate. Noradrenaline and dopamine levels in frontal cortex were detected only when the uptake inhibitor, nomifensine (10 mu M) wa s present in dialysis fluid. Under those conditions, the Na+ channel a gonist veratridine and a depolarising concentration of potassium chlor ide (60 mM), applied locally through the microdialysis probe, increase d the overflow of noradrenaline. Tetrodotoxin had an opposite effect. These results indicate that most of the noradrenaline probably arose f rom exocytotic release. Noradrenaline efflux in the frontal cortex of DSP-4 pretreated rats (52+/-6.1 fmol/sample) did not differ significan tly from that of the control animals (69+/-4.9 fmol/sample). Dopamine efflux was not changed either (64+/-9.6 and 62+/-3.9 fmol/sample, resp ectively), The alpha(2)-adrenoceptor antagonist, atipamezole (3 mg/kg i.p.), increased the overflow of noradrenaline in the frontal cortex o f saline-treated rats by 100%, whereas in DSP-4 treated rats the incre ase was only around 30%. The overflow of dopamine was not changed unde r the conditions described. The effect of atipamezole in DSP-4 treated rats may be of smaller magnitude due to the diminished pool of releas able noradrenaline or due to a downregulation of presynaptic alpha(2)- adrenoceptors in the frontal cortex. The perfusion of 60 mM KCl at the end of the experiment unexpectedly produced equivalent increases in n oradrenaline and dopamine content in dialysates of both vehicle and DS P-4 treated rats. We conclude that the uptake inhibitor, nomifensine, and atipamezole, which had a stronger effect in vehicle-treated animal s, reduced the effect of KCl-stimulation and masked the true differenc e in changes of noradrenaline efflux. Post-mortem tissue concentration s of noradrenaline 7 days after DSP-4 administration (50 mg/kg) were s ignificantly reduced in the frontal cortex (54%), hippocampus (62.5%) and to lesser extent in the hypothalamus (27%) as compared to vehicle- treated rats. Dopamine and 3,4-dihydroxyphenylacetic acid concentratio ns were not changed confirming the efficacy and selectivity of the DSP -4 lesion. These results demonstrate that one week after DSP-4 treatme nt the extracellular levels of noradrenaline and dopamine as assessed by in vivo microdialysis are not changed in the frontal cortex, but at ipamezole-stimulated release of noradrenaline is decreased in DSP-4 tr eated rats.