DUAL EFFECT OF DMPP ON THE RESTING RELEASE OF NORADRENALINE FROM RAT HIPPOCAMPAL SLICES

The effect of the nicotinic receptor agonist dimethylphenylpiperaziniu m iodide (DMPP) on the resting release of [H-3]noradrenaline from supe rfused hippocampal slices was studied in rat. Continuous administratio n of DMPP at a concentration range of 1-100 mu M increased the [H-3]no radrenaline release in, a dose-dependent manner. The response to DMPP was, characterized by an immediate steep increase (peak response) foll owed by a sudden decline to a lower level that was constant with; time (tail response) and still was significantly higher than the spontaneo us release. Further analysis revealed that the release of noradrenalin e in response to DMPP consists of two components. While nicotinic rece ptor antagonists (mecamylamine 10 mu M, pancuronium 10 mu M, pipecuron ium 10 mu M), the nonselective Ca-antagonist Cd2+ (125 mu M) and tetro dotoxin (TTX, 1 mu M) completely abolished the peak response (phase I) , they had no effect on the tail response (phase II). Ca2+-free medium containing 1 mM EGTA also blocked phase I but in contrast with other drugs enhanced phase II. The release during phase I is subject to pres ynaptic feedback modulation, since the alpha(2)-adrenoceptor agonist x ylazine (3 mu M) inhibited the DMPP-evoked stimulation of [H-3]noradre naline release, that inhibition was antagonized by a selective alpha(2 )-adrenoceptor antagonist, -[7,8-(methylenedioxy)-14-alpha-hydroxyallo berbane hydrochloride [(+/-)CH-38083] (2 mu M). (+/-)-CH-38083 (2 mu M ) alone significantly enhanced the DMPP-evoked increase of [H-3]noradr enaline release. Phase II was not affected by alpha(2)-adrenergic drug s. Whereas the noradrenaline uptake blockers despramine (DMI, 1-10 mu M), nisoxetine (1-10 mu M), and nomifensine (10 mu M) inhibited both p hases, nomifensine at a concentration of 1 mu M selectively blocked on ly phase II. Our data indicate that DMPP has a dual effect on the hipp ocampal noradrenaline release: phase I is a transient, nicotinic recep tor-mediated exocytotic release, and phase II is a maintained, carrier -mediated process. (C) 1997 Elsevier Science Inc.