Dual effect of DMPP on the resting release of noradrenaline from rat hippocampal slices.
The effect of the nicotinic receptor agonist dimethylphenylpiperazinium iodide (DMPP) on the resting release of [3H]noradrenaline from superfused hippocampal slices was studied in rat. Continuous administration of DMPP at a concentration range of 1-100 microM increased the [3H]noradrenaline release in a dose-dependent manner. The response to DMPP was characterized by an immediate steep increase (peak response) followed by a sudden decline to a lower level that was constant with time (tall response) and still was significantly higher than the spontaneous release. Further analysis revealed that the release of noradrenaline in response to DMPP consists of two components. While nicotinic receptor antagonists (mecamylamine 10 microM, pancuronium 10 microM, pipecuronium 10 microM), the nonselective Ca-antagonist Cd2+ (125 microM) and tetrodotoxin (TTX, 1 microM) completely abolished the peak response (phase I), they had no effect on the tall response (phase II). Ca(2+)-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 presynaptic feedback modulation, since the alpha 2-adrenoceptor agonist xylazine (3 microM) inhibited the DMPP-evoked stimulation of [3H]noradrenaline release, that inhibition was antagonized by a selective alpha 2-adrenoceptor antagonist, (+/-)-[7,8-(methylenedioxy)-14-alpha-hydroxyalloberbane hydrochloride [(+/-)-CH-38083] (2 microM). (+/-)-CH-38083 (2 microM) alone significantly enhanced the DMPP-evoked increase of [3H]noradrenaline release. Phase II was not effected by alpha 2-adrenergic drugs. Whereas the noradrenaline uptake blockers despramine (DMI, 1-10 microM), nisoxetine (1-10 microM), and nomifensine (10 microM) inhibited both phases, nomifensine at a concentration of 1 microM selectively blocked only phase II. Our data indicate that DMPP has a dual effect on the hippocampal noradrenaline release: phase I is a transient, nicotinic receptor-mediated exocytotic release, and phase II is a maintained, carrier-mediated process.
Kiss
J P
JP
Department of Pharmacology, Hungarian Academy of Sciences, Budapest, Hungary.
Windisch
K
K
Balla
A
A
Sershen
H
H
Lajtha
A
A
D000818:Animals; D004246:Dimethylphenylpiperazinium Iodide / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects*; D008297:Male; D009638:Norepinephrine / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
D004246:Dimethylphenylpiperazinium Iodide; D009638:Norepinephrine