Endogenous noradrenaline activates alpha 2-adrenoceptors on serotonergic nerve endings in human and rat neocortex.
Slices from human neocortex preincubated with [3H]serotonin ([3H]5-HT) were superfused and stimulated electrically to investigate whether the alpha 2-adrenoceptors on serotonergic terminals can be stimulated by endogenous noradrenaline (NA) released from neighboring noradrenergic fibers. The stimulation-evoked 3H overflow, representing action potential-induced, exocytotic release of 5-HT, was depressed by the NA uptake blocker (+)-oxaprotiline. Rauwolscine (a mixed alpha 2-adrenoceptor antagonist/5-HT autoreceptor agonist) or phentolamine [a combined alpha-adrenoceptor/5-HT autoreceptor antagonist; the latter drug in the presence of (+)-oxaprotiline] enhanced the release when the 5-HT autoreceptors had previously been blocked by metitepine. Under hypothermia the release of 5-HT was found to be decreased and that of NA to be increased; under these conditions idazoxan (an alpha 2-adrenoceptor antagonist) enhanced the release of 5-HT. In neocortex slices from rats (+)-oxaprotiline similarly depressed the release of 5-HT (measured with the same methods) as in human tissue. When rats were pretreated with 6-hydroxydopamine, the inhibitory effect of exogenous NA on 5-HT release was increased, and in slices from rats pretreated with desipramine, it was decreased. In conclusion, alpha 2-heteroreceptors can be activated by endogenous NA released from neighboring noradrenergic fibers. Because regulatory processes analogous to those in rats probably occur in humans as well, an up- or down-regulation of alpha 2-heteroreceptors in depressed patients with a (pathological) decrease or a (therapeutic) enhancement of the noradrenergic neurotransmission may also be assumed to occur.
Neuropharmakologisches Labor der Neurologischen Universitätsklinik, Freiburg, F.R.G.
T J
TJ
Feuerstein
A
A
Mutschler
A
A
Lupp
V
V
Van Velthoven
E
E
Schlicker
M
M
Göthert
D000200:Action Potentials; D000328:Adult; D000368:Aged; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000502:physiology*; D003080:Cold Temperature; D004558:Electric Stimulation; D005089:Exocytosis; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008376:Maprotiline / Q000031:analogs & derivatives / Q000494:pharmacology; D008875:Middle Aged; D009411:Nerve Endings / Q000502:physiology*; D009638:Norepinephrine / Q000494:pharmacology / Q000502:physiology*; D010646:Phentolamine / Q000494:pharmacology; D051381:Rats; D011942:Receptors, Adrenergic, alpha / Q000502:physiology*; D012701:Serotonin / Q000502:physiology*; D015016:Yohimbine / Q000494:pharmacology
D011942:Receptors, Adrenergic, alpha; D008376:Maprotiline; D015016:Yohimbine; D012701:Serotonin; C027299:hydroxymaprotilin; D009638:Norepinephrine; D010646:Phentolamine