Rate-independent inhibition by norepinephrine of 5-HT release from the somadendritic region of serotonergic neurons.
Endogenous adrenergic drive regulates the firing rate of serotonergic neurons. However, advocates of feedback theory assert that 5-hydroxytryptamine (5-HT) released in the somatodendritic region of raphe neurons regulates both rate and release of 5-HT. Experiments were done to determine if the somatodendritic region might have receptors for norepinephrine that inhibit release of 5-HT independently of rate, as this would allow for discrete effects of norepinephrine on rate and release, even in the presence of functional feedback by 5-HT. The release of 5-HT at fixed frequencies of stimulation was substantially reduced when norepinephrine (1 and 3 x 10(-7) M) was present. Norepinephrine also inhibited the release of 3H-5-HT with delivery of a single stimulation pulse ruling out a remote action of the catecholamine. The alpha(1) antagonist prazosin did not modify the profile of norepinephrine inhibition. Further, the alpha(1) agonist phenylephrine had no effect on 3H-5-HT efflux. The alpha(2) antagonist yohimbine antagonized almost entirely the inhibition by norepinephrine at 1 Hz, and reduced it substantially at 3 Hz. Blockade of 5-HT(1) receptor sites with methiothepin did not reduce the inhibitory effect of norepinephrine on 3H-5-HT efflux. It is proposed that release of endogenous norepinephrine at synapses with 5-HT neurons could activate 5-HT neuron firing rate through alpha(1) receptors located at the soma and simultaneously short-circuit ongoing 5-HT feedback inhibition by inhibiting release through adrenergic alpha two receptors likely located at the dendrites.
Kalsner
S
S
Department of Physiology and Pharmacology, City University of New York Medical School, New York, NY 10031, USA.
Abdali
S A
SA
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D003712:Dendrites / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D005246:Feedback / Q000187:drug effects / Q000502:physiology*; D005473:Fluoxetine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008636:Mesencephalon / Q000187:drug effects / Q000378:metabolism; D008719:Methiothepin / Q000494:pharmacology; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism* / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D011817:Rabbits; D011903:Raphe Nuclei / Q000187:drug effects / Q000378:metabolism*; D011941:Receptors, Adrenergic / Q000187:drug effects / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D015016:Yohimbine / Q000494:pharmacology
D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D011941:Receptors, Adrenergic; D012702:Serotonin Antagonists; D005473:Fluoxetine; C011386:nisoxetine; D010656:Phenylephrine; D015016:Yohimbine; D012701:Serotonin; D008719:Methiothepin; D009638:Norepinephrine; D011224:Prazosin