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Antagonism of 5‐HT 1A receptors uncovers an excitatory effect of SSRIs on 5‐HT neuronal activity, an action probably mediated by 5‐HT 7 receptors
Author(s) -
Bosker Fokko J.,
Folgering Joost H. A.,
Gladkevich Anatoliy V.,
Schmidt Anne,
Van Der Hart Marieke C. G.,
Sprouse Jeffrey,
Den Boer Johan A.,
Westerink Ben H. C.,
Cremers Thomas I. F. H.
Publication year - 2009
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2008.05850.x
Subject(s) - serotonin , 5 ht receptor , microdialysis , receptor , dorsal raphe nucleus , chemistry , agonist , pharmacology , autoreceptor , neurotransmitter , 5 ht2 receptor , reuptake inhibitor , 5 ht1 receptor , reuptake , excitatory postsynaptic potential , electrophysiology , medicine , endocrinology , neuroscience , extracellular , biology , serotonergic , biochemistry
Both microdialysis and electrophysiology were used to investigate whether another serotonin (5‐HT) receptor subtype next to the 5‐HT 1A autoreceptor is involved in the acute effects of a selective serotonin reuptake inhibitor on 5‐HT neuronal activity. On the basis of a previous study, we decided to investigate the involvement of the 5‐HT 7 receptors. Experiments were performed with the specific 5‐HT 7 antagonist SB 258741 and the putative 5‐HT 7 agonist AS19. In this study WAY 100.635 was used to block 5‐HT 1A receptors. Systemic administration of SB 258741 significantly reduced the effect of combined selective serotonin reuptake inhibitor and WAY 100.635 administration on extracellular 5‐HT in the ventral hippocampus as well as 5‐HT neuronal firing in the dorsal raphe nucleus. In the microdialysis study, co‐administration of AS19 and WAY 100.635 showed a biphasic effect on extracellular 5‐HT in ventral hippocampus, hinting at opposed 5‐HT 7 receptor mediated effects. In the electrophysiological experiments, systemic administration of AS19 alone displayed a bell‐shaped dose–effect curve: moderately increasing 5‐HT neuronal firing at lower doses while decreasing it at higher doses. SB 258741 was capable of blocking the effect of AS19 at a low dose. This is consistent with the pharmacological profile of AS19, displaying high affinity for 5‐HT 7 receptors and moderate affinity for 5‐HT 1A receptors. The data are in support of an excitatory effect of selective serotonin reuptake inhibitors on 5‐HT neuronal activity mediated by 5‐HT 7 receptors. It can be speculated, that the restoration of 5‐HT neuronal firing upon chronic antidepressant treatment, which is generally attributed to desensitization of 5‐HT 1A receptors alone, in fact results from a shift in balance between 5‐HT 1A and 5‐HT 7 receptor function.