Induction of burst firing in ventral tegmental area dopaminergic neurons by activation of serotonin (5-HT)1A receptors: WAY 100,635-reversible actions of the highly selective ligands, flesinoxan and S 15535.
This study examined the influence of the highly selective 5-HT1A receptor ligands, flesinoxan, S 15535, and WAY 100,635, upon the electrical activity of dopaminergic neurons in the ventral tegmental area (VTA), as compared to serotonergic neurons in the dorsal raphe nucleus (DRN) of anesthetized rats. Flesinoxan, a high-efficacy agonist at both pre- and postsynaptic 5-HT1A receptors, dose-dependently (inhibitory dose (ID)50 = 19.5 microg/kg, i.v.) inhibited the firing of DRN serotonergic neurons. This action was abolished by WAY 100,635 (31 microg/kg i.v.) which is an antagonist at pre- and postsynaptic 5-HT1A receptors. S 15535, which behaves as an agonist and partial agonist at pre- and postsynaptic 5-HT1A receptors, respectively, similarly abolished DRN firing in a WAY 100,635-reversible fashion with an ID50 of 6.1 microg/kg, i.v. In contrast to these actions, both flesinoxan (> or = 500 microg/kg, i.v.) and S 15535 (> or = 125 microg/kg, i.v.) dose-dependently and monophasically increased the firing rate of dopaminergic neurons in the VTA, with maximal effects of 70.1 +/- 17.2% and 33.7 +/- 5.3%, respectively. Further, VTA dopaminergic neurons displaying a regular firing pattern were transformed into a bursting mode. This influence of flesinoxan and S 15535 on VTA cells was abolished by WAY 100,635. Administered alone, WAY 100,635 did not significantly modify the activity of either serotonergic or dopaminergic neurons. In conclusion, the present findings show that selective activation of 5-HT1A receptors not only inhibits serotonergic neurones but also elicits a (possibly related) increase in VTA dopaminergic output. A facilitatory influence of flesinoxan, S 15535, and other selective 5-HT1A receptor ligands upon mesocortical dopaminergic pathways may contribute to their putative antidepressant properties.
Department of Psychopharmacology, Institut de Recherches Servier, Centre de Recherches de Croissy, Croissy-sur-Seine, France.
F
F
Lejeune
M J
MJ
Millan
D000818:Animals; D004298:Dopamine / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D010879:Piperazines / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000166:cytology / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology*; D011903:Raphe Nuclei / Q000166:cytology / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000187:drug effects*; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D017557:Ventral Tegmental Area / Q000166:cytology / Q000187:drug effects / Q000502:physiology*
D010879:Piperazines; D011725:Pyridines; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C079549:4-(benzodioxan-5-yl)-1-(indan-2-yl)piperazine; C056895:flesinoxan; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D004298:Dopamine