title: Electrophysiological impact of trazodone on the dopamine and norepinephrine systems in the rat brain.
abstract: Previous study has documented the long-term effects of the antidepressant trazodone on the serotonin (5-HT) system. The present work examined the impact of sustained trazodone on ventral tegmental area (VTA) dopamine (DA) and locus ceruleus (LC) norepinephrine (NE) neurons firing activity, and characterized its effects at 5-HT(2C), 5-HT(2A) receptors and α₁- and α₂-adrenoceptors. Electrophysiological recordings were carried out in anesthetized rats. Subcutaneously implanted minipumps delivered vehicle or trazodone (10 mg/kg/day) for 2 or 14 days. Administration of trazodone for 2 and 14 days did not alter the firing activity of DA neurons. Systemic injection of trazodone, however, reversed the inhibitory effect of the 5-HT(2C) receptor agonist Ro 60,0175 on the DA neuronal firing, suggesting an antagonistic action of trazodone at this receptor. Administration of trazodone for 2 days significantly enhanced the NE neurons firing. Despite a return of the NE neurons firing rate to the baseline following 14-day trazodone, the percentage of neurons discharging in burst was increased by this regimen. Administration of trazodone for 14 days enhanced the tonic activation of postsynaptic α₂-adrenoceptors, as indicated by the disinhibitory effect of the α₂-adrenoceptor antagonist idazoxan on hippocampus pyramidal neurons firing. The inhibitory effect of acute trazodone on dorsal raphe (DR) 5-HT neurons firing was shown to be through the 5-HT(1A) receptor. Systemic injection of trazodone reversed the inhibitory action of 5-HT(2A) agonist DOI on the NE neurons firing rate, indicating its antagonistic action at 5-HT(2A) receptors. The enhancement in α₂-adrenergic transmission by trazodone, and its 5-HT(2A) and 5-HT(2C) receptor antagonism may contribute to its therapeutic action in major depression.
authors.affiliation: University of Ottawa Institute of Mental Health Research, Ottawa, Ontario, Canada.
authors.forename: Ramez
authors.initials: R
authors.lastname: Ghanbari
authors.forename: Mostafa
authors.initials: M
authors.lastname: El Mansari
authors.forename: Pierre
authors.initials: P
authors.lastname: Blier
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001921:Brain / Q000166:cytology*; D058256:Brain Waves / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005021:Ethylamines / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008297:Male; D009474:Neurons / Q000187:drug effects*; D009638:Norepinephrine / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013997:Time Factors; D014196:Trazodone / Q000494:pharmacology*
chemical_list: D014151:Anti-Anxiety Agents; D005021:Ethylamines; D007211:Indoles; D010879:Piperazines; D011725:Pyridines; C103848:Ro 60-0175; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D004298:Dopamine; D009638:Norepinephrine; D014196:Trazodone