Electrophysiological studies in the rat brain on the basis for aripiprazole augmentation of antidepressants in major depressive disorder.
BACKGROUND
Aripiprazole (ARI) is an atypical antipsychotic approved by the Food and Drug Administration for use in major depressive disorder as an adjunct to antidepressants. However, the precise mechanisms responsible for the effectiveness of ARI augmentation are not fully understood.


OBJECTIVE
The current study was aimed at examining the effects of ARI administration alone and in combination with the selective serotonin reuptake inhibitors (SSRI) escitalopram (ESC) on the firing of serotonin (5-HT), norepinephrine (NE), and dopamine (DA) neurons.


METHODS
Electrophysiological experiments were carried out in anesthetized Sprague-Dawley rats. ESC was delivered via subcutaneously implanted osmotic minipumps at a dose of 10 mg/kg/day. ARI was subcutaneously injected daily at a dose of 2 mg/kg/day. Both drugs were administered for 2 and 14 days alone and in combination. Control rats received physiological saline in analogous regimens.


RESULTS
Two-day ESC administration resulted in a significant decrease in the firing rate of 5-HT, NE, and DA neurons. Following 14 days of ESC administration, 5-HT firing returned to the baseline. The firing rate of NE and DA neurons remained significantly decreased. ARI administered for 2 or 14 days significantly increased the firing rate of 5-HT neurons by 36% and 48%, respectively, but not those of DA and NE neurons. Desensitization of somatodendritic 5-HT autoreceptors was observed after 2 days of ARI administration. The combination of the two drugs reversed the inhibitory action of ESC on the firing rate of 5-HT, NE, and DA neurons.


CONCLUSIONS
The present study showed that addition of ARI to an SSRI regimen reverses the inhibitory action of the SSRI on monoaminergic neuronal firing.
Chernoloz
Olga
O
Institute of Mental Health Research, University of Ottawa, 1145 Carling Avenue, Ottawa, ON, K1Z 7K4, Canada. Olga.Chernoloz@rohcg.on.ca
El Mansari
Mostafa
M
Blier
Pierre
P
D000200:Action Potentials / Q000187:drug effects; D000704:Analysis of Variance; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D014150:Antipsychotic Agents / Q000494:pharmacology*; D000068180:Aripiprazole; D001921:Brain / Q000166:cytology*; D015283:Citalopram / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D008238:Lysergic Acid Diethylamide / Q000494:pharmacology; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D015363:Quinolones / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism; D018490:Serotonin Agents / Q000494:pharmacology; D013997:Time Factors
D000928:Antidepressive Agents; D014150:Antipsychotic Agents; D010879:Piperazines; D015363:Quinolones; D018490:Serotonin Agents; D015283:Citalopram; D012701:Serotonin; D000068180:Aripiprazole; D008238:Lysergic Acid Diethylamide; D004298:Dopamine; D009638:Norepinephrine