Synergistic effect of aripiprazole and escitalopram in increasing serotonin but not norepinephrine neurotransmission in the rat hippocampus

In addition to schizophrenia and bipolar disorder, aripiprazole is approved as an adjunct for major depressive disorder (MDD). Adding aripiprazole to the 5-HT reuptake inhibitor escitalopram reverses the inhibitory action of escitalopram on firing activity of rat 5-HT, norepinephrine (NE) and DA neurons. This study investigated how aripiprazole, escitalopram and their combination affect the net effect of 5-HT and NE neurotransmission in the rat hippocampus. Electrophysiological recordings of hippocampus CA(3) pyramidal neurons were conducted in anesthetized Sprague-Dawley rats after 2- and 14-day administration regimens. Aripiprazole and escitalopram (2 and 5 mg/kg/day, respectively) were delivered alone or in combination through subcutaneous injections and implanted osmotic minipumps, respectively. Overall neurotransmission of 5-HT and NE were assessed by determining possible enhancements in tonic activation of 5-HT1A receptors and alpha(1)- and alpha(2)-adrenoceptors. This was achieved by assessing increases of firing rate of pyramidal neurons due to disinhibition induced by injections of antagonists for these three types of receptors. While neither 2-and 14-day administration of escitalopram nor aripiprazole significantly altered firing rate of pyramidal neurons following injection of 5-HT1A antagonist WAY100635, their combination for 14 days significantly increased this parameter. Fourteen days of the same drug regimens did not change firing following injection of the alpha(l)- and alpha(2)-adrenoceptor antagonists prazosin and idazoxan, respectively. A synergy between aripiprazole and escitalopram was thus documented by an increase in the tonic activation of 5-HT1A receptors after 14 days of administration that may account, at least in part, for the benefits of this strategy in MDD.