Abstract
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 CA3 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 α1- and α2-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 α1- and α2-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.
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