Effect of Multi-Target Antidepressant Strategies on Monoamine Systems: Electrophysiological Studies in the Rat Brain

Abstract

There is a vast degree of heterogeneity in clinical presentations of major depressive disorder (MDD) symptoms among individual patients. Efficacious treatment strategies for individual MDD patients should address this heterogeneity and if necessary, modulate different neurotransmitter systems based on the individual profile of each patient. The overarching objective of the studies presented in chapters 2-4 was to determine how three different antidepressant strategies modulated the neurotransmission of monoamines. Single-unit electrophysiological experiments were carried out using adult male Sprague-Dawley rats under chloral hydrate anesthesia. Recordings were obtained from the dorsal raphe nucleus (DRN) serotonin (5-HT), locus coeruleus (LC) norepinephrine (NE), and ventral tegmental area (VTA) dopamine (DA) neurons and the pyramidal neurons of the CA3 region of the hippocampus. Long-term (14-day) administration of vortioxetine dampened the DA and NE neuronal activity, but to a lesser degree compared to escitalopram while increasing the N-methyl-D-aspartate (NMDA)-evoked responses of CA3 pyramidal neurons. Long-term combined administration of aripiprazole with escitalopram has been previously shown to recover the escitalopram-induced inhibition of NE and DA neurotransmission. The same regimen (presented in chapter 3) resulted in a synergistic increase in overall 5-HT neurotransmission in the hippocampus. xxvii Long-term individual administration of cariprazine increased the overall 5-HT neurotransmission while its combination with escitalopram was devoid of any effects. Furthermore, long-term administration of cariprazine increased the firing rate and bursting activity of LC NE neurons, and when combined with escitalopram it reversed the escitalopram-induced inhibition of the activity of these neurons. The results of the abovementioned experiments demonstrated the distinctly heterogeneous effects of three different, yet comparable, pharmacotherapeutic strategies on neurotransmission modulation of monoamines. Based on the hypothesized neurotransmitter-symptom relations for MDD, the current results (along with findings of other preclinical and clinical studies) would offer clinicians potentially valuable information that provides them with the possibility of making evidence-based decisions for devising more efficacious pharmacotherapeutic strategies for individual MDD patients.