Escitalopram Regulates Expression of TRH and TRH-Like Peptides in Rat Brain and Peripheral Tissues

Abstract

Background: Escitalopram (eCIT) is a highly selective serotonin reuptake inhibitor (SSRI) that can be an effective treatment for a number of neuropsychiatric disorders including major depression. We, and others, have previously reported that thyrotropin-releasing hormone (TRH, pGlu-His-Pro-NH₂) and TRH-like peptides with the general structure pGlu-X-Pro-NH₂, where ‘X’ can be any amino acid residue, have neuroprotective, antidepressant, analeptic, arousal, and anti-epileptic effects that could mediate the neuropsychiatric and therapeutic effects of a variety of neurotropic agents. The present work explores the possible mediation of the therapeutic effects of eCIT by TRH and TRH-like peptides. Methods: In order to extend our understanding of the range of neurotransmitter systems that are modulated by and, in turn, influence the expression of TRH and TRH-like peptides, 16 male Sprague-Dawley rats were injected i.p. with eCIT (24 mg/kg BW) and the brain levels of TRH and TRH-like peptides in various brain regions involved in mood regulation and peripheral tissues with serotonergic innervation were measured 0, 2, 4, and 6 h later by combined HPLC and RIA. Results and Conclusion: Remarkable 3- to 25-fold increases in TRH and TRH-like peptide levels were observed 2 h after i.p. eCIT in the epididymis. This reproductive tissue has the highest level of serotonin found in most mammals. The acute (2 h) effect of eCIT in brain regions involved in mood regulation, particularly the nucleus accumbens and medulla oblongata, cerebellum, and striatum was to increase the levels of TRH-like peptides, most consistently Phe-TRH. An important exception was a decrease in the level of TRH in the nucleus accumbens. These responses, in general, were the opposite of those we have previously observed after acute restraint stress in this same rat strain. We conclude that some of the therapeutic effects of inhibition of serotonin reuptake are mediated by altered release of TRH and TRH-like peptides.

TRH and TRH-Like Peptide Levels Co-Vary with Reproductive and Metabolic Rhythms

“…2) were all highest (minimum release/clearance) during the daytime when peptide release and sexual activity are at a minimum. One of the functions of the epididymis is activation of sperm motility, which depends, in part, on its high concentration of Glu-TRH (also termed Fertilization Promoting Peptide, FPP) [43,44], an established sperm capacitation factor [44,45]. Human sperm collected in the afternoon have higher number, concentration and motility compared to sperm collected in the morning [11].…”

TRH-Receptor-Type-2-Deficient Mice are Euthyroid and Exhibit Increased Depression and Reduced Anxiety Phenotypes

“…Indeed, depletion of serotonin increases while antidepressant-induced activation of serotonergic and/or noradrenergic neurotransmission reduces immobility time in FST and TST (Porsolt et al , 1978; Page et al , 1999; Cryan et al , 2002). We speculate that the increased immobility of TRH-R2-/- mice in the FST and TST indicates reduced serotonergic and/or adrenergic neurotransmission in these mice (Sattin et al , 2008). The depression-like behavior of TRH-R2-/- mice is also consistent with the reported antidepressant effect of TRH (Sattin, 1999) although not all studies support this effect (Gary et al , 2003).…”

Escitalopram affects spexin expression in the rat hypothalamus, hippocampus and striatum

“…Interestingly, 2 hours after escitalopram administration the level of TRH-like peptides was increased in the rat nucleus accumbens, striatum, cerebellum and medulla oblongata, while TRH concentration was decreased in the nucleus accumbens. It should not be therefore excluded that SSRI action is mediated by modulation of TRH and TRH-like neuropeptides [22]. Potential direct or …”