Abstract
The main goal of the present study was to evaluate the influence of the adenosine A1 receptor (A1R) antagonist — DPCPX — on depressive-like behavior in mice, as well as the effect of DPCPX on the activity of imipramine, escitalopram, and reboxetine, each at non-effective doses. The influence of DPCPX on behavior and its influence on the activity of selected antidepressants was evaluated in the forced swim test (FST) and the tail suspension test (TST) in mice. Locomotor activity was measured to verify and exclude false-positive data obtained in the FST and TST. Moreover, serum and brain concentrations of tested antidepressants were determined using HPLC. DPCPX, at doses of 2 and 4 mg/kg, exhibited antidepressant activity in the FST and TST, which was not related to changes in the spontaneous locomotor activity. Co-administration of DPCPX with imipramine, escitalopram, or reboxetine, each at non-active doses, significantly reduced the immobilization period in the FST and TST in mice, which was not due to the increase in locomotor activity. Both antagonists of 5-HT receptors (WAY 100635 and ritanserin) completely antagonized the effect elicited by DPCPX in the behavioral tests. Results of assessment of the nature of the interaction between DPCPX and test drugs show that in the case of DPCPX and imipramine or reboxetine, there were pharmacodynamic interactions, whereas the DPCPX-escitalopram interaction is at least partially pharmacokinetic in nature. Presented outcomes indicate that an inhibition of A1Rs and an increase of monoaminergic transduction in the CNS may offer a novel strategy for the development of antidepressant drugs.
Highlights
It is known that adenosine is involved in the regulation of a wide range of behaviors, moods, and emotions (Boison 2008; Cunha et al 2008; El Yacoubi et al 2000; Ruby et al 2010; Asatryan et al 2011), and cognitive processes (Kopf et al 1999) and motor activity (Brockwell and Beninger 1996)
Spontaneous locomotor activity was measured using OptoVarimex-4 Auto-Track (Columbus Instruments, Columbus, OH, USA) which consist of four cages made of Plexiglas with lids (43 × 43 × 32 cm)
Results obtained in the spontaneous locomotor activity test are presented as the average distance traveled by mice ± standard error of the mean (SEM) for each experimental group
Summary
It is known that adenosine is involved in the regulation of a wide range of behaviors, moods, and emotions (Boison 2008; Cunha et al 2008; El Yacoubi et al 2000; Ruby et al 2010; Asatryan et al 2011), and cognitive processes (Kopf et al 1999) and motor activity (Brockwell and Beninger 1996). Adenosine as a neuromodulator exerts its functions through the activation of four G-protein-coupled adenosine receptors (AR) — A1, A2A, A2B, and A3 (Fredholm et al 2001, 2005a, b; Jacobson and Gao 2006; Boison 2008) Their roles and pharmacology have been analyzed in detail, with respect to control of transmitter release, modulation of neuronal excitability, and regulation of ion channel function (Fredholm et al 1999, 2005a, b; Ferré et al 2010). Much data indicate that a non-selective pharmacological inhibition of adenosine receptors (e.g., administration of methylxanthines such as caffeine, theophylline) may reduce depressive-like behaviors in laboratory animals (Minor et al 1994a, b; El Yacoubi et al 2003; Minor and Hanff 2015; Szopa et al 2016). Kaster et al (2004, 2005a, b, 2007) presented the contrary data, which indicated that the non-selective activation of adenosine receptors decreased the immobilization period in the forced swim test (FST) and tail suspension test (TST) in mice
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