Antidepressant-Like Activity of Typical Antidepressant Drugs in the Forced Swim Test and Tail Suspension Test in Mice Is Augmented by DMPX, an Adenosine A2A Receptor Antagonist

Abstract

Unsatisfactory therapeutic effects of currently used antidepressants force to search for new pharmacological treatment strategies. Recent research points to the relationship between depressive disorders and the adenosinergic system. Therefore, the main goal of our studies was to evaluate the effects of DMPX (3 mg/kg, i.p.), which possesses selectivity for adenosine A2A receptors versus A1 receptors, on the activity of imipramine (15 mg/kg, i.p.), escitalopram (2.5 mg/kg, i.p.), and reboxetine (2 mg/kg, i.p.) given in subtherapeutic doses. The studies carried out using the forced swim and tail suspension tests in mice showed that DMPX at a dose of 6 and 12 mg/kg exerts antidepressant-like effect and does not affect the locomotor activity. Co-administration of DMPX at a dose of 3 mg/kg with the studied antidepressant drugs caused the reduction of immobility time in both behavioral tests. The observed effect was not associated with an increase in the locomotor activity. To evaluate whether the observed effects were due to a pharmacokinetic/pharmacodynamic interaction, the levels of the antidepressants in blood and brain were measured using high-performance liquid chromatography. It can be assumed that the interaction between DMPX and imipramine was exclusively pharmacodynamic in nature, whereas an increased antidepressant activity of escitalopram and reboxetine was at least partly related to its pharmacokinetic interaction with DMPX.

The Interaction of Selective A1 and A2A Adenosine Receptor Antagonists with Magnesium and Zinc Ions in Mice: Behavioural, Biochemical and Molecular Studies

“…In turn, some non-typical drugs (i.e., rolipram and levoprotillin) show antidepressant-like activity in the FST, but not in the TST [36,37], whereas shortening the immobility time in both the FST and TST is observed when using drugs, such as tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), atypical antidepressant (i.e., mianserin) [36,38,39], and also antagonists of the NMDA [36,40,41] and agonists of the AMPA receptor [42]. As demonstrated in our previous research, A1 and A2A receptor antagonists also have antidepressant-like activity in both of these behavioural tests [31,32]. Though both these despair behavioural tests are generally based on the same principle, the neurological mechanisms underlying the observed antidepressant effect are different, which may be the reason for the observed disagreement between the antidepressant-like activity of various compounds in the FST and TST [36].…”

Behavioral Abnormalities in Knockout and Humanized Tau Mice

“…The tail suspension (TST) and forced swim (FST) tests are commonly used for the detection of behavior despair in mice and for the screening of antidepressants (48). In this context, increased immobility time indicates depressive-like behavior (36,39).…”

Selecting an Appropriate Animal Model of Depression

“…Imipramine is a tricyclic antidepressant that can disrupt DMPX in a pharmacodynamic manner and provide a therapeutic effect. It has been evaluated in a forced swimming test and a tail suspension test [110,111]. Fluoxetine is an SSRI that could ameliorate depression by blocking astrocyte activation and repairing oligodendrocyte dysfunction.…”