Creatine, similarly to ketamine, affords antidepressant-like effects in the tail suspension test via adenosine A1 and A2A receptor activation

Abstract

The benefits of creatine supplementation have been reported in a broad range of central nervous systems diseases, including depression. A previous study from our group demonstrated that creatine produces an antidepressant-like effect in the tail suspension test (TST), a predictive model of antidepressant activity. Since depression is associated with a dysfunction of the adenosinergic system, we investigated the involvement of adenosine A 1 and A 2A receptors in the antidepressant-like effect of creatine in the TST. The anti-immobility effect of creatine (1 mg/kg, po) or ketamine (a fast-acting antidepressant, 1 mg/kg, ip) in the TST was prevented by pretreatment of mice with caffeine (3 mg/kg, ip, nonselective adenosine receptor antagonist), 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) (2 mg/kg, ip, selective adenosine A 1 receptor antagonist), and 4-(2-[7-amino-2-{2-furyl}{1,2,4}triazolo-{2,3-a}{1,3,5}triazin-5-ylamino]ethyl)-phenol (ZM241385) (1 mg/kg, ip, selective adenosine A 2A receptor antagonist). In addition, the combined administration of subeffective doses of creatine and adenosine (0.1 mg/kg, ip, nonselective adenosine receptor agonist) or inosine (0.1 mg/kg, ip, nucleoside formed by the breakdown of adenosine) reduced immobility time in the TST. Moreover, the administration of subeffective doses of creatine or ketamine combined with N-6-cyclohexyladenosine (CHA) (0.05 mg/kg, ip, selective adenosine A 1 receptor agonist), N-6-[2-(3,5-dimethoxyphenyl)-2-(methylphenyl)ethyl]adenosine (DPMA) (0.1 mg/kg, ip, selective adenosine A 2A receptor agonist), or dipyridamole (0.1 μg/mouse, icv, adenosine transporter inhibitor) produced a synergistic antidepressant-like effect in the TST. These results indicate that creatine, similarly to ketamine, exhibits antidepressant-like effect in the TST probably mediated by the activation of both adenosine A 1 and A 2A receptors, further reinforcing the potential of targeting the purinergic system to the management of mood disorders.

Low dose of caffeine enhances the efficacy of antidepressants in major depressive disorder and the underlying neural substrates

“…It has been indicated that stimulation of both hippocampal and striatal adenosine A1 receptors reduces monoaminergic transmission, whereas blockade of adenosine A1 receptor increases monoaminergic transmission . It was demonstrated that creatine and ketamine produced rapid antidepressant‐like effects by activating both adenosine A1 and A2A receptors . However, caffeine abolished the anti‐immobility effect in the tail suspension test, indicating the importance of the adenosinergic system in the antidepressant‐like effect of creatine and ketamine.…”

Signaling pathways underlying the antidepressant-like effect of inosine in mice

“…Mice were suspended 50 cm above the floor by adhesive tape placed approximately 1 cm from the tip of the tail. The immobility time was manually recorded during a 6-min session, and mice were considered immobile only when they hung passively and completely motionless [49][50][51].…”

Withdrawal of caffeine after its chronic administration modifies the antidepressant-like activity of atypical antidepressants in mice. Changes in cortical expression of Comt, Slc6a15 and Adora1 genes

“…It was also shown that increasing A 1 receptor expression evokes resilience against a depressive-like behavior in the FST and TST as well as exerts an antidepressant-like effect in a chronic stress model (Serchov et al 2015). These data suggest that antidepressant-like effect is related to activation of A 1 receptors, but this observation may not be relevant to classic antidepressants in view of the fact that DPCPX and ZM241385 did not prevent the anti-immobility effect of fluoxetine in the FST (Cunha et al 2015). Of note, in a chronic stress model of depression, contradictory results on the effectiveness of classic antidepressants and an agent transformed in vivo to endogenous glutamate N -methyl- d -aspartate (NMDA) receptor antagonist, kynurenic acid, were shown (Biagini et al 1993).…”

“…On the other hand, the antidepressant-like effect of creatine and ketamine, fast-acting antidepressant agents targeting the glutamatergic system, but not fluoxetine, was abolished by caffeine, DPCPX (a selective adenosine A 1 receptor antagonist), and ZM241385 (a selective adenosine A 2A receptor antagonist), while the administration of ineffective doses of creatine or ketamine combined with CHA (a selective adenosine A 1 receptor agonist), DPMA (a selective adenosine A 2A receptor agonist), or dipyridamole (an adenosine transporter inhibitor) produced a synergistic antidepressant-like effect in the TST (Cunha et al 2015). It was also shown that increasing A 1 receptor expression evokes resilience against a depressive-like behavior in the FST and TST as well as exerts an antidepressant-like effect in a chronic stress model (Serchov et al 2015).…”

“…Adora1 encodes A 1 receptor, whose antagonism mediates caffeine-induced wakefulness (Fredholm et al 2016). A 1 receptors participate in mediating antidepressant-like effect (Cunha et al 2015; Serchov et al 2015). Moreover, sleep deprivation, which represents one of the therapeutic strategies in depression, was shown to be accompanied by an A 1 receptor upregulation in the human brain (Elmenhorst et al 2017).…”