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

Abstract

RationaleDepressed patients often present increased consumption of caffeine.ObjectivesWe aimed to investigate the effects of chronic treatment with caffeine (5 mg/kg, twice daily for 14 days) on the activity of single, ineffective doses of agomelatine (20 mg/kg) or mianserin (10 mg/kg) given on day 15 alone or simultaneously with caffeine.MethodsWe used the forced swim test (FST), tail suspension test (TST), and locomotor activity test in mice and quantitative real-time PCR analysis of the selected genes in the cerebral cortex (Cx).ResultsThere were no changes in the immobility time between mice that received saline and caffeine for 14 days. Administration of agomelatine or mianserin on day 15 did not produce an antidepressant-like effect, but such effect was observed after administration of agomelatine or mianserin simultaneously with caffeine on day 15, in both mice that received saline and caffeine for 14 days. In mice treated with caffeine for 14 days, joint administration of agomelatine or mianserin and caffeine on day 15 decreased solute carrier family 6, member 15 (Slc6a15), messenger RNA (mRNA) level in the Cx, compared to the group which received only the respective antidepressant on this day. Moreover, in mice treated with caffeine for 14 days, joint administration of mianserin and caffeine on day 15 decreased adenosine A1 receptor (Adora1) and catechol-O-methyltransferase (Comt) mRNA level in the Cx, compared to the group which received mianserin without caffeine on this day.ConclusionsWithdrawal of caffeine after its chronic intake can modify the activity of antidepressants. Adora1, Slc6a15, and Comt may be involved in the antidepressant-like effect observed after joint administration of caffeine and mianserin or agomelatine, following chronic treatment with caffeine.

Genomic-Analysis-Oriented Drug Repurposing in the Search for Novel Antidepressants

“…Another target gene that we identified in the present study was ADORA1 , which regulates various biological functions, including the mechanisms underlying sleep [ 101 , 102 ], and psychiatric disorders including depression [ 103 , 104 , 105 ]. ADORA1 activation has been found to induce antidepressant-like effects [ 106 , 107 ]. In addition, the therapeutic effects of sleep deprivation [ 108 ] and ECT [ 109 ] are mediated by the activation or upregulation of ADORA1 .…”

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“…ADORA1 is involved in down regulating inflammatory factors and promoting smooth muscle cell proliferation. 26 After long-term caffeine treatment, combined with caffeine and gossypol or agomelatonin, ADORA1 was involved in an antidepressant like effect, 27 and caffeine withdrawal resulted in a decrease in the level of ADORA1 mRNA in the cerebral cortex. 28 Through the mechanism of no/cGMP/PKG/ KATP intracellular signaling pathway, peripheral activation of ADORA1 reduces inflammatory pain sensation.…”