Anxiolytic and antidepressant effects of ACPA and harmaline co-treatment.

Combining low, ineffective doses of the cannabinoid CB1 receptor agonist ACPA and the β-carboline harmaline produced both anxiolytic- and antidepressant-like effects in male NMRI mice, whereas either compound alone at higher doses caused anxiogenic-like responses. ACPA at 1 mg/kg reduced open-arm activity in the elevated plus maze and decreased immobility in the forced swim test, indicating anxiogenic and antidepressant effects, respectively. β-carbolines such as harmane, norharmane, and harmaline also induced anxiogenic behavior at certain doses, with some doses showing antidepressant-like effects. Only the combination of subthreshold ACPA (0.5 mg/kg) and harmaline (1.25 mg/kg) yielded beneficial behavioral changes and reduced locomotion, suggesting a potential therapeutic strategy for anxiety and depression.

Study at a glance

Abstract

Depression and anxiety disorders are among the most common illnesses and a close relationship between them has been found. Because the psychotropic effects and abuse liability of cannabis prevent its therapeutic application in depression and anxiety states, we decided to investigate the effects of the combination of ineffective doses of cannabinoid CB1 receptor agonist arachidonylcyclopropylamide (ACPA) and β-carbolines on anxiety- and depression-related behaviors in male NMRI mice. Anxiety- and depression-related behaviors were assesses using elevated plus maze (EPM) and forced swim test (FST), respectively. Intraperitoneal administration of ACPA (1 mg/kg) decreased the percentage of time spent in the open-arms (%OAT) and the number of entries to the open-arms (OAE) in the EPM, indicating an anxiogenic-like effect. ACPA also decreased immobility time in the FST compared to the control group, suggesting an antidepressant-like effect. β-carbolines including harmane (5 and 10 mg/kg), norharmane (5 mg/kg) and harmaline (2.5 and 5 mg/kg) produced an anxiogenic-like response, while the highest dose of harmane or harmaline and the middle dose of norharmane induced an antidepressant-like behavior. Furthermore, co-administration of a subthreshold dose of ACPA (0.5 mg/kg) and harmaline (1.25 mg/kg), but not harmane or norharmane (both at the dose of 2.5 mg/kg), caused anxiolytic- and antidepressant-like behaviors and decreased locomotor activity. Our findings suggest a therapeutic potential for combined ineffective doses of ACPA and harmaline on anxiety- and depression-related processes.