The Effect of Sympathetic Antagonists on the Antidepressant Action of Alprazolam

Abstract

Alprazolam is an anti-anxiety drug shown to be effective in the treatment of depression. In this study, the effect of sympathetic receptor antagonists on alprazolam–induced antidepressant action was studied using a mouse model of forced swimming behavioral despair. The interaction of three sympathetic receptor antagonists with benzodiazepines, which may impact the clinical use of alprazolam, was also studied. Behavioral despair was examined in six groups of albino mice. Drugs were administered intraperitoneally. The control group received only a single dose of 1% Tween 80. The second group received a single dose of alprazolam, and the third group received an antagonist followed by alprazolam. The fourth group was treated with imipramine, and the fifth group received an antagonist followed by imipramine. The sixth group was treated with a single dose of an antagonist alone (atenolol, a β1-selective adrenoceptor antagonist; propranolol, a non selective β-adrenoceptor antagonist; and prazocin, an α1-adrenoceptor antagonist). Results confirmed the antidepressant action of alprazolam and imipramine. Prazocin treatment alone produced depression, but it significantly potentiated the antidepressant actions of imipramine and alprazolam. Atenolol alone produced an antidepressant effect and potentiated the antidepressant action of alprazolam. Propranolol treatment alone produced depression, and antagonized the effects of alprazolam and imipramine, even producing depression in combined treatments.In conclusion, our results reveal that alprazolam may produce antidepressant effects through the release of noradrenaline, which stimulates β2 receptors to produce an antidepressant action. Imipramine may act by activating β2 receptors by blocking or down-regulating β1 receptors.

Are Noradrenergic Transmission Reducing Drugs Antidepressants?

“…In contrast to these potentially therapeutic properties of beta blockers, it has also been suggested that these drugs can promote depression-like behavior in rodents (Abel and Hannigan, 1994 ; Stone and Quartermain, 1999 ; Al-Tubuly et al, 2008 ) including in the presence of other putative antidepressants (Zhang et al, 2009 ; Gu et al, 2012 ), or under some circumstances, they have no substantial effect either alone or when co-administered with other putative antidepressants (Danysz et al, 1986 ; Evangelista et al, 1987 ; Finnegan et al, 1987 ; Teste et al, 1990 ; Beĭer, 1994 ; Detke et al, 1995 ; Pesarico et al, 2014 ; Sekio and Seki, 2015 ; Zaidi et al, 2020 ). A number of studies also suggest that the beta3 agonist amibegron (also called SR58611A) has antidepressant-like properties in rodents (Consoli et al, 2007 ; Overstreet et al, 2008 ; Stemmelin et al, 2008 , 2010 ; Tamburella et al, 2010 ), and it may achieve these effects by modulating serotonergic and noradrenergic signaling that is triggered by activation of beta3 receptors (Claustre et al, 2008 ).…”

“…Alpha1 antagonists such as prazosin and benoxathian can also exhibit antidepressant-like activity in the FST or TST (Sekio and Seki, 2015 ; Kurosawa et al, 2016 ; Wu et al, 2017 ), including potentiation of other putative antidepressants such as imipramine (Al-Tubuly et al, 2008 ). In contrast, it has also been suggested that alpha1 antagonists can promote depression-like behavior (Stone and Quartermain, 1999 ; Al-Tubuly et al, 2008 ), including in the presence of other putative antidepressants or electroconvulsive therapy (ECT; Danysz et al, 1986 ; Poncelet et al, 1987 ; Teste et al, 1990 ; Kaster et al, 2007 ; Sugimoto et al, 2011 ; Gu et al, 2012 ; Ribeiro and Pupo, 2015 ).…”

“…Alpha1 antagonists such as prazosin and benoxathian can also exhibit antidepressant-like activity in the FST or TST (Sekio and Seki, 2015 ; Kurosawa et al, 2016 ; Wu et al, 2017 ), including potentiation of other putative antidepressants such as imipramine (Al-Tubuly et al, 2008 ). In contrast, it has also been suggested that alpha1 antagonists can promote depression-like behavior (Stone and Quartermain, 1999 ; Al-Tubuly et al, 2008 ), including in the presence of other putative antidepressants or electroconvulsive therapy (ECT; Danysz et al, 1986 ; Poncelet et al, 1987 ; Teste et al, 1990 ; Kaster et al, 2007 ; Sugimoto et al, 2011 ; Gu et al, 2012 ; Ribeiro and Pupo, 2015 ). Under some circumstances they have no substantial depression-related behavioral effect either alone or when co-administered with other putative antidepressants (Evangelista et al, 1987 ; Malinge et al, 1988 , 1989 ; Cervo and Samanin, 1991 ; Schreiber and De Vry, 1993 ; Detke et al, 1995 ; Sugimoto et al, 2011 ; Pesarico et al, 2014 ).…”