Abstract
N-methyl-D-aspartate receptor (NMDAR) modulators induce rapid and sustained antidepressant like-activity in rodents through a molecular mechanism of action that involves the activation of Ca2+ dependent signaling pathways. Moreover, ketamine, a global NMDAR antagonist is a potent, novel, and atypical drug that has been successfully used to treat major depressive disorder (MDD). However, because ketamine evokes unwanted side effects, alternative strategies have been developed for the treatment of depression. The objective of the present study was to determine the antidepressant effects of either a single dose of hyperforin or lanicemine vs. their combined effects in mice. Hyperforin modulates intracellular Ca2+ levels by activating Ca2+-conducting non-selective canonical transient receptor potential 6 channel (TRPC6) channels. Lanicemine, on the other hand, blocks NMDARs and regulates Ca2+ dependent processes. To evaluate the antidepressant-like activity of hyperforin and lanicemine, a set of in vivo (behavioral) and in vitro methods (western blotting, Ca2+ imaging studies, electrophysiological, and radioligand binding assays) was employed. Combined administration of hyperforin and lanicemine evoked long-lasting antidepressant-like effects in both naïve and chronic corticosterone-treated mice while also enhancing the expression of the synapsin I, GluA1 subunit, and brain derived neurotrophic factor (BDNF) proteins in the frontal cortex. In Ca2+ imaging studies, lanicemine enhanced Ca2+ influx induced by hyperforin. Moreover, compound such as MK-2206 (Akt kinase inhibitor) inhibited the antidepressant-like activity of hyperforin in the tail suspension test (TST). Hyperforin reversed disturbances induced by MK-801 in the novel object recognition (NOR) test and had no effects on NMDA currents and binding to NMDAR. Our results suggest that co-administration of hyperforin and lanicemine induces long-lasting antidepressant effects in mice and that both substances may have different molecular targets.
Highlights
Chronic intake, delayed onset of action, drug resistance, and numerous side effects of current antidepressants have forced researchers to look for new and safer drugs with rapid onset and longer acting times (Rosenblat et al, 2015; Sanacora and Schatzberg, 2015)
We showed that a combination of a single dose of hyperforin and the N-methyl-D-aspartate receptor (NMDAR) antagonist lanicemine evoked long-lasting antidepressant effects 72 h after administration in both naïve and chronic Cort-treated male mice
In our preliminary study, we observed the long-lasting antidepressant-like effects of hyperforin+lanicemine in naïve female mice. It seems that this interaction is not exclusive to lanicemine and hyperforin because the co-administration of hyperforin and MK-801, another NMDAR antagonist induced the same longlasting antidepressant-like responses in the TST in naïve mice
Summary
Chronic intake, delayed onset of action, drug resistance, and numerous side effects of current antidepressants have forced researchers to look for new and safer drugs with rapid onset and longer acting times (Rosenblat et al, 2015; Sanacora and Schatzberg, 2015). The antidepressant-like activity of ketamine has been shown in many preclinical studies (Maeng et al, 2008; Li et al, 2010, 2011; Autry et al, 2011; Gideons et al, 2014; Miller et al, 2014). A single non-anesthetic dose of ketamine reversed the symptoms of MDD (Berman et al, 2000). The antidepressant effects of ketamine were observed in patients who suffered from treatment-resistant depression or suicidal ideations (Zarate et al, 2006a; DiazGranados et al, 2010; Murrough et al, 2013; Price et al, 2014). Ketamine can induce unwanted side effects such as psychotomimetic symptoms and cognitive disturbances (Rajagopal et al, 2016)
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