Involvement of Sigma-1 Receptors in the Antidepressant-like Effects of Dextromethorphan

Dextromethorphan is an antitussive with a high margin of safety that has been hypothesized to display rapid-acting antidepressant activity based on pharmacodynamic similarities to the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine. In addition to binding to NMDA receptors, dextromethorphan binds to sigma-1 (σ1) receptors, which are believed to be protein targets for a potential new class of antidepressant medications. The purpose of this study was to determine whether dextromethorphan elicits antidepressant-like effects and the involvement of σ1 receptors in mediating its antidepressant-like actions. The antidepressant-like effects of dextromethorphan were assessed in male, Swiss Webster mice using the forced swim test. Next, σ1 receptor antagonists (BD1063 and BD1047) were evaluated in conjunction with dextromethorphan to determine the involvement of σ receptors in its antidepressant-like effects. Quinidine, a cytochrome P450 (CYP) 2D6 inhibitor, was also evaluated in conjunction with dextromethorphan to increase the bioavailability of dextromethorphan and reduce exposure to additional metabolites. Finally, saturation binding assays were performed to assess the manner in which dextromethorphan interacts at the σ1 receptor. Our results revealed dextromethorphan displays antidepressant-like effects in the forced swim test that can be attenuated by pretreatment with σ1 receptor antagonists, with BD1063 causing a shift to the right in the dextromethorphan dose response curve. Concomitant administration of quinidine potentiated the antidepressant-like effects of dextromethorphan. Saturation binding assays revealed that a Ki concentration of dextromethorphan reduces both the Kd and the Bmax of [3H](+)-pentazocine binding to σ1 receptors. Taken together, these data suggest that dextromethorphan exerts some of its antidepressant actions through σ1 receptors

Involvement of Sigma-1 Receptors in the Antidepressant-Like Effects of Dextromethorphan

Dextromethorphan is an antitussive with a high margin of safety that has been hypothesized to display rapid-acting antidepressant activity based on pharmacodynamic similarities to the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine. In addition to binding to NMDA receptors, dextromethorphan binds to sigma-1 (s1) receptors, which are believed to be protein targets for a potential new class of antidepressant medications. The purpose of this study was to determine whether dextromethorphan elicits antidepressant-like effects and the involvement of s1 receptors in mediating its antidepressant-like actions. The antidepressant-like effects of dextromethorphan were assessed in male, Swiss Webster mice using the forced swim test. Next, s1 receptor antagonists (BD1063 and BD1047) were evaluated in conjunction with dextromethorphan to determine the involvement of s receptors in its antidepressant-like effects. Quinidine, a cytochrome P450 (CYP) 2D6 inhibitor, was also evaluated in conjunction with dextromethorphan to increase the bioavailability of dextromethorphan and reduce exposure to additional metabolites. Finally, saturation binding assays were performed to assess the manner in which dextromethorphan interacts at the s1 receptor. Our results revealed dextromethorphan displays antidepressant-like effects in the forced swim test that can be attenuated by pretreatment with s1 receptor antagonists, with BD1063 causing a shift to the right in the dextromethorphan dose response curve. Concomitant administration of quinidine potentiated the antidepressant-like effects of dextromethorphan. Saturation binding assays revealed that a Ki concentration of dextromethorphan reduces both the Kd and the Bmax of [3H](+)-pentazocine binding to s1 receptors. Taken together, these data suggest that dextromethorphan exerts some of its antidepressant actions through s1 receptors

Role of Sigma-1 Receptors in Neurodegenerative Diseases

Neurodegenerative diseases with distinct genetic etiologies and pathological phenotypes appear to share common mechanisms of neuronal cellular dysfunction, including excitotoxicity, calcium dysregulation, oxidative damage, ER stress and mitochondrial dysfunction. Glial cells, including microglia and astrocytes, play an increasingly recognized role in both the promotion and prevention of neurodegeneration. Sigma receptors, particularly the sigma-1 receptor subtype, which are expressed in both neurons and glia of multiple regions within the central nervous system, are a unique class of intracellular proteins that can modulate many biological mechanisms associated with neurodegeneration. These receptors therefore represent compelling putative targets for pharmacologically treating neurodegenerative disorders. In this review, we provide an overview of the biological mechanisms frequently associated with neurodegeneration, and discuss how sigma-1 receptors may alter these mechanisms to preserve or restore neuronal function. In addition, we speculate on their therapeutic potential in the treatment of various neurodegenerative disorders

Binding parameters for σ₁ receptors in the absence and presence of dextromethorphan.

<p>Saturation binding assays in brain homogenates for σ₁ receptors were conducted using [³H](+)-pentazocine as the radioligand. The assays were performed in the absence or presence of dextromethorphan (400 nM). The K_d and B_max were determined using nonlinear regression. Dextromethorphan produced a significant decrease in K_d and B_max. Data shown are expressed as mean ± S.E.M. ^a<i>P</i><0.05, compared with [³H](+)-pentazocine alone; paired t-test.</p

Antidepressant-like effects of imipramine and dextromethorphan in the forced swim test in mice.

<p>Imipramine (0–20 mg/kg, i.p.) significantly decreased immobility time (A), but had no significant effects on locomotor activity (B). Dextromethorphan (0–30 mg/kg, i.p.) significantly decreased immobility time (C), and significantly increased locomotor activity (D). However, there was no correlation between dextromethorphan (30 mg/kg)-induced locomotor stimulatory effects and decreased immobility times (E). Data shown are expressed as mean ± S.E.M. *<i>P</i><0.05, **<i>P</i><0.01, ***<i>P</i><0.001, compared with the saline-treated group; one-way ANOVA followed by <i>post-hoc</i> Dunnett's tests. Pearson's r correlation test for correlation analysis. IM, imipramine. DM, dextromethorphan.</p

Behavioral and Biochemical Effects of Ketamine and Dextromethorphan Relative to Its Antidepressant-Like Effects in Swiss Webster Mice

Ketamine has been shown to produce rapid and robust antidepressant effects in depressed individuals, however its abuse potential and adverse psychotomimetic effects limit its widespread use. Dextromethorphan may serve as a safer alternative based on pharmacodynamic similarities to ketamine. In this proof of concept study, behavioral and biochemical analyses were undertaken to evaluate the potential involvement of brain derived neurotrophic factor (BDNF) in the antidepressant-like effects of dextromethorphan in mice, with comparisons to ketamine and imipramine. Male Swiss, Webster mice were injected with dextromethorphan, ketamine or imipramine and their behaviors evaluated in the forced swim test (FST) and open field test. Western blots were used to measure brain derived neurotrophic factor (BDNF) and its precursor, pro-BDNF, protein expression in the hippocampus and frontal cortex of these mice. Our results show dextromethorphan and imipramine each reduced immobility time in the FST without affecting locomotor activity, whereas ketamine reduced immobility time and increased locomotor activity. Ketamine also rapidly (within 40 min) increased pro-BDNF expression in an AMPA receptor-dependent manner in the hippocampus, while DM and imipramine did not alter pro-BDNF or BDNF levels in either the hippocampus or frontal cortex within this timeframe. These data demonstrate that dextromethorphan shares some features with both ketamine and imipramine. Additional studies looking at dextromethorphan may aid in the development of more rapid, safe, and efficacious antidepressant treatment

Potentiation of the antidepressant-like effects of dextromethorphan by quinidine.

<p>A single dose of the CYP2D6 inhibitor quinidine (30 mg/kg, i.p.) administered concomitantly with dextromethorphan (0–30 mg/kg, i.p.) significantly potentiated the decrease in immobility time for dextromethorphan at 10 mg/kg (A). In contrast, in the locomotor study, dextromethorphan in combination with quinidine had no stimulatory effects (B). Data shown are expressed as mean ± S.E.M. ***<i>P</i><0.001, compared with the saline-treated group; one-way ANOVA followed by <i>post-hoc</i> Tukey's tests. QND, quinidine. DM, dextromethorphan.</p

Attenuation of the antidepressant-like effects of dextromethorphan, but not imipramine, by σ₁ receptor antagonism.

<p>Pretreatment with the σ₁ receptor antagonist BD1063 (10 mg/kg, i.p.) prevented the dextromethorphan (30 mg/kg, i.p.)-induced decrease in immobility time (A). BD1047 (10 mg/kg, i.p.) pretreatment also produced a noticeable, albeit not statistically significant, trend toward the prevention of the decreased immobility time induced by dextromethorphan (B). In contrast, the antidepressant-like effect of imipramine (20 mg/kg, i.p.) in the forced swim test was not significantly prevented by BD1063 pretreatment (C). Data shown are expressed as mean ± S.E.M. *<i>P</i><0.05, ***<i>P</i><0.001, compared with the saline-treated group; #<i>P</i><0.05, compared with the dextromethorphan-treated group; one-way ANOVA followed by <i>post-hoc</i> Tukey's tests. IM, imipramine. DM, dextromethorphan.</p