Background: Rates of major depressive disorder (MDD) increase with living at altitude. In our model, rats housed at moderate altitude (in hypobaric hypoxia) exhibit increased depression-like behavior, altered brain serotonin and a lack of antidepressant response to most selective serotonin reuptake inhibitors (SSRIs). A forebrain deficit in the bioenergetic marker creatine is noted in people living at altitude or with MDD. Methods: Rats housed at 4500 ft were given dietary creatine monohydrate (CRMH, 4% w/w, 5 weeks) vs. un-supplemented diet, and impact on depression-like behavior, brain bioenergetics, serotonin and SSRI efficacy assessed. Results: CRMH significantly improved brain creatine in a sex-based manner. At altitude, CRMH increased serotonin levels in the female prefrontal cortex and striatum but reduced male striatal and hippocampal serotonin. Dietary CRMH was antidepressant in the forced swim test and anti-anhedonic in the sucrose preference test in only females at altitude, with motor behavior unchanged. CRMH improved fluoxetine efficacy (20 mg/kg) in only males at altitude: CRMH + SSRI significantly improved male striatal creatine and serotonin vs. CRMH alone. Conclusions: Dietary CRMH exhibits sex-based efficacy in resolving altitude-related deficits in brain biomarkers, depression-like behavior and SSRI efficacy, and may be effective clinically for SSRI-resistant depression at altitude. This is the first study to link CRMH treatment to improving brain serotonin.
The effectiveness of ketamine for treatment-resistant depression along with several other clinical advantages, such as rapid onset and reduced adverse effects associated with serotonin transporter inhibition, has garnered interest in other similar acting psychedelics as novel antidepressant drugs. The antitussive dextromethorphan exhibits glutamate N-methyl-d-aspartate receptor antagonism, sigma-1 receptor agonism, and serotonin reuptake inhibition, which has exhibited antidepressant effects in limited human studies and animal models. The present study sought to further examine dextromethorphan using a differential reinforcement of low-rate 72-s schedule, which can be used to screen antidepressant drugs, in male and female rats. The tricyclic antidepressant drug imipramine and the psychostimulant d-amphetamine also were examined. Sex differences were not shown for baseline performance or for the drugs tested. Further, performance did not differ between the estrus and diestrus stages. Dextromethorphan alone and with quinidine produced an antidepressant-like effect by reducing the number of responses emitted, increasing the number of reinforcers earned, and shifting inter-response times to the right, although significant response suppression occurred at these doses. An antidepressant-like effect was shown with imipramine, but d-amphetamine increased the number of responses emitted and did not affect the number of reinforcers earned. The present findings provide additional support for antidepressant effects produced by dextromethorphan.
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