Assessment of antidepressant-like effects of dextromethorphan on differential reinforcement of low-rate 72-s performance in rats

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.