Major depressive disorder (MDD) is a widespread psychiatric disorder that affects millions of people worldwide and is hypothesized to occur due to impairments in several neurotransmitter systems, including the monoaminergic and glutamatergic neurotransmitter systems. Antidepressant medications targeting multiple monoamine neurotransmitters have been shown to be effective for the treatment of depression. Racemic amisulpride is an atypical antipsychotic that has been used at low doses to treat dysthymia, a mild form of depression, and functions as an antagonist at DA2/3, 5-HT2B, and 5-HT7 receptors. Recent preclinical studies have suggested that the S(+) isomer may be more critical for amisulpride’s antidepressant-like effects; however, this interpretation has not been fully characterized in comparison to the R(-) isomer. The glutamatergic system also has been shown to play a critical role in alleviating depression. Several studies have demonstrated that the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine produces rapid and sustained antidepressant-like effects in clinical trials; however, few studies have examined the degree to which ketamine’s isomers contribute to antidepressant-like effects. Fully characterizing these differences in a preclinical model of depression may offer important insight into the role of these neurotransmitter systems on depression. The present study used a 72-sec differential-reinforcement-of-low-rate (DRL) task to assess the antidepressant-like effects of amisulpride, ketamine, and their isomers in mice. The DRL 72-sec task has shown to be a reliable and sensitive screen for drugs that possess antidepressant-like activity as reflected by an increase in the number of reinforcers, a decrease in the number of responses, and a right-ward shift in the interresponse time distributions (IRTs; i.e. the elapsed time between two successive responses). For comparison, the effects of the tricyclic antidepressant imipramine and the N-methyl-D-aspartate antagonist MK-801 as positive and negative controls, respectively, were determined. Consistent with previous findings, we hypothesized that amisulpride and S(-)-amisulpride, but not R(+)-amisulpride, would produce antidepressant-like effects, and all formulations of ketamine would produce antidepressant effects. Racemic amisulpride and S(-)-amisulpride, but not R(+)-amisulpride, produced an antidepressant-like effect, evidenced by a significant increase in the number of reinforcers and a significant decrease in the number of responses. Racemic ketamine and R(-)-ketamine significantly increased the number of reinforcers and decreased the number of responses, while S(+)-ketamine significantly increased the number of reinforcers, but did not decrease the number of responses (at the doses tested). Overall, these results indicate that the racemic formulations of amisulpride and ketamine, S(-)-amisulpride, and both ketamine isomers demonstrate antidepressant-like effects as assessed in the DRL task and may be useful in a clinical context. If either of the ketamine isomers can be shown to produce fewer psychotomimetic effects in humans, then the isomers may offer a significant clinical advantage over the parent compound ketamine. Regarding amisulpride, the present results demonstrate that the S(-) isomer, but not the R(+) isomer, possess antidepressant-like activity similar to racemic amisulpride.
| Identifer | oai:union.ndltd.org:vcu.edu/oai:scholarscompass.vcu.edu:etd-6099 |
| Date | 01 January 2017 |
| Creators | Smith, Doug |
| Publisher | VCU Scholars Compass |
| Source Sets | Virginia Commonwealth University |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | Theses and Dissertations |
| Rights | © The Author |
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