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Locomotor effects of 3,4-methylenedioxymethamphetamine (MDMA) and its deuterated form in mice: psychostimulant effects, stereotypy, and sensitization.
Psychopharmacology (Berl). 2020 Feb; 237(2):431-442.P

Abstract

RATIONALE

There is a renewed interest in the use of 3,4-methylenedioxymethamphetamine (MDMA) for treating psychiatric conditions. Although MDMA has entered phase II clinical trials and shows promise as an adjunct treatment, there is an extensive literature detailing the potential neurotoxicity and adverse neurobehavioral effects associated with MDMA use. Previous research indicates that the adverse effects of MDMA may be due to its metabolism into reactive catechols that can enter the brain and serve directly as neurotoxicants. One approach to mitigate MDMA's potential for adverse effects is to reduce O-demethylation by deuterating the methylenedioxy ring of MDMA. There are no studies that have evaluated the effects of deuterating MDMA on behavioral outcomes.

OBJECTIVES

The purpose of the present study was to assess the motor-stimulant effects of deuterated MDMA (d2-MDMA) and compare them to MDMA in male mice.

METHODS

Two experiments were performed to quantify mouse locomotor activity and to vary the drug administration regimen (single bolus administration or cumulative administration).

RESULTS

The results of Experiments 1 and 2 indicate that d2-MDMA is less effective at eliciting horizontal locomotion than MDMA; however, the differences between the compounds diminish as the number of cumulative administrations increase. Both d2-MDMA and MDMA can elicit sensitized responses, and these effects cross-sensitize to the prototypical drug of abuse methamphetamine. Thus, d2-MDMA functions as a locomotor stimulant similar to MDMA, but, depending on the dosing regimen, may be less susceptible to inducing sensitization to stereotyped movements.

CONCLUSIONS

These findings indicate that d2-MDMA is behaviorally active and produces locomotor effects that are similar to MDMA, which warrant additional assessments of d2-MDMA's behavioral and physiological effects to determine the conditions under which this compound may serve as a relatively safer alternative to MDMA for clinical use.

Authors+Show Affiliations

Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, 4301 W. Markham #611, Little Rock, AR, 72205, USA.Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100, København Ø, Denmark.Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100, København Ø, Denmark.Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, 4301 W. Markham #611, Little Rock, AR, 72205, USA. WEFantegrossi@uams.edu.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31729537

Citation

Berquist, Michael D., et al. "Locomotor Effects of 3,4-methylenedioxymethamphetamine (MDMA) and Its Deuterated Form in Mice: Psychostimulant Effects, Stereotypy, and Sensitization." Psychopharmacology, vol. 237, no. 2, 2020, pp. 431-442.
Berquist MD, Leth-Petersen S, Kristensen JL, et al. Locomotor effects of 3,4-methylenedioxymethamphetamine (MDMA) and its deuterated form in mice: psychostimulant effects, stereotypy, and sensitization. Psychopharmacology (Berl). 2020;237(2):431-442.
Berquist, M. D., Leth-Petersen, S., Kristensen, J. L., & Fantegrossi, W. E. (2020). Locomotor effects of 3,4-methylenedioxymethamphetamine (MDMA) and its deuterated form in mice: psychostimulant effects, stereotypy, and sensitization. Psychopharmacology, 237(2), 431-442. https://doi.org/10.1007/s00213-019-05380-3
Berquist MD, et al. Locomotor Effects of 3,4-methylenedioxymethamphetamine (MDMA) and Its Deuterated Form in Mice: Psychostimulant Effects, Stereotypy, and Sensitization. Psychopharmacology (Berl). 2020;237(2):431-442. PubMed PMID: 31729537.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Locomotor effects of 3,4-methylenedioxymethamphetamine (MDMA) and its deuterated form in mice: psychostimulant effects, stereotypy, and sensitization. AU - Berquist,Michael D, AU - Leth-Petersen,Sebastian, AU - Kristensen,Jesper Langgaard, AU - Fantegrossi,William E, Y1 - 2019/11/15/ PY - 2019/05/23/received PY - 2019/10/16/accepted PY - 2021/02/01/pmc-release PY - 2019/11/16/pubmed PY - 2020/8/5/medline PY - 2019/11/16/entrez KW - 3,4-Methylenedioxymethamphetamine KW - Cross-sensitization KW - Cumulative administration KW - Deuterium substitution KW - Locomotor activity KW - MDMA KW - Methamphetamine KW - Sensitization KW - Stereotypy SP - 431 EP - 442 JF - Psychopharmacology JO - Psychopharmacology (Berl.) VL - 237 IS - 2 N2 - RATIONALE: There is a renewed interest in the use of 3,4-methylenedioxymethamphetamine (MDMA) for treating psychiatric conditions. Although MDMA has entered phase II clinical trials and shows promise as an adjunct treatment, there is an extensive literature detailing the potential neurotoxicity and adverse neurobehavioral effects associated with MDMA use. Previous research indicates that the adverse effects of MDMA may be due to its metabolism into reactive catechols that can enter the brain and serve directly as neurotoxicants. One approach to mitigate MDMA's potential for adverse effects is to reduce O-demethylation by deuterating the methylenedioxy ring of MDMA. There are no studies that have evaluated the effects of deuterating MDMA on behavioral outcomes. OBJECTIVES: The purpose of the present study was to assess the motor-stimulant effects of deuterated MDMA (d2-MDMA) and compare them to MDMA in male mice. METHODS: Two experiments were performed to quantify mouse locomotor activity and to vary the drug administration regimen (single bolus administration or cumulative administration). RESULTS: The results of Experiments 1 and 2 indicate that d2-MDMA is less effective at eliciting horizontal locomotion than MDMA; however, the differences between the compounds diminish as the number of cumulative administrations increase. Both d2-MDMA and MDMA can elicit sensitized responses, and these effects cross-sensitize to the prototypical drug of abuse methamphetamine. Thus, d2-MDMA functions as a locomotor stimulant similar to MDMA, but, depending on the dosing regimen, may be less susceptible to inducing sensitization to stereotyped movements. CONCLUSIONS: These findings indicate that d2-MDMA is behaviorally active and produces locomotor effects that are similar to MDMA, which warrant additional assessments of d2-MDMA's behavioral and physiological effects to determine the conditions under which this compound may serve as a relatively safer alternative to MDMA for clinical use. SN - 1432-2072 UR - https://www.unboundmedicine.com/medline/citation/31729537/Locomotor_effects_of_34_methylenedioxymethamphetamine__MDMA__and_its_deuterated_form_in_mice:_psychostimulant_effects_stereotypy_and_sensitization_ L2 - https://dx.doi.org/10.1007/s00213-019-05380-3 DB - PRIME DP - Unbound Medicine ER -