3,4‐Methylenedioxymethamphetamine counteracts akinesia enantioselectively in rat rotational behavior and catalepsy

Abstract

We have shown recently that 3,4-methylenedioxymethamphetamine (MDMA) has symptomatic antiparkinsonian activity in rodent models of Parkinson's disease. In search of its mechanism of action, we further investigated the enantiomers of MDMA in the rotational behavioral model and catalepsy test. Catalepsy testing was done in drug-naive unlesioned animals. The parkinsonian symptoms rigor and akinesia (i.e., catalepsy) were induced by intraperitoneal administration of haloperidol 0.5 mg/kg and measured repeatedly as descent latency from a horizontal bar and a vertical grid. MDMA and both its enantiomers were effective in counteracting haloperidol-induced catalepsy, but if given as racemic, the effects were more pronounced than with the enantiomers. For testing of rotational behavior, male Sprague Dawley rats were lesioned unilaterally with 6-hydroxydopamine (6-OHDA) at the medial forebrain bundle. Administration of S-MDMA (5 mg/kg) produced ipsilateral rotations. R-MDMA was far less effective in inducing ipsilateral rotations in 6-OHDA unilaterally lesioned rats, but when S-MDMA was given additionally rotations immediately increased. Regarding their overall antiparkinsonian effects, the S-enantiomer of MDMA was more effective than its R-congener. R-MDMA was able to increase the actions of S-MDMA.

PRECLINICAL STUDY: Atypical development of behavioural sensitization to 3,4‐methylenedioxymethamphetamine (MDMA, ‘Ecstasy’) in adolescent rats and its expression in adulthood: role of the MDMA chirality

“…Thus, only in the presence of S‐MDMA is R‐MDMA able to further increase the S‐MDMA induced hyperactivity. Some studies that report a similar observation have been published: Lebsanft and colleagues (2005) showed that R‐MDMA produces negligible rotational behaviour in unilaterally 6‐OHDA‐lesioned rats. However, the substance significantly increased the ipsilateral rotations of S‐MDMA‐treated animals, which represents a valuable measure for psychomotor activation (see Anagnostaras & Robinson 1996 for example).…”

“…Some studies show that S‐MDMA is more potent in eliciting several aspects of behaviour such as sniffing, head weaving and other stereotypies (Hiramatsu et al. 1989) or rotational behaviour in hemiparkinsonian rats (Lebsanft et al. 2005).…”

MDMA (N-methyl-3,4-methylenedioxyamphetamine) and its stereoisomers: Similarities and differences in behavioral effects in an automated activity apparatus in mice

“…On the other hand, amphetamine produces circling to the right because it can only release dopamine from the intact dopamine terminals in the left caudate. Recent studies indicate that (±)-MDMA, S(+)-MDMA, and R(-)-MDMA induced ipsilateral rotation in unilateral 6-hydroxydopamine lesioned rats, which suggests a prominent role for the release of dopamine at the doses employed (Lebsanft et al 2003(Lebsanft et al , 2005. In the present study, the administration of (±)-, S(+)-, and R(-)-MDMA to mice (without brain injury, lesion, or neurotransmitter depletion) produced statistically significant increases in rotations ( Figure 5), differences in potencies and, in the case of S(+)-MDMA, a preference to induce counterclockwise (versus clockwise) rotations ( Figure 6).…”

Monoamine Reuptake Inhibitors in Parkinson’s Disease

“…In the rat, racemic MDMA (1, 2.5, and 5 mg/kg s.c.) and each of its enantiomers (2.5 mg/kg s.c.) effectively counteracted haloperidol-induced catalepsy [736–738]. In the 6-OHDA-lesioned rat, racemic MDMA (2.5 and 5 mg/kg s.c.) and its S-enantiomer (5 mg/kg s.c.) elicited rotations ipsilateral to the lesioned side, whereas R-MDMA (5 mg/kg s.c.) did not trigger rotational behaviour [738–740]. Interestingly, administration of citalopram (10 mg/kg s.c.) resulted in a reduction of racemic MDMA-induced rotations [740].…”