Cannabinoids prevent the acute hyperthermia and partially protect against the 5-HT depleting effects of MDMA (“Ecstasy”) in rats
Introduction
3,4-Methylenedioxymethamphetamine (MDMA, “Ecstasy”) is a widely used illicit drug. The possible adverse effects of MDMA use are a matter of some considerable concern. In laboratory animals, MDMA causes 5-HT nerve terminal degeneration with a concomitant reduction in brain 5-HT content (for reviews see Ricaurte et al., 2000, Green et al., 2003). Human MDMA users also exhibit several effects consistent with 5-HT depletion (Boot et al., 2000, McCann et al., 1998, Parrott, 2001, Reneman et al., 2001) and this may be linked to a number of adverse psychological effects including anxiety, depression and impaired cognition (Morgan, 2000; Parrott, 2001). However, a specific causal relationship between MDMA use and psychological dysfunction is difficult to demonstrate. This is because of the polydrug use that is typical of human MDMA users and the possibility of pre-existing psychopathology in users (Cole et al., 2002, Croft et al., 2001).
Brief exposure to MDMA in rats causes a long-lasting syndrome consisting of greater anxiety-like behaviours, impaired memory and depressive-like symptoms (Bull et al., 2003, Fone et al., 2002, Gurtman et al., 2002, McGregor et al., 2003a, McGregor et al., 2003b, Morley et al., 2001). Such effects are consistent with human reports and may reflect MDMA-induced 5-HT depletion and/or alterations in the density of 5-HT receptors and transporters (McGregor et al., 2003a, McGregor et al., 2003b).
The neurotoxic effects of MDMA are modulated by dose, frequency and route of administration (O’Shea et al., 1998, Ricaurte et al., 2000) as well as the hyperthermic action of the drug (Malberg et al., 1996, Malberg and Seiden, 1998; but see also McGregor et al., 2003b). Interventions that prevent MDMA-induced hyperthermia protect against the neurotoxic effects of the drug (Colado et al., 1998, Malberg et al., 1996, O’Shea et al., 2001). Drugs with antioxidant properties also attenuate the neurotoxic effects of MDMA (Colado and Green, 1995, Colado et al., 1997, Shankaran et al., 2001).
The drug most commonly taken with MDMA in human users is cannabis. More than 90% of ecstasy users take cannabis regularly (Siliquini et al., 2001, Topp et al., 1999). Cannabis is frequently used to mitigate the MDMA “comedown” (Winstock et al., 2001) but is also commonly used before and during dance parties at which MDMA is taken (Boys et al., 1997).
The primary psychoactive constituent of cannabis, Δ9-tetrahydrocannabinol (THC), and synthetic cannabinoid receptor agonists such as CP 55,940, cause hypothermia (Arnold et al., 2001, Fennessy and Taylor, 1978, Pryor et al., 1978). Recent research also indicates that these cannabinoids have antioxidant properties (Hampson et al., 1998, Leker et al., 1999, Marsicano et al., 2002, Nagayama et al., 1999, Shohami and Mechoulam, 2000). This suggests that co-administered cannabinoids might modulate the long-term neurotoxic properties of MDMA either through a hypothermic action, an antioxidant action, or both.
The present study addressed this possibility. Firstly, the effects of co-administered THC on the acute hyperthermia and long-term behavioural and neural effects of MDMA were investigated. Then the possible neuroprotective effects arising from the co-administration of the synthetic cannabinoid CP 55,940 and the cannabinoid CB1 receptor antagonist SR 141716 were examined.
Section snippets
Animals
Inbred male albino Wistar rats were used in all experiments. They were housed in large plastic tubs in groups of 6–8 per cage in a temperature-controlled environment (mean 22 °C) with food and water freely available. A 12 h reversed light cycle was in operation with lights off at 8:30 am. Testing took place during the dark cycle. All experimental procedures were carried out in accordance with the National Institute of Health Guide for the Care and Use of Laboratory Animals (NIH Publications No.
Body temperature
Body temperature changes on the 2 days of drug administration are depicted in Fig. 1. For day 1, ANOVA revealed significant differences between groups for highest (F(3,48)=12.10, P<0.0001) and lowest (F(3,48)=6.73, P<0.001) body temperature recorded (expressed as change from pre-drug baseline). Similar results were obtained on day 2 of drug treatment (F(3,48)=16.43, P<0.0001) and (F(3,48)=23.69, P<0.0001), respectively. Post-hoc analyses (Fig. 1) revealed a significant hyperthermic effect of
Discussion
The present study indicates that co-administration of the main psychoactive constituent of cannabis (THC) or the synthetic cannabinoid CP 55,940 prevents the hyperthermia and partially attenuates the long-term 5-HT depletion produced by MDMA. Furthermore, these results indicate that the CB1 receptor antagonist SR 141716, while reversing cannabinoid agonist effects on MDMA-induced hyperthermia, does not prevent the prophylactic effects of cannabinoid agonists on MDMA-induced 5-HT depletion.
MDMA
Acknowledgements
This work was supported by a National Health and Medical Research Council grant to ISM and GEH and an Australian Research Council grant to ISM and PEM. Kirsten Morley is the recipient of an Australian Postgraduate Award.
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