STUDIES ON THE ACUTE AND LONG-TERM EFFECTS OF MDMA (3,4- METHYLENEDIOXYMETHAMPHETAMINE)

3,4-Methylenedioxymethamphetamine (MDMA, “ecstasy”) is a popular recreational drug. Administration of MDMA to rats produces an acute, rapid release of cerebral 5-HT and dopamine and depletion of 5-HT. After an initial recovery, 5-HT concentrations then decline for 3-12 months due to neurotoxic loss of the amine. However, in mice there is a long-term loss of cerebral dopamine. MDMA produces acute, dose-dependent hyperthermia in rats and humans. There is also evidence of long-term psychological consequences of MDMA ingestion in both species. This project examined the consequences of administering MDMA to rats housed at different ambient temperatures. Rats were pre-treated with MDMA (12.5 mg/kg) or saline and 6 weeks later received either a single dose of MDMA (5 mg/kg) or 3 doses of MDMA (2 or 4 mg/kg), every 3 hours whilst housed at 30°C. Rats pre-treated with MDMA showed a significantly greater MDMA-induced increase in rectal temperature than those pre-treated with saline. Depleting cerebral 5-HT content by 80% using PCPA also prolonged MDMA-induced hyperthermia in rats housed at an ambient temperature of 30°C. A similar prolonged hyperthermic response was seen after rats were pre-treated with methysergide or WAY 100635. These data suggest that the impaired thermoregulation is due to reduced 5-HT acting at 5-HTia receptors. Administration of MDMA to rats housed at an ambient temperature of 15°C produced a rapid decrease in rectal temperature. This response was blocked by pre-treatment with the dopamine Di antagonist remoxipride but not the Di antagonist SCH23390. Repeated administration of MDMA (2 or 6 doses of 20 mg/kg) to guinea pigs produced an acute hyperthermic response after the first injection but not subsequent injections. A 70% loss of striatal 5-HT and 5-HlAA was found 7 days later, indicating that MDMA produces neurotoxicity in this species without inducing repeated acute hyperthermia. The effect of MDMA on marble burying behaviour in mice was also studied. Acute MDMA administration produced dose-dependent inhibition of marble burying but did not alter locomotor activity. Other monoamine releasing drugs produced a similar effect. A neurotoxic dose of MDMA (3 doses of 25 mg/kg) decreased striatal dopamine by 60% but marble burying was unaltered 18 and 40 days later. A neurotoxic dose of PCA reduced striatal dopamine by 60% and striatal 5-HT by 70% and marble burying was attenuated 28 days later, suggesting that acute MDMA decreases marble burying behaviour by increasing 5-HT function. Long-time 5-HT loss also increased marble burying behaviour probably due to adaptive changes in the brain. In rats, a neurotoxic dose of MDMA (3 doses of 5 mg/kg) increased impulsivity in the short term (24 h), but not long term (7-80 days), as measured by a visual operant discrimination procedure. The acute change appeared to result from general behavioural disruption. These data suggest that impulsivity is not changed by a MDMA-induced neurotoxic loss of cerebral 5-HT. To conclude, the project has found that MDMA administration produces a long-term alteration in themoregulation and alters some behavioural responses in rodents. The observations may have relevance for human users of “ecstasy” (MDMA).

Name dc:type.qualificationname

PhD

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

De Montfort University

Year dc:date.issued

2006

Author dc:creator

• Saadat, Kathryn S.

Licence

• https://dora.dmu.ac.uk/bitstreams/5c8bdef2-bbbe-4a10-88e8-79fb3beee8d3/download