Elsevier

Neuroscience

Volume 110, Issue 1, 1 March 2002, Pages 41-48
Neuroscience

Altered forebrain neurotransmitter responses to immobilization stress following 3,4-methylenedioxymethamphetamine

https://doi.org/10.1016/S0306-4522(01)00539-5Get rights and content

Abstract

(±)3,4-Methylenedioxymethamphetamine (MDMA, ‘ecstasy’) is an increasingly popular drug of abuse that acts as a neurotoxin to forebrain serotonin neurons. The neurochemical effects of the serotonin depletion following high doses of MDMA were investigated in response to acute immobilization stress. Male rats were treated with a neurotoxic dosing regimen of MDMA (10 mg/kg, i.p. every 2 h for four injections) or equivalent doses of saline. Seven days after treatment, in vivo microdialysis was used to assess extracellular dopamine and serotonin in the dorsal hippocampus and prefrontal cortex during 1 h of immobilization stress. In saline treated control rats, serotonin in the hippocampus and serotonin and dopamine in the prefrontal cortex were increased during immobilization stress. Rats pretreated with MDMA, however, showed blunted neurotransmitter responses in the hippocampus and the prefrontal cortex. In the drug pretreated rats, basal serotonin levels in the hippocampus, but not the prefrontal cortex, were lower compared to saline pretreated controls. Stress-induced increases in plasma corticosterone and body temperature were not affected by the pretreatment condition.

From these studies we suggest that depletion of serotonin stores in terminal regions with the neurotoxin MDMA compromises the ability of the serotonergic neurons to activate central systems that respond to stressful stimuli. This altered responsiveness may have implications for long-term functional consequences of MDMA abuse as well as the interactions between the serotonergic system and stress.

Section snippets

Animals

Male Sprague–Dawley rats (175–250 g) were purchased from Zivic Miller Labs (Allison Park, PA, USA). Rats were housed individually, with food and water available ad libitum, on a 12-h light–dark cycle in a temperature controlled room. All procedures were in adherence to the National Institutes of Health Guide for the Care and Use of Laboratory Animals (NIH Publications No. 80-23) and approved by the local institutional animal care committee.

Drugs

All rats were given i.p. injections with 10 mg/kg MDMA

Neurochemical content of monoamines

Serotonin tissue content of rats treated with MDMA was significantly decreased by 55% in the dorsal hippocampus (t(28)=6.28, P<0.01) and 48% in the frontal cortex (t(28)=3.09, P<0.01) compared to saline treated rats (Table 1). There was no effect of MDMA pretreatment on the concentration of dopamine in the frontal cortex (t(26)=0.674).

Extracellular serotonin response to stress

In the dorsal hippocampus, there was a significant difference between the treatment groups in 5-HT concentrations throughout the experiment as indicated by the

MDMA pretreatment attenuates stress-induced neurotransmitter release

The primary, novel finding of the current study is that MDMA pretreatment can inhibit acute 5-HT and dopamine responses to a behavioral challenge, i.e. immobilization stress. The attenuated 5-HT responsiveness is consistent with previous studies using less subtle pharmacological challenges that activate striatal and cortical 5-HT systems (Series et al., 1994, Shankaran and Gudelsky, 1999). A similar attenuation of 5-HT release following a pharmacological challenge has also been reported

Overall conclusions

Pretreatment with MDMA resulted in 5-HT tissue depletions in the hippocampus and the frontal cortex. MDMA pretreatment blunted the dopamine and 5-HT increases during acute immobilization stress observed in non-depleted or saline pretreated rats. While previous studies have shown that the release of 5-HT in response to a pharmacological agent may be impaired by MDMA pretreatment, the present study indicates that the release of neurotransmitters induced by an environmental change (i.e. stress)

Acknowledgements

This work was supported by the National Institutes of Health DA07606, DA07427, DA05837 and AA10760, the Department of Defense DAMD 17-99-1-9479, and the Department of Veterans Affairs.

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    Present address: Boston University Medical School, Department of Pharmacology, Boston, MA 02118, USA.

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