Neonatal Citalopram Treatment Inhibits the 5-HT Depleting Effects of MDMA Exposure in Rats
Tori L. Schaefer, Curtis E. Grace, Matthew R. Skelton, Devon L Graham, Gary A. Gudelsky, Charles V. Vorhees, Michael T. Williams
ACS Chemical Neuroscience October 21, 2011 DOI: 10.1021/cn2000553 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Animal experimental study Peer reviewed |
|---|---|
| Population | Neonatal rats exposed to MDMA from postnatal day 11 to 20 |
| Interventions | MDMA Citalopram |
| Dose | MDMA 4×10 mg/kg/day; citalopram 5 mg/kg twice daily |
| Duration | Treatment interval postnatal days 11–20, with measurements at P12, P16, and P21 |
| Measures | serotonin (5-HT) levels, striatal dopamine, hippocampal NGF, BDNF, plasma corticosterone |
| Topics | MDMA Serotonin |
| Citations | 5 |
| Key findings | Citalopram at 5 mg/kg twice daily significantly attenuated MDMA-induced serotonin depletions in hippocampus, entorhinal cortex, and neostriatum at P12, P16, and P21, though protection was incomplete at some ages. Striatal dopamine was unaffected; MDMA increased hippocampal NGF at P16 and plasma corticosterone at P21, with no change in BDNF. The authors propose citalopram as a means to test whether MDMA's cognitive and anxiety effects are mediated by early serotonin disruption. |
Abstract
Neonatal exposure to 3,4-methylenedioxymethamphetamine (MDMA) produces long-term learning and memory deficits and increased anxiety-like behavior. The mechanism underlying these behavioral changes is unknown but we hypothesized that it involves perturbations to the serotonergic system as this is the principle mode of action of MDMA in the adult brain. During development 5-HT is a neurotrophic factor involved in neurogenesis, synaptogenesis, migration, and target region specification. We have previously showed that MDMA exposure (4×10 mg/kg/day) from P11-20 (analogous to human third trimester exposure) induces ~50% decreases in hippocampal 5-HT throughout treatment. To determine whether MDMA-induced 5-HT changes are determinative, we tested if these changes could be prevented by treatment with a selective serotonin reuptake inhibitor (citalopram: CIT). In a series of experiments we evaluated the effects of different doses and dose regimens of CIT on MDMA-induced 5-HT depletions in three brain regions (hippocampus, entorhinal cortex, and neostriatum) at three time-points (P12, P16, P21) during the treatment interval (P11-20) known to induce behavioral alterations when animals are tested as adults. We found that 5 mg/kg CIT administered twice daily significantly attenuated MDMA-induced 5-HT depletions in all three regions at all three ages but that the protection was not complete at all ages. Striatal dopamine was unaffected. We also found increases in hippocampal NGF and plasma corticosterone following MDMA treatment on P16 and P21, respectively. No changes in BDNF were observed. CIT treatment may be a useful means of interfering with MDMA-induced 5-HT reductions and thus permit tests of the hypothesis that the drug's cognitive and/or anxiety effects are mediated through early disruptions to 5-HT dependent developmental processes.
Comparable studies
Other preclinical and animal studies on MDMA, most cited first.
Citations in the library
Cites 14
- The molecular mechanism of "ecstasy" [3,4-methylenedioxy-methamphetamine (MDMA)]: serotonin transporters are targets for MDMA-induced serotonin release. Proceedings of the National Academy of Sciences March 1, 1992
- Human Pharmacology of MDMA Therapeutic Drug Monitoring March 19, 2004
- 3,4-Methylenedioxymethamphetamine (MDMA) neurotoxicity in rats: a reappraisal of past and present findings Psychopharmacology March 15, 2006
- 3,4-Methylenedioxymethamphetamine (Ecstasy)-Induced Learning and Memory Impairments Depend on the Age of Exposure during Early Development Journal of Neuroscience May 1, 2001
- The mechanisms involved in the long‐lasting neuroprotective effect of fluoxetine against MDMA (‘ecstasy’)‐induced degeneration of 5‐HT nerve endings in rat brain British Journal of Pharmacology September 1, 2001
and 9 more in the library