Abnormal ACTH and prolactin responses to fenfluramine in rats exposed to single and multiple doses of MDMA

Abstract

The present study examined the persistent functional consequences associated with exposure to single and multiple doses of (+/-) 3,4-methylenedioxymethamphetamine (MDMA) as reflected by the neuroendocrine responses to d,l-fenfluramine (FEN). Adult male rats were administered a single dose of MDMA (20 mg/kg, s.c.) and challenged 2 weeks later with saline or FEN (2, 4, 6 and 8 mg/kg, s.c.). The corticotropin (ACTH) response to FEN (6 and 8 mg/kg) was blunted and the prolactin response to FEN (4 and 6 mg/kg) was enhanced in MDMA pre-treated rats. The ACTH and prolactin responses to FEN (6 mg/kg, s.c.) were then evaluated 4, 8 and 12 months after exposure to single and multiple doses MDMA (20 mg/kg, s.c. and 20 mg/kg, s.c., bid, x 4 days, respectively). The ACTH response to FEN was significantly reduced at 4 and 8 months in both MDMA treatment groups, and at 12 months in the multiple dose group only. In contrast, the prolactin response to FEN was enhanced in both groups of MDMA treated rats at 4 months, but only in the multiple dose group at 8 months. By 12 months, the prolactin response to FEN had normalized. Following multiple doses of MDMA, 5-HT concentrations were reduced significantly in the frontal cortex at 4 and 12 months. The results indicate that exposure to single or multiple doses of MDMA can produce functional alterations which can persist for months, whereas the biochemical sequelae were less robust and shorter lived.

Tolerance to 3,4-methylenedioxymethamphetamine in rats exposed to single high-dose binges

“…Not all studies report blunted neuroendocrine responses after pretreatment with MDMA. For example, Poland and coworkers (Poland et al, 1997) demonstrated that rats pretreated with high-dose MDMA exhibit decreases in fenfluramine-induced ACTH and corticosterone secretion, but increases in prolactin secretion. While we can not explain the discrepancies between our prolactin data and those of Poland et al, most evidence indicates that at least some hormone responses evoked by 5-HT-releasing agents are reduced in rats and humans exposed to MDMA.…”

“…For example, rats pretreated with high-dose MDMA are reported to exhibit tolerance or reverse tolerance (i.e., sensitization) to locomotor effects of the drug (Kalivas et al, 1998, Brennan andSchenk, 2006). Similarly, neuroendocrine studies show that rats given neurotoxic doses of MDMA can display a reduction or enhancement in pituitary hormone responses to serotonergic drug challenge (Poland et al, 1997, Baumann et al, 2007. Our preliminary data indicate that neuroendocrine responses to MDMA are uniformly blunted in rats previously exposed to the drug, in agreement with findings in human Ecstasy users (Gerra et al, 1998, Gerra et al, 2000, Verkes et al, 2001.…”

“…Tolerance to behavioral actions of MDMA is also well documented in non-human primates (Frederick et al, 1995, Frederick and Paule, 1997, Fantegrossi et al, 2004, Fantegrossi, 2007. On the other hand, a number of studies in rodents provide evidence for sensitized responsiveness after repeated MDMA exposure (Poland et al, 1997, Kalivas et al, 1998, Giorgi et al, 2005, suggesting tolerance development is not a universal outcome. In humans, the emergence of tolerance to subjective effects of MDMA is a chief complaint which often leads to dangerous dose escalation in an attempt to recapture the "magic" of the initial Ecstasy experience (Verheyden et al, 2003, Parrott, 2005.…”

Ascorbic acid prevents 3,4-methylenedioxymethamphetamine (MDMA)-induced hydroxyl radical formation and the behavioral and neurochemical consequences of the depletion of brain 5-HT

“…The results of the present study are in accord with this earlier report. Poland et al (1997) and Series et al (1994Series et al ( , 1995 have also demonstrated that the depletion of brain 5-HT by MDMA results in suppressed behavioral, neurochemical, and hormonal responses to another 5-HT releasing agent, fenfluramine. A similar blunting of hormonal responses to fenfluramine has been reported in human abusers of MDMA (Gerra et al, 1998).…”

The Effect of Catecholamine Depletion by Alpha-Methyl-Para-Tyrosine on Measures of Cognitive Performance and Sleep in Abstinent MDMA Users

“…Although it could be argued that the development of compensatory mechanisms diminishes the clinical importance of MDMA-induced neurotoxicity, an alternative view is that MDMA-induced lesions produce a brain milieu of diminished functional reserve that may become clinically apparent under various forms of stress. One method that has proved useful for unmasking such 'subclinical' deficits in animals treated with neurotoxic doses of MDMA has been the use of pharmacological challenge (Poland et al, 1997;Virden and Baker, 1999;Shankaran and Gudelsky, 1999;Gardani et al, 2005). The foregoing studies demonstrate that animals with MDMA-induced lesions that exhibit normal behaviors or physiology at baseline have abnormal thermal, behavioral and circadian responses to pharmacological challenges with drugs that influence these 5-HTmediated functional domains.…”