Altered prolactin response to M-chlorophenylpiperazine in monkeys previously treated with 3,4-methylenedioxymethamphetamine (MDMA) or fenfluramine.
3,4-Methylenedioxymethamphetamine ("Ecstasy," MDMA) and fenfluramine, widely used by humans, are potent brain serotonin (5-HT) neurotoxins in animals. Thus, there is concern that humans previously exposed to these amphetamine derivatives may have incurred brain 5-HT neurotoxicity. However, assessing the status of brain 5-HT neurons in the living organism is challenging. To determine whether MDMA- and/or fenfluramine-induced 5-HT neurotoxicity can be detected during life using neuroendocrine methods, groups of monkeys previously treated with neurotoxic regimens of MDMA or fenfluramine, along with saline-treated controls, underwent neuroendocrine challenge with the direct 5-HT agonist and 5-HT-releasing drug, m-chlorophenylpiperazine (m-CPP). Animals treated 2 weeks previously with MDMA exhibited a nonsignificant reduction in the prolactin response to m-CPP. In contrast, monkeys treated 3 1/2 years previously with MDMA or 2 years previously with fenfluramine exhibited significantly increased prolactin responses to m-CPP. No significant differences in cortisol concentrations were noted between groups at any time point. These data indicate that neuroendocrine challenge with m-CPP is capable of detecting substituted amphetamine-induced 5-HT neurotoxicity in living primates, but that the recency of drug exposure is an important consideration. Changes in the neuroendocrine response to m-CPP over time in animals with substituted amphetamine-induced neurotoxicity may be related to aberrant 5-HT reinnervation of the basal forebrain that occurs over time in monkeys previously treated with neurotoxic doses of MDMA or fenfluramine.
Hatzidimitriou
George
G
Department of Neurology, The Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
Tsai
Elizabeth H
EH
McCann
Una D
UD
Ricaurte
George A
GA
D000818:Animals; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005277:Fenfluramine / Q000633:toxicity*; D006854:Hydrocortisone / Q000097:blood / Q000378:metabolism; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000633:toxicity*; D009498:Neurotoxins / Q000633:toxicity*; D010879:Piperazines / Q000494:pharmacology*; D017729:Presynaptic Terminals / Q000187:drug effects* / Q000473:pathology; D011388:Prolactin / Q000097:blood / Q000378:metabolism*; D011903:Raphe Nuclei / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D011930:Reaction Time / Q000187:drug effects / Q000502:physiology; D012453:Saimiri; D018490:Serotonin Agents / Q000633:toxicity*
D009498:Neurotoxins; D010879:Piperazines; D018490:Serotonin Agents; D005277:Fenfluramine; D011388:Prolactin; D018817:N-Methyl-3,4-methylenedioxyamphetamine; C015068:1-(3-chlorophenyl)piperazine; D006854:Hydrocortisone