Effects of fenfluramine, m-CPP and triazolam on repeated-acquisition in squirrel monkeys before and after neurotoxic MDMA administration.
BACKGROUND
Establishing functional deficits as a result of neurotoxic dosing regimens of MDMA has been difficult. However, moderate success has been achieved when sensitive animal models and drug challenge have been used together.


OBJECTIVE
The present study used a repeated-acquisition technique and dose-effect determinations before, during and after neurotoxic MDMA exposure to characterize the effects of serotonergic drugs on learning, and to determine if MDMA-induced serotonin (5-HT) neurotoxicity is associated with learning deficits as measured by changes in response rate or the percentage of errors.


METHODS
The effects of various serotonergic drugs were characterized in six squirrel monkeys responding under a repeated-acquisition procedure before and after neurotoxic dose regimens of MDMA. Specifically, cumulative dose-effect curves for m-CPP (0.032-1 mg/kg), fenfluramine (0.1-3.2 mg/kg) and triazolam (0.0032-0.1 mg/kg) were obtained prior to MDMA administration, with the latter drug serving as a non-5-HT control.


RESULTS
In general, all of the drugs tested decreased overall response rate as the cumulative dose increased, whereas only triazolam markedly increased the percentage of errors. MDMA treatment produced significant (80-99%) decreases in brain 5-HT and 5-HIAA axonal markers, but did not lead to changes in either dependent measure of responding or shifts in the dose-effect curves obtained during pharmacological challenges with m-CPP, fenfluramine or triazolam.


CONCLUSIONS
Taken together, these results demonstrate that serotonergic drugs can disrupt learning in monkeys, but indicate that MDMA-induced 5-HT neurotoxicity does not lead to disruptions in this particular type of serial learning task.
Winsauer
Peter J
PJ
Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, 1901 Perdido Street, New Orleans, LA 70112-1393, USA. pwinsa@lsuhsc.edu
McCann
Una D
UD
Yuan
J
J
Delatte
Marcus S
MS
Stevenson
Michael W
MW
Ricaurte
George A
GA
Moerschbaecher
Joseph M
JM
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005277:Fenfluramine / Q000494:pharmacology*; D018757:GABA Modulators / Q000494:pharmacology; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D007858:Learning / Q000187:drug effects / Q000502:physiology; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000633:toxicity*; D010879:Piperazines / Q000494:pharmacology*; D011930:Reaction Time / Q000187:drug effects* / Q000502:physiology; D012453:Saimiri; D012701:Serotonin / Q000378:metabolism; D018490:Serotonin Agents / Q000633:toxicity*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D014229:Triazolam / Q000494:pharmacology*
D018757:GABA Modulators; D010879:Piperazines; D018490:Serotonin Agents; D017366:Serotonin Receptor Agonists; D014229:Triazolam; D005277:Fenfluramine; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D018817:N-Methyl-3,4-methylenedioxyamphetamine; C015068:1-(3-chlorophenyl)piperazine