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Effects of fenfluramine, m-CPP and triazolam on repeated-acquisition in squirrel monkeys before and after neurotoxic
Peter J Winsauer1, Una D McCann, J Yuan
1Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, 1901 Perdido Street, New Orleans, LA 70112-1393, USA. pwinsa@lsuhsc.edu
Rationale:
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.
Method:
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.
Insights
MDMA neurotoxicity did not impair learning in monkeys, despite causing significant serotonin depletion. Serotonergic drugs, however, did disrupt learning, showing their distinct effects on cognitive function.
Area of Science:
- Neuroscience
- Pharmacology
- Behavioral Science
Background:
- Establishing functional deficits from MDMA neurotoxicity is challenging.
- Sensitive animal models and drug challenges show moderate success.
Purpose of the Study:
- Characterize serotonergic drug effects on learning using a repeated-acquisition technique.
- Determine if MDMA-induced serotonin (5-HT) neurotoxicity is linked to learning deficits.
Main Methods:
- Six squirrel monkeys were tested under a repeated-acquisition procedure.
- Dose-effect curves for m-CPP, fenfluramine, and triazolam were determined before and after MDMA exposure.
- MDMA's effects on brain 5-HT and 5-HIAA markers were assessed.
Main Results:
- Serotonergic drugs decreased response rates; triazolam increased errors.
- MDMA caused significant decreases (80-99%) in brain 5-HT and 5-HIAA.
- MDMA did not alter learning measures or shift drug dose-effect curves.
Conclusions:
- Serotonergic drugs can disrupt learning in monkeys.
- MDMA-induced 5-HT neurotoxicity is not associated with deficits in this serial learning task.
