Acute Effects of Dexfenfluramine (d‐FEN) and Methylenedioxymethamphetamine (MDMA) before and after Short‐Course, High‐Dose Treatment

In rhesus monkeys, the acute behavioral effects of MDMA and dexfenfluramine (d-FEN) were assessed using five food-reinforced tasks measuring learning, memory, attention, time estimation, motivation, and discrimination. After a short-course, high-dose exposure to MDMA (10 mg/kg twice daily for four days), monkeys became less sensitive to the acute behavioral disruption by both drugs, especially d-FEN, and this tolerance was task-specific. In contrast, monkeys similarly exposed to high-dose d-FEN (5 mg/kg) showed no change in sensitivity. Surprisingly, both groups showed similar neurochemical effects—approximately 50% decreases in serotonin in the frontal cortex and hippocampus six months later—yet only MDMA pretreatment induced behavioral tolerance.

Study at a glance

Abstract

ABSTRACT: The acute behavioral effects of methylenedioxymethamphetamine (MDMA) and dexfenfluramine (d‐FEN) were assessed in six rhesus monkeys using performance in the National Center for Toxicological Research (NCTR) Operant Test Battery (OTB); three additional animals served as controls for neurochemical endpoints. The OTB consists of five food‐reinforced tasks designed to model aspects of learning, short‐term memory and attention, time estimation, motivation, and color and position discrimination. Shortly after the acute effects of each drug were determined, three of the monkeys received a short‐course, high‐dose exposure (2×/day × 4 days, intramuscular (i.m.) injections) of MDMA (10 mg/kg), while three monkeys were exposed to an identical regimen of d‐FEN (5 mg/kg). Approximately one month later, the acute effects of each drug were again determined. In monkeys exposed to high‐dose d‐FEN, the sensitivities of the OTB tasks to acute disruption by either MDMA or d‐FEN were essentially unchanged. Conversely, monkeys treated with high‐dose MDMA were less sensitive to the acute behavioral effects of both drugs, although such an effect was seen more frequently for d‐FEN and was OTB task specific. Thus a residual behavioral tolerance to the acute behavioral effects of MDMA and d‐FEN was noted after high‐dose MDMA exposure, but not after high‐dose d‐FEN exposure. These findings are surprising, as similar neurochemical effects ( i.e. , significant decreases of ca. 50% in serotonin in frontal cortex and hippocampus) were observed in all monkeys approximately six months after short‐course, high‐dose MDMA or d‐FEN treatment.