Examining the role of oxytocin in the interoceptive effects of 3,4‐methylenedioxymethamphetamine (MDMA, ‘ecstasy’) using a drug discrimination paradigm in the rat

Abstract

3,4-Methylenedioxymethamphetamine (MDMA, 'ecstasy') use results in distinctive mood changes of a prosocial nature, most likely through its enhancement of serotonin (5HT) neurotransmission. Activation of 5HT-1A postsynaptic receptors has been shown to stimulate the release of oxytocin in the central nervous system where it regulates aspects of mood and behavior. Using a drug discrimination paradigm, we examined whether modulation of oxytocin receptor activity would affect conditioned behavioral responses to MDMA. Male and female Sprague Dawley rats (n=24) were trained to reliably differentiate between MDMA and a related stimulant, amphetamine (AMP), and saline using a three-lever drug discrimination paradigm. The extent to which substitution with carbetocin (an oxytocin analog) or co-administration with atosiban (an oxytocin receptor antagonist) affected drug-appropriate responding was evaluated. The tricyclic antidepressant imipramine was included as a negative control. The results supported the hypotheses that substitution with an oxytocin analog (carbetocin) would partially generalize to the MDMA training cue, whereas blocking oxytocin receptors with atosiban would result in a selective disruption of MDMA--but not AMP-appropriate responding. These findings were specific to the oxytocin receptor ligands as imipramine pre-treatment did not affect drug-appropriate responding. The results of this study implicate oxytocin receptor activation as a key MDMA-specific interoceptive cue in male and female rats and support the conclusion that this is one of the features of MDMA's subjective effects that distinguishes it from AMP.