Repeated exposure to MDMA triggers long-term plasticity of noradrenergic and serotonergic neurons

Abstract

3,4-Methylenedioxymethamphetamine (MDMA or 'ecstasy') is a psychostimulant drug, widely used recreationally among young people in Europe and North America. Although its neurotoxicity has been extensively described, little is known about its ability to strengthen neural circuits when administered in a manner that reproduces human abuse (i.e. repeated exposure to a low dose). C57BL/6J mice were repeatedly injected with MDMA (10 mg kg(-1), intraperitoneally) and studied after a 4-day or a 1-month withdrawal. We show, using in vivo microdialysis and locomotor activity monitoring, that repeated injections of MDMA induce a long-term sensitization of noradrenergic and serotonergic neurons, which correlates with behavioral sensitization. The development of this phenomenon, which lasts for at least 1 month after withdrawal, requires repeated stimulation of α(1B)-adrenergic and 5-hydroxytryptamine (5-HT)(2A) receptors. Moreover, behavioral and neuroendocrine assays indicate that hyper-reactivity of noradrenergic and serotonergic networks is associated with a persistent desensitization of somatodendritic α(2A)-adrenergic and 5-HT1A autoreceptor function. Finally, molecular analysis including radiolabeling, western blot and quantitative reverse transcription-polymerase chain reaction reveals that mice repeatedly treated with MDMA exhibit normal α(2A)-adrenergic and 5-HT(1A) receptor binding, but a long-lasting downregulation of Gαi proteins expression in both locus coeruleus and dorsal raphe nucleus. Altogether, our results show that repeated MDMA exposure causes strong neural and behavioral adaptations and that inhibitory feedback mediated by α(2A)-adrenergic and 5-HT(1A) autoreceptors has an important role in the physiopathology of addictive behaviors.

Inhibition of serotonin transporters disrupts the enhancement of fear memory extinction by 3,4-methylenedioxymethamphetamine (MDMA)

“…MDMA increases levels of extracellular NE in the prefrontal cortex (Lanteri et al 2014), where inhibiting beta-adrenergic receptors in the infralimbic sub-region prior to extinction training impairs the retention of fear memory extinction the following day (Mueller et al 2008). Conversely, extinction retention is enhanced by direct administration of MDMA into the infralimbic cortex (Young et al 2015).…”

The Kappa Opioid Receptor: From Addiction to Depression, and Back

“…In particular, available evidence indicates that the KOR exerts multiple controls over the main monoamines in rodents. Interestingly, addiction research suggests that repeated exposure to drugs of abuse disrupts mutual inhibitory feedback mechanisms between monoaminergic nuclei, which may mediate long-term behavioral dysfunction ( 163 , 164 ). Whether such mechanisms also impair KOR-dependent mood regulation is an intriguing hypothesis in the context of comorbidity.…”

The Combination of Marketed Antagonists of α1b-Adrenergic and 5-HT2A Receptors Inhibits Behavioral Sensitization and Preference to Alcohol in Mice: A Promising Approach for the Treatment of Alcohol Dependence

“…Since 2006, we have shown that the development and the expression of behavioral sensitization to most drugs of abuse were under the control of two monoaminergic receptors, the α1b-adrenergic and 5-HT2A receptors [ 12 – 15 ]. This led us to propose that the repeated consumption of drugs of abuse could, through repeated activations of noradrenergic and/or serotonergic neurons, uncouple a mutual control between the two systems [ 12 , 16 ].…”