Glutamatergic mechanisms of comorbidity between acute stress and cocaine self-administration.

There is substantial comorbidity between stress disorders and substance use disorders (SUDs), and acute stress augments the locomotor stimulant effect of cocaine in animal models. Here we endeavor to understand the neural underpinnings of comorbid stress disorders and drug use by determining whether the glutamatergic neuroadaptations that characterize cocaine self-administration are induced by acute stress. Rats were exposed to acute (2 h) immobilization stress, and 3 weeks later the nucleus accumbens core was examined for changes in glutamate transport, glutamate-mediated synaptic currents and dendritic spine morphology. We also determined whether acute stress potentiated the acquisition of cocaine self-administration. Acute stress produced an enduring reduction in glutamate transport and potentiated excitatory synapses on medium spiny neurons. Acute stress also augmented the acquisition of cocaine self-administration. Importantly, by restoring glutamate transport in the accumbens core with ceftriaxone the capacity of acute stress to augment the acquisition of cocaine self-administration was abolished. Similarly, ceftriaxone treatment prevented stress-induced potentiation of cocaine-induced locomotor activity. However, ceftriaxone did not reverse stress-induced synaptic potentiation, indicating that this effect of stress exposure did not underpin the increased acquisition of cocaine self-administration. Reversing acute stress-induced vulnerability to self-administer cocaine by normalizing glutamate transport poses a novel treatment possibility for reducing comorbid SUDs in stress disorders.

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

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.