Effects of Methamphetamine Self-Administration and Extinction on Astrocyte Structure and Function in the Nucleus Accumbens Core.

Astrocytes provide support for neurons, regulate metabolic processes, and influence neuronal communication in a variety of ways, including through the homeostatic regulation of glutamate. Following 2-h cocaine or methamphetamine self-administration (SA) and extinction, rodents display decreased levels of basal glutamate in the nucleus accumbens core (NAcore), which transitions to elevated glutamate levels during drug seeking. We hypothesized that, like cocaine, this glutamate 'overflow' during methamphetamine seeking arises via decreased expression of the astroglial glutamate transporter GLT-1, and withdrawal of perisynaptic astroglial processes (PAPs) from synapses. As expected, methamphetamine self-administration and extinction decreased the level of contact made by PAPs in the NAcore, yet did not impact glutamate uptake, GLT-1 expression, or the general structural characteristics of astrocytes. Interestingly, systemic administration of N-acetylcysteine (NAC), a drug that both upregulates GLT-1 and promotes glial-glutamate release, reduced cued methamphetamine seeking. In order to test the impact of astrocyte activation and the induction of glial glutamate release within the NAcore, we employed astrocyte-specific expression of designer receptors exclusively activated by designer drugs (DREADDs). We show here that acute activation of Gq-coupled DREADDs in this region inhibited cued methamphetamine seeking. Taken together, these data indicate that cued methamphetamine seeking following two-hour SA is not mediated by deficient glutamate clearance in the NAcore, yet can be inhibited by engaging NAcore astrocytes.

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.

Cross-sensitization between cocaine and acute restraint stress is associated with sensitized dopamine but not glutamate release in the nucleus accumbens.

Repeated administration of psychostimulant drugs or stress can elicit a sensitized response to the stimulating and reinforcing properties of the drug. Here we explore the mechanisms in the nucleus accumbens (NAc) whereby an acute restraint stress augments the acute locomotor response to cocaine. This was accomplished by a combination of behavioral pharmacology, microdialysis measures of extracellular dopamine and glutamate, and Western blotting for GluR1 subunit of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor (AMPAR). A single exposure to restraint stress 3 weeks before testing revealed that enduring locomotor sensitization to cocaine was paralleled by an increase in extracellular dopamine in the core, but not the shell subcompartment, of the NAc. Wistar rats pre-exposed to acute stress showed increased basal levels of glutamate in the core, but the increase in glutamate by acute cocaine was blunted. The alterations in extracellular glutamate seem to be relevant, as blocking AMPAR by 6-cyano-7-nitroquinoxaline-2,3-dione microinjection into the core prevented both the behavioral cross-sensitization and the augmented increase in cocaine-induced extracellular dopamine. Further implicating glutamate, the locomotor response to AMPAR stimulation in the core was potentiated, but not in the shell of pre-stressed animals, and this was accompanied by an increase in NAc GluR1 surface expression. This study provides evidence that the long-term expression of restraint stress-induced behavioral cross-sensitization to cocaine recapitulates some mechanisms thought to underpin the sensitization induced by daily cocaine administration, and shows that long-term neurobiological changes induced in the NAc by acute stress are consequential in the expression of cross-sensitization to cocaine.