Background As a more detailed picture of nervous system function emerges, diversity of astrocyte function becomes more widely appreciated. While it has been shown that cocaine experience impairs astroglial glutamate uptake and release in the nucleus accumbens (NAc), few studies have explored effects of self-administration on the structure and physiology of astrocytes. We investigated the effects of extinction from daily cocaine self-administration on astrocyte characteristics including GFAP expression, surface area, volume, and colocalization with a synaptic marker. Methods Cocaine or saline self-administration and extinction were paired with GFAP Westerns, immunohistochemistry, and fluorescent imaging of NAc core astrocytes (30 saline-administering and 36 cocaine-administering male Sprague Dawley rats were employed). Imaging was performed using a membrane-tagged Lck-GFP driven by the GFAP promoter, coupled with synapsin I immunohistochemistry. Results GFAP expression was significantly reduced in the NAc core following cocaine self-administration and extinction. Similarly, we observed an overall smaller surface area and volume of astrocytes, as well as reduced colocalization with synapsin I, in cocaine-administering animals. Cocaine-mediated reductions in synaptic contact were reversed by the β-lactam antibiotic ceftriaxone. Conclusions Multiple lines of investigation indicate that NAc core astrocytes exist in a hypo-reactive state following cocaine self-administration and extinction. Decreased association with synaptic elements may be particularly meaningful, as cessation of chronic cocaine use is associated with changes in synaptic strength and resistance to the induction of synaptic plasticity. We hypothesize that the reduced synaptic colocalization of astrocytes represents an important maladaptive cellular response to cocaine and the mechanisms underlying relapse vulnerability.

Complex roles for astrocytes in health and disease continue to emerge, highlighting this class of cells as integral to function and dysfunction of the nervous system. In particular, escalating evidence strongly implicates a range of changes in astrocyte structure and function associated with neuropsychiatric diseases including major depressive disorder, schizophrenia, and addiction. These changes can range from astrocytopathy, degeneration, and loss of function, to astrogliosis and hypertrophy, and can be either adaptive or maladaptive. Evidence from the literature indicates a myriad of changes observed in astrocytes from both human postmortem studies as well as preclinical animal models, including changes in expression of glial fibrillary protein, as well as changes in astrocyte morphology and astrocyte-mediated regulation of synaptic function. In this review, we seek to provide a comprehensive assessment of these findings and consequently evidence for common themes regarding adaptations in astrocytes associated with neuropsychiatric disease. While results are mixed across conditions and models, general findings indicate decreased astrocyte cellular features and gene expression in depression, chronic stress and anxiety, but increased inflammation in schizophrenia. Changes also vary widely in response to different drugs of abuse, with evidence reflective of features of astrocytopathy to astrogliosis, varying across drug classes, route of administration and length of withdrawal.

Anhedonia, a cardinal symptom of depression defined as difficulty experiencing pleasure, is also a possible endophenotype and prognostic factor for the development of depression. The onset of depression typically occurs during adolescence, a period in which social status and affiliation are especially salient. The medial prefrontal cortex (mPFC), a region implicated in reward, self-relevant processing, and social cognition, exhibits altered function in adults with anhedonia, but its association with adolescent anhedonia has yet to be investigated. We examined neural response to social reward in 27 late adolescents, 18–21 years old, who varied in social anhedonia. Participants reported their social anhedonia, completed ratings of photos of unfamiliar peers, and underwent a functional magnetic resonance imaging task involving feedback about being liked. Adolescents with higher social anhedonia exhibited greater mPFC activation in response to mutual liking (i.e., being liked by someone they also liked) relative to received liking (i.e., being liked by someone whom they did not like). This association held after controlling for severity of current depressive symptoms, although depressive severity was also associated with greater mPFC response. Adolescents with higher levels of social anhedonia also had stronger positive connectivity between the nucleus accumbens and the mPFC during mutual versus received liking. These results, the first on the pathophysiology of adolescent anhedonia, support altered neural reward-circuit response to social reward in young people with social anhedonia.

Environmentally induced relapse to cocaine seeking requires the retrieval of context-response-cocaine associative memories. These memories become labile when retrieved and must undergo reconsolidation into long-term memory storage to be maintained. Identification of the molecular underpinnings of cocaine-memory reconsolidation will likely facilitate the development of treatments that mitigate the impact of cocaine memories on relapse vulnerability. Here, we used the rat extinction-reinstatement procedure to test the hypothesis that the Src family of tyrosine kinases (SFK) in the dorsal hippocampus (DH) critically controls contextual cocaine-memory reconsolidation. To this end, we evaluated the effects of bilateral intra-DH microinfusions of the SFK inhibitor, PP2 (62.5 ng per 0.5 μl per hemisphere), following re-exposure to a cocaine-associated (cocaine-memory reactivation) or an unpaired context (no memory reactivation) on subsequent drug context-induced instrumental cocaine-seeking behavior. We also assessed alterations in the phosphorylation state of SFK targets, including GluN2A and GluN2B N-methyl-D-aspartate (NMDA) and GluA2 α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunits at the putative time of memory restabilization and following PP2 treatment. Finally, we evaluated the effects of intra-DH PEAQX (2.5 μg per 0.5 μl per hemisphere), a GluN2A-subunit-selective NMDAR antagonist, following, or in the absence of, cocaine-memory reactivation on subsequent drug context-induced cocaine-seeking behavior. GluN2A phosphorylation increased in the DH during putative memory restabilization, and intra-DH PP2 treatment inhibited this effect. Furthermore, PP2-as well as PEAQX-attenuated subsequent drug context-induced cocaine-seeking behavior, in a memory reactivation-dependent manner, relative to VEH. These findings suggest that hippocampal SFKs contribute to the long-term stability of cocaine-related memories that underlie contextual stimulus control over cocaine-seeking behavior.