Effects of Cocaine on Nucleus Accumbens Core Astrocyte Calcium Dynamics and Control of Synaptic Plasticity

Psychostimulant use disorders present a major public health concern within the United States. These drugs are associated with particularly high relapse vulnerability, and deaths associated with cocaine overdose have consistently increased since 2015. Despite this, there are currently no FDA-approved pharmacological treatments for psychostimulant use disorder. In order to develop more effective therapeutic interventions, it is imperative to develop a complete understanding of the changes in the brain that occur as a consequence of drug abuse. While much is known about neuronal changes that are observed with drug use and the development of dependence, relatively little is known about cocaine-mediated functional changes in astrocytes that affect synaptic transmission. Astrocytes form tripartite synapses with neuronal pre- and postsynapses, at which they respond to synaptic transmission with elevations in intracellular calcium and accordingly, respond by modulating synaptic function. Published data from the Reissner lab indicate that astrocytes in the nucleus accumbens (NAc) core exhibit significantly reduced structure and synaptic colocalization following long-access (LgA, 6 h/day, 10 days) cocaine self-administration and 45 days of abstinence, as evidenced by a ~40% reduction in surface area, volume, and synaptic colocalization (Kim et al., 2022). While these structural changes suggest reduced physical interaction between neurons and astrocytes, it remains unknown exactly how neuron-astrocyte communication is affected at NAc core tripartite synapses at the timepoint that corresponds with structural changes. Accordingly, experiments performed and described in this dissertation tested the overarching hypothesis that LgA cocaine self-administration and prolonged abstinence impairs the ability of astrocytes to “listen” and respond to synaptic activity via calcium responses, and in turn, “talk to” and regulate synaptic transmission. Specifically, the first aim examined astrocyte calcium dynamics and the ability of astrocytes to respond to synaptic transmission after LgA cocaine self-administration and abstinence. While astrocytes were not impaired in their ability to respond to glutamatergic input between cocaine and saline groups, astrocytes from the NAc core of the cocaine group exhibited significantly reduced microdomain calcium activity. Aim 2 examined astrocyte ability to regulate synaptic transmission following cocaine self-administration and abstinence. This experiment revealed hypoactivity at prelimbic to NAc core projections, as measured by paired-pulse ratio (PPR) and excitatory postsynaptic current (EPSC) amplitude. It further identified projection-specific and MSN subtype-specific cocaine-mediated changes in astrocyte regulation of synaptic transmission. Specifically at PL to NAc core synapses, astrocyte stimulation affected only PPR in D2-MSNs in saline rats. When astrocytes within the terminal field in the NAc core were stimulated, D1- and D2-MSN EPSC amplitude was significantly increased in both saline and cocaine rats. In summary, this dissertation identifies nuanced changes in neuron-astrocyte communication at the timepoint in abstinence from cocaine that corresponds with significant changes in astrocyte structure and synaptic colocalization in the NAc core. These data expand the understanding of astrocyte contributions to the neurobiological mechanisms underlying drug dependence and relapse vulnerability.