THE EFFECTS OF COCAINE SELF-ADMINISTRATION ON STRUCTURAL PLASTICITY OF ASTROCYTES

One of the hallmark features of cocaine use disorder is susceptibility toward relapse following cessation of use. It is thus imperative to elucidate neurobiological factors of relapse, to inform more targeted treatment approaches. Previous studies have reported decreases in expression of astrocyte-associated proteins in the nucleus accumbens core following rat cocaine self-administration and extinction training, pointing to possible glial control of relapse vulnerability. Recent results from our laboratory have further revealed remarkable decreases in morphometric features of accumbens astrocytes, as well as decreased colocalization with neuronal synaptic elements. Here I explore the regional specificity of astrocytic responsiveness to cocaine self-administration, as well as the necessity of the withdrawal for its manifestation. Results indicate that the reduced astrocytic phenotype is specific for astrocytes in nucleus accumbens and are not observed in other brain reward centers following cocaine self-administration and extinction. Further, the extinction period was necessary for the development of the atrophic phenotype, with rats undergoing self-administration only not showing morphometric impairments. To understand the subcellular nature of the atrophic phenotype, the second part of the study explored astrocyte branching complexity as well the number and density of accumbens astrocyte processes associated with two commonly utilized cocaine self-administration paradigms. To this end, novel 3-dimensional branching and Sholl analyses were employed as well as end-point and segment analyses, in order to delineate between qualitative and quantitative changes to astrocyte structure following cocaine self-administration. Results showed similar directional changes to subcellular features of astrocytes, with a more severe atrophic phenotype across the analyzed features associated with longer cocaine access and prolonged abstinence. Lastly, segment analysis revealed changes in segment number but not average length, indicating atrophic phenotype is not due to astrocyte shrinkage but rather loss of branching complexity and segments. In summary, this dissertation expands knowledge regarding structural plasticity of astrocytes following cocaine use and withdrawal, revealing specific vulnerability of nucleus accumbens astrocytes to cocaine self-administration, and a common observation of decreased interactions between astrocytes and synapses across self-administration paradigms, which is exacerbated by prolonged cocaine access and abstinence.Doctor of Philosoph