Characterizing the role of cortical neuronal subtypes and drug intake pattern in cocaine addiction

Thesis (Ph.D.)--University of Washington, 2018Drug addiction is a complex neuropsychiatric disorder that takes a great emotional and financial toll on those who suffer from it as well as society as a whole. Psychologically, drugs of abuse produce an unusual mix of symptoms characterized by euphoric reward states and the desire to seek more drug as well as aversive states characterized by dysphoria and physical discomfort. It is of great importance to understand how drugs of abuse are able to induce these different psychological symptoms and how these components combine to create a disease that is chronic with high rates of recidivism. The corticolimbic circuitry is composed of several nuclei that are involved in motivated and affective behaviors under normal conditions. During drug use, many molecular and synaptic adaptations occur in this circuit, which is believed to underlie the transition to a compulsive drug use state. In order to study drug addiction effectively, it must first be effectively modeled in animals. In the first chapter, I describe an intermittent access self-administration paradigm that captures many aspects considered crucial to compulsive drug use. Intermittent access self-administration produces a coherent behavioral variability that allows for the separation of animals into compulsive and non-compulsive groups. Compulsive animals demonstrate an enhanced sensitization to cocaine, an increased susceptibility to cue-induced reinstatement, escalation of their drug intake over time, and a change in seeking patterns that are indicative of binge-type behaviors. Continuous access self-administration, while producing animals that individually score highly on individual aspects of addiction behaviors, fails to produce a group of compulsive animals that score highly across many different measures. In chapter 2 and 3, we begin to characterize the contributions of striatum-projecting anterior cingulate cortical (ACC) neurons in a cell-type specific manner. Although corticostriatal projections play an important role in addiction, no attempts have been made to study the contributions of these projections in a manner that accounts for cortical cell-type specificity. The cortex is composed of two striatal projection populations (IT and PT-type neurons), which differ in a multitude of ways. First, we show that IT and PT-type neurons selectively participate in the negative and positive aspects of cocaine use, respectively. Next, we demonstrate that activity in PT-type neurons is not inherently rewarding and does not contribute to the experience of hedonic natural rewards. Finally, we show that inhibition of PT-type neurons in the ACC transiently enhances cocaine-induced locomotor sensitization, but does not affect the motivation to obtain drug or seek drug on progressive ratio and reinstatement tests