Neuropeptidergic Modulation of Canonical Reward Circuitry Underlying Escalation of Cocaine Consumption

Abstract

Substance use disorder (SUD) and its related harms are a major public health concern in the United States and across the globe. Pharmacological treatment options are limited or nonexistent for many types of SUDs. Harm reductionist approaches to SUD, including pharmacological and non-pharmacological, have proven more effective at reducing individual and society impact of SUD than traditional abstinence only based approaches. However, our incomplete understanding of the neurobiology underlying the progression and sustainment of SUD hinders the development of new, more effective treatment. This dissertation focuses specifically on one specific SUD-like phenotype characterized by an increase in drug consumption over time (termed escalation). Preventing escalation and/or reversing escalation decreases harm through decreasing the likelihood of infection, overdose, and potential monetary/social loss of the individual with a SUD. Understanding the neurobiological basis of escalation will inform future therapeutic strategies. The neurotransmitter dopamine has a long history of being implicated in addictive drugs and there is evidence suggesting its causal relationship to escalation. Here, I will investigate two systems – dynorphin / kappa opioid receptors and corticotropin releasing factor – in their ability to modulate drug consumption, specifically escalation of cocaine self-administration. Both of these systems are capable of modulating dopamine, modulating each other, and have been implicated in the negative affect and withdrawal symptoms of SUD that are theorized to escalate drug consumption. Through pharmacological and gene editing techniques, I demonstrate in Chapter 2 that the kappa opioid receptor system, specifically expressed in ventral tegmental area neurons, is necessary for escalation of cocaine consumption. Using the same techniques, I demonstrate in Chapter 3 that the corticotropin releasing factor system in the nucleus accumbens, specifically CRF-R1, is not necessary for the development nor sustainment of escalation of cocaine consumption. Additionally, in Chapter 4 I provide a survey of cocaine self-administration in female versus male rats and provide evidence that this behavioral paradigm is capable of producing the SUD-like phenotype of escalation equally in females and males. These data provide further evidence for the dynorphin/kappa system to contribute to the β-process of the opponent process theory of SUD, independent of corticotropin releasing factor modulation through CRF-R1. I specifically implicating the dynorphin/kappa system of ventral tegmental area neurons that project to the nucleus accumbens. In the discussion, I theorize about downstream mechanisms and future experiments to investigate the temporal dynamics of dynorphin in the nucleus accumbens and its potential to modulate dopamine release during cocaine self-administration to escalate drug consumption.