Investigating the Impact of Drug History and Cortical Circuitry on Substance Use and Decision-Making

Abstract

While substance use is commonplace within the United States, a subset of users will develop a substance use disorder (SUD). SUDs are characterized by binge-like intake with compulsive seeking and consumption, even in the face of adverse consequences. Extensive research has characterized phenotypes underlying various drugs on a behavioral, pharmacological, and circuit level. However, these models do not necessarily capture the patterns and combinations typical to clinical populations, leaving a significant gap in our understanding of the risks and unique alterations of substance use pathology that translates to SUDs. The public health significance of developing translatable models is highlighted and discussed in Chapter 1. Furthermore, an overview of relevant circuitry in regulating motivated behaviors impacted by substance use are described. In Chapter 2, one proposed behavioral model for investigating behavioral differences with different patterns of cocaine and heroin consumption, including polysubstance use, is explored. Here, we find that, largely, drug class produces the starkest differences in motivated consumption and cue sensitivity, but that polysubstance use produces subtle phenotypical differences in these measures. A significant area of study in substance use models examines the delineation between nucleus accumbens and dorsal striatum projection subtypes. The striatum is known to be involved in the processing of motivated behaviors and reward and is altered in substance users, as well as in preclinical models. Two types of medium spiny neurons (MSNs) – D1 and D2 MSNs – form direct and indirect pathways, respectively. Their opponent regulation of behavioral outputs and changes to activity and behavior impacted by manipulation of these subtypes in SUDs models has illuminated the role of circuit specificity in the SUDs pathology. The striatum integrates many inputs, including innervation from glutamatergic afferents from the prefrontal cortex (PFC). It is also known that cortical activity is altered in substance users, making regional and circuit characterization of cortex critical for fully understanding the development and progression of SUDs. However, while parsing the role of MSN subtypes is extensively investigated, further delineation of cell types in other parts of the cortico-basal-ganglia (CBG) pathway have largely been uncharacterized. Of note are the glutamatergic projection subtypes within cortex, intratelencephlaic (IT) and pyramidal tract (PT) neurons, which are known to have distinct morphology, firing patterns, and projections, but how these correspond to their function roles in behavioral outputs is not well understood. Previous work demonstrates that these cortical subtypes indeed play unique roles in the processing of rewarding and aversive aspects of drug use. Chapters 3 and 4 extend this role to our understanding of subtype-specific modulation in the anterior cingulate cortex (ACC) from psychomotor sensitization to cocaine, as well as the impact of cortical neurons on volitional cocaine use. Our results demonstrate that dampening activity of IT neurons in the ACC augments initial expression, but prevents further escalation of psychomotor activity with repeated cocaine administration, in contrast to previous studies showing PT inhibition reducing expression, but enhancing escalating psychomotor activity. We also show that IT and PT neurons do not produce preference or aversion in the absence of drug treatments, but that PT neurons are involved in effort-based cocaine consumption with self-administration. In Chapter 5, we explore how cortical subtype activity in the OFC may be involved in behavioral outputs under normal conditions, examining decision-making and behavioral flexibility in the absence of drug use. Here, we find that IT inhibition increases behavioral flexibility and PT inhibition produces outcome-dependent alterations to reversal learning, whereas neither population impacts probabilistic decision-making.