Date of Award

Fall 2026

Abstract

Tobacco use, primarily smoking, is the leading preventable cause of death, causing eight million deaths annually. Nicotine, the main addictive constituent of tobacco, acts as a reinforcer and as an interoceptive conditioned stimulus. While its pharmacology is well studied, the neural mechanisms of learning with nicotine remain underexplored. We examined the role of prelimbic cortex (PL) projections to the anterior dorsomedial caudate putamen (a-dmCPu) in nicotine-evoked goal-tracking. To achieve pathway-specific inhibition, we expressed Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) in male and female rats. Subsequently, rats underwent self-administration conditioning in which active responses delivered intravenous (IV) nicotine followed 30 s later by sucrose. The nicotine–sucrose pairing procedure rapidly established Pavlovian goal-tracking. Test sessions with noncontingent nicotine infusions followed systemic clozapine-N-oxide (CNO; 0.0, 1.0, 3.0, 9.0 mg/kg; within-subject). Dependent variables were dipper entries and entry duration during 8-min tests (32 × 15 s bins; infusion at bin 17), as well as a composite goal-tracking score calculated from the two measures. Male rats expressing DREADDs showed relative preservation of goal-tracking behavior across measures compared to CNO-suppressed control rats. In contrast, female rats expressing DREADDs showed reduced dipper entry duration, but not number of dipper entries. Similarly, male control rats showed CNO-induced suppression of goal-tracking across all dependent measures, whereas female controls only showed reduced dipper entry duration. Taken together, these results suggest that the PL–a-dmCPu pathway may normally inhibit expression of learning with nicotine as a conditioned stimulus, although this interpretation is limited by nonspecific suppressive effects of CNO observed in control rats. In females, the pattern of effects is more complex, with suppression of dipper entry duration but not dipper entries in both groups. This suggests there may be sex-dependent interactions between nicotine and the corticostriatal pathway in learning.

Document Type

Dissertation

First Advisor

Sergios Charntikov

Second Advisor

Sergios Charntikov

Third Advisor

William Stine

Department or Program

Psychology

Degree Name

Doctor of Philosophy

Download

Share

COinS