Rationale. Nicotine is often considered a ‘gateway’ drug because people typically experiment with tobacco before illicit drugs such as cocaine and amphetamine. We have shown that nicotine increases approach to reward-associated stimuli, this is referred to as ‘sign-tracking’, and that this effect persists after nicotine is discontinued. Individuals who are high in sign-tracking also show increased cocaine self-administration. Objectives. The goal of this experiment was to determine whether nicotine enhanced sign tracking could result in greater cocaine self-administration. Method. Rats were randomly assigned to one of 2 groups (NIC or SAL), and injected with their assigned solution (0.4 mg/kg base or placebo, respectively) 15 min before conditioning sessions. During conditioning sessions, a lever/light stimulus was inserted into the chamber for 15 s and immediately followed by sucrose delivery. Approach to the sucrose receptacle was recorded by monitoring head entries and defined as goal tracking. Contact with the lever was recorded and defined as ‘sign-tracking’. After 29 conditioning sessions, the rats were instrumented for cocaine self-administration and were shaped to respond for cocaine on the same lever that served as the CS. After 10 days of acquisition of cocaine self-administration (0.16 mg/inf), demand for cocaine was tested over 6 days using a within session procedure that increased cocaine price every 10 min. Results. We showed increased sign-tracking, but not goal tracking in the NIC group relative to the SAL group. The NIC group also showed increased demand for cocaine during the price manipulation, but the essential value of cocaine did not differ, relative to the SAL group. Conclusion. Our results support a gateway interpretation of substance use – when both the gateway drug (nicotine) and drug-associated rewards (the lever/light) occur together, they can promote future self-administration of illicit drugs such as cocaine.

This prospective longitudinal study evaluated the effect of prenatal cocaine exposure (PCE) on executive functioning in 5- and 7-year-old children. In total, 154 pregnant cocaine users, identified by urine toxicology and structured interviews, were matched to 154 nonusers. Children were assessed by certified masked evaluators, and caregivers were interviewed by experienced staff during home visits. In approximately 90% of the surviving sample tested at ages 5 and 7 years, structural equation modeling demonstrated that an increased head circumference at birth (adjusted for gestation) significantly predicted better performance on executive functioning, and that PCE was indirectly related to executive functioning through its significant negative effect on head circumference at birth. At age 5 years, quality of environment also predicted executive functioning, and the R2 for the total model was 0.24. At 7 years, caregiver functioning predicted quality of environment, which in turn was positively related to executive functioning, and girls had better executive functioning. The total model at age 7 years accounted for 30% of the variance in executive functioning.

Strategies that provide access to alternative non-drug rewards are among the most effective at reducing substance use in individuals with substance use disorders, but relapse often occurs when alternative rewards are removed. Relapse induced by the loss of alternative rewards is called resurgence, and represents a challenge to otherwise effective strategies for reducing drug use. An animal model has been useful for studying resurgence, but the extant model has two limitations. First, humans usually refer to the negative consequences of drug use as the reason they stop taking drugs, but the extant model uses drug unavailability to reduce drug seeking. Second, individuals with substance use disorders display behaviors that can be summarized as uncontrolled drug seeking, but the extant model does not simulate uncontrolled drug seeking. Chapter 2 addressed the first concern by studying resurgence of previously-punished cocaine seeking. Chapter 3 addressed the second concern by using procedures shown to simulate uncontrolled drug seeking in rats to study resurgence of previously-punished cocaine seeking. Chapter 2 showed that resurgence of cocaine seeking can occur following suppression by punishment, and Chapter 3 showed that resurgence may be unaffected following procedures shown to increase relapse in other models. The models developed herein should contribute to future research into resurgence by better simulating the conditions under which individuals with substance use disorders experience relapse.

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