Impact of adolescent nicotine exposure on methamphetamine self-administration in female rats

Cigarette smoking during adolescence is common and leads to several long-term adverse consequences. Preclinical studies have found that adolescent rats are more sensitive to the rewarding effects of nicotine and that adolescent rats exposed to nicotine are more sensitive to illicit drug administration including methamphetamine in adulthood. This increased sensitivity to methamphetamine after adolescent nicotine exposure may be a result of enhanced neuroinflammation. Specifically, nicotine increases microglia activation during adolescence and microglia activation is now known to be an important contributor to addictive behavior. The current project proposes to use an intravenous methamphetamine self-administration procedure to further explore the effects of nicotine exposure on the reinforcing properties of methamphetamine in adolescent rats. Both male and female rats will be used as female rats are typically excluded from preclinical investigations, however our preliminary data using oral self-administration indicate that female rats show a greater nicotine enhancement of methamphetamine intake after adolescent nicotine exposure. In Specific Aim 1, we will use intravenous self-administration to determine if adolescent nicotine increases methamphetamine intake, reinstatement, or relapse in male and female rats in a sex dependent manner. In Specific Aim 2 we will determine if inflammation is responsible for alterations in methamphetamine self-administration. To this end we will treat rats with the anti-inflammatory drug, roflumilast before assessing drug seeking and methamphetamine intake. We will also determine the impact of inflammation by measuring if rats treated with nicotine during adolescence have greater expression of inflammatory markers including IBA1, TNF-α and IL-6. Understanding the relationship between adolescent nicotine exposure and later methamphetamine abuse will help identify new and hopefully better therapeutic interventions.