The goal of this project is to develop animal models of nicotine exposure reduction and to use these models to study the determinants of compensation, the consequences of compensation, and potential interventions to facilitate reduction. Smoking reduction is of interest as an alternative to cessation or as a transitional goal toward cessation for smokers who cannot or will not quit. However, meaningful reduction of smoke intake is difficult to achieve because of compensatory changes in smoking behavior. Understanding the mechanisms underlying compensation is important for assessing the viability of smoking reduction as a treatment strategy, selection of candidates for this approach, and development of interventions to facilitate cessation. In this study, two models of nicotine exposure reduction are being examined using rats trained for nicotine self-administration (NSA): (1) reduction of access duration from 23 hours per day to 2 hours per day and (2) reduction of the NSA dose from 0.06 to 0.03 mg/kg/infusion. Specific Aim #1 is to identify potential determinants of compensation. Studies will relate the degree of compensation to baseline nicotine intake, diurnal nicotine intake pattern, nicotine clearance and elimination half-life, and reward deficit after termination of a nicotine infusion as measured by intracranial self-stimulation thresholds.

Specific Aim #2 is to assess the effects of nicotine exposure reduction on subsequent reacquisition. These experiments will study a potential adverse consequence of nicotine exposure reduction--whether the increased responding rate associated with compensation is maintained when access to nicotine is no longer restricted, resulting in higher than baseline NSA rates. Specific Aim #3 is to study the effects of vaccination against nicotine on NSA compensation. Because vaccination against nicotine markedly prolongs nicotine's elimination half-life, we will study whether it reduces compensation and thereby facilitates nicotine exposure reduction. Specific Aim #4 is to study the effects of pregnancy on NSA and compensation.

 Many women reduce their smoking during pregnancy, and smoking reduction in pregnant women has been shown to improve birth outcomes, thus identifying a key target population for this intervention. We will study whether NSA is altered by pregnancy, and the effects of pregnancy on compensation. These data should be helpful in understanding the determinants of compensation, identifying potential strategies to reduce compensation, and identifying individuals or populations in whom smoking reduction is likely to be feasible. This study provides the preclinical component of our Center's vertically integrated investigation of the role of tobacco exposure reduction in a comprehensive tobacco control strategy. In addition, this study parallels and provides complimentary information to Dr. Hatsukami's human laboratory studies of smoking reduction.