Intravenous (IV) Nicotine Self Administration: Dose Ranging and Sex Differences in Smokers

The proposed study will examine the threshold for nicotine self-administration using four different nicotine doses in male and female smokers with or without nicotine dependence (light and intermittent smokers). The investigators propose a double-blind, placebo-controlled study that will enroll 150 individuals with 32 male and 32 female smokers with a total of 64 completers, (16 of each group will be dependent and 16 will be non-dependent). Smokers will participate in four sessions: four test sessions. In each of the four test sessions, smokers will be randomly assigned to one of the four doses of nicotine (1.5, 3.0, 4.5, and 6.0 mcg/kg, or about 0.1, 0.2, 0.3, and 0.4 mg/70 kg). At the beginning of each test session, smokers will sample the assigned nicotine dose and placebo (saline) and then have the opportunity to choose between nicotine and placebo for a total of five choices over a 90-minute period. The main outcomes will be threshold dose (the minimum dose of nicotine that is self-administered more than placebo) and the slope of dose-response for nicotine self-administration (changes in nicotine self-administration per unit change in nicotine dose).

Aim #1: To further characterize the reinforcing threshold and dose-response curve for IV nicotine self-administration in male and female smokers with or without nicotine dependence. The reinforcing effects of nicotine will be determined by the number of IV nicotine self-administrations.

Hypothesis 1a) female smokers, compared to males, will have a lower threshold and a steeper slope for nicotine reinforcement, indicating greater sensitivity to nicotine.

Hypothesis 1b) non-dependent smokers, compared to dependent smokers, will have a lower threshold and a steeper slope for nicotine reinforcement.

Aim#2: To further characterize the threshold and dose-response curve for the subjective-rewarding effects of self-administered IV nicotine in male and female smokers with or without nicotine dependence. The subjective-rewarding effects of nicotine will be determined by the "good effects" and "drug liking" items of the Drug Effects Questionnaire.

Hypothesis 2a) female smokers, compared to males, will have a lower threshold and a steeper slope for the subjective-rewarding effects of nicotine.

Hypothesis 2b) non-dependent smokers, compared to dependent smokers, will have a lower threshold and a steeper slope for the subjective-rewarding effects of nicotine, indicating greater sensitivity to nicotine.

• Drug: Saline
  5cc's of saline give at least once.
• Drug: Nicotine
  1.5, 3.0, 4.5, or 6.0 mcg/kg.

• Active Comparator: Nicotine
  subjects will be randomly assigned to one of the four doses of nicotine: 1.5, 3.0, 4.5, or 6.0 mcg/kg. Subjects will first receive saline and the assigned nicotine dose in a randomized order and double-blind fashion. Subjects will be informed that they will be receiving drug A or B, which may be nicotine or saline. This procedure will allow subjects to sample the nicotine and saline that will be available during that session. In addition, subjective and physiological responses to the sample nicotine dose and saline will be assessed.
  Intervention: Drug: Saline
• Placebo Comparator: Saline
  Subjects will have sample A and B, one being nicotine and one being saline. The doses will be blinded from PI, subject and staff. The subject must choose A or B for the next six choices.
  Intervention: Drug: Nicotine

Inclusion Criteria:

• Female and male smokers, aged 18 to 50 years, who have been smoking for at least a year;
• for non-dependent smokers, urine cotinine levels < 200 ng/mL and not-fulfill DSM-IV criteria for nicotine dependence;
• for dependent smokers, urine cotinine levels ≥ 200 ng/mL and fulfill DSM-IV criteria for nicotine dependence;
• not seeking treatment at the time of the study for nicotine dependence;
• in good health as verified by medical history, screening examination, and screening laboratory tests;
• for women, not pregnant as determined by pregnancy screening, nor breast feeding, and using acceptable birth control methods.

Exclusion Criteria:

• history of major medical illnesses that the physician investigator deems as contraindicated for the subject to be in the study;
• regular use of psychotropic medication (antidepressants, antipsychotics, or anxiolytics) and recent psychiatric diagnosis and treatment for Axis I disorders including major depression, bipolar affective disorder, schizophrenia or panic disorder; and
• abuse of alcohol or any other recreational or prescription drugs.