IV Nicotine Induced Changes in Hormone Function, Mood States and Behavior

These clinical studies are designed to examine the acute effects of intravenous nicotine on
anterior pituitary (ACTH, LH) and adrenal hormones (DHEA and cortisol). We also plan to
study norepinephrine (NE) and epinephrine (E), because nicotine stimulates rapid release of
NE and E in preclinical and clinical studies. The studies will examine the acute effects of
intravenous nicotine on the gonadal steroid hormones and the reciprocal feedback regulation
by LH. The temporal covariance of hormonal changes with serum nicotine levels and
nicotine-induced changes in subjective states and cardiovascular measures will be measured.
The covariance between nicotine-induced changes in endocrine, subjective and cardiovascular
effects and the temporal concordance with increases in serum nicotine and cotinine levels
will be determined. Gender and menstrual cycle phase influences on the effects of nicotine
on HPA and HPG hormones and subjective effects will be assessed.

Inclusion Criteria:

- Men and women between the ages of 18 and 40 who currently smoke at least 15
cigarettes every day, and who fulfill DSM-IV diagnostic criteria for nicotine
dependence (305.10) will be eligible for participation.

- No evidence of clinically significant disease based upon complete medical history and
physical examination by Dr. Arthur Siegel (Chief of Internal Medicine, McLean
Hospital).

- Absence of DSM-IV Axis I Disorders other than nicotine dependence (305.10) as
measured by the Structured Clinical Interview (SCID).

- Routine laboratory blood tests including complete blood count, electrolytes, BUN and
creatinine, liver function test, hepatitis panel and urinalysis will be performed.
Laboratory parameters must be within the normal range. HBsAg must be negative but
subjects who have hepatitis serology consistent with previous exposure to Hepatitis
A, Hepatitis B, or Hepatitis C, but who do not have clinical and biochemical evidence
of acute infection, will be acceptable.

- Hematocrit levels ≥ 39% for males and ≥ 35% for females.

- Serum pregnancy test (hCG beta subunit) results must be negative within 24 hrs of the
study day.

- Normal ECG.

- Subjects must be able to read and understand instructions, as well as provide a valid
informed consent.

Exclusion Criteria:

- Women and men with any lifetime DSM-IV Axis I disorder other than nicotine abuse or
dependence will be excluded.

- Women who are pregnant will be excluded.

- Women who use hormonal contraceptive medications will not be accepted for
participation because this would confound the hormonal measures.

- Men and women with clinically significant medical disorders will be excluded.

- Obese and underweight subjects will be excluded. A mean Body Mass Index (ratio of
weight (W) to height (H) squared; W/H2=kg/m2) will be calculated. Women with a mean
Body Mass Index (BMI) of between 18.0-27.0 and men with a BMI between 21.4-29.0 will
be accepted.

- Treatment seeking subjects will not be selected but will be referred to local smoking
cessation programs.