Progesterone treatment, compared to placebo, enhanced the ratings of “bad effects,” from IV nicotine and attenuated the rating of “drug liking” in male and female smokers. These effects of progesterone were unlikely due to non-specific mood-alteration, since measures of mood did not show changes in response to progesterone alone. We previously reported that progesterone treatment at 200 mg, attenuated the rating of “good effects” from smoking in female smokers who were in the follicular phase of their menstrual cycles (Sofuoglu, Babb et al. 2001
). Consistent with these findings, in previous studies progesterone treatment attenuated some of the subjective responses to cocaine (Sofuoglu, Babb et al. 2002
; Sofuoglu, Mitchell et al. 2004
; Evans and Foltin 2006
). This study further extends these findings by demonstrating that progesterone alters some of the subjective responses to pure nicotine in male and female smokers.
In this study, progesterone treatment, compared to placebo, enhanced nicotine’s effect in suppressing urges for smoking, as indexed by Factor 1 (urge to smoke for stimulation) of the BQSU and the total score of the BQSU. Consistent with these findings, in a previous study we reported progesterone treatment was associated with decreases in craving for cigarettes in female smokers (Sofuoglu, Babb et al. 2001
). In that study, there was a trend for reduced smoking under progesterone treatment using a choice procedure. We are currently examining progesterone’s effects on tobacco withdrawal severity and smoking behavior in male and female smokers.
In our study, progesterone had opposite effects on the aversive and pleasurable effects of nicotine, simultaneously enhancing ratings of “bad effect” while attenuating “drug liking.” Both the aversive and rewarding nicotine effects seem to be require dopaminergic system activation, although more recent studies have demonstrated differences in the neurobiological mechanisms of nicotine reward and aversion (Becerra, Breiter et al. 2001
; Jensen, McIntosh et al. 2003
). Progesterone and its active metabolites, allopregnenolone and pregnenolone, have not been shown to directly affect the dopaminergic system, but they interact with other neurotransmitter receptors that modulate dopaminergic functioning, including positive modulatory effects on GABAA
receptors, negative modulatory effects on NMDA receptors (Smith 1991
; Cyr, Ghribi et al. 2000
), as well as blockage of nicotinic receptors including the neuronal α4β2 subtype (Bullock, Clark et al. 1997
; Dar and Zinder 1997
; Paradiso, Sabey et al. 2000
). Further studies are needed to clarify the neurobiological effects of progesterone on the reward system.
Plasma progesterone levels achieved following progesterone treatment were higher than those in our previous study with female smokers (43 vs. 14 pg/ml), although the same micronized progesterone formulation was used in both studies. These differences are possibly due to the effect of food on progesterone absorption. In our current study, to prevent nausea from intravenous nicotine, breakfast was provided early in the session, just after progesterone treatment. Food has been shown to increase the peak plasma concentrations of progesterone levels without affecting the time to reach the peak concentration (Simon, Robinson et al. 1993
). Similar to previous studies, a significant variation was observed among subjects in plasma progesterone levels due to erratic absorption of micronized progesterone. Men had greater average plasma levels than women but this difference was not statistically significant.
This study also had other limitations. First, dose-dependent effects of progesterone were not examined. We selected a progesterone dose that would achieve plasma levels found during the luteal phase of the menstrual cycle. Second, the study had a single dose of treatment. It is possible that longer treatment duration might be associated with different treatment effects. Third, due to small sample size, sex differences in progesterone effects on nicotine response could not be addressed. Lastly, levels of active metabolites of progesterone, pregnenolone or allopregnenolone were not measured. These metabolites are likely play an important role in the CNS effects of progesterone (Baulieu 1998