Sex hormones became a target of
research due to noted sex differences in response to nicotine. Booze et al. (1999) states that in intact
male and female mice, acute nicotine administration stimulated locomotor
activity. In castrated and
ovariectomized mice, acute nicotine administration depressed locomotor activity. Chronic administration led to increased
locomotor activity of intact mice, with female mice being most sensitive to the
effect. However, castrated mice
increased locomotor activity when compared to intact males, and ovariectomized
females lessened their activity when compared to intact females (Figure 2).
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| Figure 2 (Booze et al., 1999) |
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| Figure 3 (Harrod et al., 2007) |
Harrod, Booze, and Mactutus (2007) analyzed
sex differences in plasma nicotine levels in intact and gonadectomized rats. The rats were given one intravenous injection
of nicotine each day. Female rats had
higher plasma nicotine levels than male rats, showing possible sex differences
in metabolism and distribution leads to higher lasting levels of nicotine in
females, thus explaining the differences in behavior. Male and female rats that were gonadectomized
displayed similar levels of plasma nicotine, showing plasma nicotine levels are
dependent upon gonadal hormones and may account for the higher sensitivity of
females to nicotine (Figure 3).
Estrogen is believed to be
responsible for increased vulnerability to the effects of nicotine, while
progesterone may serve as a protective factor (Lynch & Sofuoglu, 2010;
Schiller, Saladin, Gray, Hartwell, & Carpenter, 2014). Lynch (2009) reported varying amounts of lever presses in female mice
at different phases of the estrous cycle.
Rats responded most in the estrus phase, which is associated with
increasing concentrations of estradiol and decreasing concentrations of
progesterone. These findings are
consistent with the findings about other reinforcing drugs as well; leading to
the conclusion that estradiol modulates dopamine in the striatum and enhances the
rewarding effects of nicotine. Lynch and Sofuoglu (2010) speculate that
progesterone and its metabolites regulate neuronal signaling, which in turn may
regulate the effects of nicotine.
Progesterone has been implicated in interacting with GABA receptors,
serotonin receptors, and nicotinic acetylcholine receptors. Enhanced GABA transmission may serve to
decrease the rewarding effects of a drug, thus decreasing sensitivity to the
addictive properties of nicotine. Progesterone
seems to negatively modulate nicotinic receptors through a mechanism that may
be comparable to smoking cessation medications. (Lynch & Sofuoglu,
2010). Progesterone may have a function
in smoking cessation, by decreasing the rewarding effects of using nicotine,
attenuating smoking urges, and increasing cognitive performance.
Schiller et
al. (2014) used smoking topography to measure acute smoking changes with
different concentrations of progesterone and estradiol. The topography variables that were included
were puff number, flow rate, and puff intensity. The progesterone to estradiol ratio had some
influence on smoking behavior, but the magnitude and reliability of this effect
is limited. When both estradiol and
progesterone were decreasing, participants had a greater puff intensity than
baseline. A high level of progesterone
to estradiol was associated with decreased smoking behavior, but not absolute
progesterone levels. (Figure 4). Only about 5% of variance in smoking behavior
could be explained by ovarian hormones (Schiller et al., 2014).
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| Figure 4 (Schiller et al., 2014) |
Researchers
have looked for a connection between nicotine use and cessation at different
points of the menstrual cycle. Allen,
Mooney, Chakraborty, and Allen (2009) had female subjects record a diary of
their smoking behavior and menstrual status.
No differences were found in regular smoking patterns at different
stages of the menstrual cycle. However,
in the morning when cigarettes are being used to alleviate overnight
withdrawal, women smoked more in the menses phase than in the follicular
phase. Menstrual phase was determined
not to influence circadian smoking patterns, but may play a role in severity of
withdrawal symptoms. Mello (2011) confirmed these findings and elaborates on menstrual
phase modulating withdrawal symptoms associated with short-term nicotine
abstinence. For example, women in the follicular phase reported higher craving
for a cigarette and a higher rush from smoking a cigarette than women in the
luteal phase (Mello, 2011).
Sex differences in sensitivity
to the effects of nicotine are apparent.
Testosterone seems to be unrelated, while estradiol and progesterone
have contrasting effects in modulating the response to nicotine (Damaj, 2000). Estradiol enhances sensitivity to nicotine
while progesterone does the opposite, however, research analyzing different
phases of the menstrual cycle and nicotine-related behaviors are inconclusive
(Lynch, 2009; Mello, 2011). The most
important question that must be answered is the mechanism through which ovarian
hormones and nicotine are related, as there are multiple theories but none seem
to gain a general consensus across the literature.
