Gorkem Yararbas

Sex differences in nicotine action.

Accumulating evidence suggests that the antecedents, consequences, and mechanisms of drug abuse and dependence are not identical in males and females and that gender may be an important variable in treatment and prevention. Although there has been a decline in smoking prevalence in developed countries, females are less successful in quitting. Tobacco use is accepted to be a form of addiction, which manifests sex differences. There is also evidence for sex differences in the central effects of nicotine in laboratory animals. Although social factors impact smoking substantially in humans, findings from nonhuman subjects in controlled experiments provide support that sex differences in nicotine/tobacco addiction have a biological basis. Differences in the pharmacokinetic properties of nicotine or the effect of gonadal hormones may underlie some but not all sex differences observed. Laboratory-based information is very important in developing treatment strategies. Literature findings suggest that including sex as a factor in nicotine/tobacco-related studies will improve our success rates in individually tailored smoking cessation programs.

Nicotine-induced conditioned place preference in rats: sex differences and the role of mGluR5 receptors.

To elucidate sex differences in nicotine addiction and the underlying mechanisms of the conditioning aspects of nicotine, nicotine-induced conditioned place preference (CPP) was evaluated in male and female Sprague Dawley rats using a three-chambered CPP apparatus and a biased design. In a series of experiments, the dose-response curve was obtained, pairings between the drug and initially non-preferred versus preferred compartments were compared, and the involvement of mGluR5 receptors in nicotine-induced CPP was evaluated. Modulation of nicotine-induced CPP with mGluR5 inhibition was obtained by MPEP (2-methyl-6-(phenylethynyl)-pyridine hydrochloride). Our results show that nicotine induces CPP dose-dependently in male rats but not in female rats. The comparison of the biased protocol, pairing nicotine with the initially preferred and non-preferred chambers, indicated that nicotine-induced CPP in male rats under both conditions, but the effect was stronger when nicotine was paired with the initially non-preferred side. The selective mGluR5 antagonist MPEP inhibited nicotine-induced CPP in male rats. In conclusion, the results of the current study in rats demonstrate that the conditioning effect of nicotine is more important in males than in females. Furthermore, in line with reported findings, our results suggest that mGluR5 antagonism may be therapeutically useful in smoking cessation during the maintenance of smoking behavior when conditioning plays an important role, notwithstanding the fact that this effect is observed only in male rats, not in females.

CART expression in limbic regions of rat brain following forced swim stress : Sex differences

Our previous studies showed the modulation of cocaine and amphetamine regulated transcript (CART) positive neurons and CART mRNA by adrenalectomy and corticosterone replacement in hypothalamic nuclei of male rat brain. More recently, we have shown by CART immunohistochemistry that restraint and forced swim (FS) stress have sexually dimorphic and regionally specific effects on CART expression in the hypothalamic nuclei of male and female Sprague-Dawley rats. This study aimed to evaluate the effects of FS stress on CART peptide expression in hypothalamus, amygdala and hippocampus of male and female (in or near estrus) Sprague-Dawley rats. Initially basal CART levels in regions of interest were determined in male and female rats; no sex differences were observed. In FS test, rats were forced to swim on two consecutive days, in a Plexiglas cylinder for 15 and 6 min, respectively. Rats were decapitated on the second day, 10 min after the stress procedure. Hypothalami, amygdalae and hippocampi were dissected and homogenized. CART peptide expression in these regions was measured by Western blotting. In males, FS increased CART expression in hypothalamus and amygdala. On the other hand, in females, FS lowered CART expression in amygdala. CART expression in hippocampus was not affected by the stress procedure in either sex. Our results suggest sexually dimorphic modulation of CART expression in hypothalamus and amygdala by FS procedure. Although modulation of the CART peptide by glucocorticoids and gonadal hormones appears likely, future studies are needed to elucidate the underlying mechanisms in the involvement of CART peptide in stress response.

The effect of nitric oxide synthase inhibition on cognitive ability and strategies employed for place learning in the water maze: sex differences

Male and female rats use different cognitive strategies in the solution of place-learning problems in the water maze despite similar abilities. The female-type strategy has been negatively correlated with cortical nitric oxide (NO) metabolites. The present study aimed to examine the effect of NO synthase (NOS) inhibition (N(omega)-nitro-L-arginine, L-NA) on cognitive ability and strategy in the water maze, and to evaluate possible sex differences. In a 2 (male versus female) x2 (L-NA versus saline) factorial design, rats were trained to find the platform (visible or hidden), always in the same position, for 12 days. L-NA impaired acquisition, during the earlier phases and more prominently in females. This impairment was quite dramatic and unique to females during the first day that the platform was hidden following 3 days of visible-platform conditions. After acquisition, the visible platforms position was shifted, thereby presenting the rats with a choice (searching for the hidden platform in the previous location, i.e. adopting a conceptual cognitive style, or escaping to the visible platform in a new position, i.e. adopting a perceptual style). On the first of the four shift trials (where the newly positioned platform was proximal to the rats starting position), female rats showed the previously found tendency to adopt a perceptual style escape directly in clear contrast to saline-treated males. The L-NA-treated males tended to manifest female-like perceptual style, suggesting that inhibition of NO synthesis in males weakened the tendency to choose a conceptual style in this shifted-platform task. The role of NO in both cognitive and non-cognitive psychological functions is discussed.

Sex differences in nicotine preference

Smoking is the major cause of preventable deaths worldwide, and although there is a decline in overall smoking prevalence in developed countries, the decline in women is less pronounced than in men. Women become dependent faster and experience greater difficulties in quitting. Similar trends have been observed in animal models of nicotine/tobacco addiction. Individual differences in vulnerability to drug abuse are also observed in nicotine/tobacco addiction and point to the importance of sex differences. This Review, summarizes findings from three experimental approaches used to depict nicotine preference in animal models, intravenous and oral nicotine self‐administration and nicotine‐induced conditioned place preference. Nicotine preference is considered to be reflected in the animals motivation to administer the drug (intravenously or orally) or to prefer an environment paired with the presence of the drug (conditioned place preference). These approaches all point to the importance of sex and age of the subjects; the preference of females and adolescents appear to be more pronounced than that of males and adults, respectively. A closer look at these factors will help us understand the mechanisms that underlie nicotine addiction and develop strategies to cope. Ignoring sex differences and reaching conclusions based only on studies using male subjects has resulted in erroneous generalizations in the past. Sex differences in nicotine preference have been clearly documented, and awareness on this aspect of nicotine dependence will significantly impact our success in translational research.

Tamoxifen and mifepriston modulate nicotine induced conditioned place preference in female rats.

An increasing number of studies suggest that nicotine/tobacco addiction is modulated by ovarian hormones. The levels of estrogen and progesterone appear to be important in the success of quit attempts and smoking cessation. In women smokers with the diagnosis or risk of breast cancer, the estrogen receptor modulator tamoxifen (TAM) is widely used, and even though the detrimental health effects of smoking are known, this vulnerable group has difficulty quitting and continues to smoke. The current study tested the effect of the estrogen receptor modulator TAM and the progesterone receptor antagonist mifepriston (RU486) on nicotine-induced conditioned place preference (CPP) in adult female rats. A three chambered CPP apparatus was used and nicotine was paired with the initially non-preferred chamber. Rats received nicotine or saline and hormone receptor modulators (vehicle, TAM, RU486) in a 2×3 experimental design. We have previously shown that nicotine induces CPP in male Sprague-Dawley rats but not in females. Our results show that while nicotine alone does not induce CPP in female rats, rats treated with TAM exhibit nicotine-induced CPP. Although RU486 has an aversive effect when applied alone, this is ameliorated by nicotine. These results confirm the role of ovarian hormone receptors in nicotine-induced CPP and may have clinical implications for developing more efficient smoking cessation approaches in women smokers.