Sakire Pogun

Nitric oxide inhibits [3H]dopamine uptake

Sodium nitroprusside (SNP), a generator of nitric oxide (NO), decreased [3H]dopamine uptake into rat striatal synaptosomal preparations in a dose-, time- and temperature-dependent fashion. Reduced hemoglobin, a substance that binds NO, prevented the SNP-induced decrease in uptake. Potassium ferri- and ferrocyanide, compounds similar to SNP that do not produce NO, were without effect on uptake. SNP inhibited [3H]dopamine uptake in synaptosomes from nucleus accumbens and olfactory tubercle as well but with a lower potency. SNP inhibited [3H]serotonin and [3H]glutamate uptake but had no effect on [3H]norepinephrine uptake. S-Nitroso-N-acetylpenicillamine (SNAP), another generator of NO, had effects similar to those of SNP. The SNP-induced decrease in [3H]dopamine uptake was due to a Vmax decrease at 100 microM SNP and to both a Vmax and Km change at 300 microM SNP. Depletion of calcium by omission of calcium from buffers and addition of EGTA increased the potency of SNP in inhibiting uptake. There was no change in [3H]WIN 35428 binding to the dopamine transporter with doses of SNP that inhibited uptake. These data indicate that NO can decrease [3H]dopamine transporter function.

Chronic cigarette smoking and the microstructural integrity of white matter in healthy adults: A diffusion tensor imaging study

Results from recent studies suggest that chronic cigarette smoking is associated with increased white matter volume in the brain as determined by in vivo neuroimaging. We used diffusion tensor imaging to examine the microstructural integrity of the white matter in 10 chronic smokers and 10 nonsmokers. All individuals were healthy, without histories of medical or psychiatric illness. Fractional anisotropy (FA) and trace were measured in the genu, body, and splenium of the corpus callosum. FA provides a measure of directional versus nondirectional water diffusion, whereas trace provides a measure of nondirectional water diffusion. Lower FA and higher trace values are considered to reflect less brain integrity. Voxel-based morphometry was used to define volumes in each of these regions of the corpus callosum. Chronic smokers exhibited significantly higher FA in the body and whole corpus callosum and a strong trend for higher FA in the splenium compared with nonsmokers. FA did not differ between groups in the genu, and neither trace nor white matter volumes differed between groups in any of the regions of interest. When subdivided by Fagerström score (low vs. high), the low Fagerström group exhibited significantly higher FA in the body of the corpus callosum compared with the high Fagerström group and the nonsmokers. These results suggest that, among healthy adults, lower exposure to cigarette smoking is associated with increased microstructural integrity of the white matter compared with either no exposure or higher exposure. Additional studies are needed to further explore differences in white matter integrity between smokers and nonsmokers.

Cocaine and amphetamine regulated transcript (CART) and the stress response

CART is expressed abundantly in the hypothalamic paraventricular nucleus and locus coeruleus, major corticotropin releasing factor (CRF) and noradrenaline sources, respectively. There is a bidirectional relation between CART and hypothalamo-pituitary-adrenal axis activity. CART stimulates CRF, adrenocorticotropic hormone and glucocorticoid secretion, whereas CRF and glucocorticoids increase the transcriptional activity of the CART gene; adrenalectomy declines CART expression in the hypothalamus. Stress exposure modulates CART expression in hypothalamus and amygdala in rat brain in a region and sex specific manner. CART may be a mediator peptide in the interaction between stress, drug abuse, and feeding. The review discusses the established role of CART as it relates to the stress response.

Sexually dimorphic cognitive style in rats emerges after puberty.

In a water maze (WM), rats employ different and sexually dimorphic behavioral strategies to solve a place-learning task, a test of cognitive/propositional ability. Puberty is the last step in brain development and marks an important phase with regard to sexually dimorphic cognitive performance and behavior. The present study assessed possible sex differences in cognitive style before and after puberty in a WM place-learning task. Since nitric oxide (NO) is implicated in spatial learning and hippocampal function, and since brain NO(-)(2) + NO(-)(3) levels (stable metabolites of NO) display region-specific sex differences in rat brain, NO(-)(2) + NO(-)(3) levels were determined after behavioral testing. The sex-related style difference emerged very clearly but only in the adult rats, which suggests that the female behavioral strategy in the WM place-learning task requires the presence of female sex hormones at puberty. Although NO(-)(2) + NO(-)(3) levels were higher in the adult rats and males compared to prepubertal and female rats, respectively, no significant correlations emerged between brain NO and behavior. The fact that the behavioral sexually dimorphic cognitive-style effect observed here and in previous studies appears to emerge only after puberty suggests that awareness of such postpubertal sex differences may also be important in human educational and therapeutic contexts.

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.

Cognitive status of young and older cigarette smokers: Data from the international brain database

Previous studies that have examined the impact of cigarette smoking on cognition have revealed mixed results; some studies report no impact and others report detrimental effects, especially in older individuals. Few studies, however, have examined the effects of cigarette smoking on both young and old healthy individuals using highly robust and standardized methods of cognitive assessment. This study draws on an international database to contrast cognitive differences between younger and older individuals who regularly smoke cigarettes and non-smokers. Data were sampled from 1000 highly screened healthy individuals free of medical or psychiatric health complications. A cohort of 62 regular smokers (n = 45 < 45 years of age; n = 1745 years) with a Fagerstrom nicotine dependency score of 1 or more were identified and matched to a cohort of 62 healthy nonsmokers (n = 43 < 45 years; n = 1945 years) on demographic variables and estimated intelligence. Performances on cognitive measures of attention, reaction time, cognitive flexibility, psychomotor speed, and memory were considered for analysis. As a group, smokers performed more poorly than nonsmokers on one measure of executive function. A significant age and smoking status interaction was identified with older smokers performing more poorly than older nonsmokers and younger smokers on a measure of long-delayed recall of new information. Cigarette smoking is associated with isolated and subtle cognitive difficulties among very healthy individuals.

Sex differences in brain and behavior: emphasis on nicotine, nitric oxide and place learning

Although males and females are unmistakably different, the recognition of sex as a key variable in science and medicine is considered a revolution in some circles. Sex differences transcend reproductive functions, are evident in the structural and functional organization of the brain, and are reflected in group differences in cognitive abilities and behavior. Males and females have different neural organizational patterns for information processing and different strategies in problem solving. Research on sex differences not only provides descriptive data, but also allows us to elucidate mechanisms that underlie our behavior. In this review, sex differences in the central actions of nicotine (an addictive substance) and nitric oxide, and performance on active avoidance and place learning tasks are discussed as examples, and biobehavioral approaches relating to these topics are presented.

Sex differences in nitrite/nitrate levels and antioxidant defense in rat brain.

THIS study assessed sex differences in stable metabolites of nitric oxide and major enzymes involved in antioxidant defense in various regions of rat brain. Nitrite/ nitrate levels and activities of superoxide dismutase and catalase were determined in cortex, hippocampus, corpus striatum, midbrain and cerebellum of adult male and female Sprague–Dawley rats. Nitrite/nitrate levels were significantly higher in the cortex and the hippocampus of male than female rats, while catalase activity was higher in the cortex of females than in males. These sex differences may have significant effects on brain function in health and disease.

The effect of adrenalectomy on cocaine and amphetamine-regulated transcript (CART) expression in the hypothalamic nuclei of the rat.

CART peptide is a neurotransmitter involved in various physiological processes including feeding, sensory processing, development, addiction, and stress. Substantial amounts of CART mRNA and CART peptide expression have been demonstrated in the hypothalamic periventricular area, the paraventricular nucleus of hypothalamus, the anterior lobe of the pituitary gland and the adrenal gland in addition to many other brain areas. This localization defines the HPA axis, responsible for the stress response. The aim of the present study was to assess the possible mediation of the CART peptides in the stress response by testing for changes in CART in adrenalectomized animals. Three groups of male Sprague-Dawley rats were used for the study: sham operated, adrenalectomized (ADX), and ADX+hormone replacement (corticosterone, 30 microg/ml in drinking water/5 days). All rats were perfused 7 days after the surgery, brains were removed and serial coronal sections were prepared. Immunohistochemistry was used to assess CART peptide expression in paraventricular and supraoptic cells. ADX lowered both the number and percentage of CART-positive cells compared to the sham-operated group, and hormone replacement partially restored the decrease in the CART cell numbers in ADX animals. There were no significant changes in the supraoptic nucleus. Our results suggest a role for CART peptides in the stress response.

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.