Individual differences in oral nicotine intake in rats

To study individual differences in nicotine preference and intake, male and female rats were given free access to a choice of oral nicotine (10 or 20?mg/L) or water for 24?h/day for periods of at least six weeks, starting at adolescence or adulthood. A total of 341 rats, were used in four different experiments; weight, nicotine intake and total liquid consumption were recorded weekly. Results show that rats can discriminate nicotine from water, can regulate their intake, and that there are readily detected individual differences in nicotine preference. Ward analyses indicated that the animals could be divided into minimum, median and maximum preferring subgroups in all experiments. The effect of saccharine on nicotine intake was also evaluated; although the addition of saccharine increased total intake, rats drank unsweetened nicotine solutions and those with higher preferences for nicotine, preferred nicotine over water with or without saccharine added. Nicotine reduced weight gain and the effect was more pronounced in females than males. The average nicotine consumption of adolescent rats was higher than adults and nicotine exposure during adolescence reduced nicotine intake in adult rats. About half of the rats which had access to nicotine as adolescents and also as adults had a persistent pattern of consumption; the behavior was very stable in the female minimum preferring groups and a much higher ratio of rats sustained their adolescent behavior as adults. The change in preference was more pronounced when there was an interval between adolescent and adult exposure; female rats showed a more stable behavior than males suggesting a greater role for environmental influences on males. In conclusion, marked individual differences were observed in oral nicotine intake as measured in a continuous access 2-bottle choice test. Age and sex of the subjects and previous exposure to nicotine are significant factors which affect preference in rats.     

Plasma nicotine and cotinine levels following intravenous nicotine self-administration in rats

  Rationale: The route of nicotine administration between animal models and humans is very different and further investigation by determining levels of nicotine entering into the circulatory system is warranted. Objective: The present study addresses the validity of the rat self-administration procedure by comparing plasma levels of nicotine in the rat with levels reported in smokers following cigarette consumption. Methods: Plasma levels of nicotine and its metabolite cotinine were measured in 17 rats following intravenous self-administration of a range of nicotine doses (0.015, 0.03 and 0.06 mg/kg per infusion). Results: The two larger unit doses supported reliable self-administration behaviour with no overall difference in the patterns of nicotine intake. However, the total nicotine intake over the 2-h session was related to unit dose and this correlated highly with nicotine and cotinine levels measured in blood collected from the tail vein. On average, cotinine levels (50–200 ng/ml) were approximately 2-fold higher than nicotine levels (40–120 ng/ml) in plasma. Following an extinction test for one session in which saline was substituted for nicotine, no change in behaviour was observed in the two groups, while plasma levels of nicotine and cotinine dropped to nominal levels. Conclusions: The concentrations of nicotine attained following nicotine self-administration appear to be similar to levels reported in smokers after cigarette consumption, providing further validation of this procedure as an animal model of nicotine dependence. Received: 14 November 1998 / Final version: 4 January 1999     

Sexual dimorphism of nicotine metabolism and distribution in the rat. Studies in vivo and in vitro

Interpretation of sex differences in nicotine metabolism and disposition in rats required studies both in vivo and in vitro to provide both metabolic and pharmacokinetic data. In each of four rat strains studied in vitro, males metabolized nicotine faster than did females. In Sprague-Dawley rats, studies of nicotine kinetics after a single iv dose of [14C]nicotine revealed a larger nicotine volume of distribution in females than in males. A prolonged plasma nicotine half-life in females balanced the larger volume of distribution, so that no sex difference appeared in plasma clearance of nicotine. Nevertheless, sex differences in nicotine metabolism are indicated inasmuch as 1) females had lower plasma cotinine concentrations than did males; 2) urinary recoveries of nicotine were higher in female than in male rats; 3) total urinary output of nicotine metabolites was higher in male than female rats, consistent with the enhanced N- and C-oxidation of nicotine by male rats observed in vitro. In female rats the reduced rate of nicotine metabolism, as well as a larger volume of distribution of nicotine, explains in part the reported increased lethality of female compared with male rats.     

Nicotine's effects on female rats' body weight: caloric intake and physical activity

Caloric intake and physical activity contribute to the inverse relationship between nicotine and body weight in male rats. In contrast, the relative contribution of these behavioral variables to the nicotine/body weight relationship in female rats has has not been investigated. Recent research indicates that males and females respond differently to nicotine. The present study was designed to determine the role of physical activity and food consumption in body weight changes associated with nicotine administration in female rats. Nicotine or saline was administered chronically to 24 female rats for 19 days. Body weight, food consumption, water consumption, and physical activity were measured before, during, and after nicotine administration. Body weight and food consumption decreased during and increased after nicotine administration. However, there were no changes in physical activity that could account for these changes in body weight. These results corroborate the report that males and females respond differently to nicotine.     

Adult vs. adolescent rats differ in biobehavioral responses to chronic nicotine administration

More than 90% of smokers begin smoking during adolescence, suggesting that nicotine's actions may differ in adults vs. adolescents in ways that render adolescents vulnerable to smoking initiation. This experiment tested the hypothesis that nicotine's biobehavioral actions differ in adult and adolescent rats. Forty-two male (21 adolescents, 21 adults) and 41 female (21 adolescents, 20 adults) Sprague–Dawley rats were administered saline or 12 mg/kg/day nicotine via osmotic minipump for 21 days. Body weight, feeding, and locomotion (horizontal activity, vertical activity, center time) were measured before, during, and after saline or nicotine administration. Nicotine's effects depended on age and sex. Nicotine reduced body weight and feeding of adult males and females, and of adolescent males, but not of adolescent females. In addition, adolescent males were more sensitive than adults or adolescent females to nicotine's activity-enhancing effects. In cessation, nicotine-exposed adolescent males continued to exhibit greater activity than saline-exposed animals. Results indicate that nicotine's biobehavioral actions differ depending on age and sex.     

The effect of smoking on nicotine metabolism in vivo in man

Nicotine and a basic metabolite, cotinine, were determined in the urine by gas-liquid chromatography after intravenous administration of (—)-nicotine hydrogen (+)-tartrate to groups of male and female smokers and non-smokers in whom the urine was maintained at an acid pH. The urinary recoveries of nicotine and cotinine from male smokers fell in two groups. One showed a lower recovery of both alkaloids than was seen with male non-smokers. The other showed a similar recovery of nicotine but more cotinine than the male non-smokers. Female smokers excreted less nicotine but more cotinine than female non-smokers. More nicotine but less cotinine was excreted by female non-smokers than by male non-smokers. The results show sex dependent metabolism of nicotine occurs in non-smoking humans and that smoking causes alterations in nicotine metabolism.     

Combined exposure to nicotine and ethanol in adolescent mice differentially affects anxiety levels during exposure, short-term, and long-term withdrawal.

Smoking and consumption of alcoholic beverages are frequently associated during adolescence. This association could be explained by the cumulative behavioral effects of nicotine and ethanol, particularly those related to anxiety levels. However, despite epidemiological findings, there have been few animal studies of the basic neurobiology of the combined exposure in the adolescent brain. In the present work we assessed, through the use of the elevated plus maze, the short- and long-term anxiety effects of nicotine (NIC) and/or ethanol (ETOH) exposure during adolescence (from the 30th to the 45th postnatal day) in four groups of male and female C57BL/6 mice: (1) Concomitant NIC (nicotine free-base solution (50 microg/ml) in 2% saccharin to drink) and ETOH (ethanol solution (25%, 2 g/kg) i.p. injected every other day) exposure; (2) NIC exposure; (3) ETOH exposure; (4) Vehicle. C57BL/6 mice were selected, in spite of the fact that they present slower ethanol metabolism, because they readily consume nicotine in the concentration used in the present study. During exposure (45th postnatal day: PN45), our results indicated that ethanol was anxiolytic in adolescent mice and that nicotine reverted this effect. Short-term drug withdrawal (PN50) elicited sex-dependent effects: exposure to nicotine and/or ethanol was anxiogenic only for females. Although neither nicotine nor ethanol effects persisted up to 1 month postexposure (PN75), the coadministration elicited an anxiogenic response. In spite of the fact that generalizations based on the results from a single strain of mice are prone to shortcomings, our results suggest that the deficient response to the anxiolytic effects of ethanol in adolescents co-exposed to nicotine may drive higher ethanol consumption. Additionally, increased anxiety during long-term smoking and drinking withdrawal may facilitate relapse to drug use.     

A comparative study of the disposition of nicotine and its metabolites in three inbred strains of mice

The disposition of nicotine, cotinine, and nicotine N-oxide was investigated in male C57BL, DBA, and C3H mice following an ip injection of nicotine (1.0 mg/ml). The half-lives (t1/2) of nicotine in blood were 5.9 to 6.9 min. The rapid elimination of nicotine was accompanied by a rapid accumulation of metabolites; maximal concentrations of cotinine in blood (204 to 364 ng/ml) were achieved in 10 min and nicotine N-oxide (23 ng/ml in C3H mice) in 15 min. The t1/2 in blood was 20.1 to 39.8 min for cotinine and 18.4 min for nicotine N-oxide. The t1/2 values for nicotine in brain were similar to those in blood, but the values for liver were slightly larger (6.3 to 9.2 min) and interstrain differences were significant. A large strain-related difference in the t1/2 for cotinine was found; the metabolite was eliminated from the blood of DBA mice at only about one-half the rate determined for the other strains. The t1/2 for nicotine N-oxide in liver ranged from 12.7 to 27.3 min; the values were significantly different with C57BL greater than DBA greater than C3H. Strain-related differences were also observed in response to chronic exposure to cigarette smoke. The t1/2 of injected nicotine appeared to be slightly decreased in C57BL and DBA mice but was increased by 60% in livers of C3H mice compared to a control group.     

Adolescent vs. adult-onset nicotine self-administration in male rats: duration of effect and differential nicotinic receptor correlates

Adolescence is the life stage when tobacco addiction typically begins. Adolescent neurobehavioral development may be altered by nicotine self-administration in a way that persistently potentiates addiction. Previously, we showed that female adolescent rats self-administer more nicotine than do adults and that the increased nicotine intake then persists through the transition to adulthood [E.D. Levin, A. Rezvani, D. Montoya, J. Rose, H. Swartzwelder, Adolescent-onset nicotine self-administration modeled in female rats, Psychopharmacology 169 (2003) 141-149.]. In the current study, male Sprague-Dawley rats were given access to nicotine via the standard operant IV self-administration procedure (nicotine bitartrate dose of 0.03 mg/kg/infusion). One group of male rats started during adolescence the other group started in young adulthood. After the end of the four-week period of self-administration brain regions of the rats were assessed for alpha4beta2 nicotinic receptor binding. We found that male rats, like females, show higher nicotine self-administration when starting during adolescence as compared to starting in adulthood (p<0.001). Indeed, the effect in adolescent males was even greater than that in females, with more than triple the rate of nicotine self-administration vs. the adult-onset group during the first 2 weeks. The adolescent onset nicotine-self-administering rats also had significantly greater high affinity nicotinic receptor binding in the midbrain and the striatum, whereas hippocampal binding did not differ between the age groups. Striatal values significantly correlated with nicotine self-administration during the first 2 weeks in the adult-onset group but not the adolescent-onset rats, suggesting that the differences in self-administration may depend in part on underlying disparities in synaptic responses to nicotine. After the initial 2 weeks, nicotine self-administration in male rats declined toward adult-like levels, as the adolescent rats approached adulthood. This study showed that adolescent male rats self-administer significantly more nicotine than do male adult rats, but that adolescent-onset nicotine self-administration in male rats declines over weeks of continued use to approach adult-onset levels. In a previous study, we found that female rats also show greater nicotine self-administration with adolescent onset vs. adult onset, but that the females continued higher rates of self-administration into adulthood. Our results thus reinforce the concept that the adolescent brain is unusually receptive to the effects of nicotine in a manner that reinforces the potential for addiction.     

Strain and sex alter effects of stress and nicotine on feeding, body weight, and HPA axis hormones

Gender and genotype result in differential sensitivity to stress and to nicotine. Male and female Sprague–Dawley and Long–Evans rats exhibit different behavioral responses to immobilization stress and to chronically-administered nicotine, suggesting that these animals may be useful to model human variability in stress and nicotine sensitivity. It is possible that differences in sensitivity of the hypothalamo–pituitary–adrenocortical (HPA) axis might account for these sex and strain differences. This experiment examined corticosterone (CORT) and adrenocorticotropin hormone (ACTH) responses of male and female Sprague–Dawley (n=117) and Long–Evans (n=120) rats administered 0, 6, or 12 mg/kg/day nicotine for 14 days; half of each treatment group was exposed to immobilization stress (20 min/day). Feeding and body weight also were measured. Nicotine increased CORT and ACTH levels of Sprague–Dawley females only. Stress increased CORT and ACTH levels of all groups except for Long–Evans females. Nicotine and stress decreased feeding and body weight with greatest effects in Long–Evans females. CORT, feeding, and body weight were positively correlated among stressed females. These findings suggest that strain differences in HPA axis, body weight, and feeding responses to nicotine and to stress are robust among females but not among males. CORT reactivity and female sex hormones may explain these differences.     

Hubble-bubble (water pipe) smoking: levels of nicotine and cotinine in plasma,saliva and urine

OBJECTIVES: The purpose of the present study was to assess the levels of nicotine and cotinine in biological fluids (plasma, saliva, and urine) following hubble-bubble (HB) smoking. METHODS: Fourteen healthy male volunteers, aged 28 +/- 8 years, body weight of 82.7 +/- 13.53 kg, participated in the study. All volunteers were habitual HB smokers for 3.29 +/- 1.90 years who smoked at least 3 runs per week with an average of 20 g Mua'sel per run. Volunteers were requested to avoid smoking, at least 84 hours prior to the time of the study. After baseline samples were taken, volunteers started smoking 20 g of Mua'sel for a period of 45 minutes. Heparinized blood samples (5 or 10 ml each) were drawn for nicotine and cotinine analysis before, during and after the smoking period. Saliva samples were collected just before smoking (time 0) and at the end of smoking (45 min). Urine also was collected at time 0 and 24-hour urine collection was also taken to measure nicotine and cotinine excretion. Nicotine and cotinine were extracted from samples and assayed by gas chromatography. All data are presented as mean +/- SEM throughout the text, Tables and Figures unless indicated otherwise. RESULTS: Plasma nicotine levels rose from 1.11 +/- 0.62 ng/ml at baseline to a maximum of 60.31 +/- 7.58 ng/ml (p < 0.001) at the end of smoking (45 min). Plasma cotinine levels increased from 0.79 +/- 0.79 ng/ml at baseline to its highest concentration of 51.95 +/- 13.58 ng/ml (p < 0.001) 3 hours following the end of smoking. Saliva nicotine levels significantly rose from 1.05 +/- 0.72 to 624.74 +/- 149.3 ng/ml and also saliva cotinine levels significantly increased from 0.79 +/- 0.79 ng/ml to 283.49 +/- 75.04 ng/ml. Mean amounts of nicotine and cotinine excreted in urine during the 24-hour urine collection following smoking were equal to 73.59 +/- 18.28 and 249 +/- 54.78 microg, respectively. CONCLUSION: Following a single run of HB smoking, plasma, saliva and urinary nicotine and cotinine concentration increased to high values. This observation suggests that HB may not be an innocent habit, as people believe.     

Peculiar vulnerability to nicotine oral self-administration in mice during early adolescence.

A "gateway" function toward substance abuse has been suggested for early tobacco smoking. Nicotine actually represents an easily available drug for human adolescents, who are very likely to use a number of different psychoactive agents. Surprisingly, the psychobiological factors involved in this age-related willingness have been poorly investigated. In Experiment 1, nicotine consumption was studied in outbred CD-1 mice during Early (postnatal day (pnd) 24 to 35), Middle (pnd 37 to 48) or Late (pnd 50 to 61) adolescence, in an oral self-administration paradigm. During the drinking session (2 h/day), animals had free choice between either tap water or a nicotine solution (10 mg/l). After a 6-day period, a fading study was carried out, in which nicotine concentration was reduced to 7 mg/l (days 7-9) and 5 mg/l (days 10-12), to assess whether animals would compensate by increasing their intake from the nicotine solution. In Experiment 2, psychopharmacological effects on locomotion induced by the nicotine solution (0, 10, 30 mg/l) during the 1-h drinking session were assessed in Early and Late adolescent mice. In Experiment 1, Early adolescents expressed a marked and stable preference for the nicotine solution, showing a daily nicotine intake of 1.15 +/- 0.04 mg/kg. Middle adolescents did not show any preference for either bottle, whereas a tendency toward avoidance for the nicotine solution was found for Late adolescents. In the fading study, Early adolescents were the only group to show increased consumption from the nicotine bottle as far as nicotine concentration was reduced. A time-course analysis of plasma levels of cotinine (the principal biomarker of nicotine consumption) revealed some pharmacokinetic differences between the three age-groups. In Experiment 2, drinking from a nicotine solution produced a prominent hyperactivity in Early adolescents, whereas a quite opposite profile was associated with older subjects. In summary, even if a role for taste factors cannot be completely ruled out, a peculiar spontaneous drive toward oral nicotine consumption, as well as a nicotine-induced arousal, is specific to Early adolescence in mice. The present animal model might be useful to investigate psychobiological determinants involved in early tobacco smoking in human adolescents     

Population characteristics and cigarette yield as determinants of smoke exposure

Relationships of population characteristics, smoking history, and cigarette yield with smoke exposure as measured by peripheral blood concentrations of thiocyanate, carboxyhemoglobin, nicotine and cotinine were sought in 170 male smokers. This population of smokers had significant elevations of serum thiocyanate, blood carboxyhemoglobin and plasma nicotine and cotinine concentrations as compared with an equal number of age- and sex-matched nonsmokers and these concentrations correlated significantly with past 24-hour cigarette consumption. Although the nicotine yield of the cigarette correlated significantly with plasma cotinine and marginally with plasma nicotine, the reduction in plasma nicotine and cotinine was not proportionate to the reduced yield of the cigarettes, suggesting that smokers partially compensate for the lower yields of their cigarettes. Blood levels of carboxyhemoglobin, nicotine and cotinine were also significantly associated with the weight of the subjects, presumably due to the relationship between weight and the volume of distribution. Univariate and multiple regression analyses provided evidence that coffee and alcohol consumption and years smoked also may be important determinants of smoke exposure.     

Effects of nicotine on weight change and food consumption in rats

The present study was designed to test the effects of nicotine and nicotine withdrawal on weight change and food consumption in rats. Twelve male and 12 female three month old Sprague-Dawley rats were divided 3nto three treatment groups: 0.2, 0.4, and 0.6 mg nicotine/kg body wt. Half were given subcutaneous nicotine treatment for three weeks and then saline for three weeks; treatment sequence was reversed for the other half. Injections were administered three times daily throughout the experimental period. Prior to treatment, baseline measures were established for both food consumption and weight. Mean differences in weight change were calculated on a weekly basis throughout the experiment. Overall tests indicate that nicotine withdrawal produced significant (p<0.05) weight gains and nicotine administration produced inhibition of weight gain. A significant sex × drug × time interaction (p<0.05) demonstrated that food consumption increased when nicotine was discontinued and decreased when nicotine was administered. Specific comparison tests showed these effects on food consumption and weight were strongest at the 0.6 level and that larger effects were obtained for males than for females.     

Development and Characterization of an Elisa for Cotinine in Biological Fluids

Abstract

Cotinine is a major metabolite of nicotine and serves as an important biomarker of tobacco smoke exposure. To monitor exposure to tobacco smoke or nicotine, a sensitive enzyme-linked immunosorbent assay (ELISA) for cotinine was developed. The test had an 1–50 of between 0.5 and 1.0 ng/ml for cotinine and about 500-fold less affinity for nicotine. Few matrix effects were not detectable in human saliva, although relatively small matrix effects (1–50 for cotinine, 2.8 ng/ml) were observed in human serum and urine. The test accurately measured the levels of cotinine in NI5T standards in freeze-dried human urine derivative material (r = .9999) indicating its reliability for measurement of cotinine. The test readily detected low levels (5–500 nglml) of cotinine in human saliva and serum samples. Also, the levels of cotinine in plasma and urine samples from smoke-exposed mice and rats could be rapidly analyzed for cotinine. This ELISA is therefore a sensitive and accurate test for the determination of cotinine in plasma, serum, saliva, and urine samples from humans and animals, and can be successfully used for monitoring and quantifying exposure to tobacco smoke or nicotine.     

Influence of sex, estrous cycle, and drug-onset age on cocaine self-administration in rats (Rattus norvegicus)

The influence of sex, phase of the estrous cycle, and age of drug onset on cocaine self-administration was examined. Adult male, adult female, and adolescent male rats (Rattus norvegicus) were evaluated using low fixed-ratio (FR) schedules of drug delivery with a single fixed cocaine unit dose or a range of cocaine unit doses with a single FR schedule. Sex differences in adults were observed for mg/kg consumption of the 3.0-mg/kg unit dose, with consumption being significantly less in estrus females than in males. Over the estrous cycle, mg/kg consumption of this unit dose was significantly less during estrus than during metestrus-diestrus. Differences due to age of drug onset were also observed, with mg/kg consumption of the 3.0-mg/kg unit dose being significantly less in adolescent males than adult males or adult females during metestrus-diestrus. In contrast, these various groups did not have significantly different mg/kg intakes of cocaine unit doses <3.0 mg/kg, nor did they significantly differ in the rates and patterns of responding and number of infusions earned as a function of FR schedule or unit dose of cocaine available. The role of sex, estrus cycle, and drug-onset age on cocaine self-administration appears to be minimal under these experimental conditions. Experimental conditions that favor no sex or age differences in cocaine intake (1.0-mg/kg unit dose and low FR) may be useful for evaluating potential sex or age differences in the consequences of cocaine self-administration more reliably, as cocaine intake would not be an uncontrolled factor.     

Sex differences in nicotine levels following repeated intravenous injection in rats are attenuated by gonadectomy

Previous research demonstrates that repeated intravenous (i.v.) nicotine injection resulted in increased locomotor sensitization in female relative to male rats. In order to determine if increased nicotine levels are detected in females compared to males the present experiment examined the plasma nicotine levels of male, female, castrated (CAST), and ovariectomized (OVX) rats (n=7-11 rats/group) following repeated i.v. nicotine injection (50 microg/kg/injection). All rats received 14 i.v. nicotine injections, one/day. Approximately 1 min after the 14th nicotine injection, rats were rapidly decapitated and trunk blood was collected immediately. Gas chromatography revealed a sex difference in nicotine content: higher plasma nicotine levels were measured from female rats (>10 x increase) relative to males, and the sex difference was attenuated by gonadectomy. These data suggest that the sex difference in plasma nicotine levels is due to alteration in distribution or nicotine metabolism as a function of circulating gonadal hormones. These findings indicate that gonadal hormones may influence nicotine pharmacokinetics and therefore nicotine-induced sex differences in behavior.     

Dietary restriction and nicotine can reduce anxiety in female rats.

Anxiety may play a role in the initiation of smoking and there is evidence to suggest that sex and age may predetermine responses to nicotine. At present, the greatest increase in smoking is in women and it is often accompanied by dieting. The purpose of the present study was to investigate how the impact of dietary restriction might modify the effects of nicotine in female adult and adolescent rats. The effects of nicotine in the elevated plus-maze test of anxiety were compared in free-feeding animals and those subjected to dietary restriction that reduced body weight to 85% of free-feeding weight. In nondeprived adult females, nicotine (0.05-0.5 mg/kg, s.c.) reduced the percentage of time spent on the open arms, indicating anxiogenic effects. However, the effects of nicotine were dramatically changed in food-restricted adult females and 0.05 mg/kg had a striking anxiolytic effect. No significant effects of nicotine were found in the adolescent female rats, suggesting a role of circulating sex hormones in modulating nicotine's effects on anxiety. However, in the adolescent females, dietary restriction significantly increased the percentages of time spent and entries onto the open arms, without changing closed arm entries, indicating an anxiolytic effect. These results raise the important possibility that, in prepubertal girls, dietary restriction may have anxiolytic effects and this might contribute to the onset of anorexia. Circulating female hormones reduce this effect, but in adult females the combination of dietary restriction and nicotine may have important anxiolytic effects that impact on the initiation of regular smoking.     

Nicotine self-administration in rats: estrous cycle effects, sex differences and nicotinic receptor binding

RATIONALE: Research on smoking behavior and responsiveness to nicotine suggests that nicotine's effects may depend on the sex of the organism. OBJECTIVE: The present study addressed four questions: 1) Will female rats self-administer nicotine? 2) Does self-administration by females vary as a function of estrous cycle? 3) Does self-administration by females differ from that of males? 4) Does self-administration of nicotine result in up-regulation of nicotinic receptor binding and are these changes similar in males and females? METHODS: Male and female Sprague-Dawley rats were allowed to self-administer nicotine at one of four doses (0.02-0.09 mg/kg, free base) on both fixed and progressive ratio schedules of reinforcement. RESULTS: Females acquired nicotine self-administration across the entire range of doses. Acquisition of self-administration at the lowest dose was faster in females than males. However, few sex differences were found in the number of active responses, number of infusions, or total intake of nicotine during stable fixed ratio self-administration. In contrast, females reached higher break points on a progressive ratio. For both schedules, females had shorter latencies to earn their first infusion of each session and demonstrated higher rates of both inactive and timeout responding. There was no effect of estrous cycle on self-administration during either fixed or progressive ratio sessions. Self-administered nicotine resulted in average arterial plasma nicotine levels between 53 and 193 ng/ml and left hemi-brain levels between 174 and 655 ng/g, depending on dose. Nicotine self-administration produced similar up-regulation of nicotinic receptor binding sites in males and females, as reflected by increased right hemi-brain binding of [3H]-epibatidine, when compared to the brains of untreated control rats. CONCLUSIONS: These results suggest that while males and females may regulate their intake of nicotine similarly under limited access conditions, the motivation to obtain nicotine is higher in females.     

Ethanol intake patterns in female mice: influence of allopregnanolone and the inhibition of its synthesis

The neurosteroid allopregnanolone (ALLO) is a positive modulator of GABA(A) receptors that exhibits a psychopharmacological profile similar to ethanol (i.e., anxiolytic, sedative-hypnotic). Based on research suggesting that manipulation of ALLO levels altered ethanol self-administration in male rodents, the current studies determined whether exogenous ALLO administration or the inhibition of its synthesis in vivo modulated ethanol intake patterns in female C57BL/6J mice. Lickometer circuits collected temporal lick records of ethanol (10%, v/v) and water consumption during daily 2h limited access sessions. Following the establishment of stable ethanol intake, studies examined the effect of an acute ALLO challenge (3.2-24.0 mg/kg) or a 7-day blockade of ALLO production with finasteride (FIN; 50 or 100 mg/kg) on ethanol intake in a within-subjects design. In contrast to results in male mice, ethanol dose (g/kg), ethanol preference and most of the bout parameters were unaltered by ALLO pretreatment in female mice. Ethanol intake in females also was recalcitrant to 7-day treatment with 50 mg/kg FIN, whereas 100 mg/kg FIN significantly reduced the ethanol dose consumed by 35%. The FIN-attenuated ethanol intake was attributable to a significant decrease in bout frequency (up to 45%), with lick patterns indicating reduced maintenance of consumption throughout the 2-h session. FIN also produced a dose-dependent decrease in brain ALLO levels. In conjunction with data in male mice, the present findings indicate that there are sex differences in the physiological regulation of ethanol intake patterns by GABAergic neurosteroids.