Sex differences in conditioned nicotine reward are age-specific (original) (raw)
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Psychopharmacology, 2009
Introduction The objective of this study was to examine age-, hormone-, and sex-dependent differences to the behavioral effects of nicotine using place-conditioning procedures in female rats. Methods Animals received nicotine in their initially non-preferred side and saline on alternate days in their initially preferred side. Following four conditioning trials, rats were re-tested for their preference. To examine developmental differences, we compared the effects of various nicotine doses in female and male adolescent and adult rats. To examine whether our developmental differences are specific to nicotine, we included adolescent and adult females that were conditioned with various amphetamine doses. To examine the influence of hormones on the behavioral effects of nicotine, we compared the effects of various nicotine doses in intact females that were tested during different phases of the estrous cycle and in separate females that were ovariectomized. Results The rewarding effects of nicotine were observed at a lower nicotine dose in adolescents versus adults. Amphetamine produced similar rewarding effects across age groups in females. The shifts in preference produced by nicotine were similar across the different phases of estrous. Females lacking ovarian hormones did not display rewarding effects of nicotine at any dose. The rewarding effects of nicotine were enhanced in adult female versus male rats. An intermediate nicotine dose produced rewarding effects in adolescent male but not female rats, suggesting that developmental differences to nicotine may be enhanced in males. Conclusion In females, nicotine reward is enhanced during adolescence and is facilitated by the presence of ovarian hormones.
Nicotine-induced conditioned place preference in adolescent and adult rats
Physiology & Behavior, 2002
About 1 million American adolescents start smoking every year. Adolescents may be unusually sensitive to certain consequences of nicotine, demonstrating, for instance, significantly higher rates of dependence than adults at the same level of nicotine use. To explore whether adolescents may be more sensitive to rewarding properties of nicotine than adults, the present study used an animal model to assess the rewarding effects of a low nicotine dose (0.6 mg/kg) in a conditioned place preference (CPP) paradigm. Locomotor activity during conditioning and testing was also evaluated. Nicotine was observed to induce place preference conditioning in adolescent Sprague-Dawley rats, whereas the training dose of 0.6 mg/kg failed to produce convincing place preference in their adult counterparts. Age differences were also apparent in terms of nicotine influences on motor activity, with adults being more sensitive to nicotine-suppressant effects and only adolescents showing an emergence of nicotine-stimulatory effects upon repeated exposures. An increased predisposition to stimulatory nicotine effects during adolescence may contribute to age-specific rewarding properties of the drug as revealed using the CPP paradigm in this experiment. Increased sensitivity to stimulatory and rewarding effects during adolescence could potentially contribute to the high rate of nicotine use and dependence among human adolescents.
Biomolecules & Therapeutics, 2014
Nicotine addiction is a worldwide problem. However, previous studies characterizing the rewarding and reinforcing effects of nicotine in animal models have reported inconsistent findings. It was observed that the addictive effects are variable on different factors (e.g. route, dose, and age). Here, we evaluated the rewarding and reinforcing effects of nicotine in different routes of administration, across a wide dose range, and in different age groups. Two of the most widely used animal models of drug addiction were employed: the conditioned place preference (CPP) and self-administration (SA) tests. Nicotine CPP was evaluated in different routes [intraperitoneal (i.p.) and subcutaneous (s.c.)], doses (0.05 to 1.0 mg/kg) and age [adolescent and adult rats]. Similarly, intravenous nicotine SA was assessed in different doses (0.01 to 0.06 mg/kg/infusion) and age (adolescent and adult rats). In the CPP test, s.c. nicotine produced greater response than i.p. The 0.2 mg/kg dose produced highest CPP response in adolescent, while 0.6 mg/kg in adult rats; which were also confirmed in 7 days pretreated rats. In the SA test, adolescent rats readily self-administer 0.03 mg/kg/infusion of nicotine. Doses that produced nicotine CPP and SA induced blood nicotine levels that corresponded well with human smokers. In conclusion, we have demonstrated that nicotine produces reliable CPP [0.2 mg/ kg dose (s.c.)] in adolescents and [0.6 mg/kg dose (s.c.)] in adults, and SA [0.03 mg/kg/infusion] in adolescent rats. Both tests indicate that adolescent rats are more sensitive to the rewarding and reinforcing effects of nicotine.
Psychopharmacology, 2005
Rationale: Sex differences have been reported for the impact of nicotine and nonpharmacological cues on smoking. While nonpharmacological environmental stimuli have also been shown to influence nicotine selfadministration in rats, there have been no attempts to examine the impact of sex differences in the contributions of nicotine and nondrug stimuli to this behavior. Objectives: This experiment investigated sex differences in operant responding for nicotine in rats when drug infusions were delivered either in the absence of, or in combination with, a nonpharmacological stimulus. Methods: Initially, male and female rats acquired selfadministration for nicotine alone across a range of doses (0.03, 0.06, and 0.15 mg kg −1 inf −1 , freebase). After stable acquisition, nicotine infusions were combined with a weakly reinforcing, compound visual stimulus. Results: While there was no overall effect of dose on active lever responding for nicotine in the absence of the visual stimulus, female rats responded more on the reinforced lever than males at 0.06 and 0.15 mg kg −1 inf −1 on an FR5 schedule. However, they also showed increased responding on the nonreinforced lever compared to males at the same doses.
Age-Dependent Effects of Nicotine on Locomotor Activity and Conditioned Place Preference In Rats
Psychopharmacology, 2004
Rationale: Most adult smokers start smoking during their adolescence. This adolescent initiation may be due to multiple factors, but little evidence is available regarding whether their brains are differentially sensitive to the addictive effects of nicotine during adolescence. Objective: To test the hypothesis that adolescents are more sensitive than adults to nicotine's rewarding actions. Methods: An unbiased, counterbalanced, place-conditioning procedure was used to examine drug-induced reward and locomotor activity. Early adolescent (postnatal day 28), late adolescent (P38) and adult (P90) rats received either saline or nicotine (0.125, 0.25 or 0.5 mg/ kg, s.c.) and were tested for place conditioning. Results: During early adolescence, a single nicotine injection (0.5 mg/kg) induced significant conditioned place preference (CPP). In contrast, during late adolescence or adulthood, nicotine did not induce CPP after either one or four conditioning trials. Initial locomotor responses to acute nicotine administration during the first conditioning trial also differed with age, with no effect at P28, but substantial inhibitory responses at all doses studied (0.125-0.5 mg/kg) at later ages. Although not differing in their initial locomotor response to nicotine, there was a significantly greater tolerance/sensitization during the second and subsequent drug exposures in late adolescents than in adults. Conclusions: These findings provide evidence that adolescent brain is differentially sensitive to both the acute and repeated effects of nicotine relative to adult brain. Furthermore, there are significant differences in nicotine sensitivity between early and late phases of adolescence.
2004
Recent studies with adolescent rodents offer valuable information regarding the neurochemical and behavioral effects of adolescent nicotine exposure. One hundred twenty-one male and 125 female adolescent (35 days of age) C57BL/6J mice were tested for voluntary nicotine consumption by providing 24-h access to both saccharin-only (SAC) and one of six nicotine-containing solutions [10, 25, 50, 75, 100, 200 ug (-)-freebase nicotine/ml in 2% SAC] in the home cage for 7 days. Although males and females drank similar volumes (ml) of nicotine, the female mice consumed more nicotine adjusted for body weight (mg/kg) and as a percentage of total fluid intake than did the male mice. In contrast, there was no sex difference in overall serum cotinine levels (adjusted for liver weight). For all mice, nicotine consumption and serum cotinine levels increased in a dose-dependent manner, and the volume of nicotine intake (ml), percent nicotine intake, and nicotine dosage (mg/kg) on the last day of the experiment were positively correlated with cotinine levels. Cotinine levels were inversely related to body weight only for females. Sex differences in nicotine consumption, but not in cotinine levels, suggest sex differences in pharmacokinetic processes that may contribute to oral nicotine consumption behavior during periadolescence.
Sex differences in nicotine preference
Journal of Neuroscience Research, 2016
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 selfadministration and nicotine-induced conditioned place preference. Nicotine preference is considered to be reflected in the animal's 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. V
Sex differences in response to nicotine in C57Bl/6:129SvEv mice
Nicotine & Tobacco Research, 2009
their smoking behavior. For example, in women, the subjective and reinforcing effects of smoking are less dependent on the amount of nicotine present in cigarettes (Perkins, Jacobs, Sanders, & Caggiula, 2002). Relative to men, women demonstrate reduced sensitivity to changes in nicotine dose via nasal spray (Perkins, 1999). By contrast, manipulations of nonpharmacological aspects of smoking, such as blocking the visual and olfactory stimuli from smoking, may reduce smoking behavior to a greater extent in women (Perkins et al., 2001). Taken together, these studies suggest a reduced infl uence of nicotine and a greater infl uence of conditioned cues on smoking behaviors in women compared with men. Consistent with human studies, several animal studies evaluating sex differences have found that male and female rats have different sensitivities to the pharmacological effects of nicotine (
Psychopharmacology, 2006
Rationale: Initiation of tobacco use typically begins during adolescence, and the nature of these first experiences with nicotine may affect the probability of continued use. In rodents, a number of studies suggest that periadolescents are more responsive to the rewarding effects of nicotine compared to adults. Objectives: This study was designed to determine if there are age differences in the rewarding and aversive effects of nicotine by using the conditioned place preference (CPP) and conditioned taste avoidance (CTA) paradigms, respectively. We also examined age differences in locomotor responses to nicotine. Methods: In the CPP paradigm, male periadolescent and adult Wistar rats received nicotine (0.2, 0.4, or 0.8 mg/kg, s.c.) or vehicle prior to place conditioning trials. In the CTA paradigm, in separate groups of rats, periadolescents and adults were exposed to a 0.1% saccharin solution, followed by the administration of nicotine (0.2, 0.4, or 0.8 mg/kg, s.c.) or vehicle. Four saccharinnicotine pairings were followed by a preference test and three extinction sessions. Results: In the CPP paradigm, nicotine produced a dose-dependent place preference in periadolescent, but not in adult, rats. In the CTA paradigm, adult rats expressed a dose-dependent avoidance of saccharin after pairings with nicotine, whereas periadolescents were resistant to CTA formation. With regard to locomotor activity, adults and periadolescents showed comparable locomotor responses to nicotine.
Nicotine induces conditioned place preferences over a large range of doses in rats
2005
Rationale: Conditioned place preference (CPP) procedures provide one measure of potential rewarding effects of abused drugs. Many attempts to induce CPP with nicotine have been unsuccessful. Objectives: To assess the influence of nicotine dose and stimulus assignment procedure on development of nicotine-induced CPP. Methods: Initial preferences for one side of a twocompartment apparatus were first determined in Sprague-Dawley rats. In subsequent conditioning trials, the compartment paired with nicotine was the initially preferred side for half of the rats, and the initially nonpreferred side for the other half. Rats received either an injection of nicotine (0.01-2 mg/kg SC) before being placed in one compartment (three trials) or saline before being placed in the other compartment (three trials). Control rats had saline injections associated with both compartments. A final test trial with no injection assessed final place preference. Results: Significant CPP were induced by 0.1-1.4 mg/kg doses of nicotine. Nicotineinduced CPP were only apparent when nicotine was paired with the initially non-preferred side. Moreover, a very high dose of nicotine (2 mg/kg) induced conditioned place aversion when paired with the initially preferred side of the apparatus. Conclusions: Nicotine induced significant CPP across a wide range of doses, in accordance with its role as the primary addictive component of tobacco. Small preferences for one side of the apparatus played a major role in the development of nicotine-induced CPP. These findings suggest that biased procedures may be more suitable than unbiased procedures for evaluation of rewarding effects of nicotine using CPP paradigms.