Nicotine-induced conditioned place preference in adolescent and adult rats (original) (raw)
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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.
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.
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.
The effect of previous exposure to nicotine on nicotine place preference
Psychopharmacology, 2012
Rationale Prior exposure to drugs of abuse may increase or decrease the reinforcing effects of the drug in later consumptions. Based on the initial locomotor activity (LA) response to an acute drug administration or to novelty in an open-field arena, animals can be classified as low or high LA responders (LR or HR). Few studies have used this classification with nicotine, and the results are controversial. Some authors suggested that nicotine can induce conditioned-place preference (CPP) following prior nicotine exposure, whereas others suggested that previous nicotine exposure extinguishes nicotine-CPP. Objective To explore if the administration of nicotine in a novel environment without explicit behavioral consequences to classify animals in low and high nicotine responders (LNR and HNR) could affect the establishment of nicotine CPP in male Sprague-Dawley rats. Results Prior exposure to a single dose of nicotine (0.4 mg/ kg, subcutaneously) induced CPP in LNR rats after 14 days of conditioning (seven-trial) but not after two or eight conditioning days. In contrast, HNR rats did not show CPP under any condition. In addition, our results indicated that previous exposure to nicotine decreased its rewarding effects in eight conditioning days CPP (four-trial), which can be regularly established without prior exposure to nicotine. Conclusion The results suggested that response to a single exposure to nicotine predicts the acquisition of nicotine preference in a 14-day conditioning protocol only for LNR rats. Thus, our findings demonstrated the relevance of using LNR and HNR classification when the individual susceptibility to nicotine preference is studied.
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.
Sex differences in conditioned nicotine reward are age-specific
Pharmacology Biochemistry and Behavior, 2015
Women constitute half of all smokers and many studies suggest that adult males and females differ in factors that maintain tobacco smoking, yet there is limited information about sex differences in nicotine reward during adolescence. Limited studies suggest that adolescent male rats selfadminister more nicotine than adults, suggesting that drug administration during adolescence leads to different behavioral effects than during adulthood. In the present study, male rats developed a significant conditioned place preference (CPP) to lower doses of nicotine than females, regardless of age. In addition, adolescents were more sensitive than adults. In female rats, adolescents exhibited a CPP of greater magnitude than adult females. In males, the magnitude of the CPP did not differ as a function of age, but adolescents exhibited CPP to lower doses than adults. There also were differences in nicotinic acetylcholinergic receptor binding in nucleus accumbens and caudate putamen in response to nicotine across age and sex. These findings suggest that it is necessary to consider sex-and age-specific effects of drugs such as nicotine when developing strategies for improving smoking cessation treatments.
Psychopharmacology, 2006
Rationale: Many people come in contact with psychoactive drugs, yet not all of them become addicts. Epidemiology shows that a late approach with cigarette smoking is associated with a lower probability to develop nicotine dependence. Exposure to nicotine during periadolescence, but not similar exposure in the postadolescent period, increases nicotine self-administration in rats, but underlying mechanisms remain poorly understood. Objective: We investigated whether exposure to nicotine during or after adolescence would alter rewarding properties of the same drug at adulthood, as assessed by place conditioning. Materials and methods: Periadolescent (PND 34-43) or postadolescent (PND 60-69) rats were injected with saline or nicotine (0.4 mg kg −1 ) for 10 days. The rats received three pairings with saline and three pairings with nicotine (0, 0.3, or 0.6 mg kg −1 ) 5 weeks after pretreatment. The rats were then tested for place conditioning in a drug-free state. Results: Upon first exposure to the apparatus, animals pretreated with nicotine during adolescence showed elevated novelty-induced activation. The 0.3 (but not the 0.6) mg kg −1 dose failed to produce both ongoing locomotor sensitization and place conditioning in animals pretreated with nicotine following adolescence. This suggests a rightward shift in the doseresponse curve, namely, a reduced efficacy of nicotine. Conversely, the same dose was effective in saline-pretreated controls and noteworthy in rats pretreated during adolescence. Conclusion: Exposure following the adolescent period might diminish the risk to develop nicotine dependence. As for human implications, findings are consistent with a reduced vulnerability to nicotine addiction in people who start smoking late in their life.
Pharmacology Biochemistry and Behavior, 2008
This study compared the rewarding and aversive effects of nicotine in adolescent, adult, and adult rats pre-exposed to nicotine during adolescence. Prior to conditioning, the rats were tested for their initial preference for either of 2 distinct compartments. Adolescent and adult rats then received various nicotine doses in their initially non-preferred side on one day and saline in the other side on alternate days. This 2-day procedure was repeated over 8 consecutive days. Following conditioning, rats were re-tested for their preference. Another cohort of adolescent and adult rats were conditioned with various doses of d-amphetamine. Nicotine produced CPP in an inverted U-shaped manner in both age groups. However, adolescents displayed a larger upward shift in CPP that was significant across a wider dose range relative to adults. There were no developmental differences to CPP produced by d-amphetamine. In a final study, adolescents were prepared with pumps that delivered nicotine for 14 days. These rats were conditioned later as adults using the same procedures used previously. Pre-exposure to nicotine during adolescence diminished the aversive effects produced by the highest nicotine dose in naïve adults. Taken together, these studies provide a basis for enhanced vulnerability to nicotine during adolescence.
Nicotine place preference using the biased method of conditioning
Progress in Neuro-Psychopharmacology and Biological Psychiatry, 1994
1. The objective of the experimentation was to determine whether nicotine (NIC, 0.8 mg/kg subcutaneously administered) would produce a conditioned place preference (CPP) in rats confined for thirty min to their less-preferred side in a three compartment apparatus, or an aversion when another group of rats were confined to their more preferred side. 2. On the non-drugged test day following eight conditioning trials, the rats spent more time in the compartment paired with NIC that was initially less-preferred, whereas animals that were conditioned with NIC in their preferred compartment had no significant change in time spent in that side. 3. Subsequently, locomotor activity was measured during a 30 min test session following the injection of NIC at the dose tested in CPP (0.8 mg/kg). A possible common mechanism on NIC-induced CPP and locomotor stimulation, as they may be regulated by mesolimbic dopamine neurons is discussed.
Rodent models of nicotine reward: What do they tell us about tobacco abuse in humans?
Pharmacology Biochemistry and Behavior, 2009
Tobacco products are widely abused in humans, and it is assumed that nicotine is the key substrate in these products that produces addiction. Based on this assumption, several pre-clinical studies have utilized animal models to measure various aspects of nicotine addiction. Most of this work has focused on behavioral measures of nicotine and how other variables contribute to these effects. Here we discuss the most commonly used animal models including, self-administration (SA), place conditioning (PC), and the intracranial self-stimulation (ICSS) paradigms in rodents. The strengths, limitations and procedural variables of these models are reviewed, followed by a discussion of how the animal models have been used to study factors such as age, sex, stress, and the effects of tobacco products other than nicotine. These factors are discussed in light of their influences on human tobacco abuse. The rodent models are evaluated in the context of face, predictive, and construct validity, and we propose that inclusion of factors such as age, sex, stress and other constituents of tobacco aside from nicotine can increase the utility of these animal models by more closely mimicking human tobacco abuse.