[show abstract][hide abstract] ABSTRACT: Mechanisms that mediate age differences during nicotine withdrawal are unclear.
This study compared kappa-opioid receptor (KOR) activation in naïve and nicotine-treated adolescent and adult rats using behavioral and neurochemical approaches to study withdrawal.
The behavioral models used to assess withdrawal included conditioned place and elevated plus maze procedures. Deficits in dopamine transmission in the nucleus accumbens (NAcc) were examined using microdialysis procedures. Lastly, the effects of KOR stimulation and blockade on physical signs produced upon removal of nicotine were examined in adults.
Nicotine-treated adults displayed a robust aversion to an environment paired with a KOR agonist versus naïve adults. Neither of the adolescent groups displayed a place aversion. KOR activation produced an increase in anxiety-like behavior that was highest in nicotine-treated adults versus all other groups. KOR activation produced a decrease in NAcc dopamine that was largest in nicotine-treated adults versus all other groups. Lastly, KOR activation facilitated physical signs of withdrawal upon removal of nicotine and KOR blockade reduced this effect.
Chronic nicotine enhanced the affective, anxiogenic, and neurochemical effects produced by KOR activation in adult rats. Our data suggest that chronic nicotine elicits an increase in KOR function, and this may contribute to nicotine withdrawal since KOR activation facilitated and KOR blockade prevented withdrawal signs upon removal of nicotine. Given that chronic nicotine facilitated the neurochemical effects of KOR agonists in adults but not in adolescents, it is suggested that KOR regulation of mesolimbic dopamine may contribute to age differences in nicotine withdrawal.
[show abstract][hide abstract] ABSTRACT: IntroductionThe 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.
MethodsAnimals 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.
ResultsThe 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.
ConclusionIn females, nicotine reward is enhanced during adolescence and is facilitated by the presence of ovarian hormones.
[show abstract][hide abstract] ABSTRACT: The behavioral effects of nicotine withdrawal are lower in adolescent versus adult rats. However, the neurochemical mechanisms that mediate these developmental differences are unknown. Previous studies have shown that extracellular levels of dopamine in the nucleus accumbens (NAcc) are reduced in adult rats experiencing withdrawal. This study compared dopamine levels in the NAcc of male adolescent and adult rats experiencing nicotine withdrawal. Animals were prepared with subcutaneous pumps that delivered an equivalent nicotine dose in these age groups. Following 13 days of nicotine exposure, rats were implanted unilaterally with microdialysis probes into the NAcc and ipsilateral ventral tegmental area (VTA). The next day, dialysate levels were collected following systemic administration of the nicotinic-receptor antagonist mecamylamine to precipitate withdrawal. Mecamylamine produced an average % decrease in NAcc dopamine that was lower in adolescents (20%) versus adults (44%). Similar developmental differences were observed with the dopaminergic (DOPAC and HVA) but not serotonergic (5-HIAA) metabolites. A follow-up study compared NAcc dopamine in adolescent and adult rats receiving intra-VTA administration of bicuculline, which reduces gamma-aminobutyric acid (GABA) inhibition of dopamine transmission. The results revealed that blockade of GABA(A) receptors in the VTA produced a two-fold increase in NAcc dopamine of adults but not adolescents. These results provide a potential mechanism involving dopamine that mediates developmental differences in nicotine withdrawal. Specifically, they suggest that GABA systems are underdeveloped during adolescence and this reduced inhibition of dopamine neurons in the VTA may lead to reduced decreases in NAcc dopamine of young animals experiencing withdrawal.
[show abstract][hide abstract] ABSTRACT: This study compared the rewarding and aversive effects of nicotine in adolescent, adult, and adult rats preexposed 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 naive adults. Taken together, these studies provide a basis for enhanced vulnerability to nicotine during adolescence.
Pharmacology Biochemistry and Behavior 06/2008; 90(4):658-63. · 2.61 Impact Factor
[show abstract][hide abstract] ABSTRACT: Vulnerability to nicotine addiction is significantly increased in individuals who begin smoking during adolescence; however, the underlying mechanisms of this phenomenon remain unclear. This study examined the motivational effects of nicotine withdrawal in adolescent (PND 27-42) and adult (PND 60-75) rats using the conditioned place aversion paradigm. Male Wistar rats were tested for their initial preference for either of two distinct compartments of our conditioning apparatus. Rats were then implanted with subcutaneous (sc) pumps that produce equivalent blood plasma levels of nicotine for 14 days. Conditioning was conducted over the last 8 days of nicotine exposure. Rats received the nicotinic antagonist mecamylamine (1.5 or 3.0 mg/kg, sc) to precipitate withdrawal in their initially preferred compartment, and on alternate days they received saline in their non-preferred compartment. Following conditioning, rats were re-tested for their preference for each compartment. A subsequent study was conducted to examine potential developmental differences in learning place aversion produced by another aversive stimulus, lithium chloride (LiCl). Rats received LiCl (0, 10, 30, or 100 mg/kg, sc) in their initially preferred side using similar conditioning procedures. Adults displayed robust place aversion produced by nicotine withdrawal. This effect was lower in adolescent rats even in a group of young rats that received 7 additional days of nicotine exposure prior to conditioning. This developmental difference was specific to nicotine withdrawal since there were no differences between adolescents and adults in learning place aversion with LiCl. Our findings demonstrating reduced effects of nicotine withdrawal constitute a powerful basis for the increased vulnerability to nicotine dependence during adolescence.
Neurotoxicology and Teratology 01/2007; 29(1):17-22. · 3.18 Impact Factor