Age-Related Differences in the Disposition of Nicotine and Metabolites in Rat Brain and Plasma

Vieira-Brock, Paula L.; Andrenyak, David M.; Nielsen, Shannon M.; Fleckenstein, Annette E.; Wilkins, Diana G.

doi:10.1093/ntr/ntt067

Cited by 22 publications

(15 citation statements)

References 38 publications

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“…The lower serum and brain nicotine levels in adolescents versus adults following injection of 0.5 mg/kg nicotine in Experiment 2 is consistent with recent findings ( Vieira-Brock et al, 2013 ; Craig et al, 2014 ). We also found higher brain:serum nicotine concentration ratios in adolescents compared to adults, suggesting greater penetration of nicotine into brain.…”

Section: Discussionsupporting

confidence: 91%

“…A secondary goal was to examine age differences in these effects. Therefore, following establishment of nicotine dosing conditions that accounted for age differences in nicotine pharmacokinetics (see Vieira-Brock et al, 2013 ; Craig et al, 2014 ) and produced similar nicotine serum levels across ages (Experiment 2), we evaluated effects of mecamylamine alone and mecamylamine combined with acute nicotine on somatic signs in both adolescents and adults (Experiment 3).…”

Section: Introductionmentioning

confidence: 99%

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Blockade of cholinergic transmission elicits somatic signs in nicotine-naïve adolescent rats

et al. 2015

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High doses of the nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine can elicit somatic signs resembling those associated with nicotine withdrawal in nicotine-naïve adult rats. Understanding this phenomenon, and its possible modulation by acute nicotine and age, could inform the use of mecamylamine as both an experimental tool and potential pharmacotherapy for tobacco dependence and other disorders. This study evaluated the ability of high-dose mecamylamine to elicit somatic signs in adolescent rats, and the potential for acute nicotine pretreatment to potentiate this effect as previously reported in adults. Single or repeated injections of mecamylamine (1.5 or 3.0 mg/kg, s.c.) elicited somatic signs in nicotine-naïve adolescents, but this effect was not influenced by 2 h pretreatment with acute nicotine (0.5 mg/kg, s.c.). In an initial evaluation of the effects of age in this model, mecamylamine (2.25 mg/kg, s.c.) elicited somatic signs in nicotine-naïve adolescents and adults. This effect was modestly enhanced following acute nicotine injections in adults but not in adolescents, even when a higher nicotine dose (1.0 rather than 0.5 mg/kg, s.c.) was used in adolescents to account for age differences in nicotine pharmacokinetics. These studies are the first to show that mecamylamine elicits somatic signs in nicotine-naïve adolescent rats, an effect that should be considered when designing and interpreting studies examining effects of high doses of mecamylamine in adolescents. Our findings also provide preliminary evidence that these signs may be differentially modulated by acute nicotine pretreatment in adolescents versus adults.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Blockade of cholinergic transmission elicits somatic signs in nicotine-naïve adolescent rats

et al. 2015

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“…Developmental differences in nicotine metabolism could be a source of difference in the threshold dose of nicotine that supports initiation of self-administration behavior seen here. Vieira-Brock et al 32 and Craig et al 33 found that following a subcutaneous injection of nicotine, blood and brain nicotine levels were lower in adolescent male rats compared to adult male rats. Similarly, following an intravenous injection Craig et al 33 observed that although the initial peak in blood nicotine levels did not differ between adolescents and adults, the levels declined more rapidly in adolescents.…”

Section: Discussionmentioning

confidence: 99%

Adolescent Rats Self-Administer Less Nicotine Than Adults at Low Doses

Schassburger

Pitzer

Smith

et al. 2016

NICTOB

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Introduction: Although nearly 90% of current smokers initiated tobacco use during adolescence, little is known about reinforcement by nicotine in adolescents. Researchers are currently investigating whether a potential public health policy setting a tobacco product standard with very low nicotine levels would improve public health, and it is essential to understand whether data generated in adults translates to adolescents, particularly as it relates to the threshold dose of nicotine required to support smoking. The present study compared self-administration of low doses of nicotine between adolescent and adult rats. Methods: Adolescent (postnatal day [P] 30) and adult (P90) male and female rats were allowed to nosepoke to receive intravenous infusions of nicotine (3-100 μg/kg/infusion) during 16 daily 1-hour sessions. Results: At 10 μg/kg/infusion nicotine, adolescent rats earned significantly fewer infusions than adults. When responding for 30 μg/kg/infusion nicotine, rats of both ages earned a similar number of infusions; however, there were subtle differences in the distribution of infusions across the 1-hour session. No sex differences were apparent in either age group at any dose. Conclusions: These results demonstrate that adolescent rats are less sensitive than adults to the primary reinforcing effects of nicotine. However, at nicotine doses that support self-administration in both age groups, adolescent and adult rats do not differ in acquisition or number of infusions earned. These results suggest that reducing nicotine levels in cigarettes to a level that does not support smoking in adults may be sufficient to reduce the acquisition of smoking in adolescents. Implications: The results of the present studies demonstrate that adolescent rats are less sensitive than adults to the primary reinforcing effects of nicotine. These results suggest that reducing nicotine levels in cigarettes to a level that does not support smoking in adults will be sufficient to reduce the acquisition of smoking in adolescents.

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“…For plasma quantification, 100 μl plasma samples were prepared as previously described (Craig et al , 2014; Vieira-Brock et al , 2013). The prepared dialysate and plasma samples were then analyzed by LC-MS as previously described (Craig et al , 2014).…”

Section: Methodsmentioning

confidence: 99%

Brain CYP2B induction can decrease nicotine levels in the brain

2016

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Nicotine can be metabolized by the enzyme CYP2B; brain CYP2B is higher in rats and monkeys treated with nicotine, and in human smokers. A 7-day nicotine treatment increased CYP2B expression in rat brain but not liver, and decreased the behavioral response and brain levels (ex vivo) to the CYP2B substrate propofol. However, the effect of CYP2B induction on the time course and levels of circulating brain nicotine in vivo has not been demonstrated. Using brain microdialysis, nicotine levels following a subcutaneous nicotine injection were measured on day one and after a 7-day nicotine treatment. There was a significant time x treatment interaction (p = 0.01); peak nicotine levels (15–45 minutes post-injection) were lower after treatment (p = 0.04) consistent with CYP2B induction. Following a two-week washout period, brain nicotine levels increased to day one levels (p = 0.02), consistent with brain CYP2B levels returning to baseline. Brain pretreatment of the CYP2B inhibitor, C8-xanthate, increased brain nicotine levels acutely and after 7-day nicotine treatment, indicating the alterations in brain nicotine levels were due to changes in brain CYP2B activity. Plasma nicotine levels were not altered for any time or treatment sampled, confirming no effect on peripheral nicotine metabolism. These results demonstrate that chronic nicotine, by increasing brain CYP2B activity, reduces brain nicotine levels, which could alter nicotine’s reinforcing effects. Higher brain CYP2B levels in smokers could lower brain nicotine levels; as this induction would occur following continued nicotine exposure it could increase withdrawal symptoms and contribute to sustaining smoking behavior.

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Age-Related Differences in the Disposition of Nicotine and Metabolites in Rat Brain and Plasma

Cited by 22 publications

References 38 publications

Blockade of cholinergic transmission elicits somatic signs in nicotine-naïve adolescent rats

Blockade of cholinergic transmission elicits somatic signs in nicotine-naïve adolescent rats

Adolescent Rats Self-Administer Less Nicotine Than Adults at Low Doses

Brain CYP2B induction can decrease nicotine levels in the brain

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