Adult and periadolescent rats differ in expression of nicotinic cholinergic receptor subtypes and in the response of these subtypes to chronic nicotine exposure

Doura, Menahem B.; Gold, Allison; Keller, Ashleigh B.; Perry, David C.

doi:10.1016/j.brainres.2008.03.056

Cited by 115 publications

(130 citation statements)

References 40 publications

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“…Likewise, after 2 weeks of twice-daily injections of saz-A, its brain concentration 10 min after the last injection was also approximately only 10% that of blood, which agrees with a recent study that measured brain and blood concentrations of saz-A in mice after a single intraperitoneal injection (Caldarone et al, 2011). This is in marked contrast to both nicotine and varenicline, which were highly concentrated in brain during both methods of chronic administration; moreover, both the concentrations and the brain-to-blood ratios of nicotine and varenicline were similar to previously reported values (Ghosheh et al, 1999;Doura et al, 2008;Rollema et al, 2010).…”

Section: Discussionsupporting

confidence: 92%

Chronic Sazetidine-A at Behaviorally Active Doses Does Not Increase Nicotinic Cholinergic Receptors in Rodent Brain

Hussmann

Turner

Lomazzo

et al. 2012

J Pharmacol Exp Ther

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Chronic nicotine administration increases ␣4␤2 neuronal nicotinic acetylcholine receptor (nAChR) density in brain. This upregulation probably contributes to the development and/or maintenance of nicotine dependence. nAChR up-regulation is believed to be triggered at the ligand binding site, so it is not surprising that other nicotinic ligands also up-regulate nAChRs in the brain. These other ligands include varenicline, which is currently used for smoking cessation therapy. Sazetidine-A (saz-A) is a newer nicotinic ligand that binds with high affinity and selectivity at ␣4␤2* nAChRs. In behavioral studies, saz-A decreases nicotine self-administration and increases performance on tasks of attention. We report here that, unlike nicotine and varenicline, chronic administration of saz-A at behaviorally active and even higher doses does not up-regulate nAChRs in rodent brains. We used a newly developed method involving radioligand binding to measure the concentrations and nAChR occupancy of saz-A, nicotine, and varenicline in brains from chronically treated rats. Our results indicate that saz-A reached concentrations in the brain that were ϳ150 times its affinity for ␣4␤2* nAChRs and occupied at least 75% of nAChRs. Thus, chronic administration of saz-A did not upregulate nAChRs despite it reaching brain concentrations that are known to bind and desensitize virtually all ␣4␤2* nAChRs in brain. These findings reinforce a model of nicotine addiction based on desensitization of up-regulated nAChRs and introduce a potential new strategy for smoking cessation therapy in which drugs such as saz-A can promote smoking cessation without maintaining nAChR up-regulation, thereby potentially increasing the rate of long-term abstinence from nicotine.

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Section: Discussionsupporting

confidence: 92%

Chronic Sazetidine-A at Behaviorally Active Doses Does Not Increase Nicotinic Cholinergic Receptors in Rodent Brain

Hussmann

Turner

Lomazzo

et al. 2012

J Pharmacol Exp Ther

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“…Plasma nicotine and cotinine levels, measured at a single time point, were significantly lower in adolescent compared with adult rats (Shram et al, 2008). Adolescent rats also had enhanced upregulation of brain nicotinic acetylcholine receptors in response to nicotine and significantly lower brain nicotine levels than those reported in adults (Doura et al, 2008). These studies suggest that pharmacokinetic differences may contribute to the behavioral differences observed between adolescent and adult rats.…”

Section: Introductionmentioning

confidence: 45%

Nicotine Pharmacokinetics in Rats Is Altered as a Function of Age, Impacting the Interpretation of Animal Model Data

et al. 2014

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Several behavioral studies report that adolescent rats display a preference for nicotine compared with adults. However, age-related pharmacokinetic differences may confound the interpretation of these findings. Thus, differences in pharmacokinetic analyses of nicotine were investigated. Nicotine was administered via acute s.c. (1.0 mg base/kg) or i.v. (0.2 mg base/kg) injection to early adolescent (EA; postnatal day 25) and adult (AD; postnatal day 71) male Wistar rats. Nicotine and its primary metabolite, cotinine, and additional metabolites nornicotine, nicotine-19-N-oxide, trans-39-hydroxycotinine, and norcotinine were sampled from 10 minutes to 8 hours (plasma) and 2 to 8 hours (brain) post nicotine and analyzed by liquid chromatography-tandem mass spectrometry. Following s.c. nicotine, the EA cohort had lower levels of plasma nicotine, cotinine, and nicotine-19-N-oxide at multiple time points, resulting in a lower area under the plasma concentration-time curve (AUC) for nicotine (P < 0.001), cotinine (P < 0.01), and nicotine-19-Noxide (P < 0.001). Brain levels were also lower for these compounds. In contrast, the EA cohort had higher plasma and brain AUCs (P < 0.001) for the minor metabolite nornicotine. Brain-to-plasma ratios varied for nicotine and its metabolites, and by age. Following i.v. nicotine administration, similar age-related differences were observed, and this route allowed detection of a 1.6-fold-larger volume of distribution and 2-fold higher plasma clearance in the EA cohort compared with the AD cohort. Thus, unlike in humans, there are substantial age differences in nicotine pharmacokinetics such that for a given nicotine dose, adolescent rats will have lower plasma and brain nicotine compared with adults, suggesting that this should be considered when interpreting animal model data.

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“…Particularly, upregulation of the a4b2 subtypes and downregulation of the a6b2 subtypes of nAChRs are more robust in adolescent rats compared with adult rats (Doura et al, 2008). Assuming that these alterations in nAChRs contribute to protection, then the protection observed in our studies would be affected by age and could explain the shorter nicotine exposure necessary for neuroprotection to occur in adolescent versus adult rats.…”

Section: Discussionmentioning

confidence: 61%

Chronic Nicotine Exposure Attenuates Methamphetamine-Induced Dopaminergic Deficits

Vieira-Brock

McFadden

Nielsen

et al. 2015

J Pharmacol Exp Ther

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Repeated methamphetamine (METH) administrations cause persistent dopaminergic deficits resembling aspects of Parkinson's disease. Many METH abusers smoke cigarettes and thus selfadminister nicotine; yet few studies have investigated the effects of nicotine on METH-induced dopaminergic deficits. This interaction is of interest because preclinical studies demonstrate that nicotine can be neuroprotective, perhaps owing to effects involving a4b2 and a6b2 nicotinic acetylcholine receptors (nAChRs). This study revealed that oral nicotine exposure beginning in adolescence [postnatal day (PND) 40] through adulthood [PND 96] attenuated METH-induced striatal dopaminergic deficits when METH was administered at PND 89. This protection did not appear to be due to nicotine-induced alterations in METH pharmacokinetics. Short-term (i.e., 21-day) high-dose nicotine exposure also protected when administered from PND 40 to PND 61 (with METH at PND 54), but this protective effect did not persist. Short-term (i.e., 21-day) high-dose nicotine exposure did not protect when administered postadolescence (i.e., beginning at PND 61, with METH at PND 75). However, protection was engendered if the duration of nicotine exposure was extended to 39 days (with METH at PND 93). Autoradiographic analysis revealed that nicotine increased striatal a4b2 expression, as assessed using [125 I]epibatidine. Both METH and nicotine decreased striatal a6b2 expression, as assessed using [125 I]aconotoxin MII. These findings indicate that nicotine protects against METH-induced striatal dopaminergic deficits, perhaps by affecting a4b2 and/or a6b2 expression, and that both age of onset and duration of nicotine exposure affect this protection.

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Adult and periadolescent rats differ in expression of nicotinic cholinergic receptor subtypes and in the response of these subtypes to chronic nicotine exposure

Cited by 115 publications

References 40 publications

Chronic Sazetidine-A at Behaviorally Active Doses Does Not Increase Nicotinic Cholinergic Receptors in Rodent Brain

Chronic Sazetidine-A at Behaviorally Active Doses Does Not Increase Nicotinic Cholinergic Receptors in Rodent Brain

Nicotine Pharmacokinetics in Rats Is Altered as a Function of Age, Impacting the Interpretation of Animal Model Data

Chronic Nicotine Exposure Attenuates Methamphetamine-Induced Dopaminergic Deficits

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