Brain Uptake Kinetics of Nicotine and Cotinine after Chronic Nicotine Exposure

Lockman, Paul R.; McAfee, Ghia; Geldenhuys, Werner J.; Schyf, Cornelis J. Van der; Abbruscato, Thomas J.; Allen, David

doi:10.1124/jpet.105.085381

Cited by 46 publications

(47 citation statements)

References 37 publications

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“…Indeed, studies show that cotinine exhibits several nicotinelike properties, including effects on acoustic startle, attention, and neuroprotection (Buccafusco and Terry, 2003;Buccafusco et al, 2009). The lack of effect of administered cotinine in the current study may be caused by insufficient cotinine entry into the brain such that the CNS levels were too low for efficacy (Lockman et al, 2005). It may also relate to mode of administration.…”

Section: Discussionmentioning

confidence: 65%

Nicotinic Receptor-Mediated Reduction in l-DOPA-Induced Dyskinesias May Occur via Desensitization

Bordia

Campos

McIntosh³

et al. 2010

The Journal of Pharmacology and Experimental Therapeutics

108

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L-DOPA-induced dyskinesias in Parkinson's disease are a significant clinical problem for which few therapies are available. We recently showed that nicotine reduces L-DOPA-induced abnormal involuntary movements (AIMs) in parkinsonian animals, suggesting it may be useful for the treatment of L-DOPAinduced dyskinesias. The present experiments were performed to understand the mechanisms whereby nicotine reduces L-DOPA-induced AIMs. We used a well established model of dyskinesias, L-DOPA-treated unilateral 6-hydroxydopamine-lesioned rats. Dose-ranging studies showed that injection of 0.1 mg/kg nicotine once or twice daily for 4 or 10 days most effectively reduced AIMs, with no worsening of parkinsonism. Importantly, a single nicotine injection did not reduce AIMs, indicating that nicotine's effect is caused by long-term rather than short-term molecular changes. Administration of the metabolite cotinine did not reduce AIMs, suggesting a direct effect of nicotine. Experiments with the nicotinic receptor (nAChR) antagonist mecamylamine were done to determine whether nicotine acted via a receptor-mediated mechanism. Unexpectedly, several days of mecamylamine injection (1.0 mg/kg) alone significantly ameliorated dyskinesias to a comparable extent as nicotine. The decline in AIMs with combined nicotine and mecamylamine treatment was not additive, suggesting that nicotine exerts its effects via a nAChR interaction. This latter finding, combined with data showing that mecamylamine reduced AIMs to a similar extent as nicotine, and that nicotine or mecamylamine treatment both decreased ␣6␤2* and increased ␣4␤2* nAChR expression, suggests that the nicotine-mediated improvement in L-DOPA-induced AIMs may involve a desensitization block. These data have important implications for the treatment of L-DOPA-induced dyskinesias in Parkinson's disease.

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Section: Discussionmentioning

confidence: 65%

Nicotinic Receptor-Mediated Reduction in l-DOPA-Induced Dyskinesias May Occur via Desensitization

Bordia

Campos

McIntosh³

et al. 2010

The Journal of Pharmacology and Experimental Therapeutics

108

View full text Add to dashboard Cite

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“…‫ءء‬ denotes significance of p Ͻ 0.01, and ‫ءءء‬ denotes significance of p Ͻ 0.001 using one-way ANOVA with Newman-Keuls post hoc analysis. 114 to 143 g/g/day and cotinine at a rate of 43 to 61 g/g/day (Lockman et al, 2005a). Water content representing cytotoxic edema increased after a 1-week exposure to nicotine when hippocampal slices were exposed to OGD compared with control and NF-CSE exposures.…”

Section: Discussionmentioning

confidence: 95%

Nicotine Exacerbates Brain Edema during In Vitro and In Vivo Focal Ischemic Conditions

Paulson¹,

Yang²,

Selvaraj³

et al. 2010

The Journal of Pharmacology and Experimental Therapeutics

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We have previously shown that nicotine, the addictive component of tobacco products, alters the blood-brain barrier (BBB) Na ϩ ,K ϩ ,2Cl Ϫ cotransporter (NKCC) during in vitro hypoxiaaglycemia exposure. Attenuation of abluminal NKCC suggests that accumulation of ions in the brain extracellular fluid would result in an increase of fluid or cytotoxic edema in the brain during hypoxia-aglycemia or stroke conditions. To further investigate whether nicotine products have the potential to worsen stroke outcome by increasing edema formation, two separate models to mimic stroke conditions were utilized to decipher the effects of short-term and long-term administrations of nicotine products on brain edema following stroke. Oxygen glucose deprivation (OGD) was studied in rat hippocampal slices with short-term or long-term exposure to nicotine and cigarette smoke constituents. During short-term exposure, the presence of nicotine at a concentration mimicking heavy smokers increased water content of hippocampal slices during OGD. Furthermore, long-term 1-week administration of nicotine increased water content in hippocampal slices that could be attenuated with nicotine acetylcholine receptor (nAChR) antagonists, suggesting nicotine increase edema during OGD via nAChRs. A second model of focal ischemia, middle cerebral artery occlusion, showed an increase of infarct size during short-term exposure to nicotine and an increase of edema during both short-term and long-term administration of nicotine, compared with saline controls. These findings support the paradigm that nicotine products not only increase the incidence of stroke but also have the potential to worsen stroke outcome by increased edema formation.

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“…Thus, further research with methods that may more closely model extended, intermittent human exposure to tobacco (e.g., O'Dell et al, 2007 ) may also be necessary to generalize the current time-related dissipation of the reinforcement enhancement to human behavior. Additionally, the current dose of nicotine delivered via osmotic minipump (3.16 mg/kg/day) reportedly results in plasma levels of 44 ng/ml ( Kenny et al, 2003 ), but other reports have variable estimates of plasma levels from similar doses and route of administration ( Ghosheh, Dwoskin, Miller, & Crooks, 2001 ;LeSage et al, 2002 ;Lockman et al, 2005 ;Nguyen, Rasmussen, & Perry, 2004 ). Given this discrepancy in the literature, the current model system may not be in complete correspondence with plasma levels observed in human research although it is problematic to equate plasma levels across species such as humans and rats.…”

Section: Nicotine and Tobacco Researchmentioning

confidence: 99%

Precipitated Withdrawal From Nicotine Reduces Reinforcing Effects of a Visual Stimulus for Rats

Weaver

Sweitzer

Coddington

et al. 2012

Nicotine & Tobacco Research

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Introduction: Research has identifi ed at least two positive reinforcement-related effects of nicotine: (a) primary reinforcement and (b) enhancement of reinforcement from concurrently available stimuli. Prior examples of the reinforcement-enhancing effects with rats showed that repeated, intermittent nicotine exposure increased responding for non-nicotine reinforcers, and this effect remained robust over several weeks. However, the effects of continuous nicotine exposure on responding for a non-nicotine reinforcer are unknown, as are the effects of abruptly withdrawing continuous nicotine on behavior maintained by the same reinforcer.Methods: Lever pressing for a visual reinforcer under a fi xed ratio schedule was assessed while rats were maintained on a chronic, continuous infusion of nicotine (3.16 mg/kg/day; osmotic minipump). The effects of precipitated withdrawal on responding, following 16 days of continuous nicotine exposure, were assessed by pre-session subcutaneous injections of mecamylamine (1.0 mg/kg).Results: Continuous nicotine initially increased active responding for the visual reinforcer; however, continued exposure resulted in an attenuation of this effect. Precipitated withdrawal from nicotine resulted in a signifi cant decline in active responding. Conclusions:The initial increase in responding for the visual reinforcer with chronic nicotine exposure is consistent with prior research showing that intermittent exposure to nicotine acts as a reinforcement enhancer. However, the attenuation of this enhancement following prolonged nicotine exposure is in contrast with the persistent effects previously reported. Finally, the decrease in visual reinforcers below control levels (nicotinenaive animals) following nicotine withdrawal highlights a potential for affective withdrawal, which may serve as a motive for continued nicotine use.

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Brain Uptake Kinetics of Nicotine and Cotinine after Chronic Nicotine Exposure

Cited by 46 publications

References 37 publications

Nicotinic Receptor-Mediated Reduction in l-DOPA-Induced Dyskinesias May Occur via Desensitization

Nicotinic Receptor-Mediated Reduction in l-DOPA-Induced Dyskinesias May Occur via Desensitization

Nicotine Exacerbates Brain Edema during In Vitro and In Vivo Focal Ischemic Conditions

Precipitated Withdrawal From Nicotine Reduces Reinforcing Effects of a Visual Stimulus for Rats

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