Nicotinic antagonist effects in the mediodorsal thalamic nucleus: Regional heterogeneity of nicotinic receptor involvement in cognitive function

Cannady, Reginald; Weir, Ruth K.; Wee, Boyoung; Gotschlich, Emily; Kolia, Nadeem; Lau, Edward; Brotherton, Jesse; Levin, Edward D.

doi:10.1016/j.bcp.2009.05.021

Cited by 22 publications

(17 citation statements)

References 35 publications

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“…Data show that local infusions of α7 and α4β2 nicotinic antagonists (MLA and DHβE) into the dorsal or ventral hippocampus or basolateral amygdala in rats significantly impaired working memory function (Addy et al, 2003; Levin et al, 2002; Nott and Levin, 2006). In contrast, acute or chronic local infusion of the α4β2 antagonist DHβE into the dorsomedial thalamic nucleus caused a significant improvement in working memory function (Cannady et al, 2009). …”

Section: Discussionmentioning

confidence: 99%

Decreasing nicotinic receptor activity and the spatial learning impairment caused by the NMDA glutamate antagonist dizocilpine in rats

Burke

Heshmati

Kholdebarin

et al. 2014

European Journal of Pharmacology

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Nicotinic systems have been shown by a variety of studies to be involved in cognitive function. Nicotinic receptors have an inherent property to become desensitized after activation. The relative role of nicotinic receptor activation vs. net receptor inactivation by desensitization in the cognitive effects of nicotinic drugs remains to be fully understood. In these studies, we tested the effects of the α7 nicotinic receptor antagonist methyllycaconitine (MLA), the α4β2 nicotinic receptor antagonist dihydro-β-erythroidine (DHβE), the nonspecific nicotinic channel blocker mecamylamine and the α4β2 nicotinic receptor desensitizing agent sazetidine-A on learning in a repeated acquisition test. Adult female Sprague-Dawley rats were trained on a repeated acquisition learning procedure in an 8-arm radial maze. MLA (1–4 mg/kg), DHβE (1–4 mg/kg), mecamylamine (0.125–0.5 mg/kg) or sazetidine-A (1 and 3 mg/kg) were administered in four different studies either alone or together with the NMDA glutamate antagonist dizocilpine (0.05 and 0.10 mg/kg). MLA significantly counteracted the learning impairment caused by dizocilpine. The overall choice accuracy impairment caused by dizocilpine was significantly attenuated by co-administration of DHβE. Low doses of the non-specific nicotinic antagonist mecamylamine also reduced dizocilpine-induced repeated acquisition impairment. Sazetidine-A reversed the accuracy impairment caused by dizocilpine. These studies provide evidence that a net decrease in nicotinic receptor activity can improve learning by attenuating learning impairment induced by NMDA glutamate blockade. This adds to evidence in cognitive tests that nicotinic antagonists can improve cognitive function. Further research characterizing the efficacy and mechanisms underlying nicotinic antagonist and desensitization induced cognitive improvement is warranted.

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Section: Discussionmentioning

confidence: 99%

Decreasing nicotinic receptor activity and the spatial learning impairment caused by the NMDA glutamate antagonist dizocilpine in rats

Burke

Heshmati

Kholdebarin

et al. 2014

European Journal of Pharmacology

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“…Another potential undesired consequence of nAChR antagonism is cognitive impairment. Conflicting evidence exists as to whether the mechanistically similar DHβE interferes with cognitive function, likely a byproduct of different cognitive domains assessed by various tasks and other procedural variations (Cannady et al 2009; Davis and Gould 2006; Davis et al 2007; Levin et al 2002; Raybuck and Gould 2009). Certainly, this area merits further examination.…”

Section: Discussionmentioning

confidence: 99%

Effects of the specific α4β2 nAChR antagonist, 2-fluoro-3-(4-nitrophenyl) deschloroepibatidine, on nicotine reward-related behaviors in rats and mice

et al. 2012

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Rationale Alleviating addiction to tobacco products could prevent millions of deaths. Investigating novel compounds selectively targeting α4β2 nAChRs hypothesized to have a key role in the rewarding effects of nicotine may be a useful approach for future treatment. Objectives The present study was designed to evaluate 2-fluoro-3-(4-nitrophenyl) deschloroepibatidine (4-nitro-PFEB), a potent competitive antagonist of neuronal α4β2 nAChRs, in several animal models related to nicotine reward: drug discrimination, intracranial self-stimulation (ICSS), conditioned place preference, and limited access to self-administration. Methods Long Evans rats were trained in a two-lever discrimination procedure to discriminate 0.4 mg/kg nicotine (s.c.) from saline. Male Sprague–Dawley rats were stereotaxically implanted with electrodes and trained to respond for direct electrical stimulation of the medial forebrain bundle. ICR mice were evaluated using an unbiased place preference paradigm, and finally, male Wistar rats were implanted with intrajugular catheters and tested for nicotine self-administration under limited access (1 h/day). Results 4-Nitro-PFEB attenuated the discriminative stimulus effects of nicotine, but alone did not produce nicotine-like discriminative stimulus effects. Nicotine-induced facilitation of ICSS reward thresholds was reversed by 4-nitro-PFEB, which alone had no effect on thresholds. 4-Nitro-PFEB also blocked the conditioned place preference produced by nicotine, but alone had no effect on conditioned place preference. Finally, 4-nitro-PFEB dose-dependently decreased nicotine self-administration. Conclusions These results support the hypothesis that neuronal α4β2 nAChRs play a key role in mediating the rewarding effects of nicotine and further suggest that targeting α4β2 nAChRs may yield a potential candidate for the treatment of nicotine dependence.

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“…Infusions of mecamylamine to the ventral hippocampus, substantia nigra, and ventral tegmental area, but not to the nucleus accumbens, impaired choice accuracy on a radial arm maze task (Kim and Levin, 1996; Levin et al, 1994). Likewise, infusions of DHβE to the hippocampus impaired working memory (Bancroft and Levin, 2000; Bettany and Levin, 2001), but infusions to the medial thalamic nucleus improved performance on a radial arm maze task (Cannady et al, 2009). Although few studies have examined the effects of nicotine dependence treatments on memory impairment following nicotine withdrawal in rodents, both bupropion and varenicline ameliorated deficits in performance on the elevated-plus maze induced by scopolamine, a muscarinic cholinergic antagonist (Kruk-Słomka et al, 2012; Kruk et al, 2011).…”

Section: Nicotine Withdrawal and Cognitive Performancementioning

confidence: 99%

Cognitive function during nicotine withdrawal: Implications for nicotine dependence treatment

2014

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Nicotine withdrawal is associated with deficits in neurocognitive function including sustained attention, working memory, and response inhibition. Several convergent lines of evidence suggest that these deficits may represent a core dependence phenotype and a target for treatment development efforts. A better understanding of the mechanisms underlying withdrawal-related cognitive deficits may lead to improve nicotine dependence treatment. We begin with an overview of the neurocognitive effects of withdrawal in rodent and human models, followed by discussion of the neurobehavioral mechanisms that are thought to underlie these effects. We then review individual differences in withdrawal-related neurocognitive effects including genetics, gender, and psychiatric comorbidity. We conclude with a discussion of the implications of this research for developing improved therapies, both pharmacotherapy and behavioral treatments, that target cognitive symptoms of nicotine withdrawal.

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Nicotinic antagonist effects in the mediodorsal thalamic nucleus: Regional heterogeneity of nicotinic receptor involvement in cognitive function

Cited by 22 publications

References 35 publications

Decreasing nicotinic receptor activity and the spatial learning impairment caused by the NMDA glutamate antagonist dizocilpine in rats

Decreasing nicotinic receptor activity and the spatial learning impairment caused by the NMDA glutamate antagonist dizocilpine in rats

Effects of the specific α4β2 nAChR antagonist, 2-fluoro-3-(4-nitrophenyl) deschloroepibatidine, on nicotine reward-related behaviors in rats and mice

Cognitive function during nicotine withdrawal: Implications for nicotine dependence treatment

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