Self-administration of 5-iodo-A-85380, a β2-selective nicotinic receptor ligand, by operantly trained rats

Liu, Xiu; Koren, Andrei O.; Yee, Susan K.; Pechnick, Robert N.; Poland, Russell E.; London, Edythe D.

doi:10.1097/00001756-200308060-00020

Cited by 25 publications

(28 citation statements)

References 21 publications

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“…Whereas nicotine reinforcement and reward-like behavior require activation of β2*nAChRs [21]–[27], [29]–[32], [52], the studies described herein suggest that inactivation of β2*nAChRs decreases fear-like and anxiety-like behavior as measured by increased suppression ratios during CER, decreased digging behavior in a marble burying task, and increased exploratory behavior in the open arms of an elevated plus maze. Rats will self-administer A-85830, a selective agonist of β2*nAChRs [52]. Administration of selective β2*nAChR antagonists blocks nicotine conditioned place preference and greatly attenuates nicotine self-administration [21]–[25].…”

Section: Discussionmentioning

confidence: 60%

Low Dose Nicotine and Antagonism of β2 Subunit Containing Nicotinic Acetylcholine Receptors Have Similar Effects on Affective Behavior in Mice

Anderson

Brunzell

2012

PLoS ONE

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Nicotine leads to both activation and desensitization (inactivation) of nicotinic acetylcholine receptors (nAChRs). This study tested the hypothesis that nicotine and a selective antagonist of β2*nAChRs would have similar effects on affective behavior. Adult C57BL/6J male mice were tested in a conditioned emotional response (CER) assay which evaluates the ability of an aversive stimulus to inhibit goal-directed behavior. Mice lever-pressed for a saccharin reinforcer according to a variable schedule of reinforcement during sessions in which two presentations of a compound light/tone conditioned stimulus (CS) co-terminated with a 0.1 or 0.3 mA, 0.5 s footshock unconditioned stimulus (US). During testing in the absence of the US, mice received doses of i.p. nicotine (0, 0.0032, 0.01, 0.032, 0.1 mg/kg) or a selective β2 subunit containing nAChR (β2*nAChR) antagonist dihydro-beta-erythroidine (0, 0.1, 0.3, 1.0, 3.0 mg/kg DHβE). There was a dose-dependent effect of nicotine revealing that only low doses (0.01, 0.032 mg/kg) increased CER suppression ratios (SR) in these mice. DHβE also dose-dependently increased SR at the 3 mg/kg dose. In ethological measures of fear−/anxiety-like behavior, these doses of nicotine and DHβE significantly reduced digging behavior in a marble burying task and 0.3 mg/kg DHβE promoted open-arm activity in the elevated plus maze. Doses of nicotine and DHβE that altered affective behavior had no effect on locomotor activity. Similar to previous reports with anxiolytic drugs, low dose nicotine and DHβE reversed SR in a CER assay, decreased digging in a marble burying assay and increased open arm activity in the elevated plus maze. This study provides evidence that inactivation of β2*nAChRs reduces fear-like and anxiety-like behavior in rodents and suggests that smokers may be motivated to smoke in part to desensitize their β2*nAChRs. These data further identify β2*nAChR antagonism as a potential therapeutic strategy for relief of negative affect and anxiety.

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Section: Discussionmentioning

confidence: 60%

Low Dose Nicotine and Antagonism of β2 Subunit Containing Nicotinic Acetylcholine Receptors Have Similar Effects on Affective Behavior in Mice

Anderson

Brunzell

2012

PLoS ONE

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“…In the same report, nicotine was effective in provoking reward behavior in 7 knockout mice, but not in 2 knockout mice [172]. Furthermore, rats will self administer the selective 4 2 agonist A-85380, suggesting that this compound also has rewarding effects [173]. Infusion of DH E into the ventral tegmental area, a part of the mesolimbic dopamine system that is associated with reward, blocks nicotine mediated self administration and dopamine release [174,175].…”

Section: Dependencementioning

confidence: 92%

Treating the Cognitive Deficits of Schizophrenia with Alpha4Beta2 Neuronal Nicotinic Receptor Agonists

Radek

Kohlhaas²,

Rueter³

et al. 2010

CPD

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Schizophrenic patients exhibit debilitating impairments of intellectual function. Typical and atypical antipsychotic medications are largely ineffective at treating the cognitive deficits of schizophrenia (CDS), and efforts to discover compounds that treat these symptoms are ongoing. Considerable tobacco use in schizophrenic patients, genetic linkage, and receptor binding studies suggest the involvement of nicotinic acetylcholine receptors (nAChRs) in schizophrenia. Neuronal alpha4beta2 nAChRs are widely distributed in the mammalian brain, and are implicated in normal cognitive functioning in animal models. Ligands of various selectivity and potency have been used to study the role of the alpha4beta2 subtype in schizophrenia. For instance, studies in rodents show that alpha4beta2 agonists improve sensory gating, an information processing function that is deficient in schizophrenia. Pharmacological studies in animals also suggest that alpha4beta2 nAChRs are involved in other cognitive domains that are impaired in schizophrenia, including speed of processing, working memory, visual learning and memory, and social cognition. The non-selective nAChR agonist nicotine has been shown to improve CDS in several human clinical studies, and recent trials have been undertaken to evaluate the efficacy of more alpha4beta2 selective compounds. It remains to be determined whether alpha4beta2 agonists will provide greater efficacy than nicotine for CDS or reducing tobacco use in patients. Pre-clinical evidence to date suggests that agonists of the nicotinic alpha4beta2 subtype could be useful in improving cognitive function in schizophrenic patients.

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“…Recent results have shown that 5IA is also a potent activator of a6b2* receptors in vitro (Mogg et al, 2002), and based on this finding it is now generally referred to as b2*-selective nicotinic receptor ligand (Liu et al, 2003). Thanks to its high-affinity, low nonspecific binding, and lack of toxicity in mammals, 5IA has been characterized as a tool for noninvasive in vivo studies of b2* nicotinic receptor (Vaupel et al, 1998(Vaupel et al, , 2005.…”

Section: Figurementioning

confidence: 99%

Region-Specific Effects of Nicotine on Brain Activity: A Pharmacological MRI Study in the Drug-Naïve Rat

Gozzi

Schwarz

Reese

et al. 2005

Neuropsychopharmacol

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We have applied pharmacological magnetic resonance imaging (phMRI) methods to map the functional response to nicotine in drug-naïve rats. Nicotine (0.35 mg/kg intravenous (i.v.)) increased relative cerebral blood volume (rCBV) in cortical (including medial prefrontal, cingulate orbitofrontal, insular) and subcortical (including amygdala and dorsomedial hippocampus) structures. The pharmacological specificity of the effect was demonstrated by acute pretreatment with the nicotinic acetylcholine receptor (nAChR) ion-channel-blocking agent mecamylamine, which suppressed the rCBV response to nicotine. Control experiments with norepinephrine, a potent non-brain-penetrant vasopressor, at a dose that mimics the cardiovascular response induced by nicotine were performed to assess the potential confounding effects of peripheral blood pressure changes induced by nicotine. In an attempt to highlight the relative contribution of different nAChR subtypes to the observed activation pattern of nicotine, we also investigated the central phMRI response to an acute challenge with (R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-(2-pyridyl)thiophene-2-carboxamide) (cpdA, at 5, 10, 20, and 30 mg/kg i.v.) and 5-iodo-A-85380 (5IA, 5 mg/kg i.v.). CpdA is a selective agonist at homomeric alpha7 nAChRs, while 5IA features high in vivo affinity for the alpha4beta2* and other less-abundant beta2-containing nicotinic receptors. CpdA did not produce significant rCBV changes at any of the doses tested, whereas 5IA induced a pattern of activation very similar to that induced by nicotine. The lack of phMRI response to cpdA together with the high spatial overlap between the activation profile of nicotine and 5IA, suggest that the acute functional response to nicotine in drug-naïve rats is mediated by beta2-containing nAChR isoforms, presumably belonging to the alpha4beta2* subtype.

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Self-administration of 5-iodo-A-85380, a β2-selective nicotinic receptor ligand, by operantly trained rats

Cited by 25 publications

References 21 publications

Low Dose Nicotine and Antagonism of β2 Subunit Containing Nicotinic Acetylcholine Receptors Have Similar Effects on Affective Behavior in Mice

Low Dose Nicotine and Antagonism of β2 Subunit Containing Nicotinic Acetylcholine Receptors Have Similar Effects on Affective Behavior in Mice

Treating the Cognitive Deficits of Schizophrenia with Alpha4Beta2 Neuronal Nicotinic Receptor Agonists

Region-Specific Effects of Nicotine on Brain Activity: A Pharmacological MRI Study in the Drug-Naïve Rat

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