Upregulation of nicotinic receptors following continuous infusion of nicotine is brain-region-specific

doi:10.1016/0006-8993(93)91104-Z

Brain Research

Volume 617, Issue 2, 23 July 1993, Pages 349-352

https://doi.org/10.1016/0006-8993(93)91104-Z Get rights and content

Abstract

Rats receiving 4 mg nicotine/kg/day via implanted minipumps sustained plasma nicotine concentrations of 40 ng/ml throughout two weeks of nicotineinfusion. Numbers of brain [³H]nicotine binding sites were increased by about 50% in cortex and hippocampus whereas numbers of [³H]nicotine binding sites in striatum were unaffected by nicotine treatment at either of the timepoints examined (7, 14 days). Cortical [¹²⁵I]α-bungarotoxin and [³H]QNB binding sites were also unchanged. The regional selectivity of nicotinic receptor modulation may reflect the low dose of nicotine used and the mode of administration. The changes observed may be pertinent to the continuous administration of nicotine in man, via transdermal nicotine patches.

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Cited by (110)

Serine residues in the α4 nicotinic acetylcholine receptor subunit regulate surface α4β2* receptor expression and clustering
2019, Biochemical Pharmacology
Chronic nicotine exposure upregulates α4β2^* nicotinic acetylcholine receptors (nAChRs) in the brain. The goal of this study was to examine the role of three serine residues in the large cytoplasmic loop of the α4 subunit on α4β2^* upregulation in neurons.
Serine residues S336, S470 and S530 in mouse α4 were mutated to alanine and then re-expressed in primary neurons from cortex, hippocampus and subcortex of α4 KO mice. Mutant and wild type α4 expressing neurons were treated with nicotine (0.1, 1 and 10 μM) and assessed for α4β2^* upregulation.
α4β2^* nAChRs expressing S336A or S470A mutants were deficient at cell surface upregulation in both subcortex and hippocampal neurons. S530A α4β2^* mutants exhibited aberrant surface upregulation in subcortical neurons. None of the mutants affected surface upregulation in cortical neurons or upregulation of total α4β2^* binding sites in any region. Further, dense domains or clusters of α4β2^* nAChRs were observed in the neuronal surface. The impact of nicotine exposure on the intensity, area, and density of these clusters was dependent upon individual mutations.
Effects of α4 nAChR mutants on surface upregulation varied among brain regions, suggesting that the cellular mechanism of α4β2^* upregulation is complex and involves cellular identity. We also report for the first time that α4β2^* nAChRs form clusters on the neuronal surface and that nicotine treatment alters the characteristics of the clusters in an α4 mutant-dependent manner. This finding adds a previously unknown layer of complexity to the effects of nicotine on α4β2^* expression and function.
Differential effects of withdrawal from intermittent and continuous nicotine exposure on reward deficit and somatic aspects of nicotine withdrawal and expression of α4β2* nAChRs in Wistar male rats
2018, Pharmacology Biochemistry and Behavior
Citation Excerpt :
Chronic cigarette smoking in humans leads to nAChR upregulation of high affinity α4β2* nicotine binding sites in the brain (Benwell et al., 1988; Breese et al., 1997; Cosgrove et al., 2009; Gentry and Lukas, 2002; Perry et al., 1999; Staley et al., 2006). Studies in rodents showed an upregulation of high affinity nicotine binding sites after chronic non-contingent nicotine exposure via external or internal osmotic minipumps, repeated nicotine injections or intravenous infusions (Collins et al., 1990; Fasoli et al., 2016; Marks et al., 1983; Rowell and Li, 1997; Sanderson et al., 1993; Schwartz and Kellar, 1983; Ulrich et al., 1997). Similarly, exposure to chronic contingent nicotine administration also results in increased nAChR expression in rodents (Donny et al., 2000; Metaxas et al., 2010; Parker et al., 2004).
Chronic nicotine exposure produces neuroadaptations in brain reward systems and α4β2 nicotinic acetylcholine receptors (nAChRs) in the corticolimbic brain areas. We previously demonstrated opposite effects of nicotine exposure delivered by self-administration or pumps on brain reward thresholds that can be attributed to the different temporal pattern and contingency of nicotine exposure. We investigated the effects of these two factors on reward thresholds and somatic signs during nicotine withdrawal, and on nAChRs binding in corticolimbic brain areas.
The intracranial self-stimulation procedure was used to assess reward thresholds in rats prepared with pumps delivering various doses of nicotine continuously or intermittently. Separate group of rats were randomly exposed to nicotine via pumps (non-contingent) or nicotine self-administration (contingent) to determine [¹²⁵I]-epibatidine binding at α4β2* nAChRs.
Withdrawal from continuous non-contingent nicotine exposure led to significant elevations in thresholds and increases in somatic signs in rats, while there was no significant effect of withdrawal from intermittent non-contingent nicotine exposure at the same doses. nAChRs were upregulated during withdrawal from continuous non-contingent nicotine exposure. α4β2* nAChRs were upregulated in the ventral tegmental area and prelimbic cortex during withdrawal from non-contingent intermittent exposure and in the nucleus accumbens during withdrawal from contingent intermittent nicotine exposure to the same dose.
During non-contingent nicotine exposure, the temporal pattern of nicotine delivery differentially affected thresholds and somatic signs of withdrawal. Upregulation of α4β2* nAChRs was brain site-specific and depended on both temporal pattern and contingency of nicotine exposure.
Baseline impulsive choice predicts the effects of nicotine and nicotine withdrawal on impulsivity in rats
2014, Progress in Neuro-Psychopharmacology and Biological Psychiatry
Citation Excerpt :
Therefore, exposure to the chamber previously associated with nicotine injections, but not nicotine withdrawal, may have elicited increased impulsive responding (Anderson and Diller, 2010; Dallery and Locey, 2005). Upregulation of high-affinity nicotinic acetylcholine receptors (nAChRs) is observed after chronic cigarette smoking in humans (Benwell et al., 1988; Breese et al., 1997; Perry et al., 1999) and after chronic nicotine exposure in experimental animals (Collins et al., 1990; Marks et al., 1983; Rowell and Li, 1997; Sanderson et al., 1993; Ulrich et al., 1997). Decreases in nAChR function also occur with chronic nicotine exposure (Dani and Heinemann, 1996; Gentry and Lukas, 2002; Gentry et al., 2003; Marks et al., 1993; Marks et al., 2004; Wonnacott, 1990; Zambrano et al., 2012), which may compensate for nAChR upregulation.
Impulsive choice, a form of impulsivity, is associated with tobacco smoking in humans. Trait impulsivity may be a vulnerability factor for smoking, or smoking may lead to impulsive behaviors. We investigated the effects of 14-day nicotine exposure (6.32 mg/kg/day base, subcutaneous minipumps) and spontaneous nicotine withdrawal on impulsive choice in low impulsive (LI) and high impulsive (HI) rats. Impulsive choice was measured in the delayed reward task in which rats choose between a small immediate reward and a large delayed reward. HI and LI rats were selected from the highest and lowest quartiles of the group before exposure to nicotine. In non-selected rats, nicotine or nicotine withdrawal had no effect on impulsive choice. In LI rats, chronic nicotine exposure decreased preference for the large reward with larger effects at longer delays, indicating increased impulsive choice. Impulsive choices for the smaller immediate rewards continued to increase during nicotine withdrawal in LI rats. In HI rats, nicotine exposure and nicotine withdrawal had no effect on impulsive choice, although there was a tendency for decreased preference for the large reward at short delays. These results indicate that nicotine- and nicotine withdrawal-induced increases in impulsive choice depend on trait impulsivity with more pronounced increases in impulsive choice in LI compared to HI subjects. Increased impulsivity during nicotine exposure may strengthen the addictive properties of nicotine and contribute to compulsive nicotine use.
Genetic deletion of the adenosine A<inf>2A</inf>receptor prevents nicotine-induced upregulation of α7, but not α4β2* nicotinic acetylcholine receptor binding in the brain
2013, Neuropharmacology
Considerable evidence indicates that adenosine A_2A receptors (A_2ARs) modulate cholinergic neurotransmission, nicotinic acetylcholine receptor (nAChR) function, and nicotine-induced behavioural effects. To explore the interaction between A_2A and nAChRs, we examined if the complete genetic deletion of adenosine A_2ARs in mice induces compensatory alterations in the binding of different nAChR subtypes, and whether the long-term effects of nicotine on nAChR regulation are altered in the absence of the A_2AR gene. Quantitative autoradiography was used to measure cytisine-sensitive [¹²⁵I]epibatidine and [¹²⁵I]α-bungarotoxin binding to α4β2* and α7 nAChRs, respectively, in brain sections of drug-naïve (n = 6) or nicotine treated (n = 5–7), wild-type and adenosine A_2AR knockout mice. Saline or nicotine (7.8 mg/kg/day; free-base weight) were administered to male CD1 mice via subcutaneous osmotic minipumps for a period of 14 days. Blood plasma levels of nicotine and cotinine were measured at the end of treatment. There were no compensatory developmental alterations in nAChR subtype distribution or density in drug-naïve A_2AR knockout mice. In nicotine treated wild-type mice, both α4β2* and α7 nAChR binding sites were increased compared with saline treated controls. The genetic ablation of adenosine A_2ARs prevented nicotine-induced upregulation of α7 nAChRs, without affecting α4β2* receptor upregulation. This selective effect was observed at plasma levels of nicotine that were within the range reported for smokers (10–50 ng ml⁻¹). Our data highlight the involvement of adenosine A_2ARs in the mechanisms of nicotine-induced α7 nAChR upregulation, and identify A_2ARs as novel pharmacological targets for modulating the long-term effects of nicotine on α7 receptors.
86Rb+ efflux mediated by α4β 2-nicotinic acetylcholine receptors with high and low-sensitivity to stimulation by acetylcholine display similar agonist-induced desensitization
2010, Biochemical Pharmacology
Citation Excerpt :
Chronic exposure to nicotine increases the numbers of α4β2*-nAChR in brain of rodents [17–19,40–43] humans [44–46] and cell lines [47–49]. The increases observed in cell lines are generally greater than those observed in brain, but the extent of the increase of α4β2*-nAChR binding sites also varies among brain areas [17,19,42,50–53]. It has been proposed that chronic receptor desensitization is an important factor underlying the nicotine-induced increases in receptor expression [6,19,54], perhaps by inducing a conformational change or receptor state that decreases the turnover of the receptors [47].
The nicotinic acetylcholine receptors (nAChR) assembled from α4 and β2 subunits are the most densely expressed subtype in the brain. Concentration–effect curves for agonist activation of α4β2*-nAChR are biphasic. This biphasic agonist sensitivity is ascribed to differences in subunit stoichiometry. The studies described here evaluated desensitization elicited by low concentrations of epibatidine, nicotine, cytisine or methylcarbachol of brain α4β2-nAChR function measured with acetylcholine-stimulated ⁸⁶Rb⁺ efflux from mouse thalamic synaptosomes. Each agonist elicited concentration-dependent desensitization. The agonists differed in potency. However, IC₅₀ values for each agonist for desensitization of ⁸⁶Rb⁺ efflux both with high (EC₅₀ ≈ 3 μM) and low (EC₅₀ ≈ 150 μM) acetylcholine sensitivity were not significantly different. Concentrations required to elicit desensitization were higher that their respective K_D values for receptor binding. Even though the two components of α4β2*-nAChR-mediated ⁸⁶Rb⁺ efflux from mouse brain differ markedly in EC₅₀ values for agonist activation, they are equally sensitive to desensitization by exposure to low agonist concentrations. Mice were also chronically treated with nicotine by continuous infusion of 0, 0.5 or 4.0 mg/kg/h and desensitization induced by nicotine was evaluated. Consistent with previous results, chronic nicotine treatment increased the density of epibatidine binding sites. Acute exposure to nicotine also elicited concentration-dependent desensitization of both high-sensitivity and low-sensitivity acetylcholine-stimulated ⁸⁶Rb⁺ efflux from cortical and thalamic synaptosomes. Although chronic nicotine treatment reduced maximal ⁸⁶Rb⁺ efflux from thalamus, IC₅₀ values in both brain regions were unaffected by chronic nicotine treatment.
Nicotine-induced upregulation of nicotinic receptors: Underlying mechanisms and relevance to nicotine addiction
2009, Biochemical Pharmacology
A major hurdle in defining the molecular biology of nicotine addiction has been characterizing the different nicotinic acetylcholine receptor (nAChR) subtypes in the brain and how nicotine alters their function. Mounting evidence suggests that the addictive effects of nicotine, like other drugs of abuse, occur through interactions with its receptors in the mesolimbic dopamine system, particularly ventral tegmental area (VTA) neurons, where nicotinic receptors act to modulate the release of dopamine. The molecular identity of the nicotinic receptors responsible for drug seeking behavior, their cellular and subcellular location and the mechanisms by which these receptors initiate and maintain addiction are poorly defined. In this commentary, we review how nicotinic acetylcholine receptors (nAChRs) are upregulated by nicotine exposure, the potential posttranslational events that appear to cause it and how upregulation is linked to nicotine addiction.

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: This study was supported by grants from the MRC and Wellcome Trust. E.M.S. and A.L.D. were supported by postgraduate training awards from the SERC.

¹: Present address: The Biological Laboratory, University of Kent, Cantbury, UK.

²: Present address: Department of Physiology and Pharmacology, Queen's Medical Centre, Nottingham, NG7 2UH, UK.

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Abstract

Reference (21)

A rapid and sensitive method for the quantitation of microgram quantities of protein utilising the principle of protein-dye binding

Anal. Biochem.

Dissociation of the apparent relationship between nicotine tolerance and up-regulation of nicotinic receptors

Brain Res. Bull.

Receptor mechanisms of nicotibe-induced locomotor hyperactivity in chronic nicotine-treated rats

Eur. J. Pharmacol.

Alteration of nicotinic cholinergic agonist binding sites in hippocampus after fimbria transection

Brain Res.

Nicotine administration to rats: methodological considerations

Life Sci.

The paradox of nicotinic acetylcholine receptor upregulation by nicotine

Trends. Pharmacol. Sci.

Stable isotope method for studying transdermal drug absorption: the nicotine patch

Clin. Pharmacol. Ther.

Evidence that tobacco smoking increases the density of (-)-[³H]nicotine binding sites in human brain

J. Neurochem.

A high-performance liquid-chromatographic method for routine simultaneous determination of nicotine and cotinine in plasma

Clin. Chem.

Effect of chronic nicotine treatment on nicotinic autoreceptor function andN-[³H]methylcarbamylcholine binding sites in the rat brain

J. Neurochem.

Cited by (110)

Serine residues in the α4 nicotinic acetylcholine receptor subunit regulate surface α4β2<sup>*</sup> receptor expression and clustering

Differential effects of withdrawal from intermittent and continuous nicotine exposure on reward deficit and somatic aspects of nicotine withdrawal and expression of α4β2* nAChRs in Wistar male rats

Baseline impulsive choice predicts the effects of nicotine and nicotine withdrawal on impulsivity in rats

Genetic deletion of the adenosine A<inf>2A</inf>receptor prevents nicotine-induced upregulation of α7, but not α4β2* nicotinic acetylcholine receptor binding in the brain

<sup>86</sup>Rb<sup>+</sup> efflux mediated by α4β 2-nicotinic acetylcholine receptors with high and low-sensitivity to stimulation by acetylcholine display similar agonist-induced desensitization

Nicotine-induced upregulation of nicotinic receptors: Underlying mechanisms and relevance to nicotine addiction

Upregulation of nicotinic receptors following continuous infusion of nicotine is brain-region-specific

Abstract

Anal. Biochem.

Brain Res. Bull.

Eur. J. Pharmacol.

Brain Res.

Life Sci.

Trends. Pharmacol. Sci.

Stable isotope method for studying transdermal drug absorption: the nicotine patch

Clin. Pharmacol. Ther.

Evidence that tobacco smoking increases the density of (-)-[3H]nicotine binding sites in human brain

J. Neurochem.

A high-performance liquid-chromatographic method for routine simultaneous determination of nicotine and cotinine in plasma

Clin. Chem.

Effect of chronic nicotine treatment on nicotinic autoreceptor function andN-[3H]methylcarbamylcholine binding sites in the rat brain

J. Neurochem.

Evidence that tobacco smoking increases the density of (-)-[³H]nicotine binding sites in human brain

Effect of chronic nicotine treatment on nicotinic autoreceptor function andN-[³H]methylcarbamylcholine binding sites in the rat brain