Selective down-regulation of [125I]Y0-α- conotoxin MII binding in rat mesostriatal dopamine pathway following continuous infusion of nicotine

Biology Department, Psychiatry-CEDD, GlaxoSmithKline S.p.A., Medicines Research Centre, Via Fleming 4, 37135 Verona, Italy.
Neuroscience (Impact Factor: 3.36). 02/2006; 137(2):565-72. DOI: 10.1016/j.neuroscience.2005.09.008
Source: PubMed


Prolonged exposure to nicotine, as occurs in smokers, results in up-regulation of all the neuronal nicotinic acetylcholine receptor subtypes studied so far, the only differences residing in the extent and time course of the up-regulation. alpha6beta2*-Nicotinic acetylcholine receptors are selectively enriched in the mesostriatal dopaminergic system and may play a crucial role in nicotine dependence. Here we show that chronic nicotine treatment (3mg/kg/day for two weeks, via s.c. osmotic minipumps) caused a significant decrease (36% on average) in the binding of [(125)I]Y(0)-alpha-conotoxin MII (a selective ligand for alpha6beta2*-nicotinic acetylcholine receptors in this system) to all the five regions of the rat dopaminergic pathway analyzed in this study. After one week of withdrawal, binding was still lower than control in striatal terminal regions (namely the caudate putamen and the accumbens shell and core). In somatodendritic regions (the ventral tegmental area and the substantia nigra) the decrease was significant at the end of the treatment and recovered within one day of withdrawal. This effect was not due to displacement of [(125)I]Y(0)-alpha-conotoxin MII binding by residual nicotine. In fact the binding was not changed by 565 ng/g nicotine (obtained with a single injection of nicotine), a concentration much higher than that found in the brain of rats chronically treated with nicotine (240 ng/g). In addition, consistent with previous studies reporting an up-regulation of other subtypes of nicotinic acetylcholine receptors, we found that nicotine exposure significantly increased (40% on average) the binding of [(125)I]epibatidine (a non-selective agonist at most neuronal heteromeric nicotinic acetylcholine receptors) in three up to five regions containing only alpha-conotoxin MII-insensitive [(125)I]epibatidine binding sites, namely the primary motor, somatosensory and auditory cortices. In conclusion, this work is the first to demonstrate that alpha6beta2*-nicotinic acetylcholine receptors, unique within the nicotinic acetylcholine receptor family, are down-regulated following chronic nicotine treatment in rat dopaminergic mesostriatal pathway, a finding that may shed new light in the complex mechanisms of nicotine dependence.

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    • "However, autoradiography studies show very high levels of [ 3 H]-nicotine binding in the motor cortex of humans (Sihver et al., 1998). In addition, high levels of [ 125 I]-epibatidine (which binds to a wide range of nAChRs, except the α7 subtype) binding have been shown in the motor cortex of rats (Mugnaini et al., 2006). There is also extensive evidence that nicotine improves performance on motor tasks (West and Jarvis, 1986; Tucha and Lange, 2004). "
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    ABSTRACT: Acute nicotine administration potentiates brain reward function and enhances motor and cognitive function. These studies investigated which brain areas are being activated by a wide range of doses of nicotine, and if this is diminished by pretreatment with the nonselective nicotinic receptor antagonist mecamylamine. Drug-induced changes in brain activity were assessed by measuring changes in the blood oxygen level dependent (BOLD) signal using an 11.1-Tesla magnetic resonance scanner. In the first experiment, nicotine naïve rats were mildly anesthetized and the effect of nicotine (0.03-0.6mg/kg) on the BOLD signal was investigated for 10min. In the second experiment, the effect of mecamylamine on nicotine-induced brain activity was investigated. A high dose of nicotine increased the BOLD signal in brain areas implicated in reward signaling, such as the nucleus accumbens shell and the prelimbic area. Nicotine also induced a dose-dependent increase in the BOLD signal in the striato-thalamo-orbitofrontal circuit, which plays a role in compulsive drug intake, and in the insular cortex, which contributes to nicotine craving and relapse. In addition, nicotine induced a large increase in the BOLD signal in motor and somatosensory cortices. Mecamylamine alone did not affect the BOLD signal in most brain areas, but induced a negative BOLD response in cortical areas, including insular, motor, and somatosensory cortices. Pretreatment with mecamylamine completely blocked the nicotine-induced increase in the BOLD signal. These studies demonstrate that acute nicotine administration activates brain areas that play a role in reward signaling, compulsive behavior, and motor and cognitive function. © The Author 2014. Published by Oxford University Press on behalf of CINP.
    Full-text · Article · Oct 2014 · The International Journal of Neuropsychopharmacology
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    • "For example, chronic nicotine has been associated with a functional upregulation of ␣4␤2*-containing nAChRs in the striatum (Buisson and Bertrand 2001; Govind et al. 2009, 2012; Mugnaini et al. 2002; Nguyen et al. 2003; Perez et al. 2009; Vallejo et al. 2005; Xiao et al. 2009). However, recent studies have shown that chronic nicotine either downregulates or does not alter ␣6␤2*nAChR expression (Even et al. 2008; McCallum et al. 2006a, 2006b; Mugnaini et al. 2006; Nguyen et al. 2003; Perez et al. 2008; Perry et al. 2007; Walsh et al. "
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    ABSTRACT: Nicotinic acetylcholine receptors (nAChRs) are expressed presynaptically on dopamine axon terminals, and their activation by endogenous acetylcholine from striatal cholinergic interneurons enhances dopamine release both independently of and in concert with DA neuron activity. Acute nAChR inactivation is believed to enhance the contrast between low and high frequency dopamine cell activity. While these studies reveal a key role for acute activation and inactivation of nAChRs in striatal microcircuitry, it remains unknown if chronic inactivation/desensitization of nAChRs can alter DA release dynamics. Using in vivo cyclic voltammetry in anaesthetized mice, we examined whether chronic inactivation of nAChRs modulates dopamine release across a parametric range of stimulation, varying both frequency and pulse number. Deletion of β2*-nAChRs and chronic nicotine exposure greatly diminished DA release across the entire range of stimulation parameters. In addition, we observed a facilitation of dopamine release at low frequency and pulse number in wild-type mice that is absent in the β2*KO and chronic nicotine mice. These data suggest that deletion or chronic desensitization of nAChRs reduces the dynamic range of dopamine release in response to dopamine cell activity, decreasing rather than increasing contrast between high and low dopamine activity.
    Full-text · Article · Oct 2013 · Journal of Neurophysiology
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    • "However, the outcome of chronic nicotine on ongoing striatal DA signaling and the subsequent effects of nicotine are incompletely resolved. An array of b2-containing (*) nAChRs regulate DA transmission, and while striatal a4b2* nAChRs are reported to be upregulated (Nguyen et al., 2003), the evidence for striatal a6b2* receptors is conflicting, suggesting upregulation (Nguyen et al., 2003; Parker et al., 2004; Visanji et al., 2006) and downregulation (Lai et al., 2005; Mugnaini et al., 2006; Perez et al., 2008, 2009). Moreover, the effect on nAChR function cannot readily be inferred from receptor numbers; despite expression of a4 and a6 subunits in different groups of DA neurons, there is a different functional dominance of the various heteromeric receptors they form in nucleus accumbens (NAc) compared with caudate-putamen (CPu) (Exley et al., 2008, 2011, 2012). "
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    ABSTRACT: Nicotine directly regulates striatal dopamine (DA) neurotransmission via presynaptic nicotinic acetylcholine receptors (nAChRs) that are α6β2 and/or α4β2 subunit-containing, depending on region. Chronic nicotine exposure in smokers upregulates striatal nAChR density, with some reports suggesting differential impact on α6- or α4-containing nAChRs. Here, we explored whether chronic nicotine exposure modifies striatal DA transmission, whether the effects of acute nicotine on DA release probability persist and whether there are modifications to the regulation of DA release by α6-subunit-containing (*) relative to non-α6* nAChRs in nucleus accumbens (NAc) and in caudate-putamen (CPu). We detected electrically evoked DA release at carbon-fiber microelectrodes in striatal slices from mice exposed for 4-8 weeks to nicotine (200 μg/mL in saccharin-sweetened drinking water) or a control saccharin solution. Chronic nicotine exposure subtly reduced striatal DA release evoked by single electrical pulses, and in NAc enhanced the range of DA release evoked by different frequencies. Effects of acute nicotine (500 nm) on DA release probability and its sensitivity to activity were apparent. However, in NAc there was downregulation of the functional dominance of α6-nAChRs (α6α4β2β3), and an emergence in function of non-α6* nAChRs. In CPu, there was no change in the control of DA release by its α6 nAChRs (α6β2β3) relative to non-α6. These data suggest that chronic nicotine subtly modifies the regulation of DA transmission, which, in NAc, is through downregulation of function of a susceptible population of α6α4β2β3 nAChRs. This imbalance in function of α6:non-α6 nAChRs might contribute to DA dysregulation in nicotine addiction.
    Full-text · Article · Jul 2013 · European Journal of Neuroscience
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