Gestational nicotine exposure reduces nicotinic cholinergic receptor (nAChR) expression in dopaminergic brain regions of adolescent rats

Department of Pharmacology, University of Tennessee Health Science Center, Suite 115 Crowe Building, 874 Union Avenue, Memphis, TN 38163, USA.
European Journal of Neuroscience (Impact Factor: 3.18). 07/2005; 22(2):380-8. DOI: 10.1111/j.1460-9568.2005.04229.x
Source: PubMed

ABSTRACT Children of women who smoked during pregnancy are at increased risk of dependence when smoking is initiated during adolescence. We previously reported that gestational nicotine exposure attenuated dopamine release induced by nicotine delivered during adolescence. In this study, we determined the effects of gestational nicotine exposure on nicotinic cholinergic receptor (nAChR) expression. Timed pregnant rats received nicotine (2 mg/kg/day) or vehicle via mini-osmotic pumps during gestation. Treatments continued in pups via maternal nursing during postnatal days (PN) 2-14 (equivalent to the human in utero third trimester). On PN35, 125I-epibatidine binding to nAChR was measured. The Bmax values (fmol/mg) in prefrontal cortex (PFC), nucleus accumbens (NAcc), substantia nigra (SN) and ventral tegmental area (VTA) were reduced by 26.6% (P<0.05), 32.6% (P<0.01), 23.0% (P<0.01) and 27.6% (P<0.05), respectively. In addition, gender differences were found in vehicle-treated groups; in SN and VTA, females were 79.3% (P<0.005) and 82.9% (P=0.08) of males, respectively. The expression of nAChR subunit mRNAs was measured using real-time RT-PCR on laser-capture microdissected tissues. In adolescent VTA, gestational nicotine exposure reduced (P<0.05) nAChR subunit mRNAs encoding alpha3 (53.0%), alpha4 (23.9%), alpha5 (46.7%) and beta4 (61.4%). In NAcc core, the treatment increased alpha3 mRNA (75.8%). In addition, the number of neurons in VTA was reduced by 15.0% (P<0.001). These studies indicate that gestational exposure to nicotine induces long-lasting changes in nAChR expression that may underlie the vulnerability of adolescents to dependence on nicotine.

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    • "One half of the pups in each litter were given 2 mg/kg/dose nicotine (nicotine base) mixed in milk formula for a total of 6 mg/kg/day (nicotine group); the other pups were given milk formula only (controls ). This daily dose has been used by others (Levin et al., 2006; Parameshwaran et al., 2013; Pilarski and Fregosi, 2009; Slotkin et al., 2007; Vaglenova et al., 2008) and results in blood nicotine levels comparable to those found in heavy smokers (Chen et al., 2005; Murrin et al., 1987). The intermittent application of nicotine mimics the highs and lows experienced by smokers during the day (Gritz et al., 1981) and allows desensitized nAChRs to revert back to an active state (Marks et al., 1993). "
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    ABSTRACT: Developmental exposure to nicotine has been linked to long-lasting changes in synaptic transmission which may contribute to behavioral abnormalities seen in offspring of women who smoke during pregnancy. Here, we examined the long-lasting effects of developmental nicotine exposure on glutamatergic and GABAergic neurotransmission, and on acute nicotine-induced glutamate and GABA release in the adult hippocampus, a structure important in cognitive and emotional behaviors. We utilized a chronic neonatal nicotine treatment model to administer nicotine (6 mg/kg/day) to rat pups from postnatal day (P) 1-7, a period that falls developmentally into the third human trimester. Using whole-cell voltage clamp recordings from CA1 pyramidal neurons in hippocampal slices, we measured excitatory and inhibitory postsynaptic currents in neonatally control- and nicotine-treated young adult males. Neonatal nicotine exposure significantly increased AMPA receptor-mediated spontaneous and evoked excitatory signaling, with no change in glutamate release probability in adults. Conversely, there was no increase in spontaneous GABAergic neurotransmission in nicotine-males. Chronic neonatal nicotine treatment had no effect on acute nicotine-stimulated glutamate release in adults, but acute nicotine-stimulated GABA release was significantly attenuated. Thus, neonatal nicotine exposure results in a persistent net increase in excitation and a concurrent loss of nicotinic acetylcholine receptor (nAChR)-mediated regulation of presynaptic GABA but not glutamate release, which would exacerbate excitation following endogenous or exogenous nAChR activation. Our data underscore an important role for nAChRs in hippocampal excitatory synapse development, and suggest selective long-term changes at specific presynaptic nAChRs which together could explain some of the behavioral abnormalities associated with maternal smoking.
    Neuropharmacology 06/2014; 88. DOI:10.1016/j.neuropharm.2014.06.010 · 5.11 Impact Factor
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    • "Sprague-Dawley rat ♂/♀ PND35 nAchR subunit a3, a4, a5, b4 in ↓ VTA nAchR subunit a3 in ↑ NAc (Chen et al., 2005) Nicotine 100 mg/l oral GD7- PND28 "
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    ABSTRACT: Prenatal development is highly sensitive to maternal drug use due to the vulnerability for disruption of the fetal brain with its ongoing neurodevelopment, resulting in lifelong consequences that can enhance risk for psychiatric disorders. Cannabis and cigarettes are the most commonly used illicit and licit substances, respectively, among pregnant women. Although the behavioral consequences of prenatal cannabis and cigarette exposure have been well-documented in epidemiological and clinical studies, only recently have investigations into the molecular mechanisms associated with the developmental impact of early drug exposure been addressed. This article reviews the literature relevant to long-term gene expression disturbances in the human fetal brain in relation to maternal cannabis and cigarette use. To provide translational insights, we discuss animal models in which protracted molecular consequences of prenatal cannabis and cigarette exposure can be better explored and which enable future evaluation of epigenetic pathways, such as DNA methylation and histone modification, that could potentially maintain abnormal gene regulation and related behavioral disturbances. Altogether, this information may help to address the current gaps of knowledge regarding the impact of early drug exposure that set in motion lifelong molecular disturbances that underlie vulnerability to psychiatric disorders.
    European Journal of Neuroscience 11/2011; 34(10):1574-83. DOI:10.1111/j.1460-9568.2011.07884.x · 3.18 Impact Factor
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    • "This window of development coincides with the brain growth spurt, a time of rapid increase in brain weight, synaptogenesis, axonal growth and dendritic branching [8]. This is a period of vulnerability, especially for cortical regions, during which time the effects of nicotine and other teratogens can be profound [5] [11]. Exposure to nicotine during the early postnatal period has been shown to increase nicotinic receptor affinity in adulthood following exposure from P8–P16 [23], and induce permanent changes in the number of low-affinity nAChR binding sites in the adulthood following nicotine exposure from P10–P16 [10] [26]. "
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    ABSTRACT: Animal models of prenatal nicotine exposure clearly indicate that nicotine is a neuroteratogen. Some of the persisting effects of prenatal nicotine exposure include low birth weight, behavioral changes and deficits in cognitive function, although few studies have looked for neurobehavioral and neurochemical effects that might persist throughout the lifespan. Pregnant rats were given continuous infusions of nicotine (0.96mg/kg/day or 2.0mg/kg/day, freebase) continuing through the third trimester equivalent, a period of rapid brain development. Because the third trimester equivalent occurs postnatally in the rat (roughly the first week of life) nicotine administration to neonate pups continued via maternal milk until postnatal day (P) 10. Exposure to nicotine during pre- and early postnatal development had an anxiogenic effect on adult rats (P75) in the elevated plus maze (EPM), and blocked extinction learning in a fear conditioning paradigm, suggesting that pre- and postnatal nicotine exposure affect anxiety-like behavior and cognitive function well into adulthood. In contrast, nicotine exposure had no effect on anxiety-like behaviors in the EPM in adolescent animals (P30). Analysis of mRNA for the alpha4, alpha7, and beta2 subunits of nicotinic acetylcholine receptors revealed lower expression of these subunits in the adult hippocampus and medial prefrontal cortex following pre- and postnatal nicotine exposure, suggesting that nicotine altered the developmental trajectory of the brain. These long-term behavioral and neurochemical changes strengthen the case for discouraging cigarette smoking during pregnancy and clearly indicate that the use of the patch as a smoking cessation aid during pregnancy is not a safe alternative.
    Neurotoxicology and Teratology 05/2010; 32(3):336-45. DOI:10.1016/ · 2.76 Impact Factor
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