Does prenatal nicotine exposure alter the brain's response to nicotine in adolescence? A neuroanatomical analysis (original) (raw)
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Brain Research, 2013
Prenatal exposure to nicotine has been associated with many long-term cognitive and behavioral abnormalities. Based upon these observable outcomes, we hypothesized that prenatal nicotine exposure would induce lasting changes in dendritic morphology and synaptic connectivity throughout the cortex. Pregnant Long-Evans rats were administered nicotine or saline for the duration of pregnancy and offspring were sacrificed at P100 for Golgi-Cox analysis (dendritic length, dendritic branching, and spine density) of the prefrontal cortex (AID and Cg3), parietal cortex, and nucleus accumbens. In male offspring dendritic branching increased in AID and NAc, but decreased in the apical field of Cg3; spine density increased everywhere except NAc where it decreased; and dendritic length was increased in Cg3 basilar and NAc but reduced in PAR basilar . In female offspring, dendritic branching increased in NAc but decreased in AID; spine density increased in AID and PAR but decreased in Cg3 and NAc, and dendritic length was reduced in Cg3, PAR, and NAc. As changes were identified at P100, prenatal exposure to nicotine dramatically reorganized neuroanatomy in a persistent manner, likely altering the brain's response to normal and abnormal experiences. (R. Mychasiuk). b r a i n r e s e a r c h 1 4 9 9 ( 2 0 1 3 ) 5 3 -6 0
Neuropsychopharmacology, 2006
Nicotine is a neuroteratogen that disrupts neurodevelopment and synaptic function, with vulnerability extending into adolescence. We assessed the permanence of effects in rats on indices of neural cell number and size, and on acetylcholine and serotonin (5HT) systems, conducting assessments at 6 months of age, after prenatal nicotine exposure, adolescent exposure, or sequential exposure in both periods. For prenatal nicotine, indices of cell number and size showed few abnormalities by 6 months, but there were persistent deficits in cerebrocortical choline acetyltransferase activity and hemicholinium-3 binding to the presynaptic choline transporter, a pattern consistent with cholinergic hypoactivity; these effects were more prominent in males than females. The expression of 5HT receptors also showed permanent effects in males, with suppression of the 5HT 1A subtype and upregulation of 5HT 2 receptors. In addition, cell signaling through adenylyl cyclase showed heterologous uncoupling of neurotransmitter responses. Nicotine exposure in adolescence produced lasting effects that were similar to those of prenatal nicotine. However, when animals were exposed to prenatal nicotine and received nicotine subsequently in adolescence, the adverse effects then extended to females, whereas the net effect in males was similar to that of prenatal nicotine by itself. Our results indicate that prenatal or adolescent nicotine exposure evoke permanent changes in synaptic function that transcend the recovery of less-sensitive indices of structural damage; further, prenatal exposure sensitizes females to the subsequent adverse effects of adolescent nicotine, thus creating a population that may be especially vulnerable to the lasting behavioral consequences of nicotine intake in adolescence.
Neuroscience, 2013
Experience-dependent plasticity is an ongoing process that can be observed and measured at multiple levels. The first goal of this study was to examine the effects of prenatal nicotine on the performance of rats in three behavioral tasks (elevated plus maze (EPM), Morris water task (MWT), and Whishaw tray reaching). The second goal of this experiment sought to examine changes in dendritic organization following exposure to the behavioral training paradigm and/or low doses of prenatal nicotine. Female Long-Evans rats were administered daily injections of nicotine for the duration of pregnancy and their pups underwent a regimen of behavioral training in early adulthood (EPM, MWT, and Whishaw tray reaching). All offspring exposed to nicotine prenatally exhibited substantial increases in anxiety. Male offspring also showed increased efficiency in the Whishaw tray-reaching task and performed differently than the other groups in the probe trial of the MWT. Using Golgi-Cox staining we examined the dendritic organization of the medial and orbital prefrontal cortex as well as the nucleus accumbens. Participation in the behavioral training paradigm was associated with dramatic reorganization of dendritic morphology and spine density in all brain regions examined. Although both treatments (behavior training and prenatal nicotine exposure) markedly altered dendritic organization, the effects of the behavioral experience were much larger than those of the prenatal drug exposure, and in some cases interacted with the drug effects.
Synapse (New York, N.Y.), 2014
Exposure to both drugs of abuse and environmental enrichment (EE) are widely studied experiences that induce large changes in dendritic morphology and synaptic connectivity. As there is an abundance of literature using EE as a treatment strategy for drug addiction, we sought to determine whether EE could remediate the effects of prenatal nicotine (PN) exposure. Using Golgi-Cox staining, we examined eighteen neuroanatomical parameters in four brain regions [medial prefrontal cortex (mPFC), orbital frontal cortex (OFC), nucleus accumben, and Par1] of Long-Evans rats. EE in adolescence dramatically altered structural plasticity in the male and female brain, modifying 60% of parameters investigated. EE normalized three parameters (OFC spine density and dendritic branching and mPFC dendritic branching) in male offspring exposed to nicotine prenatally but did not remediate any measures in female offspring. PN exposure interfered with adolescent EE-induced changes in five neuroanatomical m...
Neuropsychopharmacology, 2004
Offspring of women who smoke during pregnancy are themselves more likely to take up smoking in adolescence. We evaluated neurotoxicant effects of prenatal and adolescent nicotine exposure in developing rats to evaluate whether these contribute to a biological basis for this relationship. Rats were given nicotine or vehicle throughout pregnancy and the offspring then again received nicotine or vehicle during adolescence (postnatal days PN30-47.5); this regimen reproduces the plasma nicotine levels found in smokers. Indices of neural cell number (DNA concentration and content), cell size (protein/DNA ratio), and cell membrane surface area (membrane/total protein) were then evaluated in brain regions during adolescent nicotine administration (PN45) and up to 1 month post-treatment. By itself, prenatal nicotine administration produced cellular alterations that persisted into adolescence, characterized by net cell losses in the midbrain and to a lesser extent, in the cerebral cortex, with corresponding elevations in the membrane/total protein ratio. The hippocampus showed a unique response, with increased DNA content and regional enlargement. Adolescent nicotine treatment alone had similar, albeit smaller effects, but also showed sex-dependence, with effects on protein biomarkers preferential to females. When animals exposed to nicotine prenatally were then given nicotine in adolescence, the net outcome was worsened, largely representing summation of the two individual effects. Our results indicate that prenatal nicotine exposure alters parameters of cell development lasting into adolescence, where the effects add to those elicited directly by adolescent nicotine; neurotoxicant actions may thus contribute to the association between maternal smoking and subsequent smoking in the offspring.
Synapse, 2010
This study investigated the dendritic morphology of neurons located in the right and left basolateral amygdala (BLA) and infralimbic (IL) cortex following chronic nicotine exposure during adolescence or adulthood. Sprague-Dawley rats were administered subcutaneous injections of nicotine (0.5 mg/kg; free base) or saline three times per week for 2 weeks (six total injections). The dose period began on either postnatal day (P) 32 (adolescent) or P61 (adult). Twenty days following the end of dosing, brains were processed for Golgi-Cox staining, and dendrites from principal neurons in the BLA and pyramidal neurons in the IL were digitally reconstructed in three dimensions. Morphometric analysis revealed a contrasting pattern of BLA dendritic morphology between the adolescent and adult pretreatment groups. In the adult control group, basilar dendritic length did not differ with respect to hemisphere. Nicotine induced robust hemispheric asymmetry by increasing dendritic length in the right hemisphere only. In contrast, adolescent nicotine exposure did not produce significant alteration of basilar dendritic morphology. There was, however, an indication that nicotine eliminated a naturally existing hemispheric asymmetry in the younger cohort. At both ages, nicotine produced a reduction in complexity of the apical tree of principal neurons. Chronic nicotine did not affect the dendritic morphology of pyramidal neurons from the IL in either age group, indicating another dimension of anatomical specificity. Collectively, these data implicate the BLA as a target for lasting neuroplasticity associated with chronic nicotine exposure. Further, hemispheric differences in dendritic morphology were uncovered that depended on the age of nicotine exposure, a finding that underscores the importance of considering laterality when investigating neurodevelopmental effects of drug exposure. Synapse 64:754-764, in Wiley InterScience (www.interscience.
Neurohistochemical studies of adolescent rats' prefrontal cortex exposed to prenatal nicotine
Ibnosina Journal of Medicine and Biomedical Sciences, 2014
Background: Exposure to tobacco has frequently been associated with adverse implications on many body organs and systems. Maternal smoking can influence fetal development, causing intrauterine growth restriction, preterm birth, or even fetal death and spontaneous abortion. Objectives: We investigated the effects of prenatal exposure to nicotine on the prefrontal cortex in adolescent rats. Materials and Methods: Twenty-four mature female Wistar rats were time mated and grouped according to Trimester into Control and Treated groups. Nicotine was administered intra-peritoneally to pregnant Wistar rats in the treated groups, while normal saline was given to the control groups, at each of the three Trimesters. The animals were allowed to litter and the pups were allowed to grow till postnatal day 35, when they were sacrificed and the brain removed and weighed. The prefrontal cortex was excised and either fixed in 4% paraformaldehyde for tissue histology or homogenized in sucrose solution...
Adolescent nicotine induces persisting changes in development of neural connectivity
Neuroscience and biobehavioral reviews, 2015
Smith, R.F., McDonald, C.G., Bergstrom, H.C., Ehlinger, D.G., and Brielmaier, J. M. Adolescent nicotine induces persisting changes in development of neural connectivity. NEUROSCI BIOBEHAV REV. A large number of brain changes occur during adolescence as the CNS matures. These changes suggest that the adolescent brain may still be susceptible to developmental alterations by substances which impact its growth. Here we review recent studies on adolescent nicotine which show that the adolescent brain is differentially sensitive to nicotine-induced alterations in dendritic elaboration, in several brain areas associated with processing reinforcement and emotion, specifically including nucleus accumbens, medial prefrontal cortex, basolateral amygdala, bed nucleus of the stria terminalis, and dentate gyrus. Both sensitivity to nicotine, and specific areas responding to nicotine, differ between adolescent and adult rats, and dendritic changes in response to adolescent nicotine persist into ad...
2010
Tobacco smoke exposure during development can result in lasting alterations in sensory processing and attention. This suggests that some constituent of smoke, such as the primary addictive component, nicotine, alters neurodevelopment. Although many effects of developmental nicotine exposure have been identified in humans and animal models, very few mechanistic studies have identified the molecular and anatomical basis for a defined behavioral consequence of developmental exposure. We show in this study that a mouse model of developmental nicotine exposure results in hypersensitive passive avoidance in adulthood. We have used transgenic mice in which b2 subunit containing nicotinic acetylcholine receptors (b2* nAChRs) are expressed exclusively on corticothalamic neurons (b2 tr(CT) mice) to identify the receptor subtypes involved and also to define the circuit level site of action responsible for this persistent, nicotine-induced behavioral phenotype. Further characterization of the native nAChRs expressed in this circuit indicates that both (a4) 2 (b2) 3 and (a4) 2 (b2) 2 a5 nAChR subtypes are present in corticothalamic projections. Consistent with a role for (a4) 2 (b2) 2 a5 nAChRs in mediating the effect of developmental nicotine exposure on adult passive avoidance behavior, constitutive deletion of the a5 nAChR subunit also alters this behavior. A critical period for this developmental consequence of nicotine exposure was defined by limiting exposure to the early post-natal period. Taken together, these studies identify a novel consequence of developmental nicotine exposure in the mouse, define the nAChR subtypes and neural circuit involved in this behavioral change and delimit the neurodevelopmental period critical for vulnerability to a behavioral alteration that persists into adulthood.
Neuropsychopharmacology, 2010
Tobacco smoke exposure during development can result in lasting alterations in sensory processing and attention. This suggests that some constituent of smoke, such as the primary addictive component, nicotine, alters neurodevelopment. Although many effects of developmental nicotine exposure have been identified in humans and animal models, very few mechanistic studies have identified the molecular and anatomical basis for a defined behavioral consequence of developmental exposure. We show in this study that a mouse model of developmental nicotine exposure results in hypersensitive passive avoidance in adulthood. We have used transgenic mice in which b2 subunit containing nicotinic acetylcholine receptors (b2* nAChRs) are expressed exclusively on corticothalamic neurons (b2 tr(CT) mice) to identify the receptor subtypes involved and also to define the circuit level site of action responsible for this persistent, nicotine-induced behavioral phenotype. Further characterization of the native nAChRs expressed in this circuit indicates that both (a4) 2 (b2) 3 and (a4) 2 (b2) 2 a5 nAChR subtypes are present in corticothalamic projections. Consistent with a role for (a4) 2 (b2) 2 a5 nAChRs in mediating the effect of developmental nicotine exposure on adult passive avoidance behavior, constitutive deletion of the a5 nAChR subunit also alters this behavior. A critical period for this developmental consequence of nicotine exposure was defined by limiting exposure to the early post-natal period. Taken together, these studies identify a novel consequence of developmental nicotine exposure in the mouse, define the nAChR subtypes and neural circuit involved in this behavioral change and delimit the neurodevelopmental period critical for vulnerability to a behavioral alteration that persists into adulthood.