Biomedical subjects

Yael Abreu-Villaça

Publications and source records attributed to Yael Abreu-Villaça.

10 recordsLinked to original sources

PubMed2006

Unilateral hemispherectomy at adulthood asymmetrically affects immobile behavior of male Swiss mice.

In order to test the hypothesis that behavioral coping with stressful situations is asymmetrically modulated by the hemispheres, we used the unilateral hemispherectomy procedure to assess the relative importance of each hemisphere in the determination of the immobility time during the forced swimming test. Under anesthesia, adult Swiss male mice were submitted to unilateral (right or left) hemispherectomy or sham surgery. Fifteen days after surgery, the immobile and turning behaviors of each mouse were measured during a 5-min forced swimming testing session. In general, while turning activity decreased significantly as the test progressed, an increase in immobility was observed. The unilateral hemispherectomy asymmetrically affected the immobility time in the forced swimming test. Particularly, the increase in immobility time of right-hemispherectomized mice was greater than that observed for sham-operated ones. In contrast, there were no differences in turning activity between the groups. The higher immobility time in males that had their right hemisphere removed supports the hypothesis that the two hemispheres contribute differentially to the behavioral response to stress.

Animals↗

PubMed2006

Early callosal absence disrupts the establishment of normal neocortical structure in Swiss mice.

In the present study, we tested the hypothesis that the ontogenetic development of the corpus callosum is relevant for the establishment of a normal neocortical structure. To that effect, neocortical morphology (thickness and neuronal density) was analyzed in adult Swiss mice rendered acallosal by midline transection at the first postnatal day (Acallosal group) and in non-manipulated mice. The neocortical thicknesses and neuronal densities of layers II+III through VI were measured in area 6 and at the 17/18a border, both of which present abundant callosal inputs, and in the relatively acallosal area 17. For the thickness measure, significant differences between Non-manipulated and Acallosal groups were only found in the areas that receive massive callosal connections. In area 6, Acallosal mice presented a reduced thickness of layer V, while at the 17/18a border, these mice presented a reduced thickness of layers II+III when compared to non-manipulated ones. No statistical difference between acallosal and non-manipulated mice was found regarding the neuronal density measure. The reduced cortical thickness associated with a comparatively normal neuronal density in neocortical regions which normally have abundant callosal connections suggest a reduction in the number of cortical neurons in acallosal mice. Altogether, the present data indicate that the input provided by callosal axons is necessary for the normal development of the neocortex.

Agenesis of Corpus Callosum↗

PubMed2005

Individual differences in novelty-seeking behavior but not in anxiety response to a new environment can predict nicotine consumption in adolescent C57BL/6 mice.

Considering that adolescence is associated with an increased motivation to seek out new stimuli and with low anxiety levels in exploring novel environments, and that both behavioral traits may be associated with substance abuse, we investigated whether the behavioral response to a novel environment can predict subsequent oral nicotine self-administration in adolescent C57BL/6 mice. On postnatal day 30 (PN30), the novelty-seeking behavior and anxiety levels were assessed in a hole board activity box. The total number of head-dips (DIP) was used to classify animals either into the high novelty (HN; DIP above median) or low novelty (LN; DIP below median) groups. The percentage of center squares crossed (CEN) was used to classify animals either into the high anxiety (HA; CEN below median) or low anxiety (LA; CEN above median) groups. From PN31 to PN41, all animals were given a free choice between tap water or a nicotine solution (10 microg/ml). LN mice did not change nicotine intake throughout the free choice procedure, however, HN mice presented a marked increase in consumption. There were no differences in consumption between HA and LA mice. Our results indicated that mice that presented a more intense novelty-seeking behavior increased their preference for nicotine during the free choice experiment but that anxiety levels did not predict nicotine consumption. These results suggest that higher motivation to seek out new experiences is a significant contributor to drug use in adolescents and that anxiety is probably not a major factor that determines differential nicotine consumption during adolescence.

Age Factors↗

PubMed2005

Modeling the developmental neurotoxicity of nicotine in vitro: cell acquisition, growth and viability in PC12 cells.

Although nicotine is a developmental neurotoxicant, it also can exert neuroprotective effects. In the current study, we used PC12 cells to determine the developmental phases in which these disparate actions are expressed and to compare the concentrations required for each. In undifferentiated cells, 1 or 10 microM nicotine had little or no effect on cell number (assessed by measuring DNA) but exerted positive trophic actions, characterized by transient enhancement of cell growth (increased total protein/DNA ratio) and persistent enhancement of cell viability (decreased proportions of cells stained with trypan blue). When differentiation was initiated with nerve growth factor, nicotine elicited a different spectrum of actions, with decreases in cell number, impaired neuritic outgrowth (reduced ratio of membrane/total protein) and weakened viability. In either undifferentiated or differentiating cells, nicotine increased lipid peroxidation (determined as thiobarbituric acid reactive species), providing evidence for oxidative damage. Our results indicate that nicotine exerts positive trophic effects primarily on undifferentiated cells, whereas with differentiation the effects undergo a transition to neurotoxicity. These findings support the view that the neurodevelopmental actions of nicotine depend not only upon the magnitude and duration of the exposure, but most importantly on the developmental stage (e.g., differentiation state) in which exposure occurs.

Analysis of Variance↗

PubMed2004

Chlorpyrifos exposure during neurulation: cholinergic synaptic dysfunction and cellular alterations in brain regions at adolescence and adulthood.

The developmental neurotoxicity of chlorpyrifos (CPF) involves multiple mechanisms, thus rendering the immature brain susceptible to adverse effects over a wide window of vulnerability. Earlier work indicated that CPF exposure at the neural tube stage elicits apoptosis and disrupts mitotic patterns in the brain primordium but that rapid recovery ensues before birth. In the current study, we assessed whether defects in cholinergic synaptic activity emerge later in development. CPF was given to pregnant rats on gestational days 9-12, using regimens devoid of overt maternal or fetal toxicity. We then examined subsequent development of acetylcholine systems and compared the effects to those on general biomarkers of cell development. Choline acetyltransferase (ChAT), a constitutive marker for cholinergic nerve terminals, was increased in the hippocampus and striatum in adolescence and adulthood. In contrast, hemicholinium-3 (HC-3) binding to the presynaptic choline transporter, an index of nerve impulse activity, was markedly subnormal. Furthermore, m2-muscarinic cholinergic receptor binding was significantly reduced, instead of showing the expected compensatory upregulation for reduced neural input. CPF also elicited delayed-onset alterations in biomarkers of cell packing density, cell number, cell size and neuritic projections, involving brain regions both with and without reductions in indices of cholinergic activity. In combination with earlier results, the current findings indicate that the developing brain, and especially the hippocampus, is adversely affected by CPF regardless of whether exposure occurs early or late in brain development, and that defects emerge in adolescence or adulthood even in situations where normative values are initially restored in the immediate post-exposure period.

Acetyl Coenzyme A↗

PubMed2004

Prenatal nicotine exposure alters the response to nicotine administration in adolescence: effects on cholinergic systems during exposure and withdrawal.

Maternal smoking during pregnancy increases the likelihood that the offspring will become smokers in adolescence. In the current study, we evaluated effects of prenatal and adolescent nicotine exposure in rats to assess whether there is a biological basis for this relationship. Pregnant rats were given nicotine or vehicle throughout pregnancy and the offspring then again received nicotine or vehicle during adolescence (postnatal days PN30-47.5), using a regimen (6 mg/kg/day by subcutaneous infusion) that produces plasma nicotine levels similar to those in smokers. Evaluations were made in the cerebral cortex and midbrain during adolescent nicotine administration (PN45) and for up to 1 month after the end of treatment. We assessed the magnitude and persistence of nicotinic acetylcholine receptor (nAChR) upregulation; in addition, we evaluated cholinergic synaptic activity by comparing the effects on choline acetyltransferase (ChAT), a constitutive marker for cholinergic nerve terminals, with those on hemicholinium-3 (HC-3) binding to the presynaptic choline transporter, which is regulated by nerve impulse activity. Prenatal nicotine exposure had only minor effects on nAChRs but produced persistent cholinergic hypoactivity (reduced HC-3 binding relative to ChAT) throughout adolescence and into adulthood (PN75). Adolescent nicotine exposure evoked robust nAChR upregulation and also suppressed cholinergic activity. Prenatal nicotine exposure reduced the upregulation of nAChRs evoked by adolescent nicotine but worsened the cholinergic hypoactivity during withdrawal. Our results indicate that prenatal nicotine exposure alters the subsequent response to nicotine in adolescence, effects that may contribute to the association between maternal smoking during pregnancy and subsequent adolescent smoking in the offspring.

Alkaloids↗

PubMed2004

Does prenatal nicotine exposure sensitize the brain to nicotine-induced neurotoxicity in adolescence?

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.

Aging↗

PubMed2003

Impact of adolescent nicotine exposure on adenylyl cyclase-mediated cell signaling: enzyme induction, neurotransmitter-specific effects, regional selectivities, and the role of withdrawal.

Recent animal studies indicate that the adolescent brain is especially vulnerable to nicotine-induced alterations in synaptic function, echoing the increased susceptibility to nicotine dependence and withdrawal noted for adolescent smokers. We administered nicotine to adolescent rats via continuous minipump infusions from PN30 to PN47.5, using 6 mg/kg/day, a dose rate that replicates the plasma nicotine levels found in smokers, and examined the effects on cell signaling mediated through adenylyl cyclase (AC) and its response to catecholamines. Studies were conducted during nicotine administration (PN45) and in the posttreatment, withdrawal period (PN50, 60, 75). Adolescent nicotine augmented AC activity as evidenced by increased responsiveness to the direct AC stimulants, forskolin and Mn(2+). The effects on AC were equally noted in brain regions enriched (striatum) or sparse (cerebellum) in cholinergic projections, implying that the effects are secondary to activation/repression of neural circuits, rather than representing direct effects on AC mediated by nicotinic cholinergic receptors. AC responses to dopaminergic and noradrenergic stimulants were also enhanced by nicotine exposure. However, in contrast to earlier work with serotonin-mediated responses, the effects on catecholaminergic stimulation were smaller and did not display the sex-dependence noted for serotonin. An alternate administration paradigm that maximizes episodic withdrawal (twice-daily nicotine injections) induced AC more rapidly at lower nicotine doses. Our results indicate that adolescent nicotine exposure elicits lasting alterations in synaptic signaling that intensify and persist during withdrawal. These findings support the concept that the adolescent brain is especially susceptible to persistent nicotine-induced alterations.

Adenylyl Cyclases↗

PubMed2003

Nicotine is a neurotoxin in the adolescent brain: critical periods, patterns of exposure, regional selectivity, and dose thresholds for macromolecular alterations.

In the fetus, nicotine is a neuroteratogen that elicits cell damage and loss and subsequent abnormalities of synaptic function. We explored whether these effects extend into adolescence, the period when most people begin smoking. Beginning on postnatal day 30, rats were given a 1 week regimen of nicotine infusions or twice-daily injections, at doses (0.6, 2 and 6 mg/kg/day) set to achieve plasma levels found in occasional to regular smokers. We assessed indices of cell packing density and cell number (DNA concentration and content), cell size (total protein/DNA ratio) and neuritic projections (membrane/total protein) in the midbrain, hippocampus and cerebral cortex, three regions known to be vulnerable to developmental effects of nicotine. With either route of administration, nicotine evoked shortfalls in DNA concentration and content, compensatory elevations of total protein/DNA, and reductions in the membrane/total protein ratio. Nearly all of the effects were apparent even at the lowest dose of nicotine and remained fully evident 1 month posttreatment. Although both males and females showed significant alterations, in general the effects were larger in females. Our results indicate that in adolescence, even a brief period of continuous or intermittent nicotine exposure, elicits lasting alterations in biomarkers associated with cellular and neuritic damage. As the effects are detected at exposures that produce plasma concentrations one-tenth of those in regular smokers, the exquisite sensitivity of the adolescent brain to nicotine neurotoxicity may contribute to lasting neurobehavioral damage even in occasional smokers.

Age Factors↗

PubMed2003

Short-term adolescent nicotine exposure has immediate and persistent effects on cholinergic systems: critical periods, patterns of exposure, dose thresholds.

In adolescents, the symptoms of nicotine dependence can appear well before the onset of habitual smoking. We investigated short-term nicotine exposure in adolescent rats for corresponding cholinergic alterations. Beginning on postnatal day 30, rats were given a 1-week regimen of nicotine infusions or twice-daily injections, at doses (0.6, 2, and 6 mg/kg/day) set to achieve plasma levels found in occasional to regular smokers. In the cerebral cortex, midbrain, and hippocampus, we assessed nicotinic cholinergic receptor (nAChR) binding, choline acetyltransferase (ChAT) activity, a constitutive marker for cholinergic nerve terminals, and [(3)H]hemicholinium-3 (HC-3) binding to the high-affinity choline transporter, which responds to cholinergic synaptic stimulation. nAChR upregulation was observed with either administration route, even at the lowest dose; in the hippocampus, increases could be detected with as little as 2 days' treatment at 0.6 mg/kg/day. In the midbrain, upregulation was still significant even 1 month post-treatment. Adolescent nicotine treatment also produced lasting decrements in HC-3 binding that were separable from effects on ChAT, suggesting cholinergic synaptic impairment. Again, these effects were obtained at the lowest dose and remained significant 1 month post-treatment. Our results indicate that in adolescence, even a brief period of continuous or intermittent nicotine exposure, elicits lasting alterations in cholinergic systems in brain regions associated with nicotine dependence. As the effects are detected at exposures that produce plasma concentrations as little as one-tenth of those in regular smokers, the exquisite sensitivity of the adolescent brain to nicotine may contribute to the onset of nicotine dependence even in occasional smokers.

Age Factors↗