Biomedical subjects

Frederic J Seidler

Publications and source records attributed to Frederic J Seidler.

At least 55 records · Page 3Linked to original sources

PubMed2004

Beta-adrenoceptor modulation of transiently overexpressed alpha 2-adrenoceptors in brain and peripheral tissues: cellular mechanisms underlying the developmental toxicity of terbutaline.

Terbutaline, a selective beta(2)-adrenoceptor (beta(2)AR) agonist, is widely used as a tocolytic to arrest preterm labor but recent studies indicate that excessive betaAR stimulation can alter the expression and function of other neurotransmitter receptors that are essential to fetal/neonatal development. In many immature tissues, alpha(2)-adrenergic receptors (alpha(2)ARs) are overexpressed and the receptors are thought to play a role in cell proliferation and architectural assembly. We evaluated whether betaAR agonists perturb the expression of alpha(2)ARs in central and peripheral tissues during various developmental stages in the fetal and neonatal rat. In peripheral tissues (heart, liver, kidney) administration of terbutaline (10mg/kg s.c. for 4 days) elicited decrements in alpha(2)AR expression only during a critical developmental window that differed for each tissue; terbutaline was more effective than isoproterenol, a mixed beta(1)/beta(2) agonist. Neonatal destruction of sympathetic nerves with 6-hydroxydopamine (6-OHDA) had a biphasic effect, initially reducing alpha(2)ARs but subsequently elevating receptor expression. In contrast to the effects in the periphery, terbutaline administration promoted alpha(2)AR expression in neonatal brain regions with effects preferential to males. As the rat is an altricial species, these results during late gestation and the early neonatal period indicate that betaAR input modulates alpha(2)AR expression during developmental stages in which betaAR tocolytics are likely to be used. Disruption of alpha(2)AR expression and function may therefore contribute to adverse effects that have been noted in the offspring of pregnant women treated with terbutaline.

Adrenergic alpha-2 Receptor Agonists↗

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↗

PubMed2004

Developmental effects of chlorpyrifos extend beyond neurotoxicity: critical periods for immediate and delayed-onset effects on cardiac and hepatic cell signaling.

The fetal and neonatal neurotoxicity of chlorpyrifos (CPF) and related insecticides is a major concern. Developmental effects of CPF involve mechanisms over and above cholinesterase inhibition, notably events in cell signaling that are shared by nonneural targets. In the present study, we evaluated the immediate and long-term effects of CPF exposure of rats during different developmental windows [gestational days (GD) 9-12 or 17-20, postnatal days (PN) 1-4 or 11-14] on the adenylyl cyclase (AC) signaling cascade in the heart and liver. In addition to basal AC activity, we assessed the responses to direct AC stimulants (forskolin, Mn2+); to isoproterenol and glucagon, which activate signaling through specific membrane receptors; and to sodium fluoride, which activates the G-proteins that couple the receptors to AC. Few immediate effects on AC were apparent when CPF doses remained below the threshold for systemic toxicity. Nevertheless, CPF exposures on GD9-12, GD17-20, or PN1-4 elicited sex-selective effects that emerged by adulthood (PN60), whereas later exposure (PN11-14) elicited smaller, nonsignificant effects, indicative of closure of the window of vulnerability. Most of the effects were heterologous, involving signaling elements downstream from the receptors, and thus were shared by multiple inputs; superimposed on this basic pattern, there were also selective alterations in receptor-mediated responses. These results suggest that the developmental toxicity of CPF extends beyond the nervous system, to include cell signaling cascades that are vital to cardiac and hepatic homeostasis. Future work needs to address the potential implications of these effects for cardiovascular and metabolic disorders that may emerge long after the end of CPF exposure.

Adenylyl Cyclases↗

PubMed2004

Developmental exposure to chlorpyrifos elicits sex-selective alterations of serotonergic synaptic function in adulthood: critical periods and regional selectivity for effects on the serotonin transporter, receptor subtypes, and cell signaling.

During brain development, serotonin (5HT) provides essential neurotrophic signals, and in earlier work, we found that developmental exposure to chlorpyrifos (CPF) elicits short-term changes in 5HT systems. In the present study, we evaluated the effects in adulthood after CPF exposures from the neural tube stage [gestational days (GD) 9-12] and the late gestational period (GD17-20) through postnatal neuronal differentiation and synaptogenesis [postnatal days (PN) 1-4 and 11-14], using treatments below the threshold for systemic toxicity. With exposure on GD9-12, CPF elicited global elevations in 5HT1A and 5HT2 receptors and in the 5HT presynaptic transporter. The GD17-20 treatment elicited larger effects that displayed selectivity for regions with 5HT nerve terminals and that were preferential for males. Although similar receptor up-regulation was seen after PN1-4 exposure, the effects were larger in regions with 5HT cell bodies; in addition, the presynaptic transporter was down-regulated in the nerve terminal zones of females. The PN11-14 exposure had much smaller effects on receptors but still elicited transporter suppression with the same regional and sex selectivity. Although CPF exposure on GD17-20, PN1-4, or PN11-14 altered the ability of 5HT to modulate adenylyl cyclase, this change did not correspond with the effects on 5HT receptors, suggesting an additional set of effects on proteins that transduce the 5HT signal. Our results indicate that CPF elicits long-lasting changes in 5HT receptors, the presynaptic 5HT transporter, and 5HT-mediated signal transduction after exposure in discrete developmental windows that range from the neural tube stage through synaptogenesis. These effects are likely to contribute to neurobehavioral teratology of CPF.

Animals↗

PubMed2004

Critical periods for chlorpyrifos-induced developmental neurotoxicity: alterations in adenylyl cyclase signaling in adult rat brain regions after gestational or neonatal exposure.

Developmental exposure to chlorpyrifos (CPF) alters the function of a wide variety of neural systems. In the present study we evaluated the effects in adulthood of CPF exposure of rats during different developmental windows, using the adenylyl cyclase (AC) signaling cascade, which mediates the cellular responses to numerous neurotransmitters. Animals were exposed on gestational days (GD) 9-12 or 17-20 or on postnatal days (PN) 1-4 or 11-14 and assessed at PN60. In addition to basal AC activity, we evaluated the responses to direct AC stimulants (forskolin, Mn2+) and to isoproterenol, which activates signaling through ss-adrenoceptors coupled to stimulatory G-proteins. CPF exposure in any of the four periods elicited significant changes in AC signaling in a wide variety of brain regions in adulthood. In general, GD9-12 was the least sensitive stage, requiring doses above the threshold for impaired maternal weight gain, whereas effects were obtained at subtoxic doses for all other regimens. Most of the effects were heterologous, involving signaling elements downstream from the receptors, and thus shared by multiple stimulants; superimposed on this basic pattern, there were also selective alterations in receptor-mediated responses, in G-protein function, and in AC expression and subtypes. Exposures conducted at GD17-20 and later all produced sex-selective alterations. These results suggest that developmental exposure to CPF elicits long-lasting alterations in cell-signaling cascades that are shared by multiple neurotransmitter and hormonal inputs; the resultant abnormalities of synaptic communication are thus likely to occur in widespread neural circuits and their corresponding behaviors.

Adenylyl Cyclases↗

PubMed2003

Nicotine is a developmental neurotoxicant and neuroprotectant: stage-selective inhibition of DNA synthesis coincident with shielding from effects of chlorpyrifos.

Although nicotine is now well recognized as a developmental neurotoxicant, it also may have neuroprotectant properties. In the current study, we used PC12 cells to characterize the specific developmental phases in which these effects are expressed. In undifferentiated cells, nicotine had a modest effect on DNA synthesis (10% reduction), which was nevertheless selective, as no significant reductions were seen for RNA or protein synthesis. The effects were blocked by mecamylamine, indicating mediation by nicotinic acetylcholine receptors. Initiation of differentiation with nerve growth factor, which greatly increases the receptor concentration, produced a commensurate increase in the sensitivity of DNA synthesis to nicotine, while RNA and protein synthesis again remained unaffected. The organophosphate insecticide, chlorpyrifos, also interferes with DNA synthesis in undifferentiated PC12 cells, but by mechanisms independent of nicotinic receptors. Accordingly, the effects of a combination of nicotine and chlorpyrifos should be additive. However, simultaneous exposure of undifferentiated cells to both agents produced less-than-additive effects at low concentrations of chlorpyrifos, and at high chlorpyrifos concentrations, nicotine produced outright protection: the combination of nicotine and chlorpyrifos had lesser effects than chlorpyrifos alone. The same neuroprotection was seen when cells were exposed to nicotine for 24 h, washed free of the drug for 24 h, and then exposed to chlorpyrifos. The results indicate that nicotine interferes with neural cell replication, with peak effects in early stages of differentiation. At the same time, nicotine promotes trophic actions that protect against neurotoxicants that work through other mechanisms.

Animals↗

PubMed2003

Terbutaline is a developmental neurotoxicant: effects on neuroproteins and morphology in cerebellum, hippocampus, and somatosensory cortex.

Beta(2)-adrenoceptor agonists, especially terbutaline, are widely used to arrest preterm labor, but they also cross the placenta to stimulate fetal beta-adrenoceptors that control neural cell differentiation. We evaluated the effects of terbutaline administration in neonatal rats, a stage of neurodevelopment corresponding to human fetal development. Terbutaline administered on postnatal days PN2 to 5 elicited neurochemical changes indicative of neuronal injury and reactive gliosis: immediate increases in glial fibrillary acidic protein and subsequent induction of the 68-kDa neurofilament protein. Quantitative morphological evaluations carried out on PN30 indicated structural abnormalities in the cerebellum, hippocampus, and somatosensory cortex. In the cerebellum, PN2 to 5 terbutaline treatment reduced the number of Purkinje cells and elicited thinning of the granular and molecular layers. The hippocampal CA3 region also displayed thinning, along with marked gliosis, effects that were restricted to females. In the somatosensory cortex, terbutaline evoked a reduction in the proportion of pyramidal cells and an increase in smaller, nonpyramidal cells; again, females were affected more than males. Although abnormalities were obtained with later terbutaline treatment (PN11 to 14), in general the effects were smaller than those seen with PN2 to 5 exposure. Our results indicate that terbutaline is a neurotoxicant that elicits biochemical alterations and structural damage in the immature brain during a critical period. These effects point to a causal relationship between fetal terbutaline exposure and the higher incidence of cognitive and neuropsychiatric disorders reported for the offspring of women receiving terbutaline therapy for preterm labor.

Adrenergic beta-Agonists↗

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

Heroin neuroteratogenicity: delayed-onset deficits in catecholaminergic synaptic activity.

Prenatal heroin exposure evokes neurochemical and behavioral deficits that, in part, reflect disruption of septohippocampal cholinergic function. In earlier studies, we found that cholinergic synaptic defects involve primary changes in cell signaling proteins that are shared by other transmitter systems. In the current study, we determined whether heroin also targets noradrenergic and dopaminergic inputs that operate through the same signaling cascades. Mice exposed to prenatal heroin showed significant deficits in norepinephrine and dopamine levels and much more pronounced effects on neurotransmitter turnover, an index of synaptic activity. Adverse effects were not present in the immediate postnatal period but rather emerged just before weaning and worsened subsequently. By young adulthood, the most highly-affected regions (hippocampus, cerebral cortex) displayed almost complete inactivation of noradrenergic and dopaminergic tonic activity. These effects arise after prior deficits in cell signaling are discernible, suggesting that the presynaptic effects are secondary to actions on signal transduction cascades shared by numerous neurotransmitter inputs and targeted by other neuroteratogens. These results may explain why apparently unrelated developmental neurotoxicants may ultimately produce a common set of neurochemical and behavioral anomalies.

Animals↗

PubMed2003

Long-lasting CNS effects of a short-term chemical knockout of ornithine decarboxylase during development: nicotinic cholinergic receptor upregulation and subtle macromolecular changes in adulthood.

Ornithine decarboxylase (ODC) and the polyamines play an essential role in brain cell replication and differentiation and polyamines also regulate the function of nicotinic acetylcholine receptors (nAChRs). We administered alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of ODC, to neonatal rats on postnatal days 5-12, during the mitotic peak of the cerebellum, a treatment regimen that achieves a chemical knockout of ODC activity and polyamine depletion limited to the treatment period. Although growth inhibition and gross dysmorphology were limited to the cerebellum, both alpha7 and alpha4beta2 nAChRs were upregulated in adulthood in the frontal cortex, hippocampus and thalamus, with the largest effect in the latter region, primarily in females. Receptor upregulation was accompanied by abnormalities in macromolecular indices of cell packing density and cell membrane surface area, but the generalized cellular alterations did not share the regional or sex selectivity shown by the effects on nAChRs. Elevated DNA concentration was most notable in the hippocampus and was associated with augmented levels of glial fibrillary acidic protein, thus implying gliosis as the cause of the increased number of cells. DFMO's effects on both nAChR expression and cellular biomarkers resembled those of developmental exposure to nicotine. Accordingly, some of the effects may represent a specific alteration in nAChR signaling evoked by polyamine depletion during a critical developmental window. Alterations in polyamine gating of cholinergic synaptic signaling may thus contribute to the adverse neurobehavioral effects of numerous neuroteratogens that directly or indirectly disrupt the ODC/polyamine pathway.

Animals↗

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

Ontogenesis of beta-adrenoceptor signaling: implications for perinatal physiology and for fetal effects of tocolytic drugs.

G-Protein-coupled receptors play an instrumental role in cellular development and function. In the mature organism, receptor signaling is controlled through the processes of desensitization and down-regulation. Recent evidence suggests that these regulatory mechanisms are not inherent properties, however, but rather are acquired during ontogenesis. This review focuses on beta-adrenoceptors (betaARs), which are found in fetal and neonatal tissues and are effectively linked through adenylyl cyclase (AC) to the production of cAMP. Agonist-induced stimulation of betaARs in the immature organism fails to produce desensitization, and instead, responsiveness increases. The unique mechanisms underlying this anomalous response involve induction of AC, a switch to more catalytically efficient AC isoforms, an increase in the ratio of stimulatory to inhibitory G-proteins, and interference with the expression and/or function of other G-protein-linked receptors that provide offsetting, inhibitory inputs. These adjustments are thus heterologous, influencing signaling mediated by a host of other G-protein-coupled neurotransmitter and hormone receptors. The net effect is to maintain and augment betaAR signaling in the face of continued stimulation, properties that disappear with maturation. The unique regulatory mechanisms for betaAR signaling in the fetus and neonate provide the necessary physiological adjustments required for the perinatal transition from intrauterine to extrauterine life. At the same time, however, the inability to restrict betaAR function may underlie adverse effects of betaAR-agonist tocolytics that are used in the treatment of preterm labor.

Adrenergic beta-Agonists↗

PubMed2003

Transcriptional biomarkers distinguish between vulnerable periods for developmental neurotoxicity of chlorpyrifos: Implications for toxicogenomics.

The widespread use of organophosphate insecticides has raised concern about neurotoxic effects of fetal and childhood exposures. Studies in rats show that chlorpyrifos (CPF) elicits CNS cell damage, in part, through noncholinergic mechanisms that involve alterations in the expression and function of nuclear transcription factors that control cell replication, differentiation, and apoptosis. In the current study, we examined mRNAs encoding c-fos and p53, in order to determine if changes in these factors correspond to the differential susceptibility of forebrain neurons and glia, when exposure is shifted from the early neonatal period (postnatal days 1-4) to a later period (days 11-14). The early treatment paradigm elicited a significant elevation of c-fos whereas the later treatment suppressed c-fos. Neither regimen altered forebrain p53 expression, but values were elevated in the cerebellum following the later treatment; the cerebellum develops later than the forebrain and has its peak of neurogenesis postnatally. Our results suggest that a wider profiling of mRNAs using genomic arrays would enable screening for developmental neurotoxicants, but that regional and temporal profiles will be required in order to draw mechanistic conclusions or to identify critical periods of vulnerability.

Age Factors↗

PubMed2003

Developmental toxicity of terbutaline: critical periods for sex-selective effects on macromolecules and DNA synthesis in rat brain, heart, and liver.

beta-Adrenoceptors (betaARs) control cell replication/differentiation, and during development, signaling is not subject to desensitization. We examined the effects of terbutaline, a beta(2)AR agonist used as a tocolytic, on development in rat brain regions and peripheral tissues with high betaAR concentrations. Prenatal terbutaline (gestational days 17-20) decreased cell numbers (DNA content) in the fetal brain and liver. Early postnatal exposure (PN2-5) reduced DNA synthesis in early-developing brain regions of females, with sensitization of the effect upon repeated terbutaline administration; after multiple terbutaline injections, DNA content was reduced in male cerebellum. The cerebellum was targeted later (PN11-14), exhibiting decreased DNA synthesis in both sexes; in contrast, cardiac DNA synthesis decreased after one injection but increased after the fourth daily injection. Our results suggest that excessive betaAR stimulation by terbutaline alters cell development in brain regions and peripheral tissues, with the net effect depending on sex and the timing of exposure. These effects may contribute to neuropsychiatric, cognitive, cardiovascular, and metabolic abnormalities reported in the offspring of women treated with beta-agonist tocolytics.

Adrenergic beta-Agonists↗

PubMed2003

Does terbutaline damage the developing heart?

BACKGROUND: Beta(2)-Adrenoceptor (betaAR) agonists, such as terbutaline, are widely used to arrest preterm labor. They also cross the placenta where they stimulate receptors in fetal tissues, which in turn use betaAR input for trophic control of cell replication and differentiation. METHODS: As rats are altricial, we administered terbutaline in two different postnatal exposure periods (10 mg/kg given daily on Days 2-5 or 11-14). RESULTS: Hearts were examined twenty-four hours after the last dose and on postnatal day 30 for cardiac damage. Neither treatment paradigm caused an increase in cardiac abnormalities compared to controls but quantitative analysis of the number of nuclei indicated reductions in females. CONCLUSIONS: These findings do not support earlier case reports of outright myocardial necrosis after terbutaline tocolysis in human infants. Nevertheless, the significant statistical association between terbutaline and cardiac anomalies in epidemiological studies suggest that terbutaline may sensitize the developing heart to other insults that affect development.

Adrenergic beta-Agonists↗

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↗

PubMed2003

Short-term adolescent nicotine exposure in rats elicits immediate and delayed deficits in T-lymphocyte function: critical periods, patterns of exposure, dose thresholds.

Prenatal nicotine exposure elicits lasting deficiencies in T-lymphocyte mitogenesis, and the period of vulnerability extends into adolescence, the stage at which smoking typically commences. We explored the importance of nicotine exposure patterns (continuous infusion vs. repeated subcutaneous injections), dose-effect relationships, and specificity of the effects. Adolescent rats were given nicotine infusions for 1 week beginning on postnatal day (PN) 30, using a regimen (6 mg/kg/day) that produces plasma nicotine levels (25 ng/ml) similar to those in smokers; another group received 2 mg/kg/day. At the end of the infusion period (PN37), T-lymphocyte mitogenic responses to concanavalin A were deficient in the group receiving 6 mg/kg/day; values for the 2 mg/kg/day group were intermediate between controls and the 6 mg/kg/day group. One week after the termination of nicotine treatment, responses returned to normal, only to reemerge in young adulthood (PN65), at which stage adverse effects were significant even for the group that received 2 mg/kg/day. In contrast to the T-cell alterations, B-lymphocyte responses were unaffected. Administering the same total doses of nicotine by twice-daily subcutaneous injections over the 1-week treatment period (1 or 3 mg/kg per injection) did not evoke deficits in responses of either T-cells or B-cells, even though the high dose produced overt systemic toxicity and persistent weight loss. Our results indicate that adolescent nicotine exposure, even at levels below those associated with active smoking, elicits selective deficits in T-lymphocyte function. Although short-term adaptations may correct the effects, deficits reemerge in young adulthood despite cessation of nicotine exposure.

Adolescent↗