Biomedical subjects

F J Seidler

Publications and source records attributed to F J Seidler.

At least 55 records · Page 3Linked to original sources

PubMed1999

Adolescent nicotine exposure causes persistent upregulation of nicotinic cholinergic receptors in rat brain regions.

Whereas numerous studies have explored the consequences of fetal or adult nicotine exposure, little or no basic research has been conducted for nicotine exposure during adolescence, the developmental period in which regular cigarette use typically begins. We administered nicotine to adolescent rats on postnatal days 30-47 via continuous infusion with implanted osmotic minipumps, using a dose rate (3-6 mg kg-1 day-1) set to achieve plasma nicotine levels found in smokers; results were compared to exposure of adult rats. During and after exposure, we assessed nicotinic cholinergic receptor binding in the midbrain, cerebral cortex, and hippocampus, using [3H]cytisine. Robust receptor upregulation was observed with both adolescent and adult nicotine exposure but there were major differences in the regional specificity and persistence of effect. In adolescents, upregulation was uniform across all regions during the infusion period, whereas in adults, there was a distinct regional hierarchy: midbrain < cerebral cortex < hippocampus; accordingly, receptors in the adolescent midbrain were upregulated far more than with adult exposure. In addition, adolescent nicotine treatment produced long-lasting effects on the receptors, with significant increases still apparent in male rats 1 month after the termination of drug exposure. We also obtained evidence for hippocampal cell damage in adolescent female rats exposed to nicotine, characterized by increases in total membrane protein concentration indicative of a decrease in overall cell size. Adolescent nicotine exposure thus elicits region- and gender-selective effects that differ substantially from those in adults, effects that may contribute to increased addictive properties and lasting deficits in behavioral performance.

Age Factors↗

PubMed1999

Chlorpyrifos releases norepinephrine from adult and neonatal rat brain synaptosomes.

Exposure of developing animals to apparently subtoxic doses of chlorpyrifos (CPF) during a critical period of synaptogenesis has been shown to affect catecholaminergic synaptic development and neuronal activity separably from its inhibition of cholinesterase. We used rat brain synaptosome preparations to examine whether CPF has a direct effect on the release of norepinephrine (NE). Synaptosomes were preloaded with [3H]NE in the absence of CPF and were then exposed to the compound during subsequent neurotransmitter release. There was a robust increase in release at 50 microg/ml of CPF. The effect was not mediated through cholinergic receptors, as neither atropine nor mecamylamine interfered with the actions of CPF. Enhanced NE release was seen in synaptosomes derived from neonatal rat brain as well as adult rat brain, albeit with a smaller effect in neonates. Our results suggest that CPF interacts directly with presynaptic nerve terminals to influence neurotransmitter release; in the context of the immature brain, these effects can alter synaptic development through the trophic actions of catecholamines.

Aging↗

PubMed1999

Neonatal chlorpyrifos exposure alters synaptic development and neuronal activity in cholinergic and catecholaminergic pathways.

After routine home application of chlorpyrifos (CPF), infant and child exposures can exceed acceptable levels. We treated neonatal rats daily on postnatal days (PN) 1-4 (1 mg/kg) or days 11-14 (5 mg/kg), treatments that evoked no overt signs of toxicity. Effects on the development of cholinergic neuronal function were assessed using choline acetyltransferase (ChAT) activity and hemicholinium-3 (HC-3) binding as indices of synaptic proliferation and synaptic activity, respectively. In the forebrain, early CPF treatment caused a decrease in ChAT without affecting HC-3 binding; late treatment decreased HC-3 binding without affecting ChAT. In the brainstem, early treatment had no effect on either parameter but late treatment decreased both ChAT and HC-3 binding. Effects of CPF were not limited to development of cholinergic synapses but also involved catecholamine pathways. For norepinephrine or dopamine, either early or late CPF treatment evoked an increase in synaptic activity (transmitter turnover). The cerebellum, a region with sparse cholinergic innervation, was affected the most. Effects on catecholamine systems were unrelated to the magnitude or temporal pattern of cholinesterase inhibition. Our results suggest that CPF exposure during the postnatal period of synaptogenesis elicits widespread disruption of cholinergic and catecholaminergic pathways. As this is the period in which patterns of synaptic responsiveness is programmed by neural input, the period of developmental vulnerability to CPF is likely to extend into childhood.

Animals↗

PubMed1999

Cholinergic receptors in heart and brainstem of rats exposed to nicotine during development: implications for hypoxia tolerance and perinatal mortality.

Cigarette smoking during pregnancy increases the incidence of perinatal mortality and Sudden Infant Death Syndrome (SIDS). We have evaluated prenatal or postnatal nicotine exposure in developing rats to examine the potential role of altered neurotransmitter receptor expression in these processes. Pregnant rats received continuous infusions of nicotine throughout gestation, at doses mimicking the plasma levels found in smokers. After birth, cardiac M2-muscarinic cholinergic receptors, which are responsible for inhibitory autonomic actions, were enhanced in the nicotine group, coincidentally with decreases in stimulatory beta-adrenergic receptors that have been demonstrated previously. Studies of adenylyl cyclase activity confirmed that the changes in receptor binding represented functional alterations: the stimulatory response to isoproterenol was obtunded by prenatal nicotine exposure, whereas the inhibitory response to carbachol was enhanced. Elevations of M2-muscarinic receptor binding were not generalized to all tissues, as the same prenatal nicotine treatment elicited a reduction in these receptors in the brainstem, an effect that has also been noted in infants who died of SIDS; we found no effects of prenatal nicotine on brainstem M1-receptor binding. Postnatal administration of nicotine produced similar brainstem receptor effects when treatment was conducted during the first postnatal week but not thereafter; postnatal nicotine treatment did not affect cardiac M2-receptor binding. Thus, during a critical developmental period, nicotine exposure produces cardiac and brainstem receptor imbalances that favor inhibitory responses, effects that can contribute to morbidity and mortality evoked by hypoxic episodes, such as those experienced during parturition, sleep apnea or airway obstruction.

Adenylyl Cyclases↗

PubMed1999

Ontogeny of cardiac beta-adrenoceptor desensitization mechanisms: agonist treatment enhances receptor/G-protein transduction rather than eliciting uncoupling.

In the fetus and neonate, beta-adrenoceptor stimulation fails to produce physiological desensitization. The current study explores the mechanisms underlying the response pattern in neonatal rats. Homologous cardiac beta-adrenergic desensitization caused by isoproterenol treatment in vivo was demonstrable in adult rats by the immediate (2h) and specific loss of the ability of isoproterenol, but not glucagon, to stimulate adenylyl cyclase in vitro. Homologous desensitization was absent when the same treatment was given to neonates. By 12 h post-treatment, the adults showed heterologous desensitization (loss of the response to glucagon), an effect which was once again absent in the immature rats. The absence of desensitization in neonates did not reflect a deficiency in the activity or subcellular distribution of beta ARK1, the enzyme that initiates the phosphorylation and consequent desensitization of beta-adrenoceptors. On the other hand, neonates showed relatively poor receptor-Gs transduction as assessed by the GTP-induced shift in receptor ligand binding. Repeated isoproterenol treatment of adult rats led to uncoupling of receptor-G-protein transduction but the same treatment in neonates enhanced transduction. Furthermore, neonatal sympathectomy with 6-OHDA interfered with the ontogenetic rise in beta-adrenoceptor-Gs interactions. These results indicate that the maintenance of agonist responses in the face of neonatal adrenergic stimulation does not reflect simply an absence of the ability to elicit homologous or heterologous desensitization but rather represents an active regulatory mechanism in which neural input exerts a positive trophic role at the level of G-protein function.

Adrenergic beta-Agonists↗

PubMed1999

Persistent c-fos induction by nicotine in developing rat brain regions: interaction with hypoxia.

Prenatal nicotine exposure evokes postnatal CNS cell loss. We administered nicotine to pregnant rats throughout gestation and neonatal brains were examined for expression of c-fos, a nuclear transcription factor involved in differentiation and cell death. The nicotine group showed persistent c-fos overexpression in the forebrain long after termination of exposure; in the brainstem, overexpression was apparent both after birth and at the end of the second postnatal week. In contrast to these effects, postnatal administration on d 1-4 caused persistent c-fos only at systemically toxic doses and treatment at subsequent ages did not cause induction at all. We also determined whether prenatal nicotine exposure would sensitize the brain to a subsequent postnatal episode of hypoxia comparable to that experienced during parturition. Hypoxia evoked acute stimulation of c-fos with a regional selectivity and ontogenetic profile differing from those of prenatal nicotine and this acute response was reduced by prenatal nicotine treatment. Persistent c-fos elevation is a harbinger of cell death, a relationship that provides an underlying mechanism for eventual cell deficits that appear after fetal nicotine exposure. Nicotine's interference with the acute c-fos stimulation caused by a subsequent episode of hypoxia may indicate a further compromise of cellular repair mechanisms.

Analysis of Variance↗

PubMed1999

Modeling geriatric depression in animals: biochemical and behavioral effects of olfactory bulbectomy in young versus aged rats.

Geriatric depression exhibits biological and therapeutic differences relative to early-onset depression. We studied olfactory bulbectomy (OBX), a paradigm that shares major features of human depression, in young versus aged rats to determine mechanisms underlying these differences. Young OBX rats showed locomotor hyperactivity and a loss of passive avoidance and tactile startle. In contrast, aged OBX animals maintained avoidance and startle responses but showed greater locomotor stimulation; the aged group also exhibited decreased grooming and suppressed feeding with novel presentation of chocolate milk, effects which were not seen in young OBX. These behavioral contrasts were accompanied by greater atrophy of the frontal/parietal cortex and midbrain in aged OBX. Serotonin transporter sites were increased in the cortex and hippocampus of young OBX rats, but were decreased in the aged OBX group. Cell signaling cascades also showed age-dependent effects, with increased adenylyl cyclase responses to monoaminergic stimulation in young OBX but no change or a decrease in aged OBX. These data indicate that there are biological distinctions in effects of OBX in young and aged animals, which, if present in geriatric depression, provide a mechanistic basis for differences in biological markers and drug responses. OBX may provide a useful animal model with which to test therapeutic interventions for geriatric depression.

Adenylyl Cyclases↗

PubMed1999

Agonist-induced sensitization of beta-adrenoceptor signaling in neonatal rat heart: expression and catalytic activity of adenylyl cyclase.

Agonist stimulation of neonatal cardiac beta-adrenoceptors produces heterologous sensitization of adenylyl cyclase (AC) signaling, rather than desensitization, as seen in adults. We examined the ontogenetic patterns of AC expression and activity, and evaluated isoproterenol effects on this pattern. [(3)H]Forskolin binding showed an increase in AC concentration across the period (birth to 25 days of age) in which agonist-induced sensitization is replaced by desensitization; binding affinity also increased, suggesting a shift in conformation and/or isoform. Indeed, catalytic properties of AC changed substantially with development, as evaluated by AC responses to forskolin versus Mn(2+). In contrast, there were only minor changes in the levels of mRNAs encoding the two major isoforms. Neonates given repeated isoproterenol treatment showed an enhancement of [(3)H]forskolin binding B(max) and a precocious shift to the mature affinity state and corresponding catalytic properties. Although isoproterenol caused significant increases in AC mRNAs, the effects were small and showed no isoform preference. Thus, a primary mode for ontogenetic increases in cardiac cellular responsiveness to adrenergic stimulation is the increase in AC activity attendant upon an absolute increase in the membrane concentration of AC molecules, along with changes in the catalytic properties of AC. The lack of correlation between mRNA and AC protein suggests that the primary regulatory events are post-transcriptional. The induction of AC by beta-adrenoceptor stimulation in the fetus and neonate accounts for heterologous, agonist-induced sensitization, a phenomenon that preserves cellular responses during the period of the perinatal transition.

Adenylyl Cyclases↗

PubMed1998

Glucocorticoid administration alters nuclear transcription factors in fetal rat brain: implications for the use of antenatal steroids.

A recent Consensus Conference endorsed antenatal steroid use in prematurity, but indicated the need for future work on molecular and cellular effects on the developing brain. In the current study, pregnant rats were given dexamethasone during late gestation, in doses spanning those recommended for use, and effects on nuclear transcription factors were evaluated. Within the first hour after a single dose of dexamethasone, and intensifying over 4 h, marked induction of brain c-fos was seen. With repeated administration, c-fos became suppressed in some brain regions, but remained elevated in others. Dexamethasone also elicited suppression of the AP-1 family of nuclear binding proteins, but with a slower time course than seen for c-fos induction. The magnitude of the effects of late gestational exposure to dexamethasone on these transcription factors was comparable to those seen when repeated doses were administered to midgestation embryos in the context of dysmorphogenesis. Similarly, the effects on brain c-fos expression were substantially greater than those in the liver, an archetypal glucocorticoid target tissue. These results indicate that even a single, low dose of glucocorticoids used in late gestation, can disrupt the transcription factors that regulate brain cell differentiation.

Animals↗

PubMed1998

Effects of aging and glucocorticoid treatment on monoamine oxidase subtypes in rat cerebral cortex: therapeutic implications.

Dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis is more common in elderly depression than in younger cohorts, resulting in elevated glucocorticoid levels. Effectiveness of antidepressant drugs is also impaired in these patients. We evaluated the effects of continuous infusions of dexamethasone on monoamine oxidase (MAO) subtypes in aged rat brain to determine whether unique interactions of glucocorticoids and aging could contribute to abnormal transmitter disposition. Aged rats given dexamethasone showed robust induction of both MAO A (threefold increase) and B (30% increase) in the frontal/parietal cortex, effects in the opposite direction from those seen in young rats treated with glucocorticoids. Our results support the view that depression in the elderly may have biologically discrete components that make it differ from depression in younger people. These distinctions may influence the etiology and therapy of depression, while at the same time providing potential biomarkers (such as platelet MAO) that may serve to predict successful treatment outcome in patient subpopulations.

Aging↗

PubMed1998

Glucocorticoid-targeting of the adenylyl cyclase signaling pathway in the cerebellum of young vs. aged rats.

Glucocorticoids exacerbate aging-induced cell death, but relatively little is known about other CNS effects in senescence. We examined noradrenergic/adenylyl cyclase signaling in the cerebellum, which is a brain region that is susceptible to deterioration of synaptic function in aging. Aged control rats had increased total cyclase catalytic activity, but showed deficits in basal adenylyl cyclase. Deficits resolved when G-proteins were stimulated with GTP, GTP and fluoride, or GTP and isoproterenol, despite reductions in beta-receptors. In young rats, long-term dexamethasone infusions evoked the same types of changes that had been seen in aging, including induction of cyclase catalytic activity and enhanced G-protein responsiveness. The same dexamethasone regimens given to aged rats failed to cause stimulation of these processes in the cerebellum, but did so in a peripheral tissue (kidney). These data indicate homology between the cellular events involved in noradrenergic signaling during aging and after glucocorticoid administration to young animals; the absence of glucocorticoid effects in the elderly cohort supports a convergent mechanism with aging. Given the high incidence of HPA axis dysregulation in the elderly, and particularly in elderly depression, effects of glucocorticoids on cell signaling may contribute to disrupted function and to altered drug reactivity.

Adenylyl Cyclases↗

PubMed1998

Developmental neurotoxicity of chlorpyrifos: delayed targeting of DNA synthesis after repeated administration.

Despite the fact that they recover more rapidly from cholinesterase inhibition than do adults, developing animals are more sensitive to delayed neurotoxicity caused by chlorpyrifos exposure. Previous studies indicate that acute, high dose chlorpyrifos exposure of developing rats interferes with synthesis of brain macromolecules, dependent upon a critical maturational stage and upon regional disparities in cholinergic innervation. In order to determine whether chronic, lower level chlorpyrifos exposure targets similar developmental events, rats were treated daily on postnatal days 1-4, using a dose (1 mg/kg, s.c.) that caused no mortality or weight deficits and that produces minimal cholinesterase inhibition. At the end of the treatment period, we examined macromolecule synthesis in three brain regions possessing disparate maturational profiles and cholinergic innervation: the brainstem, which undergoes its primary phase of neurogenesis prenatally and develops prominent cholinergic innervation, the forebrain, which develops somewhat later but also becomes cholinergically enriched, and the cerebellum, which undergoes neurogenesis postnatally and remains poor in cholinergic innervation. Four h after the last chlorpyrifos treatment, no effects were seen for DNA, RNA or protein synthesis. However, on postnatal day 5 (24 h after the last treatment), robust deficits in DNA synthesis were observed in brainstem and forebrain, with lesser effects on the cerebellum. Although the brain regional selectivity is compatible either with differences in critical maturational phases or with targeting of cholinergically-enriched brain regions, we found no significant effects in the heart, despite the fact that it is also receives cholinergic innervation. Effects on DNA synthesis were not evident 4 h after the last dose, but then appeared after 24 h. As the 4-h point is 28 h after the third dose, this suggests that a cumulative threshold needs to be exceeded in order for the delayed neurotoxicity to appear. At the point at which DNA synthesis was inhibited in brainstem and forebrain, no effects were seen for RNA or protein synthesis, indicating selectivity for macromolecule synthesis associated with cell replication. These data indicate that otherwise subtoxic, chronic exposures to chlorpyrifos nevertheless target DNA synthesis, and by inference, cell replication, in selective brain cell populations, early events that are likely contributors to the deficits in cell number that appear several days later.

Animals↗

PubMed1998

Chlorpyrifos elicits mitotic abnormalities and apoptosis in neuroepithelium of cultured rat embryos.

Chlorpyrifos is used increasingly as a pesticide in place of more toxic alternatives such as parathion. Although chlorpyrifos is not a potent dysmorphogen, recent reports that fetal or infant exposures may exceed acceptable limits have raised concern about the potentially more subtle effects on brain development. In the current study, whole rat embryo culture was used to study the effects of chlorpyrifos at the neural tube stage of development. On embryonic day 9.5, embryos were exposed to 0.5, 5, or 50 micrograms/ml of chlorpyrifos. After 48 hr (embryonic day 11.5), embryos were examined for dysmorphogenesis and were then processed for light microscopic examination of the neuroepithelium. Examination of 1-micron-thick toluidine blue-stained sections of the forebrain and hindbrain region revealed reduced and altered mitotic figures, with dispersion and disorientation of the mitotic layer. In addition, cytotoxicity was evidenced by cytoplasmic vacuolation, enlargement of intercellular spaces, and the presence of a significant number of apoptotic cells. These alterations were evident even at the lowest concentration of chlorpyrifos, which produced no dysmorphogenesis. The effects were intensified at higher concentrations, which were just at the threshold for dysmorphogenesis; the neuroepithelial abnormalities, however, were still present in embryos that were not dysmorphogenic. Our results in rat embryo culture support the idea that chlorpyrifos specifically targets brain development at low concentrations, indicating the need to reevaluate the safety of this compound for exposure in vivo.

Abnormalities, Drug-Induced↗

PubMed1998

Modeling the developmental neurotoxicity of chlorpyrifos in vitro: macromolecule synthesis in PC12 cells.

Exposure to apparently subtoxic doses of chlorpyrifos during late stages of brain development affects cell acquisition through a mixture of cholinergic and noncholinergic mechanisms. In the current study, we modeled these effects in vitro using rat pheochromocytoma (PC12), a cell line that, upon nerve-growth factor (NGF)-induced differentiation, develops the appearance and function of cholinergic target neurons, including the expression of cholinergic receptors. In the undifferentiated state (no NGF), chlorpyrifos evoked an immediate (1 h), robust, concentration-dependent inhibition of DNA synthesis as evaluated by [3H]thymidine incorporation, with a threshold of 0.5-1.5 microg/ml. Continuous exposure for up to 24 h maintained the same degree of inhibition. The effects were selective for DNA synthesis, as much smaller inhibitions were found for synthesis of RNA or protein. In contrast, direct cholinergic stimulation of the cells by 100 microM nicotine had much smaller effects on DNA synthesis. Moreover, the effects of chlorpyrifos on DNA synthesis could not be blocked by nicotinic or muscarinic antagonists, confirming that the effects were not mediated primarily through cholinergic hyperstimulation consequent to cholinesterase inhibition or to direct receptor-mediated effects. When PC12 cells underwent NGF-induced differentiation, the rate of cell replication fell dramatically and neurite extension was evident both from morphological examination and from biochemical markers (increased protein:DNA ratio). After introduction of NGF, chlorpyrifos maintained its ability to inhibit DNA synthesis acutely. However, the ability to inhibit RNA and protein synthesis initially intensified and then disappeared, indicating a shift in macromolecular targets as differentiation proceeded. We also tested the effects of long-term exposure to chlorpyrifos during the process of NGF-induced differentiation. Continuous chlorpyrifos exposure resulted in severe reductions in macromolecule synthesis and a deficit in the total number of cells, effects similar to those seen with chlorpyrifos treatment in vivo. At the highest concentrations, neurite extension was also inhibited. Our results suggest that chlorpyrifos can interact directly with developing neural cells to inhibit replication and neuritic outgrowth.

Animals↗

PubMed1998

Altered cocaine potency in the nucleus accumbens following 7-day withdrawal from intermittent but not continuous treatment: voltammetric assessment of dopamine uptake in the rat.

Using in vitro fast scan cyclic voltammetry, we measured cocaine potency for inhibiting dopamine uptake/clearance in accumbens slices 7 days after withdrawal from chronic cocaine pretreatments. Rats were pretreated with 40 mg/kg per day for 14 days, either via continuous osmotic minipumps or by once-daily injections. The cocaine potency was subsequently assessed for endogenous and exogenous dopamine applied via single-pulse electrical stimulation and caged-dopamine photolysis, respectively. Under baseline conditions, no differences in either endogenous or exogenous dopamine kinetics were observed in the two cocaine pretreatment groups. In contrast, the potency of bath-applied cocaine for inhibiting endogenous dopamine uptake was enhanced in the intermittent injection group with no change in the continuous infusion group. The selective increase in the cocaine potency following injections was also demonstrable for clearance of photo-applied DA. The enhanced cocaine potency in the accumbens slices following 7 days of withdrawal is consistent with the residual sensitization to cocaine-induced locomotion following daily cocaine injections. Behavioral tolerance following continuous infusion, on the other hand, may be mediated via a mechanism distinct from altered dopamine uptake.

Animals↗

PubMed1998

Early biochemical detection of delayed neurotoxicity resulting from developmental exposure to chloropyrifos.

Developing animals are more sensitive than adults to the delayed neurotoxicity caused by chlorpyrifos exposure. In developing rat brain, chlorpyrifos doses that cause no discernible systemic toxicity and only a minor degree of cholinesterase inhibition, nevertheless evoke alterations in cell function and number that appear after several days' delay. In the current study, neonatal rats were exposed to subtoxic doses of chlorpyrifos (no weight loss or mortality) on either postnatal days 1-4, or postnatal days 11-14, and the effects on cellular RNA levels were determined in two brain regions that are targeted for delayed neurotoxicity-the brainstem and forebrain. In both regions, chlorpyrifos exposure evoked significant alterations in RNA concentration and content, variables that are ordinarily very tightly controlled in the developing brain. The effects on RNA appeared well before the deficits in cell function and number and showed a regional selectivity similar to that of subsequent, delayed neurotoxicity. Deficits in RNA were more prominent in the brainstem, an early-developing brain region, than in the forebrain, which develops later. These results suggest that chlorpyrifos can elicit delayed developmental neurotoxicity by targeting the pivotal macromolecules that control cell differentiation in a critical postmitotic period. The lower threshold for these cellular effects compared to that for systemic toxicity indicates that the developing brain is a selective target for chlorpyrifos, effects that should be considered in assessing safety thresholds.

Animals↗

PubMed1998

Nicotine evokes cell death in embryonic rat brain during neurulation.

Maternal cigarette smoking during pregnancy represents the most prevalent exposure to a suspected neuroteratogen, nicotine. Although animal models have demonstrated brain cell loss and synaptic abnormalities after prenatal nicotine exposure, the multiple effects of nicotine on the maternal-fetal unit make it difficult to prove that nicotine itself is a neuroteratogen. In the current study, whole rat embryo culture was used to study the effects of nicotine at the neural tube stage of development. Beginning on embryonic day 9.5, embryos were exposed to 1, 10 or 100 microM nicotine. After 48 hr, embryos were examined for dysmorphogenesis and were then processed for light microscopic examination of the neuroepithelium. Examination of the forebrain, midbrain and hindbrain regions revealed extensive cytotoxicity, evidenced by cytoplasmic vacuolation, enlargement of intercellular spaces and a sharply increased incidence of pyknotic/apoptotic cells. These alterations were evident in the absence of generalized dysmorphogenesis and were detectable even at the lowest concentration of nicotine. At the highest concentration, abnormalities were present in the majority of cells. Superimposed on cell damage, we found an increase in mitotic figures. Although enhanced mitosis could represent partial compensation for cell loss, the regional selectivity and concentration dependence of the mitogenic effect differed significantly from that of cell death, suggesting separable mechanisms. The present results support the view that nicotine is a neuroteratogen, specifically targeting brain development at concentrations below the threshold for dysmorphogenesis.

Animals↗

PubMed1997

Convergent control of serotonin transporter expression by glucocorticoids and cocaine in fetal and neonatal rat brain.

Serotonin plays a trophic role in brain cell differentiation. In this study, expression of the serotonin presynaptic transporter protein, which regulates the extracellular serotonin concentration, was measured with [3H]paroxetine in rats exposed to dexamethasone or cocaine prenatally. Within 24 h of a single dose of dexamethasone, significant increases were seen in fetal brain, and the effect persisted into the postnatal period. Chronic prenatal cocaine exposure elicited similar changes. These data indicate that exposures to apparently disparate drugs can elicit similar endpoints that may lead to behavioral teratogenesis.

Animals↗