Cocaine decreases cell survival and inhibits neurite extension of rat locus coeruleus neurons

Snow, Diane; Smith, Jeffrey D.; Booze, Rosemarie M.; Welch, M.A.; Mactutus, Charles F.

doi:10.1016/s0892-0362(01)00137-4

Cited by 28 publications

(31 citation statements)

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“…No differences were seen in the number of LC TH-ir neurons between the prenatal cocaine-and saline-treated groups, and our estimate of the population agrees with previous counts of NE neurons in the LC (e.g., Monji et al, 1994). A previous ex vivo study suggested that prenatal cocaine exposure induced a loss of LC NE neurons, as a significantly lower number (20%) of adhering unstained LC neurons were observed 2 days after dissection and plating of tissue harvested from offspring at P0-1 (Snow et al, 2001). The apparent difference between this culture study and the present one may be due to differences in model systems, specificity or sensitivity.…”

Section: Discussionsupporting

confidence: 90%

“…Specifically, prenatal cocaine exposed rats were demonstrated to have altered sensitivity to the effects of a NE α2 antagonist on certain facets of an attention task (Bayer et al, 2002), and an increase in α2 adrenergic binding in the parietal cortex (Booze et al, 2006). Additionally, evidence from culture studies indicated that cocaine exposure reduced neurite outgrowth of locus coeruleus neurons (Snow et al, 2001). While these few rather disparate studies together suggest an effect of prenatal cocaine on the NE system of the offspring, we decided it was appropriate to measure several indices that relate to NE PFC function in our intravenous rat model of prenatal cocaine exposure in which we have documented deficits in short-term memory (Morrow et al, 2002).…”

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confidence: 99%

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Prenatal cocaine exposure enhances responsivity of locus coeruleus norepinephrine neurons: Role of autoreceptors

et al. 2007

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Children exposed to cocaine during gestation have a higher incidence of neurobehavioral deficits. The neurochemical bases of these deficits have not been determined, but the pharmacology of cocaine and the nature of the abnormalities suggest that disruptions in catecholaminergic systems may be involved. In the current study, we used a rat model of prenatal cocaine exposure to examine the impact that this exposure has on the locus coeruleus (LC) noradrenergic system in offspring. Pregnant rats received twice-daily intravenous injections of cocaine (3 mg/kg) or saline between gestational days 10 and 20, and progeny were tested as juveniles. Exposure to a mild stressor elevated an index of norepinephrine turnover in the prefrontal cortex and also increased Fos expression in tyrosine hydroxylase-positive LC neurons in rats exposed to prenatal cocaine but not in rats exposed to prenatal saline. No change in the number of tyrosine hydroxylase-positive neurons in the LC was observed between the two prenatal treatment groups. Specific binding of [ 125 I]-para-iodoclonidine, a radioligand with specificity for high affinity α2A-adrenergic receptors, was decreased in the LC of rats exposed to prenatal cocaine compared to prenatal saline controls. As α 2 -adrenergic receptors on LC norepinephrine neurons function as autoreceptors, their down-regulation by prenatal cocaine exposure provides a plausible mechanism for the observed heightened reactivity of norepinephrine neurons in these animals. These data indicate that prenatal cocaine exposure results in lasting changes to the regulation and responsivity of rat LC norepinephrine neurons. A similar dysregulation of LC norepinephrine neurons may occur in children exposed to cocaine during gestation, and this may explain, at least partly, the increased incidence of cognitive deficits that have been observed in these subjects.

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Section: Discussionsupporting

confidence: 90%

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confidence: 99%

Prenatal cocaine exposure enhances responsivity of locus coeruleus norepinephrine neurons: Role of autoreceptors

et al. 2007

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“…Further, numerous studies have defined a clear role for the noradrenergic system in attentional deficits following prenatal cocaine exposure (Mactutus, 1999;Bayer et al, 2002;Foltz et al, 2004). Consistent with these data, our previous in vivo and in vitro studies show that cocaine exposure specifically impairs the basic cell biology of locus coeruleus (LC), neurons that mediate attention, by inhibition of LC neurite initiation, elongation and branching during early periods of gestation (Snow et al, 2001;Foltz et al, 2004;Snow et al, 2004;Dey et al, 2006).Important for the present study, cocaine exposure not only targets LC outgrowth, but also LC neuron survival. A decreased number of tyrosine hydroxylase-immunoreactive (TH-IR) cells was noted in the LC, in rats exposed to cocaine in utero (even with dosing restricted to GD11-13), with up to a 12-15% reduction, and under some conditions a reduction in cell volume (Mactutus et al, 2005).…”

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confidence: 73%

“…When a dose response study was conducted, the treatment factor had 4 levels (cocaine dose -0, 250 ng/ml, 500 ng/ml, 1 μg/ml). Planned comparisons and orthogonal decompositions of main effects were employed and justified given the a priori hypothesized greater vulnerability to cocaine of LC, relative to SN neurons (Mactutus, 1999;Snow et al, 2001;Bayer et al, 2002;Snow et al, 2004; Dey et al., in press) regardless of the presence of significant two-and three-way interaction terms. Correlational analyses and bivariate plots were further employed to examine the degree of relationship between the effects of cocaine on LC vs. SN neurons.…”

Section: Resultsmentioning

confidence: 99%

“…A variety of studies implicate the noradrenergic system being affected by prenatal cocaine exposure, specifically locus coeruleus (LC) neurons (Mactutus, 1999;Bayer et al, 2002;Foltz et al, 2004;Dey et al, 2006). Cocaine impairs neurite initiation and elongation in GD 14 and 18 LC neurons (Snow et al, 2001), with pronounced inhibition during early gestation . Further, prenatal cocaine inhibits LC survival indicated by a decreased number of tyrosine hydroxylase immunoreactive (TH-IR) cells in rat LC when exposed to cocaine in utero, with a 12-13% reduction in cell number, which was associated with decreased LC cell volume (Mactutus et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

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Cocaine exposure in vitro induces apoptosis in fetal locus coeruleus neurons by altering the Bax/Bcl-2 ratio and through caspase-3 apoptotic signaling

et al. 2007

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Cocaine inhibits survival and growth of rat locus coeruleus (LC) neurons, which may mediate alterations in attention, following in utero exposure to cocaine. These effects are most severe in early gestation during peak neuritogenesis. Prenatal cocaine exposure may specifically decrease LC survival through an apoptotic pathway involving caspases. Dissociated fetal LC neurons or substantia nigra (SN) neurons (control) were exposed in vitro to a pharmacologically active dose of cocaine hydrochloride (500 ng/ml) and assayed for apoptosis using TUNEL and Hoechst methodologies. Cocaine exposure decreased survival and induced apoptosis in LC neurons, with no changes in survival of SN neurons. Activation of apoptotic signal transduction proteins were determined using enzyme assays and immunoblotting at 30 min, 1 h, 4 h and 24 h. In LC neurons, Bax levels were induced at 30 min and 1 h, following cocaine treatment, and Bcl-2 levels remained unchanged at all time points, altering the Bax/Bcl-2 ratio. The ratio was reversed for SN neurons (elevated Bcl-2 levels and transient reduction of Bax levels). Further, cocaine exposure significantly increased caspase-9 and caspase-3 activities at all time points, without changes in caspase-8 activity in LC neurons. In addition, cleavage of caspase-3 target proteins, α-fodrin and PARP were observed following cocaine treatment. In contrast, SN neurons showed either significant reductions, or no significant changes, in caspase-3, 8 or 9 activities or caspase-3 target proteins, α-fodrin and PARP. Thus, cocaine exposure in vitro may preferentially induce apoptosis in fetal LC neurons putatively regulated by Bax, via activation of caspases and its downstream target proteins. Keywords noradrenergic; drug abuse; apoptosis; attention; rat; cocaine Prenatal cocaine exposure has deleterious effects on the developing fetus, (Schenker et al., 1993;Keller and Snyder-Keller, 2000). One prominent behavioral abnormality associated with prenatal cocaine exposure in offspring is attentional dysfunction (Mayes et al., 1998; Singer *Author to whom correspondence should be addressed: Swatee Dey, DSc. Department of Anatomy and Neurobiology and Graduate Center for Toxicology, The University of Kentucky, Willard Medical Center -800 Rose St., MN225, Lexington, KY 40536-0298, Phone: (859) 323 3720, FAX: (859) 323-5946, Email: sdey0@uky.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. et al., 2000), however, the cellular mechanisms underlying this deficit has not been identified. A variety of studies implicate the noradrenergic system being affected by pren...

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Cognitive Outcomes of Preschool Children With Prenatal Cocaine Exposure

Singer¹

2004

JAMA

196

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OCAINE READILY CROSSES THE placental and fetal brain barriers 1-3 and has a direct effect on the developing fetal brain through alterations in the central monoamine systems and an indirect effect through maternal vascular disruptions. 4 Brain glucose metabolism is decreased in animal studies of cocaineexposed offspring, also potentially affecting neurodevelopment 5 and raising concerns about long-term cognitive outcomes. 6 A number of methodologically sound studies have found a relationship between fetal cocaine exposure and negative child developmental outcomes in the first years of life, 7-15 although others have not. 16,17 A few studies have documented outcomes in the later preschool or early school years. 17-20 Longterm studies are important because cocaine may have "sleeper" effects that are not detectable until complex functional abilities are measurable. 21,22 Compensatory mechanisms may ameliorate negative effects, 23 while environmental circumstances may exacerbate or minimize the sequelae of early brain insults. 18,24 Findings in studies with

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Cocaine decreases cell survival and inhibits neurite extension of rat locus coeruleus neurons

Cited by 28 publications

References 56 publications

Prenatal cocaine exposure enhances responsivity of locus coeruleus norepinephrine neurons: Role of autoreceptors

Prenatal cocaine exposure enhances responsivity of locus coeruleus norepinephrine neurons: Role of autoreceptors

Cocaine exposure in vitro induces apoptosis in fetal locus coeruleus neurons by altering the Bax/Bcl-2 ratio and through caspase-3 apoptotic signaling

Cognitive Outcomes of Preschool Children With Prenatal Cocaine Exposure

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