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Biomedical subjects

C F Mactutus

Publications and source records attributed to C F Mactutus.

At least 19 recordsLinked to original sources
PubMed2006

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

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 terminal deoxynucleotidyl transferase mediated DNA nick end labeling 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 was 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, alpha-fodrin and poly (ADP-ribose) polymerase (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, alpha-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 their downstream target proteins.

Animals↗
PubMed2006

Prenatal cocaine alters dopamine and sigma receptor binding in nucleus accumbens and striatum in dams and adolescent offspring.

Maternal cocaine abuse is a societal problem with serious impact on both mother and child. Few studies exist that study the mother/offspring dyad of neurological effects of maternal cocaine abuse. The present study was designed to study alterations in D2, D3 and sigma receptor density in nucleus accumbens and striatum of dams and male and female offspring following gestational cocaine. Long-Evans female rats were implanted with an intravenous (i.v.) access port prior to breeding and were administered saline or 3.0 mg/kg of cocaine from gestational day (GD) GD8-20 (1 injection/day-GD8-14, 2 injections/day-GD15-20). Offspring were raised by maternal dams and allowed to mature until postnatal days 31-35, at which time dams and offspring were sacrificed for assay of radioligand binding. In dams, decreased D2 (24.6%) and D3 (36.9%) binding was observed in striatum. Female offspring displayed no differences in receptor binding in either region. Male offspring displayed decreased D2 receptor binding (27.1%) in nucleus accumbens and increased D3 (75.2% and 33.5%) and sigma receptor binding (73.4% and 53.1%) in accumbens and striatum, respectively. Collectively, these data clearly demonstrate that male offspring exhibit significant alterations in D2, D3 and sigma receptor binding. These results suggest that dams and offspring display long-lasting alterations (5 weeks) in dopamine receptor binding. These alterations in dopamine and sigma receptor binding in offspring following prenatal cocaine and rearing by maternal dams are sex specific and could have profound effects on the development of behavior.

Analysis of Variance↗
PubMed2006

Specificity of prenatal cocaine on inhibition of locus coeruleus neurite outgrowth.

Prenatal cocaine exposure induces alterations in attentional function that presumably involve locus coeruleus noradrenergic neurons and their projections. Previous reports indicate that embryonic rat locus coeruleus neurons exposed to cocaine, both in vitro and in vivo, showed in decreased cell survival and inhibition of neurite outgrowth, and that the effects were most deleterious during early gestation. The present study performed in vitro addressed the specificity of the inhibitory effects of cocaine by comparing locus coeruleus neurite formation and extension to that of dopaminergic substantia nigra neurons following exposure to a physiologically-relevant dose of cocaine (500 ng/ml, two times a day, for four days) during peak neuritogenesis. Following cocaine treatment, immunocytochemistry (anti-norepinephrine antibody to locus coeruleus; anti-tyrosine hydroxylase antibody to substantia nigra) and image analysis were performed to measure a variety of neurite outgrowth parameters. For locus coeruleus neurons, cocaine treatment decreased the 1) number of cells initiating neurites [P<0.001], 2) mean number [P<0.05] and length of neurites [P<0.0001], 3) mean number [P<0.0016] and length of branched neurites [P<0.0006], and 4) mean length of the longest neurites [P<0.0001]. In comparison, substantia nigra neurons were not significantly affected by cocaine for any of the parameters examined. More importantly, a significant interaction between cocaine treatment and brain region was observed [P<0.0002] indicating greater vulnerability of locus coeruleus, relative to substantia nigra neurons, to cocaine exposure. These data support our hypothesis that cocaine targets the noradrenergic system by negatively regulating locus coeruleus neuronal outgrowth, which likely affects pathfinding, synaptic connectivity, and ultimately attentional behavior in cocaine-exposed offspring.

Animals↗
PubMed2002

Prenatal cocaine exposure alters sensitivity to the effects of idazoxan in a distraction task.

The present study was designed to test whether prenatal cocaine (COC) exposure alters sensitivity to the attentional effects of idazoxan (IDZ), an alpha-2 adrenergic antagonist that increases coeruleocortical NE activity. The task assessed subjects' ability to selectively attend to an unpredictable light cue and disregard olfactory distractors. IDZ increased commission errors specifically under conditions of distraction, an effect that was similar in the COC and control groups. In contrast, COC animals were significantly more sensitive than controls to the effects of IDZ on omission errors and nontrials. The pattern of effects suggests that the differential treatment response to IDZ on these latter measures resulted from an alteration in norepinephrine (NE)-modulated dopamine release in the COC animals, reflecting lasting changes in dopaminergic and/or noradrenergic systems as a result of the early cocaine exposure. Based on the behavioral measures that showed a differential response to IDZ in the COC animals, it seems likely that these changes may contribute to the alterations in sustained attention and arousal regulation that have been reported in both animals and humans exposed to cocaine in utero.

Adrenergic alpha-Antagonists↗
PubMed2001

Oxidative damage induced by the injection of HIV-1 Tat protein in the rat striatum.

Oxidative stress has been hypothesized to play a role in the pathogenesis of different neurodegenerative disorders, including HIV-related dementia. Tat, a nonstructural protein of HIV, is implicated in potentiation of neuronal apoptosis by mechanisms involving the disruption of calcium homeostasis and oxidative stress. The injection of Tat caused an increase of protein carbonyl formation in the rat striatum. Increased oxidative modification of proteins occurred early after Tat injection and preceded Tat-mediated astrogliosis. Immunostaining of brain sections demonstrated that an area of prominent protein carbonyl immunoreactivity surrounded an injection site in the striatum of Tat-injected rats. Intense protein carbonyl immunoreactivity was localized in cell bodies. Our study suggests that increased protein oxidation may be an important part of the mechanism of Tat neurotoxicity.

Animals↗
PubMed2001

Ontogeny of spatial navigation in rats: a role for response requirements?

Three experiments investigated the role of response requirements in the Morris water maze for pre- and postweanling rats. Fischer-344N pups were required to locate a hidden platform using extramaze cues in a tank modified for the pups' immature response repertoire. Weanlings (20-22 days) displayed spatial learning in a pool 1/2 the size of the adults' (Experiment 1); by 26-28 days of age, probe performance was comparable to adults' on quadrant preference and platform-crossing measures. Preweanlings (17 days), in a pool 1/3 the original size, significantly reduced escape latencies and displayed quadrant preference and platform-crossing scores indicative of spatial navigation. These results suggest that despite its protracted postnatal development, the preweanling hippocampus allows neural integration of visual-spatial information; however, the capacity to demonstrate such learning is dependent on task parameters and the pup's response repertoire.

Age Factors↗
PubMed2000

Prenatal cocaine exposure increases sensitivity to the attentional effects of the dopamine D1 agonist SKF81297.

Sensitivity to the attentional effects of SKF81297, a selective full agonist at dopamine D(1) receptors, was assessed in adult rats exposed to cocaine prenatally (via intravenous injections) and controls. The task assessed the ability of the subjects to monitor an unpredictable light cue of either 300 or 700 msec duration and to maintain performance when presented with olfactory distractors. SKF81297 decreased nose pokes before cue presentation and increased latencies and response biases (the tendency to respond to the same port used on the previous trial), suggesting an effect of SKF81297 on the dopamine (DA) systems responsible for response initiation and selection. The cocaine-exposed (COC) and control animals did not differ in sensitivity to the effects of SKF81297 on these measures. In contrast, the COC animals were significantly more sensitive than were controls to the impairing effect of SKF81297 on omission errors, a measure of sustained attention. This pattern of results provides evidence that prenatal cocaine exposure produces lasting changes in the DA system(s) subserving sustained attention but does not alter the DA system(s) underlying response selection and initiation. These findings also provide support for the role of D(1) receptor activation in attentional functioning.

Animals↗
PubMed2000

Neurotoxicity of HIV-1 proteins gp120 and Tat in the rat striatum.

HIV-associated dementia complex is a serious disabling disease characterized by cognitive, behavioral and motor dysfunction. Basal ganglia involvement in HIV-1 infection may be responsible for some of the psychomotor symptoms associated with HIV dementia. The objectives of the present study were to determine: (1) whether gp120 and Tat produce striatal toxicity, and (2) whether gp120 and Tat show synergistic toxicity in the striatum. In these studies, the recombinant proteins gp120, Tat, or saline (0.9%) were stereotaxically injected in the striatum of adult male rats. The striatal sections were evaluated for area of tissue loss (Cresyl-violet stained sections) and the number of GFAP immunoreactive cells 7 days after the injections. Doses of gp120 250 ng/microl or higher and Tat 5 microg/microl or higher produced a significant area of tissue loss and significantly increased the number of GFAP reactive cells. We found no toxicity in animals treated with immunoabsorbed gp120 or Tat. Combined gp120 (100 ng/microl)+Tat (1 microg/microl) injections into the rat striatum significantly increased the area of tissue loss and altered morphology and increased number of GFAP reactive cells, as compared to controls. Thus, the present results suggest the involvement of gp120 and Tat in striatal toxicity and provide a model for further studies to fully characterize their role in HIV-1 toxicity and to develop therapeutic strategies for HIV-1 associated dementia complex.

Animals↗
PubMed2000

Prenatal cocaine exposure impairs selective attention: evidence from serial reversal and extradimensional shift tasks.

This study assessed the effects of prenatal cocaine exposure on cognitive functioning, using an intravenous (IV) rodent model that closely mimics the pharmacokinetics seen in humans after smoking or IV injection and that avoids maternal stress and undernutrition. Cocaine-exposed males were significantly impaired on a 3-choice, but not 2-choice, olfactory serial reversal learning task. Both male and female cocaine-exposed rats were significantly impaired on extradimensional shift tasks that required shifting from olfactory to spatial cues; however, they showed no impairment when required to shift from spatial to olfactory cues. In-depth analyses of discrete learning phases implicated deficient selective attention as the basis of impairment in both tasks. These data provide clear evidence that prenatal cocaine exposure produces long-lasting cognitive dysfunction, but they also underscore the specificity of the impairment.

Animals↗
PubMed1999

Estrous cyclicity and behavioral sensitization in female rats following repeated intravenous cocaine administration.

Repeated intermittent administration of cocaine is well known to produce behavioral sensitization in male animals. The present studies explored whether intact adult female rats maintained normal estrous patterns in response to repeated IV cocaine administration and whether behavioral sensitization occurred with this route of administration. Adult female Sprague-Dawley rats (N = 48) were surgically implanted with an intravenous access port. Animals received 3.0 mg/kg IV cocaine once/day for 14 days. Daily vaginal lavages indicated that female rats continued to cycle normally throughout the experiment. Estimates of statistical power for detecting alterations in estrous cycle length ranged from 0.61-0.95 for small (0.1) to large (0.4) effect sizes. Moreover, no cocaine-treated animals displayed persistent vaginal estrus or were acyclic and cocaine treatment did not decrease body weight. Immediately after the cocaine injection, animals were placed in IR photocell activity chambers for 60 min. Female rats displayed a significant 75% increase in locomotor activity across the 14-day time course of IV cocaine injections. These data indicate that 3.0 mg/kg of IV cocaine does not interfere with normal estrous cyclicity, and that behavioral sensitization occurs in female rats following repeated daily IV cocaine dosing. Collectively, these data suggest that the IV cocaine-dosing model may be particularly useful in exploring the gender-dependent effects of cocaine using intact female rats.

Animals↗
PubMed1999

Behavioral sensitization following repeated intravenous nicotine administration: gender differences and gonadal hormones.

Repeated intermittent administration of stimulants is well known to produce behavioral sensitization in male animals. The present studies explored whether 1) behavioral sensitization occurred with the i.v. route of administration, 2) sensitization was greater in females than in males, 3) sensitization was modulated by gonadectomy, 4) intact adult female rats maintained normal estrous cytology patterns in response to repeated nicotine administration, and 5) the pharmacokinetics of i.v. nicotine dosing. Adult male, female, castrated, and ovariectomized Sprague-Dawley rats (n = 48) were surgically implanted with an intravenous access port. Animals received 50 microg/kg i.v. nicotine once/day for 14 days. Immediately after the initial nicotine injection and the final day 14 nicotine injection, animals were placed in IR photocell activity chambers for 60 min. Observational time sampling of behavior was also simultaneously performed by an observer blind to treatment condition. An increase in behavioral activity of greater than 120% occurred across the 14-day time course of i.v. nicotine injections. The magnitude of the increase, however, varied as a function of component of activity, gender, and gonadectomy. The behavioral observation data further suggested that the females demonstrated an increased sensitivity to repeated nicotine, as evidenced in a more rapid response, for example, grooming. These behavioral observations were associated with peak arterial levels of nicotine (approximately 25 ng/ml) no greater than the average venous levels of nicotine commonly maintained by cigarette smokers. Repeated i.v. nicotine, at a dose of 50 microg/kg, did not interfere with intact female vaginal cytology or body weight; the failure to detect such alterations were not due to inadequate statistical power. Moreover, no nicotine-treated animals displayed persistent vaginal estrous or were acyclic. Collectively, these data suggest that the i.v. nicotine model may be particularly useful in exploring the gender-dependent effects of nicotine.

Animals↗
PubMed1996

Repeated intravenous cocaine administration: locomotor activity and dopamine D2/D3 receptors.

The dopamine D3 receptor has been implicated as a possible mediator in the reinforcement or abuse of psychostimulants such as cocaine. The present studies examined the effects of repeated (14 day) intravenous cocaine administration (saline vehicle, 0.5, 1.0 and 3.0 mg/kg) on locomotor activity and dopamine D2 and D3 receptor density in the rat striatum and nucleus accumbens. Male Sprague-Dawley rats (n = 40) were implanted with an intravenous access port and allowed to recover for 2 days. An additional group of naive rats was included to control for surgical/injection stress (n = 10). Following 2 days of habituation trials, total, peripheral and central activity (photocell interruptions) data were collected during alternate daily 60-minute test sessions. Repeated cocaine treatment resulted in a significant dose-dependent increase in striatal D3 receptors which was predicted by daily 60-minute central locomotor activity. Conversely, D3 receptors in the nucleus accumbens exhibited a significant dose-dependent reduction which was predicted by the initial 5 minutes of central locomotor activity observed on peak sensitization days (days 6, 8 and 10). Sensitization to the locomotor stimulatory effects of cocaine was dose-dependent, with the time to peak sensitization day following the rank order of 0.5 > 1.0 > 3.0 mg/kg. The density of D2 receptors in the striatum and nucleus accumbens was unchanged by cocaine administration. These data suggest striatal and nucleus accumbens D3 receptor involvement in the expression of cocaine-induced behavioral sensitization. Thus, the D3 receptors in the striatum and nucleus accumbens may be differentially involved in the locomotor stimulation (striatal D3) and reinforcing aspects (nucleus accumbens D3) of repeated cocaine administration.

Animals↗
PubMed1993

Frequency analysis of catecholamine axonal morphology in human brain. I. Effects of postmortem delay interval.

The diverse morphologies of catecholamine axons in the human brain were examined by using tyrosine hydroxylase immunocytochemistry. Human brain tissue was obtained by either rapid autopsy (mean postmortem delay < 1 h) or routine autopsy (mean postmortem delay 5 h). Tissue blocks from the superior frontal cortex (Brodmann area 9), the hippocampal gyrus and the calcarine cortex (Brodmann area 17) were processed for tyrosine hydroxylase immunoreactivity. First, a quantitative method was developed to reliably identify differing morphologies of catecholamine axons in human brain tissue. A total of 625 tyrosine hydroxylase immunoreactive axons were randomly sampled from coded sections and classified into one of six distinct morphological categories. These categories were based upon axonal morphologies which were readily distinguished by trained observers, and moreover, further investigations demonstrated that entire tissue sections could be reliably re-sampled at intervals of up to six months. Second, regional variations in axonal distribution and the effects of increasing postmortem delay in tissue processing on the categories of tyrosine hydroxylase immunoreactive axon morphologies were examined. Postmortem delays of up to 6.5 hours were found to decrease the frequency of fine axons with varicosities (axon type 2) and increase thick-caliber straight axons (axon type 5) in all regions examined. The frequency of other morphological axon types did not change as a function of postmortem delay. In summary, the use of quantitative neuroanatomical measures of the catecholaminergic system in human brain tissue was found to be reliable and valid. It was furthermore demonstrated that postmortem delays affect selected morphological types of catecholamine axons.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1993

Frequency analysis of catecholamine axonal morphology in human brain. II. Alzheimer's disease and hippocampal sympathetic ingrowth.

We have examined the various diverse morphologies of catecholamine axons in the brains of patients with Alzheimer's disease. Alzheimer's disease and aged control brain tissue were obtained by a rapid autopsy protocol (mean postmortem delay < 1 h). Tissue blocks from the superior frontal cortex (Brodmann area 9), the hippocampal gyrus, and the calcarine cortex (Brodmann area 17) were processed for identification of catecholamine axons using tyrosine hydroxylase immunocytochemistry. A total of 1275 tyrosine hydroxylase immunoreactive axons were randomly sampled from coded sections and classified into one of six distinct axon-type categories. The axon classification from patients with Alzheimer's disease significantly differed from those of an age-matched control population in the hippocampus. The Alzheimer's disease brains were decreased in the frequency of very long, thin, tyrosine hydroxylase immunoreactive axons (type 1) and had an increased frequency of shorter, tortuous, axons (type 3). These selective quantitative shifts in hippocampal catecholaminergic axon morphology are consistent with the hypothesis that sympathetic noradrenergic axons invade the hippocampus of patients with Alzheimer's disease. Multivariate modeling of the frequency sampling data found that the axon type classification scheme successfully predicted the presence of Alzheimer's disease. In particular, the use of quantitative neuroanatomical measures of the catecholaminergic system in human brain tissue was found to have errorless predictive ability with respect to late onset (> 75 years) Alzheimer's disease. In summary, the use of quantitative neuroanatomical measures of catecholamine axonal morphologies in Alzheimer's disease brain tissue identified a specific frequency shift which may represent hippocampal sympathetic ingrowth and this unique measure was found to have predictive utility with respect to Alzheimer's disease.

Aged↗
PubMed1990

Developmental exposure to organic lead causes permanent hippocampal damage in Fischer-344 rats.

The long-term consequences of neonatal exposure to triethyl lead, the putative neurotoxic metabolite of the anti-knock gasoline additive tetraethyl lead, were examined with respect to central nervous system (CNS) development. We presently report a series of studies in which exposure of neonatal rats to organic lead produces profound CNS damage in adulthood as indicated by dose-dependent, persistent behavioral hyperreactivity as well as dose-dependent, preferential, and permanent damage to the hippocampus. General morphological parameters of brain development were not altered. Pharmacological probes of neurotransmitter system integrity suggested a functional and dose-dependent relationship between this behavioral hyperreactivity and hippocampal damage via cholinergic, but not dopaminergic, pathways. Furthermore, these alterations were not accompanied by long-term alterations in motor activity and were not attributable to the presence of lead in adult neural tissue. Finally, these behavioral, anatomical, and pharmacological indices of developmental exposure to organic lead were dissociable from any effects of early undernutrition. These data collectively indicate that organolead compounds may pose a potent neurotoxic threat to the developing CNS.

Animals↗