Biomedical subjects

C F Mactutus

Publications and source records attributed to C F Mactutus.

48 records · Page 3Linked to original sources

PubMedDate not supplied

Chronic intravenous model for studies of drug (Ab)use in the pregnant and/or group-housed rat: an initial study with cocaine.

Animal models for studying the developmental effects of maternal drug abuse are often based on chronic exposure of the pregnant rat. The suitability of animal models, however, has been constrained by the availability of an appropriate route of administration. The commonly employed SC and PO routes of administration fail to mimic the rapidly peaking pharmacokinetic profile observed in humans with licit (e.g., nicotine) and illicit (e.g., cocaine, methamphetamine) drugs abused via inhalation or i.v. injection. The present study provides a method for the routine use of an i.v. administration model in pregnant and/or group-housed rats. Prior to mating, young adult female Sprague-Dawley rats were anesthetized (ketamine/xylazine) for catheterization. A sterile Intracath i.v. catheter (22 ga., Becton/Dickinson) with a Luer-lock injection cap (Medex) was cut to approximately 8 cm and used as a SC dorsally implanted port for chronic i.v. injections. The distal end of the catheter was inserted into the jugular vein and threaded centrally. Catheter patency was maintained by daily flushing with 0.2 ml of heparinized saline. Following 1 week of surgical recovery, the mean (median)number of estrus cycles to impregnation was 2.5(2). The mean (+/- SEM) duration of catheter patency was 36.6 +/- 1.2 days and was in excess of 30 days for all animals (n = 22). Cocaine at a dose of 3 mg/kg (GD8-14 x 1/day, GD15-20 x 2/day) had no significant effect on dam weight gain, gestation length, litter size, sex ratio, or birth weight. In sum, a subcutaneously implanted port provides a procedure for the routine i.v. administration of drugs to pregnant and/or group-housed rats which avoids (a) the use of anesthesia/surgery during pregnancy, (b) the stress (restraint and/or thermal dilation) associated with tail vein injection, (c) the difficulties of mating and single housing associated with tethered i.v. catheters, and (d) in the case of cocaine, precludes the potential confounds of any drug-induced non-i.v. parenteral lesions.

Animals↗

PubMedDate not supplied

L-type calcium channels in the hippocampus and cerebellum of Alzheimer's disease brain tissue.

There is growing evidence that the selective neuronal cell death observed in Alzheimer's Disease (AD) is the result of dysregulation of intracellular calcium (Ca2+) homeostasis. In the present study, L-type voltage sensitive calcium channels (L-VSCCs) were examined in the cerebellum and hippocampus of AD (n = 6; postmortem interval less than 5 h) and age-matched control (n = 6) tissue by homogenate binding techniques and quantitative in vitro receptor autoradiography using [3H]isradipine (PN200-110). Saturation analyses of the cerebellum revealed unaltered [3H]isradipine binding parameters (Kd and Bmax) between AD and control subjects. Analysis of AD and control hippocampus demonstrated significant differences as [3H]isradipine binding increased (62%) in AD, whereas hippocampal cell density decreased (29%) in AD, relative to control subjects. Moreover, AD differentially affected L-VSCC in area CA1 and dentate gyrus. The dentate gyrus had greatly increased binding (77%) with little cell loss (16%) in AD brains, whereas area CA1 had increased binding (40%) with significant cell loss (42%) in AD brains, relative to controls. The results of the present study suggest that hippocampal area CA1 may experience greater cell loss in response to increased L-VSCCs in AD relative to other brain regions.

Alzheimer Disease↗

PubMedDate not supplied

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

Cocaine use during pregnancy is affiliated with neurobehavioral abnormalities in offspring that are associated with problems of attention. Given the putative role of the noradrenergic system in attentional processes, impairments in the noradrenergic system may underlie specific attentionally sensitive, neurobehavioral alterations. Recent data using a clinically relevant intravenous (iv) route of administration show that the norepinephrine cell bodies of the locus coeruleus (LC) are a primary target for in utero cocaine exposure. Cell survival and neurite outgrowth of LC neurons were studied using two paradigms: (1) in vitro, using a physiologically relevant concentration of cocaine, and (2) in vivo, using a clinically relevant intravenous rat model. Fetal cocaine exposure significantly decreased neuronal survival (in vitro: P=.0001, n=24; in vivo: P=.0337, n=30), reduced neurite initiation (in vitro: P=.001, n=24; in vivo: P=.0169, n=30), decreased the number of neurites elaborated (in vivo: P=.0031, n=30), and reduced total neurite length (in vivo: P=.0237, n=30). The results of this novel approach toward an understanding of noradrenergic neurons as they respond to cocaine during development suggest that cocaine may affect behavior by negatively regulating neuronal pathfinding and synaptic connectivity.

Animals↗

PubMedDate not supplied

Dose-response cocaine pharmacokinetics and metabolite profile following intravenous administration and arterial sampling in unanesthetized, freely moving male rats.

Despite the wealth of experimental data on cocaine abuse, there are no published dose-response pharmacokinetic studies with bolus i.v. cocaine injection in the male rat. The present study examined the pharmacokinetics of arterial plasma concentrations of cocaine and metabolite profile [benzoylecgonine (BE), ecgonine methyl ester (EME), norcocaine (NC)] following a single i.v. injection of 0.5, 1.0, or 3.0 mg/kg cocaine. Male Sprague-Dawley rats (N = 25) were anesthetized and surgically instrumented with both jugular vein (drug administration) and carotid artery (blood withdrawal) catheters and allowed to recover for at least 24 h. Arterial plasma samples (200 microliters) were obtained at eight time points (0.5, 1.5, 2.5, 10, 20, 30 min) following i.v. bolus injection (15-s injection, 15-s flush) and analyzed by single ion monitoring using GC/MS. Nonlinear regression and noncompartmental pharmacokinetic analysis were employed. Mean +/- SEM peak plasma concentrations of cocaine occurred at 30 s in a dose-response manner (370 +/- 14,755 +/- 119,2553 +/- 898 ng/ml for 0.5, 1.0, and 3.0 mg/kg groups, respectively). T1/2 alpha was < 1 min for all groups, but inversely related to dose. T1/2 beta was independent of dose 13.3 +/- 1.6, 13.0 +/- 1.5, and 12.0 +/- 2.0 min for 0.5, 1.0, and 3.0 mg/kg groups, respectively). MRT (16.0, 15.9, 14.5 min), VdSS (3.3, 3.2, and 2.8 l/kg), and ClTOT (204, 201, and 195 ml/min/kg) also provided little evidence of dose-dependent effects. Although the metabolic profile of i.v. cocaine was similarly ordered for all dose groups (BE > EME > NC), a quantitative shift in metabolite profile was evident as a function of increasing dose. This metabolic shift, perhaps attributable to saturation of plasma and liver esterases, suggests that the recently reported pharmacodynamic effects positively correlated with i.v. cocaine dose are unlikely attributable to NC, a minor but pharmacologically active metabolite. In sum, the i.v. pharmacokinetic profile in rats is distinct from that observed via the SC, IP, and PO routes of administration and offers the potential to provide a reasonable clinically relevant rodent model.

Analysis of Variance↗

PubMedDate not supplied

Prenatal intravenous cocaine adversely affects attentional processing in preweanling rats.

Perhaps the sole, clinically reported, deficit in infants of women that abused cocaine (COC) during pregnancy that persists through early childhood is that of an attentional disorder. Using the heart rate orienting response (HR-OR), a putative valid and reliable measure of attention, we examined the offspring of rats exposed to COC in utero via the clinically relevant intravenous (IV) route. Sprague-Dawley females, implanted with IV access ports prior to breeding, were administered saline or 3 mg/kg COC HC1, 1X/day on gestational day (GD) 8-14 and 2X/day on GD15-21. No significant effects of prenatal COC were apparent for maternal or litter parameters. Six pups/litter were tested: one of each sex on postnatal day (PD) 12, PD16, and PD21. Following 20 min of adaptation, pups were exposed to a novel odor (20 s amyl acetate) for a set of four acquisition trials; after a 4-h retention interval, the same procedure was again employed. At PD12, both prenatal COC and control pups demonstrated a significant HR-OR on the acquisition trials and both groups showed significant within-session habituation. Across the 4-h retention interval, prenatal COC-exposed pups showed habituation whereas control pups did not. At PD16, the magnitude of the HR-OR was significantly greater in prenatal COC-exposed pups relative to control pups. Within-session habituation also characterized the HR-OR of the COC, but not control, pups. For the retention data, within-subject and regression analyses suggested the COC-exposed pups displayed greater between and within-session habituation, respectively. At PD21, the prenatal COC-treated pups displayed an HR-OR that did not habituate across acquisition trials; the control pups displayed a significant HR-OR only during the initial 5 s of the first two trials. During the retention trials, regression analyses again suggested the COC-exposed pups displayed greater evidence of within-session habituation. Collectively, these data demonstrate that prenatal exposure to COC alters attention throughout the preweanling period of development. Given the putative role of norepinephrine, but not dopamine or serotonin, in central mediation of the HR-OR of preweanling rats, the effects of prenatal IV COC exposure in this task are consistent with a noradrenergically based attentional disorder.

Animals↗

PubMedDate not supplied

The influence of route of administration on the acute cardiovascular effects of cocaine in conscious unrestrained pregnant rats.

The intravenous route of administration, accessed via a subcutaneous vascular access port, has been recently suggested as an animal model for studying the developmental effects of maternal cocaine abuse in the pregnant and/or group-housed rat. The present study (1) assessed the cardiovascular effects of intravenous (IV) cocaine, delivered via bolus injection, in chronically catheterized near-term pregnant rats, and (2) compared the IV cardiovascular responses to those following cocaine delivered via the commonly employed subcutaneous (SC) and intragastric (IG) routes of administration. Pregnant gestation day 15 (GD15) young adult female Sprague-Dawley rats (n = 21) were anesthetized and catheters surgically implanted into the carotid artery, jugular vein, fundus of the stomach, and a subcutaneous pouch. On GD17-19, heart rate (HR) and mean arterial pressure (MAP) were assessed, using a within-subjects design, prior and subsequent to IV (3 mg/kg), IG (60 mg/kg), and SC (40 mg/kg) cocaine. An interval of 6 h separated IV and IG cocaine administration and an interval of 18 h separated IG and SC cocaine administration. The peak responses of HR (23% downward arrow) and MAP (37% upward arrow) following IV cocaine were noted within 0.5 min. In contrast, the peak responses of HR (4% downward arrow, 6% downward arrow) and MAP (2% upward arrow, 15% downward arrow) after IG (23 min) or SC (26 min) cocaine, respectively, were significantly smaller and markedly delayed. No significant change in aortic blood flow velocity was detected following cocaine via any route of administration, although phasic flow velocities (PFV) were differentially sensitive to route of administration (PFV(dias) not PFV(sys)); IV cocaine increased (55% upward arrow) whereas IG or SC cocaine decreased approximately 35% downward arrow) PFV(dias). The pressor effects of an equimolar dose of IV cocaine methiodide (3.9 mg/kg) were indistinguishable from those of IV cocaine (38% upward arrow vs. 37% upward arrow), as were the effects on PFV(dias) (83% upward arrow vs. 55% upward arrow). The lack of an effect of cocaine methiodide on HR was consistent with the bradycardia effect of cocaine attributable to central mediation of the baroreflex. Finally, the pressor effects of IV cocaine paralleled the rapidly peaking arterial plasma levels of cocaine noted within 30 s after the initiation of drug injection. In sum, prominent effects of IV cocaine on maternal cardiovascular physiology are noted; as such, the recent reports of a lack of maternal/fetal toxicity following daily (3-6mg/kg) IV cocaine during GD8-21 are not due to use of an ineffective drug dose. It was equally clear that the SC and IG routes of exposure did not reproduce the cardiovascular component(s) of the expected physiological response to cocaine.

Animals↗

PubMedDate not supplied

Conceptual and procedural considerations for developmental assessment of learning and memory (dys)function following neurotoxicant exposure.

Symptoms of memory impairment are often reported following neurotoxicant exposure. Untoward effects on the developing organism, potentially reflected as later learning disabilities and memory problems, deserve critical evaluation. Animal models providing rigorous experimental control are extremely important in this context. The psychological literature offers a variety of tasks and procedures for use across many developmental ages. Most recent progress has demonstrated evidence of associative capacity in infrahumans as early as birth, and under specific conditions even prenatally. Common to all assessments of learning and memory capabilities, however, is the requisite that these processes be inferred from overt behavior. This requirement confers the responsibility of differentiating alterations of an associative nature from those of a nonassociative nature (e.g., motivation, attention, perception, sensory adaptation, fatigue, activity, and reactivity, etc.). When across age comparisons are also of interest, additional attention must be paid to potential differences in available sensory processes, response repertoire, and ecologically relevant contextual determinants (e.g., ambient temperature, presence of familiar odors or conspecifics), particularly with preweanling and neonatal animals. Specific guidelines are offered for the criteria and implementation of controls typically necessary to provide a convincing demonstration of an associative impairment.

Animals↗

PubMedDate not supplied

Selective neurochemical and histological lesions in rat hippocampus following chronic trimethyltin exposure.

Trimethyltin exerts a unique and selective pattern of toxicity which may be related to the neurochemical innervation of the hippocampus. Rats were chronically administered trimethyltin and the kinetics of neurotransmitter uptake was assessed in hippocampal synaptosomes. Additional rats were prepared for histological examination. Uptake of the endogenous hippocampal amino acid neurotransmitters glutamic acid and gamma-aminobutyric acid showed dose-dependent alterations. Uptake of norepinephrine was not significantly affected. Histopathological analysis indicated differential neuronal loss within classically defined hippocampal cell fields.

Animals↗

PubMedDate not supplied

Evaluation of neonatal chlordecone neurotoxicity during early development: initial characterization.

The effects of neonatal exposure of rats to chlordecone were assessed in the preweaning period of development. On day 4 postpartum, pups received a SC injection (20 microliter) of either dimethylsulfoxide (DMSO) or 1 mg/pup of chlordecone dissolved in DMSO. Body weights on days 14 and 21 were slightly (9-14%), but significantly, depressed in both sexes by the neonatal chlordecone exposure. Whole body movements, monitored via a spectral analyzer, indicated a significant high frequency tremor in the chlordecone-exposed pups on postnatal days 10, 14, and 18. The auditory startle response to a 4 kHz, 110 dB (SPL) tone was examined on days 12, 16, and 20. A significant enhancement of startle responsiveness was noted in chlordecone-exposed pups relative to vehicle-injected littermates; this effect was localized primarily at 16 days of age and in the female pups. Evaluation of undifferentiated motor activity, as assessed by testing individual pups in the presence of homecage shavings, indicated significant chlordecone-induced hypoactivity in both sexes on postnatal day 15. Hypoactivity persisted through 21 days of age in the female, but not male, chlordecone-exposed pups. This neurotoxic profile of tremor, depressed body weight, and altered responsiveness to novel/stressful environments is detectable in early life and is similar to that observed when adult rats are exposed to chlordecone. The profile also bears similarity to the primary signs and symptoms of chlordecone exposure in adult humans. Collectively, the present observations offer a tentative working model for the further investigation of the developmental neurotoxicity of chlordecone.

Acoustic Stimulation↗

PubMedDate not supplied

Neonatal chlordecone exposure impairs early learning and retention of active avoidance in the rat.

The effect of neonatal exposure of rats to chlordecone on the acquisition and retention of active avoidance was investigated. Pups were trained and tested on one-way (preweaning) and/or two-way (post-weaning) active avoidance tasks. Offspring of Fischer-344 rats were administered 1 mg/pup of chlordecone (SC) dissolved in DMSO on postnatal day 4. Body weights were slightly, but significantly, depressed for chlordecone-exposed males (10-11%) and females (7-8%) during preweaning development. Post-weaning body weights were also slightly depressed by the chlordecone treatment (8% for the males, 7% for the females). For pups trained (day 18) on one-way (small to large compartment) active avoidance (OWA), chlordecone treatment increased the number of trials needed to attain the acquisition criterion; the effect was most pronounced in the males. A 72-hr retention test revealed a sex-dependent effect of chlordecone on response latency during the initial test trials. Acquisition of two-way avoidance (TWA) (days 28-30) was superior in female pups relative to males; chlordecone treatment significantly reduced this sex difference in pups which had prior or no prior OWA training. Perhaps most importantly, however, following prior OWA training, vehicle control pups demonstrated a directional bias to make an avoidance response from a small to a large compartment, whereas chlordecone-treated pups executed their avoidance responses in both directions at comparable rates. Similar evidence indicative of a selective retention deficit also characterized TWA performance when a "reversal" procedure was used. A final retention (extinction) session indicated that the chlordecone-treated pups made fewer responses than vehicle-treated controls during the test trials.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMedDate not supplied

Neonatal triethyl lead neurotoxicity in rat pups: initial behavioral observations and quantification.

Although alterations in development due to inorganic lead poisoning have been intensely investigated, little is known about the early toxicity of organic lead compounds. Assessment of developmental consequences due to triethyl lead (TEL) intoxication presently included (1) determination of the acute LD50 as 13 +/- 1 mg/kg, and (2) detailed examination of early neurobehavioral sequelae. The offspring of 12 Fischer-344 dams were administered on postpartum day 5 either a sham-injection, 15% ethanol, 3 mg/kg or 6 mg/kg TEL vis SC injection (20 microliters). Small, but significant, weight reductions of 6% and 13% for the 3- and 6- mg/kg TEL-dosed pups, respectively, were observed (days 14-30). Early sensory deficits of TEL pups as indicated by impaired olfactory discrimination on day 7 and decreased incidence of nipple attachment on day 9 were accompanied by the presence of fine whole body tremor (day 10). While these initial effects were transitory in nature, activity evaluations demonstrated persistent hypoactivity in high dose TEL males (days 15, 22, 24, 26, and 29). Passive avoidance acquisition was not affected by TEL treatment (day 18). However, 72 and 144 hr tests of passive avoidance retention (days 21 and 25) suggested alterations in affective behavior, i.e., hypoactivity in high dose TEL males and hyperactivity in low dose TEL females. A reduction in number, but not magnitude, of startle responses also occurred as a function of TEL exposure. The single postnatal day 5 injection of TEL thus produced transitory effects possibly reflecting direct TEL pharmacological activity, as well as apparent long-term effects suggesting potential permanent alterations in behavioral function.

Animals↗

PubMedDate not supplied

Characterization of triethyl lead chloride neurotoxicity in adult rats.

The neurotoxic effects of triethyl lead chloride (TEL) were characterized in adult male Fischer-344 rats. The single dose LD50 (and 95% CI) following SC administration was found to be 11 mg/kg (7.6-13.3 mg/kg), while the LD50 after repeated exposure over five days was found to be 14 mg/kg (8.3-19.0 mg/kg). TEL (1-2.5 mg/kg, SC) given for five days produced a phase of hyperexcitability and hyperactivity 1-2 weeks postdosing, which was followed by hypoexcitability and hypoactivity 3-4 weeks postdosing. TEL also increased hot plate and tail flick latencies during the first two weeks following TEL exposure. Subsequent experiments with an operant titration procedure indicated that TEL increased shock detection thresholds two weeks after cessation of exposure. TEL-exposed rats performed better than controls in a two-way shuttle box avoidance task three weeks after cessation of dosing. Subsequent tests indicated that flinch-jump thresholds of TEL-exposed rats were not affected. The results of these experiments indicate that TEL produces a profile of toxicity characterized by changes in reactivity or emotionality possibly similar to that of animals having lesions in limbic forebrain areas.

Animals↗