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C V Vorhees

Publications and source records attributed to C V Vorhees.

At least 37 records · Page 2Linked to original sources
PubMed1997

Methods for detecting long-term CNS dysfunction after prenatal exposure to neurotoxins.

Current U.S. Environmental Protection Agency regulatory guidelines for developmental neurotoxicity emphasize functional categories such as motor activity, auditory startle, and learning and memory. A single test of some simple form of learning and memory is accepted to meet the latter category. The rationale for this emphasis has been that sensitive and reliable methods for assessing complex learning and memory are either not available or are too burdensome, and that insufficient data exist to endorse one approach over another. There has been little discussion of the fact that learning and memory is not a single identifiable functional category and no single test can assess all types of learning and memory. Three methods for assessing complex learning and memory are presented that assess two different types of learning and memory, are relatively efficient to conduct, and are sensitive to several known neurobehavioral teratogens. The tests are a 9-unit multiple-T swimming maze, and the Morris and Barnes mazes. The first of these assesses sequential learning, while the latter two assess spatial learning. A description of each test is provided, along with procedures for their use, and data exemplifying effects obtained using developmental exposure to phenytoin, methamphetamine, and MDMA. It is argued that multiple tests of learning and memory are required to ascertain cognitive deficits; something no single method can accomplish. Methods for acoustic startle are also presented.

Animals↗
PubMed1996

Behavioral effects of prenatal exposure to pulsed-wave ultrasound in unanesthetized rats.

The present experiment examined the developmental neurotoxicity of pulsed-wave (pw) ultrasound in rats, using an exposure system designed to eliminate restraint or anesthesia from the exposure conditions. Pregnant Sprague-Dawley CD rats trained to remain immobile in a water-filled ultrasound exposure tank were scanned with 3-MHz pw ultrasound at spatial peak temporal average intensities (ISPTA) of 0, 2, 20, or 30 W/cm2 on embryonic days 4-20 for approximately 10 min/day. The data showed that such insonation produced no adverse effects on maternal weight gain or reproductive outcome, nor on the postnatal growth or survival of the offspring. No exposure-related alterations in behavioral development were observed in the offspring of rats scanned with pw ultrasound during gestation. In addition, there was no consistent evidence of an ultrasound-associated change in the adult offspring behaviors tested; i.e., no treatment effects were found on measures of locomotor activity, water maze learning, and acoustic startle reactivity. An effect on tactile startle was observed on some trials in the low exposure group male offspring, but this effect was neither dose dependent nor consistent with any other finding. Overall, these results indicate that the neurobehavioral development of rats was not altered by prenatal exposure to pw ultrasound at ISPTA levels of up to 30 W/cm2.

Animals↗
PubMed1996

Effect of methamphetamine on glutamate-positive neurons in the adult and developing rat somatosensory cortex.

The neurotoxic effects of methamphetamine (MA) on dopaminergic and serotonergic terminals have been well-documented. Another neurotoxic effect of MA is neuronal degeneration in the somatosensory cortex, as seen by silver staining. The neurochemical characteristics of these degenerating neurons are unknown. Using glutamate and glial fibrillary acid protein (GFAP) immunohistochemistry, it was found that MA exposure in adult rats (10 mg/kg given 4 times intraperotoneally (i.p.) at 2-h intervals) causes localized depletion of glutamate-positive neurons and astrogliosis in the somatosensory cortex 3 days following treatment. The affected region covered the middle one-third portion from the longitudinal fissure to the rhinal sulcus and was predominately seen in layers II-III of the cortex. This pattern of depletion is consistent with that demonstrated previously with silver staining following MA, d-amphetamine, and 3,4-methylenedioxymethamphetmine (MDMA) exposures. Comparable efforts were not found in developing animals at ages previously shown to also be resistant to MA-induced effects on dopaminergic terminals (age 20 and 40 days). Results suggest that MA exposure induces degeneration of glutamatergic neurons in the somatosensory cortex of adult rats.

Animals↗
PubMed1996

alpha-Phenyl-N-tert-butyl nitrone attenuates methamphetamine-induced depletion of striatal dopamine without altering hyperthermia.

Methamphetamine (MA) administration to adult rats (4 x 10 mg/kg s.c.) induces neurotoxicity predominately characterized by a persistent reduction of neostriatal dopamine (DA) content. Hyperthermia following MA administration potentiates the resulting DA depletion. DA-derived free radicals are postulated to be a mechanism through which MA-induced neurotoxicity is produced. The spin trapping agent PBN reacts with free radicals to form nitroxyl adducts, thereby preventing damaging free radical reactions with cellular substrates. MA with saline pretreatment (Sal-MA) reduced neostriatal DA by 55% (P < 0.01 vs. Sal-Sal). MA with PBN pretreatment (PBN-MA) at 36 or 60 mg/kg reduced neostriatal DA by 36 and 22%, respectively (P < 0.05 and P < 0.01 vs Sal-MA) indicating partial protection. PBN pretreatment did not alter MA-induced hyperthermia. Thus, PBN does not attenuate MA-induced neurotoxicity by reducing MA-induced hyperthermia. These results support a role for free radicals in the generation of MA-induced dopaminergic neurotoxicity.

Animals↗
PubMed1995

Protective effects of MK-801 on methamphetamine-induced depletion of dopaminergic and serotonergic terminals and striatal astrocytic response: an immunohistochemical study.

It has been shown previously that methamphetamine induces dopaminergic nerve terminal degeneration, serotonin depletion and striatal reactive astrogliosis, and that the noncompetitive N-methyl-D-aspartate (NMDA) antagonist MK-801 can block methamphetamine (MA)-induced depletion of dopamine and serotonin and reduction in activity of their synthetic enzymes. In this study, immunohistochemistry was used to evaluate the effect of MK-801 on methamphetamine-induced neuropathological alterations of dopaminergic and serotonergic terminals and striatal astrocytic responses. Adult male rats were treated with methamphetamine (4 injections of 10 mg/kg at 2 hour intervals) in conjunction with MK-801 which was administered 15 min before each methamphetamine administration at doses of 1 mg/kg or 2 mg/kg. Brains were examined three days following treatment. MK-801 administration prevented methamphetamine-induced depletion of 5-hydroxytryptophan (5-HT) terminals in the forebrain and depletion of tyrosine hydroxylase-positive dopaminergic terminals and astrocytic response in the neostriatum in most animals. These results support the concept that excitatory amino acids acting through an NMDA receptor are involved in methamphetamine-induced neuronal damage on dopaminergic and serotonergic terminal fields. A minor depletion of TH-positive terminals and astrogliosis in the neostriatum was seen in three of nine MA-MK-801-treated animals. This indicates that the protective effects of MK-801 on MA-induced dopaminergic terminal degeneration varies among animals with complete protection in most animals and partial protection in the others using the present doses and dosing regimen.

Animals↗
PubMed1995

Estimating intracellular pH in developing rodent embryos using a computer imaging technique: changes in embryonic pH and proliferation rates following maternal treatment with acetazolamide.

Using the transplacental distribution of the weak acid 5,5-dimethyloxazolidine-2,4-dione (DMO), a computer assisted imaging technique has been developed to permit the estimation of intracellular pH (pHi) in very specific areas of the developing rodent embryo. The study reported here demonstrates the heterogeneity of radiolabeled DMO distribution in the developing mouse forelimb. The pattern of pHi distribution shifts from one of high pHi values in the proximal core of the mesoderm on day 10 of gestation to one of higher pHi values in the mesoderm just underlying the ectoderm on day 11. Studies [Scott et al. (1990) Toxicol. Appl. Pharmacol. 103:238-254] in which DMO concentration was monitored following treatment with acetazolamide or acetazolamide plus amiloride were done in whole embryo homogenates or pooled limb samples which allow for the calculation of an average pHi but may not reflect the pHi in very specific locations of the limb. Two hours after acetazolamide administration, the pHi pattern was not significantly changed from control. Intracellular pH was raised above control levels but was not significant statistically except in the peripheral mesoderm in the ventral third of the forelimb. Fifteen hours after acetazolamide treatment, there was a significant decrease in pHi values with no change in pattern. However, treatment with acetazolamide plus amiloride for 15 hr produced a marked reduction of pHi values throughout the forelimb bud. Changes in bromodeoxyuridine labeling index (an indication of proliferative activity) following treatment with acetazolamide or acetazolamide plus amiloride are reported. The combination treatment reduced the labeling index by approximately 15% below that of control embryos in the limb region where absence of digit(s) will occur. However, we found no overall correlation of proliferative rate and pHi of limb bud mesoderm in treated embryos. Consequently, we were unable to causally associate reduced pHi with decreased proliferative rate.

Abnormalities, Drug-Induced↗
PubMed1994

The effects of amfonelic acid, a dopamine uptake inhibitor, on methamphetamine-induced dopaminergic terminal degeneration and astrocytic response in rat striatum.

Administration of methamphetamine (MA) induces degeneration of dopaminergic nerve terminals and astrogliosis, such as hypertrophy and an increase in apparent number, in the neostriatum. In this experiment adult rats were treated with MA (10 mg/kg, i.p.) 4 times in one day at 2 h intervals. Amfonelic acid (AFA), a dopamine reuptake inhibitor, was administered (20 mg/kg, i.p.) at the same time the last MA dose was given. Three days later, dopaminergic terminals and astrocytes were examined immunohistochemically and the contents of striatal dopamine and its metabolites were analyzed by HPLC. The results showed that MA-induced the typical depletion of dopaminergic terminals, reduction of dopamine content and astrogliosis in the neostriatum. AFA treatment completely prevented the effects of MA on the dopaminergic system, both morphologically and biochemically. However, the reaction of astrocytes remained in the region where the most severe depletion of dopaminergic terminals was seen in MA treated animals (ventral-lateral portion of neostriatum). The results support the concept that the dopamine transporter is involved in MA-induced dopaminergic nerve terminal degeneration. The results also indicate that blocking the dopamine transporter cannot completely prevent the reaction of astrocytes in the neostriatum, which indicates that the astrocytic reaction can be induced by factors other than degeneration of dopaminergic terminals in this region. Based on these and other data, it is hypothesized that MA may cause degeneration of corticostriatal glutamate pathways and this effect may be responsible for the astrogliosis in MA-AFA treated animals.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1994

Teratologic evaluation of rats prenatally exposed to pulsed-wave ultrasound.

While there are no known risks associated with diagnostic ultrasound, uncertainty about the safety of prenatal ultrasound exposure remains. The purpose of the present experiment was to evaluate the teratogenic potential of pulsed-wave (pw) ultrasound in rats, in the absence of maternal anesthesia or restraint. Pregnant CD rats, trained to remain immobile in a water-filled ultrasound exposure tank, were scanned with 3-MHz pw ultrasound at levels of 0, 2, 20 or 30 W/cm2 ISPTA (spatial peak, temporal average intensity) on gestational days 4-19 for approximately 10 min/day. Examination of fetuses on E20 revealed no increase in skeletal or visceral malformations in groups exposed to pw ultrasound in utero. The number of implantations/dam was significantly increased in all pw ultrasound exposure groups compared to sham-exposed animals and, in a possibly related finding, resorptions were increased in the two highest exposure groups. Although significantly increased compared to controls, resorption frequencies in these groups were low (< 10%). No exposure-related changes in fetal weights were observed in offspring of rats scanned with pw ultrasound during gestation. The results indicate that, under the conditions described, no overt embryotoxicity is associated with gestational exposure to pw ultrasound intensities of up to 30 W/cm2.

Animals↗
PubMed1994

Behavioral effects of smokeless tobacco on the neonate and young Sprague Dawley rat.

Three dosages of Smokeless Tobacco (ST) extract were given to pregnant Sprague-Dawley rats by oral gavage on gestational days (GD) 6-20. The three dosages contained ST extract equivalent to 1.33 mg/kg nicotine (STD-1), 4.0 mg/kg nicotine (STD-2), and 6.0 mg/kg nicotine (STD-3). Dams were intubated three times per day at 8 a.m., 11 a.m., and 2 p.m., providing total daily ST dosages of 4 mg/kg, 12 mg/kg, and 18 mg/kg, respectively. Controls received equivalent volumes of water by gavage. Dams were allowed to deliver, and all biological mothers raised their own pups. On postnatal day 1 (PND 1), litters were culled to 4 +/- 1 females and 4 +/- 1 males. Weights, physical landmark development, and behavioral performance of pups were monitored during pre- and post-weaning periods. Behavioral tests included surface righting, negative geotaxis, swimming development, open field activity, and active avoidance in shuttle box. Our results show that the two higher doses resulted in reduced maternal weight gain. During the pre-weaning period, significant pup weight reductions were noted in the STD-2 pups until PND6, and in the STD-3 group until PND15. In the STD-1 group no statistically significant weight reduction was noted on PNDs 1 and 3, but starting with PND6, pup weights surpassed control group weights. This weight difference persisted throughout the post-weaning period also (P < .05 on PND30 and PND42). The STD-3 pup weights continued to be consistently and significantly (P < .05) reduced throughout the post-weaning period (except on PND24); likewise, the STD-2 pups continued to have lower weights, but at a significant level (P < .05) on PND30 only. The incidence of deaths was increased in a dose-related manner. No significant differences were noted for pinna detachment and incisor eruption; however ST-treatment was significant in affecting earlier eye opening and vaginal patency. N significant ST treatment effects were seen on negative geotaxis, but for surface righting a decreased success rate was noted for the ST-treated groups. Significant differences were noted in swimming development, with the STD-2 pups performing best. Open field activity, as expected, increased from the pre-weaning to post-weaning periods. During the pre-weaning period the STD-3 pups were more active, and during post-weaning the STD-1 pups were more active, but no differences were noted in vertical activity or in the number of stereotypical movements. No treatment-related differences were noted in the active avoidance shuttle box.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1994

Trans-2-ene-valproic acid is less behaviorally teratogenic than an equivalent dose of valproic acid in rats.

Although animal experiments have shown the trans-2-ene metabolite (t-2-ene-VPA) of valproic acid (VPA) to be pharmacologically equivalent to the parent compound in terms of anticonvulsant activity, it is considerably less teratogenic in studies which have examined prenatally exposed fetuses for morphological defects. This has made t-2-ene-VPA an attractive potential antiepileptic agent. However, while neurobehavioral alterations have also been observed in rats prenatally exposed to VPA, even at doses below those which produce malformations, the developmental neurotoxicity of t-2-ene-VPA had not previously been examined. The current study evaluated the long-term behavioral effects of prenatal exposure to t-2-ene-VPA. Pregnant CD rats were treated with 300 or 400 mg/kg t-2-ene-VPA by gavage on days 7-18 of gestation, doses previously shown to produce no teratogenicity. A VPA group was administered 300 mg/kg for comparison. The pharmacokinetic profiles of the two compounds were similar. Behavioral findings in offspring prenatally exposed to VPA were consistent with previous findings, i.e., VPA offspring exhibited decreased locomotor activity, increased swimming maze errors, and reduced tactile startle responding compared to controls. In the 400 mg/kg t-2-ene-VPA group, Cincinnati maze errors and auditory startle reactivity were increased, while no significant behavioral effects were detected in the 300 mg/kg t-2-ene group. These results indicate that the developmental neurotoxicity of t-2-ene-VPA is lower than that of VPA but is still significant.

Animals↗
PubMed1994

Behavioral teratologic effects of prenatal exposure to continuous-wave ultrasound in unanesthetized rats.

While there are no known risks associated with diagnostic ultrasound, uncertainty about the safety of prenatal ultrasound exposure remains. The purpose of the present experiment was to evaluate the behavioral teratogenic potential of continuous-wave (cw) ultrasound in rats, in the absence of maternal anesthesia or restraint. Pregnant CD rats, trained to remain immobile in a water-filled ultrasound exposure tank, were scanned with 3 MHz cw ultrasound at levels of 0, 2, 10, 20, or 30 W/cm2 ISPTA (spatial peak, temporal average intensity) on gestational days 4-20 for approximately 10 min/day. Offspring were examined postnatally for survival, growth, physical landmarks of development, behavioral development, and the adult functions of locomotor activity, learning and memory, and startle reactivity. No effects of prenatal ultrasound were found on maternal characteristics, offspring survival or growth, physical or behavioral landmarks of development, or adult tests of passive avoidance or startle. Effects at the highest intensity were obtained on corner and side locomotor activity and in a multiple-T water maze on measures of errors of commission and time spent finding the goal. The results showed that prenatal cw ultrasound in rats can induce effects on some postnatal neurobehavioral functions at high exposure intensities (30 W/cm2), but at lower intensities (2-20 W/cm2) no consistent evidence of neurobehavioral effects was observed.

Animals↗
PubMed1994

A developmental neurotoxicity evaluation of the effects of prenatal exposure to fluoxetine in rats.

Fluoxetine is a widely used serotonin reuptake inhibitor effective in the treatment of depression. This experiment assessed the potential developmental neurotoxicity of fluoxetine. Sprague-Dawley CD rats were treated once per day on Days 7-20 of gestation with 0, 1, 5, or 12 mg/kg of fluoxetine (free base) dissolved in distilled water. One control group received water by gavage; animals in this group were provided food and water ad libitum. The second control group (PF) also received water by gavage; animals in this group had their food and water restricted by pair-feeding and watering them to the 12 mg/kg fluoxetine group. Litters were culled to 12 after birth and offspring (male/female pairs) were tested neurobehaviorally at three developmental stages (preweaning, juvenile, and adult). At each stage, two pairs per litter received tests of locomotor activity, acoustic startle, and startle after administration of one of two pharmacological challenges (one pair each receiving fluoxetine or apomorphine). Two pairs were also tested for spontaneous alternation, passive avoidance, and complex learning in a water maze. At the highest dose, fluoxetine caused maternal weight loss during pregnancy, reduced litter sizes at birth, and increased neonatal mortality. No effects on long-term growth or survival were seen. Prenatal fluoxetine exposure produced no significant effects on locomotor activity, spontaneous alternation, passive avoidance, or water maze performance. A few scattered interactions involving treatment group were obtained on startle, but no pattern of treatment-related changes was evident. Regional wet and dry brain weights taken at each stage were not affected by prenatal fluoxetine exposure. The data suggest that fluoxetine is not developmentally neurotoxic in the rat.

Animals↗
PubMed1994

The effects of chlordane exposure during pre- and postnatal periods at environmentally relevant levels on sex steroid-mediated behaviors and functions in the rat.

Technical chlordane is a mixture of four main isomers (i.e., heptachlor, cis-chlordane, trans-chlordane, and trans-non-achlor) found in meat and dairy products as well as in indoor air of houses treated for termites. These isomers are metabolized to more potent epoxides (heptachlor epoxide and oxychlordane) which accumulate in lipid compartments of tissues and have been shown to reduce chloride influx through GABAA receptor complex channels and to alter steroid levels. However, considering the almost universal human exposure and the potential for accumulation of these agents, very little is known about how chronic, low-level exposures during development affect adult behavior and steroid-mediated processes. Time-pregnant Sprague-Dawley dams (Day 4 of gestation through Day 21 of lactation) and offspring (Day 22 of age through Day 80) were exposed to three levels of technical chlordane (100, 500, or 5000 ng/g) on a daily schedule. The low-exposure level generated heptachlor epoxide and oxychlordane plasma levels in the dam (Day 20) and in the offspring (Day 80) representative of those found in the U.S. populace. Chlordane-dosed offspring exhibited sex- and dose-dependent effects on testosterone levels, behavioral tests, and body weight conducted between postnatal Days 77 and 85. Chlordane-dosed females, but not males, had significant decreases in testosterone levels, significant improvements in spatial abilities (i.e., decreases in Cincinnati maze errors, navigation times, and failures to escape), and significant increases in body weight and in auditory startle-evoked responses. In two other tests, only males were used. These chlordane-dosed males showed significant increases in male-typical mating behaviors and decreases in 36Cl- uptake into brain microsacs. For all behavioral and body weight measurements, dose-response effects were observed for the 100 and 500 ng/g dosed groups. However, the 5000 ng/g dose group responses were closer to those of control values. These results suggest that these cyclodienes masculinize sexually dimorphic functions and behaviors by mimicking sex steroids and/or changing their levels.

Animals↗
PubMed1994

Methamphetamine exposure during early postnatal development in rats: I. Acoustic startle augmentation and spatial learning deficits.

Methamphetamine (MA) induces neurotransmitter reductions and neurotoxicity at high doses in adult animals, but its effects on early brain development and behavior have received less attention. In this experiment the effects of MA exposure during a period equivalent to the human third trimester were examined. Rats (Sprague-Dawley CD) were injected subcutaneously with d-MA (30 mg/kg b.i.d.) early in postnatal development (days 1-10), later (postnatal days 11-20), or with water during both of these periods. Both early and later MA-exposed offspring exhibited augmented acoustic startle and impaired performance in a complex multiple-T water maze. Only the early MA exposure group showed a persistent deficit in weight while only the later MA exposure group showed impaired learning in the Morris hidden platform maze. Effects on locomoter activity are reported in the accompanying article. It was concluded that the effects of MA are both long lasting and stage dependent and involve cognitive as well as arousal functions.

Acoustic Stimulation↗
PubMed1994

Methamphetamine exposure during early postnatal development in rats: II. Hypoactivity and altered responses to pharmacological challenge.

Methamphetamine induces neurotransmitter reductions and neurotoxicity at high doses in adult animals, but its effects on early brain development and behavior have received little attention. In this experiment the effects of methamphetamine exposure during a period equivalent to the human third trimester were examined. Rats (Sprague-Dawley CD) were injected subcutaneously with d-methamphetamine (d-MA) (30 mg/kg b.i.d.) early in postnatal development (days 1-10), later (postnatal days 11-20), or with water during both of these periods. Both early and later MA-exposed offspring exhibited reduced locomotor activity. The effect was most evident at 30 days of age and was smaller at 45 and 60 days and only present at these latter ages in males. Only the early MA exposure group showed prolonged suppression of activity in response to a challenge dose of fluoxetine and a persistent deficit in weight while only the later MA exposure group showed attenuated suppression of activity in response to a challenge dose of fluoxetine. Based both on the present data and those in the preceding article, it was concluded that the effects of MA are both long lasting and stage dependent and involve arousal as well as cognitive functions.

Aging↗
PubMed1994

Developmental neurotoxicity induced by therapeutic and illicit drugs.

The developmental neurotoxicity of phenytoin, isotretinoin, and methamphetamine has been reviewed to illustrate effects from both therapeutic and illicit drugs to which people are exposed and which either induce or show the potential for inducing learning disabilities following in utero exposure. In each case both human and experimental animal data are presented and compared where possible. The findings point to several conclusions. First, some drugs in current use induce developmental neurotoxicity, and it cannot safely be assumed that there are not more as yet unidentified. Second, of the types of neurotoxicity induced by drugs, learning disabilities figure prominently. Third, the effects observed are dependent on both the drug's mechanism of action and the period of brain development during which exposure occurs. Fourth, with the exception of CNS teratogens, it is not yet possible to predict which periods of brain development are the most vulnerable for the induction of learning disabilities, as seen by the different patterns of critical periods for phenytoin and isotretinoin compared to methamphetamine. Fifth, as seen with isotretinoin, existing drugs that cause developmental neurotoxicity are not the only problem; new drugs with such effects are still being introduced. Sixth, only a small fraction of the drugs currently in use have ever been examined for developmental neurotoxicity; hence, the full scope of the problem cannot even be accurately estimated based on current information. It is concluded that prevention of new cases caused by drugs such as isotretinoin should be a high priority for future regulatory action.

Animals↗