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behavioral effects of phenytoin
NEUROBEHAVIORAL
TERATOLOGY
SOCIETY ABSTRACTS
(P4 and P21), striatal acetylcholine (ACh), dopamine (DA), and dihydroxyphenylacetic acid (DOPAC) contents were determined. ACh turnover rate was assessed on P21. A significant prenatal treatment effect was observed on P4 with striatal ACh content significantly reduced in pups from both methadone prenatal exposure groups (F1,7g = 20.662, p < 0.0001). There was statistically stgnificant effect of postnatal treatment (Fl,3u = 6.296, p < 0.05) as well as a significant interaction between the prenatal and postnatal treatments (F1,30 = 4.241, p < 0.05) on the ratio DOPAUDA. Consistent with withdawal, this ratio was significantly reduced in M/W rats. On P2 1 there was a significant prenatal treatment effect on striatal ACh turnover (F1,56 = 11.165, p < 0.005). DA metabolism was not affected in these rats. These data suggest that prenatal exposure, not neonatal withdrawal, disrupts the development of striatal cholinergic neurons. (DA05274 and DA07027).
NBTS 18 MCCARTNEY M.A., P.L. SCINTO*, S-S. WANG*, AND S. ALTAN*, Department of Drug Safety Evaluation and Preclinical Biostatistics, The R. W. Johnson Pharmaceutical Research Institute, Raritan, New Jersey. Greater sensitivitv of rat female offsorina to the developmental/behavioral effects of phenvtoin. Phenytoin, a developmental neurotoxicant, was administered orally by gavage (50, 100, 150 or 200 mg/kg) to pregnant rats on days 7-l 8 of gestation. Various developmental and behavioral indices were evaluated. Results indicated that phenytoin produced decreased mean maternal and pup body weight gains, and decreased pup hindbrain, and F, adult forebrain, whole brain and cerebellar weights in the offspring. Behavioral/developmental effects included performance deficits in a modified Morris water maze assay, increased locomotor activity, and accelerated eye opening, incisor eruption, negative geotaxis and olfactory orientation, along with decreased air righting and auditory startle response. Female offspring appeared to be more affected than males when measured in all assays with the exception of pup brain weights, olfactory orientation, auditory startle and modified Morris water maze assay. In general, the effects were dosage-dependent and only slight changes were observed with 50 mg/kg phenytoin. Our results indicate that prenatal phenytoin exposure results in cognitive deficits, slight reflex impairment, increases in activity and an acceleration of certain early developmental parameters in rats that may be
more predominant offspring.
333 in female
rather
than
male
NBTS 19 Ali”‘, S.F., G.D. Newport’, W. Slikker’, Jr, R. B. Rothman’ and M. H. Baumann*, ‘Neurochemistry Laboratory, Div. of Neurotoxicol., NCTR/FDA, Jefferson, AR, and *ARC, NIDA, Baltimore, MD, USA. Effects of ibonaine on neurohormones and neurotransmitter svstems in rat. The present study was designed to evaluate the effect of IBG on prolactin and corticosterone levels and the dopaminergic system. Adult CD-l rats were dosed with 50 mg/kg IBG, ip, and sacrificed 15, 30 minutes 1, 2 and 24 hr later. Trunk blood was collected for hormone levels and brain was dissected for neurochemical analyses. IBG produced significant elevations in prolactin levels 15 minutes after drug administration which then began to decline thereafter, and returned to control levels 2 hr after dosing. Corticosterone levels increased 15 minutes after drug administration and continued to increase for up to 2 hr and returned to control levels 24 hr after dosing. Dopamine (DA) concentrations in striatum were decreased significantly at 30 minutes, 1 and 2 hr after drug administration, however, they returned to control levels at 24 hr. DA metabolite concentrations (DOPAC and HVA) increased in a time-dependent manner up to 2 hr. At 24 hr, DOPAC concentrations were below control values, whereas HVA returned to control levels. Concentrations of serotonin and its metabolite 5HIAA were decreased only at 1 hr after the dose administration. These data suggest that a single injection of IBG can produce significant elevations of prolactin and corticosterone and depletion of DA in a time-dependent manner.
NBTS 20 BROENlNG*, H. W., C. PU*, and C.V. VORHEES, Division of Developmental Biology, Children’s Hospital Research Foundation, Cincinnati, Ohio. Methamnhetamine selectively reduces tvrosine hvdroxvlase immunoreactivitv in the core of the nucleus accumbens while snaring the shell repion. Dopaminergic innervation to the nucleus accumbens was investigated following methamphetamine (MA)-induced neurotoxicity. Four 10 mgkg doses of MA were administered subcutaneously to male Sprague-Dawley rats with a two hour
TERATOLOGY
SOCIETY ABSTRACTS
(P4 and P21), striatal acetylcholine (ACh), dopamine (DA), and dihydroxyphenylacetic acid (DOPAC) contents were determined. ACh turnover rate was assessed on P21. A significant prenatal treatment effect was observed on P4 with striatal ACh content significantly reduced in pups from both methadone prenatal exposure groups (F1,7g = 20.662, p < 0.0001). There was statistically stgnificant effect of postnatal treatment (Fl,3u = 6.296, p < 0.05) as well as a significant interaction between the prenatal and postnatal treatments (F1,30 = 4.241, p < 0.05) on the ratio DOPAUDA. Consistent with withdawal, this ratio was significantly reduced in M/W rats. On P2 1 there was a significant prenatal treatment effect on striatal ACh turnover (F1,56 = 11.165, p < 0.005). DA metabolism was not affected in these rats. These data suggest that prenatal exposure, not neonatal withdrawal, disrupts the development of striatal cholinergic neurons. (DA05274 and DA07027).
NBTS 18 MCCARTNEY M.A., P.L. SCINTO*, S-S. WANG*, AND S. ALTAN*, Department of Drug Safety Evaluation and Preclinical Biostatistics, The R. W. Johnson Pharmaceutical Research Institute, Raritan, New Jersey. Greater sensitivitv of rat female offsorina to the developmental/behavioral effects of phenvtoin. Phenytoin, a developmental neurotoxicant, was administered orally by gavage (50, 100, 150 or 200 mg/kg) to pregnant rats on days 7-l 8 of gestation. Various developmental and behavioral indices were evaluated. Results indicated that phenytoin produced decreased mean maternal and pup body weight gains, and decreased pup hindbrain, and F, adult forebrain, whole brain and cerebellar weights in the offspring. Behavioral/developmental effects included performance deficits in a modified Morris water maze assay, increased locomotor activity, and accelerated eye opening, incisor eruption, negative geotaxis and olfactory orientation, along with decreased air righting and auditory startle response. Female offspring appeared to be more affected than males when measured in all assays with the exception of pup brain weights, olfactory orientation, auditory startle and modified Morris water maze assay. In general, the effects were dosage-dependent and only slight changes were observed with 50 mg/kg phenytoin. Our results indicate that prenatal phenytoin exposure results in cognitive deficits, slight reflex impairment, increases in activity and an acceleration of certain early developmental parameters in rats that may be
more predominant offspring.
333 in female
rather
than
male
NBTS 19 Ali”‘, S.F., G.D. Newport’, W. Slikker’, Jr, R. B. Rothman’ and M. H. Baumann*, ‘Neurochemistry Laboratory, Div. of Neurotoxicol., NCTR/FDA, Jefferson, AR, and *ARC, NIDA, Baltimore, MD, USA. Effects of ibonaine on neurohormones and neurotransmitter svstems in rat. The present study was designed to evaluate the effect of IBG on prolactin and corticosterone levels and the dopaminergic system. Adult CD-l rats were dosed with 50 mg/kg IBG, ip, and sacrificed 15, 30 minutes 1, 2 and 24 hr later. Trunk blood was collected for hormone levels and brain was dissected for neurochemical analyses. IBG produced significant elevations in prolactin levels 15 minutes after drug administration which then began to decline thereafter, and returned to control levels 2 hr after dosing. Corticosterone levels increased 15 minutes after drug administration and continued to increase for up to 2 hr and returned to control levels 24 hr after dosing. Dopamine (DA) concentrations in striatum were decreased significantly at 30 minutes, 1 and 2 hr after drug administration, however, they returned to control levels at 24 hr. DA metabolite concentrations (DOPAC and HVA) increased in a time-dependent manner up to 2 hr. At 24 hr, DOPAC concentrations were below control values, whereas HVA returned to control levels. Concentrations of serotonin and its metabolite 5HIAA were decreased only at 1 hr after the dose administration. These data suggest that a single injection of IBG can produce significant elevations of prolactin and corticosterone and depletion of DA in a time-dependent manner.
NBTS 20 BROENlNG*, H. W., C. PU*, and C.V. VORHEES, Division of Developmental Biology, Children’s Hospital Research Foundation, Cincinnati, Ohio. Methamnhetamine selectively reduces tvrosine hvdroxvlase immunoreactivitv in the core of the nucleus accumbens while snaring the shell repion. Dopaminergic innervation to the nucleus accumbens was investigated following methamphetamine (MA)-induced neurotoxicity. Four 10 mgkg doses of MA were administered subcutaneously to male Sprague-Dawley rats with a two hour