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C L Ryan

Publications and source records attributed to C L Ryan.

12 recordsLinked to original sources
PubMed2006

Gender-based changes in cognition and emotionality in a new rat model of epilepsy.

Epilepsy research relies heavily on animal models that mimic some, or all, of the clinical symptoms observed. We have previously described a new developmental rat model of epilepsy that demonstrates both behavioural seizures and changes in hippocampal morphology. In the current study we investigated whether these rats also show changes in cognitive performance as measured using the Morris water maze task, and emotionality as measured using the Elevated plus maze task. In the water maze, significant differences between male and female rats were found in several performance variables regardless of treatment. In addition, female but not male rats, treated neonatally with domoic acid had significant impairments in learning new platform locations in the water maze. In the elevated plus maze, a significant proportion of female rats spent more time in the open arm of the maze following prior exposure to the maze whereas this effect was not seen in male rats. We conclude that perinatal treatment with low doses of domoic acid results in significant gender-based changes in cognition and emotionality in adult rats.

Animals↗
PubMed2005

NMDA receptor involvement in the effects of low dose domoic acid in neonatal rats.

We have previously reported that neonatal rats display enhanced sensitivity to domoic acid relative to adults, and that perinatal injections of low doses of domoic acid alter early associational learning in the newborn rat. The current study was designed to further investigate the effects of low dose domoic acid on neonatal odour conditioning and to determine if the observed effects are due in part to an action on NMDA receptors. Groups of rat pups were conditioned to a novel odour on postnatal day (PND) 8, injected with 20 microg/kg domoic acid either alone, or in combination with the NMDA antagonist CPP (or appropriate controls), daily from day 8-14, re-exposed to the conditioning odour or a novel odour on day 9, and tested for odour preference on day 13 using a standard 3-choice paradigm. Results indicated that rats treated with domoic acid spent significantly more time over the conditioning odour than did saline-treated rats when tested on PND 13. This effect was antagonized by concomitant injection of CPP, indicating an involvement of NMDA receptors in the actions of DOM in this paradigm. Rats injected with either saline or CPP alone showed the opposite effect, i.e. a preference for the alternate odour. The results indicate that a very low dose of DOM produces a conditioned odour preference in neonatal rats and that this effect is due in part to NMDA receptor involvement, thereby emphasizing a role for both kainate and NMDA glutamate receptors in implicit memory.

Animals↗
PubMed2004

Low doses of domoic acid during postnatal development produce permanent changes in rat behaviour and hippocampal morphology.

It is well established that the developing brain is a highly dynamic environment that is susceptible to toxicity produced by a number of pharmacological, chemical and environmental insults. We report herein on permanent behavioural and morphological changes produced by exposing newborn rats to very low (subconvulsive) doses of kainate receptor agonists during a critical window of brain development. Daily treatment of SD rat pups with either 5 or 20 microg/kg of domoic acid (DOM) from postnatal day 8-14 resulted in a permanent and reproducible seizure-like syndrome when animals were exposed to different tests of spatial cognition as adults. Similar results were obtained when animals were treated with equi-efficacious doses of kainic acid (KA; 25 or 100 microg/kg). Treated rats had significant increases in hippocampal mossy fiber staining and reductions in hippocampal cell counts consistent with effects seen in adult rats following acute injections of high doses of kainic acid. In situ hybridization also revealed an elevation in hippocampal brain derived neurotrophic factor (BDNF) mRNA in region CA1 without a corresponding increase in neuropeptide Y (NPY) mRNA. These results provide evidence of long-lasting behavioural and histochemical consequences arising from relatively subtle changes in glutamatergic activity during development, that may be relevant to understanding the aetiology of seizure disorders and other forms of neurological disease.

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PubMed1988

A behavioral and electrocorticographic comparison of diazepam and pentylenetetrazol in rat pups.

This experiment assessed the possibility suggested by previous research that benzodiazepines cause convulsions in infant rats. Seven-day-old Wistar rats were randomly assigned to receive either diazepam (DZP) (0, 0.5 or 2.5 mg/kg), the convulsogen pentylenetetrazol (PTZ) (50 mg/kg), or DZP followed 30 minutes later by PTZ. The amount of paddling and wall progression and head and body tremors was recorded for each group. Both DZP and PTZ elevated paddling and wall progression, but only PTZ elevated head and body tremor scores. DZP antagonized the PTZ-induced increases in head and body tremors. In a second experiment, seven-day-old pups were implanted with cortical electrodes. The following day, baseline electrocorticograms (ECoGs) were taken for each animal. Each pup subsequently received either DZP vehicle, 0.5 mg/kg DZP, 50 mg/kg PTZ, or 0.5 mg/kg DZP followed 30 minutes later by 50 mg/kg PTZ. Neither the vehicle nor the DZP injections altered ECoG activity. In contrast, PTZ-treated pups showed continuous, high-amplitude, spiking activity. Pretreatment with DZP eliminated these PTZ-induced alterations in ECoG activity. We conclude that in infant rats, the behavioral and electrophysiological effects of DZP and PTZ are distinct from one another. Furthermore, both the behavioral and the electrocorticographic effects of PTZ are blocked by DZP. It is unlikely that DZP causes seizures in neonatal rats.

Animals↗
PubMed1985

Relationship between levels and uptake of serotonin and high affinity [3H]imipramine recognition sites in the rat brain.

High affinity [3H]imipramine binding, endogenous levels of serotonin and noradrenaline, and serotonin uptake were determined in brain regions of rats with selective destruction of serotonergic neurons by 5,7-dihydroxytryptamine (5,7-DHT), of adrenergic neurons by 6-hydroxydopamine (6-OHDA), and of rats treated with reserpine. Neonatal treatment with 5,7-DHT resulted in a significant decrease of both serotonin levels and density (Bmax) of high affinity [3H]imipramine binding sites in the hippocampus. In contrast, an elevation of serotonin levels and an increase in Bmax of [3H]imipramine binding were noted in the pons--medulla region. No changes were observed in the noradrenaline content in either of these regions. Intracerebral 6-OHDA lesion produced a drastic suppression of noradrenaline levels in cerebral cortex but failed to alter the binding affinity (KD) or density (Bmax) of [3H]imipramine recognition sites. A single injection of reserpine (2.5 mg/kg) resulted in marked depletion of both serotonin (by 57%) and noradrenaline (by 86%) content and serotonin uptake (by 87%) in the cerebral cortex but had no significant influence of the parameters of high affinity [3H]imipramine binding in this brain region. The results suggest that high affinity [3H]imipramine binding in the brain is directly related to the integrity of serotonergic neurons but not to the magnitude of the uptake or the endogenous levels of the transmitter, and is not affected by damage to noradrenergic neurons or by low levels of noradrenaline.

5,7-Dihydroxytryptamine↗
PubMedDate not supplied

Prenatal exposure to antiadrenergic antihypertensive drugs: effects on neurobehavioral development and the behavioral consequences of enriched rearing.

One of the beta blockers propranolol (5 or 20 mg/kg) or atenolol (5 or 20 mg/kg) or the alpha-2 agonist clonidine (20 or 100 micrograms/kg) was administered in the drinking water to pregnant Wistar rats over gestation days 1 to 21. Maternal weight gain, litter size or litter weight were unaffected as were a number of measures of physical and behavioral development. The rats were raised after weaning in either enriched or impoverished housing. At maturity, male but not female rats that had been prenatally exposed to either of the three drugs weighed less than the controls. Testing for cognitive function using an automated version of the Hebb-Williams maze indicated impaired spatial maze problem solving ability for female rats that had been exposed to propranolol (20 mg/kg) and raised in impoverishment. Generally, enriched-reared rats committed fewer errors on the maze problems. Prenatal exposure to the drugs did not alter the beneficial effects of enriched rearing on maze solving. However, clonidine-exposed (100 micrograms/kg) female rats that were raised in enrichment showed a significantly increased mortality rate. Thus, prenatal exposure to all of these drugs exerted effects which were latent, appearing in adulthood, and which were to some extent precipitated by environmental factors. We conclude that these drugs may be physical and behavioral teratogens for the rat.

Animals↗
PubMedDate not supplied

Use of osmotic minipumps for sustained drug delivery in rat pups: effects on physical and neurobehavioural development.

Osmotic minipumps are often used as an alternative to repetitive injections for prolonged drug delivery in adult rats. The appropriateness of using this technology for sustained drug delivery in newborn rats, however, has not been validated. Our objective was to determine if implantation of osmotic minipumps, and the associated surgical stress, during a critical developmental period, affects early development and subsequent behaviour. SD rat pups were assigned to control, minipump, or sham surgery treatment conditions (n=12/group). On P8, pups were briefly anaesthetised with isoflurane in oxygen, and Alzet 1007D osmotic minipumps, loaded with normal saline, were aseptically implanted (removed on P17). Sham-treated rats received identical treatment (with the exception of pump placement), while control pups were left undisturbed. Development was examined daily using a standard test battery (P9-P21), and learning and memory in pups was assessed in a T-maze (P15, P17 and P19). Weight (P27 and P72), open-field (P25, P26 and P27) and novel water maze performance (P60-P72) were examined in the resulting adult. With the exception of a transient decrease in weight gain, pump-treated animals did not differ from either sham or control rats, on any pre- or postweaning assessment. Based on these results we conclude that the use of osmotic minipumps in rat pups is a viable alternative to repeated injections for sustained drug delivery.

Animals↗
PubMedDate not supplied

Comparative behavioural toxicity of domoic acid and kainic acid in neonatal rats.

Cumulative behavioural toxicity was measured in groups of male and female rat pups (n=6/sex) at different stages of postnatal development. Dose-response curves (DRCs) for toxicity produced by domoic acid (DOM) were generated using animals on postnatal days (PND) 0, 5, 14, and 22, using a behavioural rating scale. In a subsequent experiment, DRCs for toxicity generated by either DOM or kainic acid were produced in rats at PND 8 and 14 for comparison between the two toxins. DOM was found to be a very potent neurotoxin in newborn rats and the potency of DOM progressively decreased with increasing age (interpolated ED(50)=0.12, 0.15, 0.30, and 1.06 mg/kg at PND 0, 5, 14, and 22, respectively). In addition, the patterns of behavioural expression were found to differ with age. Comparisons between DOM and kainic acid revealed that DOM was approximately six-fold more potent than kainate at both PND 8 and PND 14 and that both toxins were approximately two-fold less potent in PND 14 rats, compared to PND 8. This implies that the mechanism(s) responsible for reduced potency is/are similar between the two compounds. Consistent with previous reports, however, there were both similarities and differences in the observed patterns of behavioural toxicity produced by the two toxins at both ages.

Animals↗
PubMedDate not supplied

Intrauterine diazepam exposure: effects on physical and neurobehavioral development in the rat.

Primiparous timed-pregnant Wistar dams were administered a single daily SC injection of diazepam (1.0 or 5.0 mg/kg) or vehicle, over gestation days 14-20. The offspring were assessed on a number of developmental parameters. Pups exposed to the lower dose exhibited a decrease in birth weight and a delay in hair growth. Although these parameters were apparently not affected in the higher dose group, a significant dose-dependent decrease in pup viability was observed, both at birth and at one week of age. No differences were manifested for incisor eruption, pinna uncurling, eye opening, righting, geotaxis, acoustic startle, swimming, or forward locomotion. Rotarod performance was affected in the prenatal DZP animals and body weight at 60 days of age was depressed in the males of the 1.0 mg/kg group. The high dose of diazepam produced an increased susceptibility to minor metrazol-induced seizures in a kindling paradigm, but these altered seizure thresholds were not evidenced in an acute metrazol dose-response study. The NE and DA contents of hypothalamus, brainstem, hippocampus, and cortex of adult brains were assessed in each group. DA was not altered in any brain region while a single significant effect on NE was found. In the 1.0 mg/kg exposed rats only males, but not females, showed higher brainstem levels than controls. These results indicate that in the rat, prenatal exposure to clinically relevant doses of diazepam causes both fetal toxicity and long-term neurobehavioral alterations.

Animals↗