PubMed Health⌕ Search

Biomedical subjects

G M Rose

Publications and source records attributed to G M Rose.

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

Carrier mediated delivery of NGF: alterations in basal forebrain neurons in aged rats revealed using antibodies against low and high affinity NGF receptors.

The distribution of low and high affinity nerve growth factor (NGF) receptors was investigated in the basal forebrain during aging and NGF treatment. A peripheral administration model for NGF was utilized. NGF was conjugated to a transferrin receptor antibody (OX-26-NGF), and this conjugate was injected into the tail vein of aged Fischer 344 male rats (24 months) twice weekly for 5 weeks (equivalent to 50 microg of NGF/injection). Controls were injected with a non-conjugated mixture of OX-26 and NGF. The aged rats treated with conjugate showed a significant increase in cell size of p75- and trkA-immunoreactive neurons in the medial septal nucleus and vertical limb of the diagonal band as compared to controls. A significant increase in cell size of trkA-immunoreactive neurons was also observed in the horizontal limb of the diagonal band in rats treated with conjugate. Rats treated with conjugate also showed a significant increase in overall staining density for p75 and trkA antibodies in the medial septal nucleus as compared to controls. A significant increase in staining density of p75-immunoreactive structures was also observed in the vertical and horizontal limbs of the diagonal band. Therefore, treatment with OX-26-NGF conjugate has regional effects on both the low and high affinity NGF receptors in terms of cell body size and staining density in the basal forebrain of aged rats. The current findings support the idea that this delivery system might be useful in therapeutic approaches involving the delivery of neurotrophic factors and other large molecules into the brain.

Aging↗
PubMed1997

Rats reared in social isolation show schizophrenia-like changes in auditory gating.

Central sensory filtering processes can be demonstrated using a paired stimulus paradigm. Normal humans show a diminished vertex-recorded midlatency auditory-evoked potential to the second of paired clicks (0.5 s apart), a phenomenon termed auditory gating. Schizophrenics routinely fail to suppress the response to the second stimulus; thus, they do not gate. Previous animal studies of auditory gating have used psychotomimetic drug administration to induce a schizophrenia-like loss. However, a nonpharmacologic model of deficient gating would be advantageous. Isolation rearing of weanling rats produces impaired prepulse startle inhibition similar to that observed in schizophrenics. The present studied examined the effects of rearing status upon auditory gating. Male Sprague-Dawley rats raised in social isolation (ISO) were compared to socially raised rats (SOC). Across 10 baseline recording sessions, SOC rats showed substantial gating, while ISO rats failed to gate. Abnormal auditory gating is transiently normalized by nicotine, but not haloperidol, in schizophrenics. ISO rats given nicotine bitartrate showed gating in the normal range for 60 min. By contrast, haloperidol failed to normalize gating in ISO rats. Thus, isolation rearing of weanling rats appears to produce a stable schizophrenia-like gating deficiency that shows the same pattern of response to pharmacological interventions.

Acoustic Stimulation↗
PubMed1997

Posttraining paradoxical sleep in rats is increased after spatial learning in the Morris water maze.

The role of posttraining paradoxical sleep (PS) in spatial or nonspatial learning in the Morris water maze was evaluated. Sprague-Dawley rats were given a 12-trial training session in either the hidden or the visible platform versions of the task. Subgroups then underwent paradoxical sleep deprivation (PSD) beginning at different times after training. Rats with PSD imposed from 1-4 hr after spatial training had poorer retest scores than any other group. Other rats, implanted with electrodes to permit continuous recording of sleep electroencephalography, were found to undergo a prolonged period of elevated PS after spatial training. By contrast, rats trained in the nonspatial version of the water maze task did not show retention deficits after PSD or elevated PS after training. These results support a role for PS in spatial, but not nonspatial, learning in the Morris water maze.

Animals↗
PubMed1996

Systemic administration of a nerve growth factor conjugate reverses age-related cognitive dysfunction and prevents cholinergic neuron atrophy.

Intraventricular administration of nerve growth factor (NGF) in rats has been shown to reduce age-related atrophy of central cholinergic neurons and the accompanying memory impairment. Intraventricular administration of NGF is necessary because NGF will not cross the blood-brain barrier (BBB). Here we have used a novel carrier system, consisting of NGF covalently linked to an anti-transferrin receptor antibody (OX-26), to transport biologically active NGF across the BBB. In our experiment, aged (24 months old) Fischer 344 rats received intravenous injections of the OX-26-NGF conjugate or a control solution (a mixture of unconjugated OX-26 and NGF) twice weekly for 6 weeks. The OX-26-NGF injections resulted in a significant improvement in spatial learning in previously impaired rats but disrupted the learning ability of previously unimpaired rats. Neuroanatomical analyses showed that OX-26-NGF conjugate treatment resulted in a significant increase in cholinergic cell size in the medial septal region of rats initially impaired in spatial learning. These results indicate the potential use of the transferrin receptor antibody delivery system for treatment of CNS disorders with neurotrophic proteins.

Aging↗
PubMed1996

Cholinergic deafferentation enhances rat hippocampal pyramidal neuron responsiveness to locally applied nicotine.

We tested whether cholinergic denervation of the hippocampus of young rats would result in an enhancement of CA1 pyramidal cell responsiveness to nicotine. Electrolytic lesions of the medial septal area were performed in young male Fisher 344 rats. One month later the rats were anesthetized with pentobarbital and nicotine was locally applied to CA1 pyramidal neurons using pressure microejection. The dose of nicotine required to excite the pyramidal neurons was significantly lower for cells recorded from rats with septal lesions. However, no changes in hippocampal cytisine or alpha-bungarotoxin binding were found.

Alkaloids↗
PubMed1996

Evidence for DNA fragmentation in the CNS of aged Fischer-344 rats.

The aged central nervous system (CNS) is characterized by a loss of neurons. Apoptosis has been reported to be responsible for neuronal death during development and may also be involved in some age-related neurodegenerative diseases of the CNS. No evidence is currently available as to whether apoptosis is also responsible for the loss of neurons associated with physiological aging. In this study, we have found fragmented DNA, a characteristic trait of cells undergoing apoptosis, in the hippocampus and, to a minor extent, in the frontal cortex and basal forebrain of aged (24-month-old) Fisher-344 rats, but not in the cerebellum. These data represent important evidence to support the idea that apoptosis may be associated with the neuronal death observed during normal aging.

Aging↗
PubMed1996

Synergy between chronic corticosterone and sodium azide treatments in producing a spatial learning deficit and inhibiting cytochrome oxidase activity.

Previously, we developed a rat model of persistent mitochondrial dysfunction based upon the chronic partial inhibition of the mitochondrial enzyme cytochrome oxidase (EC 1.9.3.1). Continuous systemic infusion of sodium azide at approximately 1 mg/kg per hr inhibited cytochrome oxidase activity and produced a spatial learning deficit. In other laboratories, glucocorticoids have been reported to exacerbate neuronal damage from various acute metabolic insults. Therefore, we tested the hypothesis that corticosterone, the primary glucocorticoid in the rat, would potentiate the sodium azide-induced learning deficit. To this end, we first identified nonimpairing doses of sodium azide (approximately 0.75 mg/kg per hr) and corticosterone (100-mg pellet, 3-week sustained-release). We now report that chronic co-administration of these individually nonimpairing treatments produced a severe learning deficit. Moreover, the low dose of corticosterone, which did not elevate serum corticosterone, acted synergistically with sodium azide to inhibit cytochrome oxidase activity. The latter result represents a previously unidentified effect of glucocorticoids that provides a candidate mechanism for glucocorticoid potentiation of neurotoxicity induced by metabolic insult. These results may have the clinical implication of expanding the definition of hypercortisolism in patient populations with compromised oxidative metabolism. Furthermore, they suggest that glucocorticoid treatment may contribute to pathology in disease or trauma conditions that involve metabolic insult.

Analysis of Variance↗
PubMed1996

Population pharmacokinetics of intravenous amiodarone in patients with refractory ventricular tachycardia/fibrillation.

A population approach was used to determine the pharmacokinetics of amiodarone in 245 patients receiving intravenous amiodarone for the short-term treatment of refractory, hemodynamically destabilizing, ventricular tachycardia and/or fibrillation. A two-compartment model employing proportional statistical models to estimate intersubject variability and an additive-proportional model to estimate residual error were found to best describe the data. The mean (% coefficient of variation, CV) value for clearance was 0.22 L/hr/kg (13%), central volume of distribution was 0.30 L/kg (11%), peripheral volume of distribution was 10.0 L/kg (9.5%), and intercompartmental clearance was 0.71 L/hr/kg (16%). The mean (%CV) intersubject variance estimates were 1.52 (31%) for clearance, 0.37 (46%) for central volume, 0.37 (67%) for peripheral volume, and 0.44 (39%) for intercompartmental clearance. The estimate of residual error (%CV) was 0.53 (13%). Age, gender, height, serum creatinine concentration, serum alkaline phosphatase activity, ejection fraction, and therapeutic response to treatment did not contribute to the variability in patient pharmacokinetics. It was concluded that the pharmacokinetic parameters of amiodarone in these patients were similar to those reported for healthy volunteers and were similarly variable. Estimates of pharmacokinetic parameters made during short periods of observation may not be entirely consistent with parameters estimated during prolonged periods of observation of healthy volunteers who receive single doses.

Aged↗
PubMed1996

Evidence for a paradoxical sleep window for place learning in the Morris water maze.

Sprague-Dawley rats were given 4 consecutive days of training in the hidden platform version of the Morris water maze. They were then given paradoxical sleep deprivation (PSD) for 12 h either immediately after each training session or after a 12-h delay. The former group showed impaired learning on the second day of training compared to the 12-h-delayed PSD group or a nondeprived control group. In a second experiment, three groups of rats were trained as before and then given PSD for a 4-h interval beginning either immediately after, 4 h after, or 8 h after the end of each training session. Only rats exposed to PSD during the period beginning 4 h after the end of training each day showed an acquisition deficit. In a third experiment, rats were trained in a visible platform version of the water maze and exposed to PSD for a 12-h period either beginning immediately after the last training trial each day or after a 12-h rest delay. Neither of these groups was impaired on the task compared to a non-PSD control group. These results suggest that there is a PS window for place, but not cue, learning in the Morris water maze.

Animals↗
PubMed1996

Effects of neonatal dopamine depletion on sensory inhibition in the rat.

Central dopamine systems appear to play an important role in sensory information processing. In particular, the filtering (or gating) of repetitive auditory stimuli is modulated by pharmacological manipulations that affect dopaminergic neurotransmission. The present study further addressed the role of dopamine in auditory gating. Three-day-old male Sprague-Dawley rats, pretreated with desipramine, received intracisternal injections of 6-hydroxydopamine (6-OHDA; 75 micrograms in 10 microliters) or the vehicle. At 4 months of age the rats were implanted for evoked potential recording and auditory gating was assessed using a paired click paradigm. Neonatally administered 6-OHDA did not alter gating in the adult rats. However, unlike for the control group, systemic amphetamine (1.83 mg/kg, IP) failed to disrupt gating in the treated rats. Apomorphine (1.0 mg/kg, SC) disrupted gating in both groups. Neonatal 6-OHDA treatment caused significant reductions in dopamine levels in the striatum, nucleus accumbens, and substantia nigra/ventral tegmental regions. There was an inverse relationship between substantia nigra/ ventral tegmental area dopamine levels and auditory gating. Overall, the results suggest that amphetamine-induced auditory gating loss requires presynaptic dopamine release, but that the deficiency occurs through postsynaptic dopamine receptor activation.

Animals↗
PubMed1996

Genetic correlation of inhibitory gating of hippocampal auditory evoked response and alpha-bungarotoxin-binding nicotinic cholinergic receptors in inbred mouse strains.

One function of the hippocampus is to ascertain the novelty of incoming sensations and encode significant new information into memory. The regulation of response to repeated stimuli may prevent overloading of this function by redundant sensory input. Recent pharmacological studies implicate the role of alpha-bungarotoxin-sensitive nicotinic cholinergic receptors in the inhibition of hippocampal response to repeated auditory stimuli. The number of hippocampal alpha-bungarotoxin-sensitive receptors has a major genetic determinant, as demonstrated by a significant variance between different inbred mouse strains. The purpose of the present study was to determine whether there was a related genetic correlation for the gating of auditory response. Nine inbred mouse strains, representing a continuum of hippocampal alpha-bungarotoxin binding, were tested for the electrophysiological response to repeated auditory stimulation, followed by whole hippocampus membrane alpha-bungarotoxin binding studies. Several parameters of the auditory evoked response showed significant genetic variance over the nine strains, and a significant correlation was found between hippocampal alpha-bungarotoxin binding and both the amplitude of the initial evoked response and its inhibition to repeated auditory stimuli. There was no correlation of the auditory evoked response with high-affinity nicotine binding. These data further support the hypothesis that alpha-bungarotoxin-sensitive nicotinic receptors are involved in the regulation of hippocampal response to repeated auditory stimuli and suggest that this function is genetically controlled.

Acoustic Stimulation↗
PubMed1996

Psychological stress impairs spatial working memory: relevance to electrophysiological studies of hippocampal function.

Stress blocks hippocampal primed-burst potentiation, a low threshold form of long-term potentiation, thereby suggesting that stress should also impair hippocampal-dependent memory. Therefore, the effects of stress on working (hippocampal-dependent) and reference (hippocampal-independent) memory were evaluated. Rats foraged for food in seven arms of a 14-arm radial maze. After they ate the food in four of the seven baited arms, they were placed in an unfamiliar environment (stress) for a 4-hr delay. At the end of the delay they were returned to the maze to locate the food in the 3 remaining baited arms. Stress impaired only working memory. Stress interfered with the retrieval of previously stored information (retrograde amnesia), but did not produce anterograde amnesia. Stress appears to induce a transient disruption of hippocampal function, which is revealed behaviorally as retrograde amnesia and physiologically as a blockade of synaptic plasticity.

Amnesia, Retrograde↗
PubMed1996

Chronic in vivo sodium azide infusion induces selective and stable inhibition of cytochrome c oxidase.

The effect of chronic subcutaneous infusion of sodium azide on the activity of mitochondrial respiratory chain enzymes was investigated in Sprague-Dawley rats. Treatment with approximately 1 mg/kg/h sodium azide induced chronic, partial inhibition of cytochrome c oxidase, whereas the activities of respiratory complexes I and III were not significantly affected. The inhibition of cytochrome c oxidase was evident by 7 days after infusion began, and the effect was stable for at least 3 weeks. The selectivity of azide for cytochrome c oxidase is discussed in the context of other findings of azide effects on enzymes. The results of the present study indicate that the sodium azide infusion paradigm described here provides a useful tool for the evaluation of selective and stable cytochrome oxidase inhibition in vivo.

Analysis of Variance↗
PubMed1995

Chronic sodium azide treatment decreases membrane-bound protein kinase C activity in the rat hippocampus.

Chronic administration of sodium azide in rats inhibits cytochrome oxidase and produces learning and memory deficits. The present experiment tested the hypothesis that chronic sodium azide treatment might also alter protein kinase C activation. Continuous infusion of sodium azide (400 micrograms/h, sc) in rats for 2 weeks significantly decreases membrane-bound protein kinase C in hippocampus, but not frontal cortex, temporal cortex, or cerebellum. Since protein kinase C activation is correlated with hippocampus-dependent learning, these results suggest a possible biochemical mechanism for azide-induced impairment of learning.

Animals↗
PubMed1995

Regional brain effects of sodium azide treatment on cytochrome oxidase activity: a quantitative histochemical study.

The objective of the present study was to determine if regional variation in brain cytochrome oxidase activity was observed following systemic administration of sodium azide. An image analysis system calibrated with internal standards of known cytochrome oxidase activity was used to quantify cytochrome oxidase in histochemically stained brain sections. Rats receiving chronic infusion of sodium azide (400 micrograms/hr), which were sacrificed after two weeks, showed a substantial decrease in brain cytochrome oxidase activity over those infused with saline. All of the 22 regions sampled from telencephalic, diencephalic, and mesencephalic levels, showed a significant activity reduction which ranged between 26% and 37%. The regions that appeared significantly more vulnerable to the sodium azide effects were the mesencephalic reticular formation and the central amygdala, which displayed the largest decrease in activity. In addition, interregional correlations of activity showed a deeply modified pattern of correlative metabolic activity between hippocampal, amygdaloid and cortical areas after azide treatment. The regional effects found were consistent with azide-induced learning and memory dysfunctions.

Animals↗
PubMed1995

Nicotinic cholinergic normalization of amphetamine-induced loss of auditory gating in freely moving rats.

The impairment in normal sensory processing which is usually observed in schizophrenics has been demonstrated using a paired-stimulus paradigm. Normal individuals show a diminished midlatency evoked potential response to the second of a pair of clicks given at a 0.5-s interval. This phenomenon is termed auditory "gating". Schizophrenics routinely fail to suppress their response to the second click in this paradigm; thus, they do not gate. Heavy tobacco use is common among schizophrenics and it has recently been shown that nicotine causes a transient normalization of auditory gating in these individuals. Our laboratory has been utilizing animal models to investigate the sensory deficit observed in schizophrenia. In the present study, rats were administered amphetamine to produce a schizophrenia-like loss of auditory gating. They were then given nicotine, which resulted in a dose-dependent normalization of the amphetamine-induced loss of gating. This effect was blocked by concurrent central administration of d-tubocurarine. Neither nicotine nor d-tubocurarine had any effect on auditory gating when administered alone. These data are in agreement with the human studies showing normalization of auditory gating with nicotine administration and suggest a possible role for the nicotinic cholinergic receptor in the modulation of auditory gating in the rat model.

Amphetamine↗
PubMed1995

Long-term potentiation disrupts auditory gating in the rat hippocampus.

The consequence of long-term potentiation (LTP) of hippocampal commissural inputs was investigated in an auditory gating paradigm. Auditory evoked potentials (AEPs) were recorded in the CA3b region of the hippocampus of rats anesthesitized with chloral hydrate. Two tones were delivered 0.5 sec apart; in this paradigm, the second AEP is diminished compared to the first. Electrical stimulation was applied to hippocampal commissural fibers to generate field potentials and population spikes which were recorded at the same site as the AEPs. LTP of the commissural input (initiated by three trains of 250 Hz/1 sec stimulation) was associated with changes in the AEPs: on average, the response to the first tone decreased and the response to the second tone increased, resulting in the disruption of auditory gating. When high-frequency stimulation of the commissural input failed to result in LTP, no effect on the AEPs was seen. If 3-(2-carboxypiperazin-4-yl)-propyl-L-phosphonic acid (CPP; 6 mg/kg, i.p.), an antagonist to the NMDA subclass of glutamate receptors, was administered prior to high-frequency stimulation, LTP induction was blocked and AEPs were not affected. Finally, reversal of LTP, achieved by high-frequency stimulation of CA3 input that was heterosynaptic to the particular commissural fibers at which the LTP was originally generated, caused disrupted auditory gating to return to normal. A model of reciprocal LTP and heterosynaptic depression of commissural and auditory input pathways is proposed to explain these findings.

Acoustic Stimulation↗