Biomedical subjects

H A Tilson

Publications and source records attributed to H A Tilson.

At least 73 records · Page 4Linked to original sources

PubMed1991

Extracellular concentrations of amino acid transmitters in ventral hippocampus during and after the development of kindling.

This study examined the possible involvement of amino acid release from ventral hippocampus in the establishment and maintenance of kindling in rats. Release of amino acids from ventral hippocampus was measured by microdialysis coupled with high-performance liquid chromatography. Samples were obtained by microdialysis perfusion of freely moving animals receiving deep prepiriform cortex (DPC) electrical stimulation. Samples of perfusate were collected before, during and after kindling was established. DPC kindling stimulation significantly increased concentrations of glutamate (Glu) and glycine (Gly) in perfusate from ventral hippocampus during kindling. Increased basal release of Glu was evident up to 30 days after the last electrical stimulation. We conclude that release of Glu and Gly in the ventral hippocampus may play an important role during establishment, but not in maintenance of kindling.

Amino Acids↗

PubMed1991

Decreased glutamate release correlates with elevated dynorphin content in the hippocampus of aged rats with spatial learning deficits.

The effects of aging on extracellular glutamate and tissue dynorphin content in the hippocampus were examined in Fischer-344 rats. Young adult (4-month-old) and aged (24-month-old) rats were trained to find a hidden platform in the Morris water task. Aged rats were unable to acquire the spatial learning task as rapidly as young controls. Following behavioral testing, an in vivo microdialysis perfusion method was used to determine extracellular glutamate levels in the hippocampus. There was a 25-35% reduction in extracellular glutamate concentration in both dorsal and ventral hippocampus of aged rats compared to young rats, in the absence of any change in tissue glutamate levels. Radioimmunoassay showed an increase in dynorphin A(1-8)-like immunoreactivity [DYN-A(1-8)LI] in both dorsal and ventral hippocampus, but not striatum, of aged rats. Immunocytochemistry indicated that this increase was localized to the dentate granule cells and mossy fibers. Furthermore, among the aged rats the increase in DYN-A(1-8)LI was inversely correlated with the decrease in extracellular glutamate. These results suggest that the disregulation of dynorphin observed in cognitively impaired aged rats is related to reduced excitatory transmission within the hippocampal formation.

Aging↗

PubMed1991

The effects of NGF and fetal cell transplants on spatial learning after intradentate administration of colchicine.

This study was performed to assess the effects of NGF infusion alone or in combination with fetal hippocampal transplants on recovery of function after damage to hippocampal dentate granule cells. Two groups of male Fischer-344 rats received bilateral infusions of colchicine (COLCH; 2.5 micrograms/site) or artificial cerebrospinal fluid (ACSF; 0.5 microliter) through chronic indwelling cannulae into the dentate gyrus. At the time of COLCH injection, a unilateral intracerebroventricular (ICV) cannula was implanted. One week later, when animals were tested in activity chambers for 60 min, COLCH-treated rats showed a significant increase in spontaneous locomotor activity. Two weeks after COLCH treatment, animals were assigned to various post-treatment groups and received 1.0 microliter of rat fetal hippocampal cell suspensions (ED-17 or 18) or Earle's basic salt solution in the same site as previous hippocampal infusions. Modified Alzet miniosmotic pumps (0.25 microliter/h) containing NGF (10 ng/microliter) or ACSF with cytochrome C (20 ng/microliter) were implanted subcutaneously and attached to the previously implanted ICV cannulae. The animals were tested for learning ability in a Morris water maze task starting 6 or 12 weeks post-COLCH. During both test periods, COLCH lesions significantly impaired acquisition and retention. At 6 weeks postlesion, NGF treatment ameliorated this COLCH-induced behavioral deficit while the presence of transplants did not ameliorate the COLCH-induced learning deficit. COLCH/transplant/NGF-treated rats performed better than both COLCH-lesioned rats with or without transplants. At 12 weeks postlesion COLCH-induced behavioral deficits were not ameliorated by NGF or transplants. Morphological examination performed after behavioral testing confirmed the presence of viable transplants and COLCH-induced granule cell loss. Exogenous NGF infusions appeared to have no effect on the morphological measures taken. These data demonstrate a time-dependent facilitative effect of exogenously applied NGF on functional deficiencies produced by experimentally induced neurodegeneration in the dentate gyrus of the hippocampus.

Animals↗

PubMed1991

Age-dependent changes in receptor-stimulated phosphoinositide turnover in the rat hippocampus.

To study the changes in the hippocampal cholinergic system of chronologically old and behaviorally impaired animals, old (21 months of age) and young (3 months of age) male, Fischer-344 rats were used. The aged animals were tested on a reference memory task (Morris water maze) and found to be functionally impaired as compared to the young controls. Carbachol-stimulated phosphoinositide metabolism was measured in hippocampal slices from young and old rats. Slices were prelabeled with 3H-inositol for 120 min and subjected to muscarinic stimulation in the presence of lithium. Following extraction of the slices with acidified solvent mixture, the inositolphosphates present in the aqueous fraction were isolated by ion exchange chromatography. Receptor-stimulated release of inositolphosphates (IPs) was found to be increased in the hippocampus of older animals. This age-related enhancement of IP release was in contrast to the decrease in choline acetyltransferase (CHAT) activity in the hippocampus. We postulate that alterations in the G-protein coupling with the muscarinic receptor leads to an increase in the phosphoinositide turnover in part as a compensatory mechanism for neuronal cell death and reduced transmitter levels.

Aging↗

PubMed1991

Long-term changes in phosphoinositide hydrolysis following colchicine lesions of the nucleus basalis magnocellularis.

The effect of bilateral colchicine lesions of the nucleus basalis magnocellularis (NBM) on agonist-stimulated phosphoinositide (PI) hydrolysis was examined in cortical slices 1, 3, or 14 months after surgery. Colchicine lesions resulted in a loss of acetylcholinesterase staining in the cortex which recovered to control levels by 14 months. Choline acetyltransferase activity in the cortex was decreased by 43% one month after lesioning, but returned to control levels by 3 months. In vitro stimulation with carbachol produced a concentration-dependent increase in PI hydrolysis, which was enhanced 3 and 14 months after NBM lesions. Norepinephrine and quisqualate-stimulated PI hydrolysis was also enhanced 14 months after NBM lesions. These results suggest a slow up-regulation of postsynaptic receptor function following presynaptic loss of transmitter.

Acetylcholinesterase↗

PubMed1991

Compensatory alterations in receptor-stimulated phosphoinositide hydrolysis in the hippocampus vary as a function of dose of colchicine.

The stimulation of inositol phospholipid (PI) hydrolysis by various receptor agonists was measured in the hippocampus of rats 12 weeks after various concentrations (0.5-2.0 microgram/site) of colchicine were infused into the dentate gyrus. Colchicine produced a dose-related decrease in the average width and length of the granule cell line; the pyramidal cells in CA1 and CA3 regions of the hippocampus were affected only at higher concentrations of colchicine. Compensatory increases in receptor-mediated hydrolysis of phosphoinositides (PI) in hippocampal slices were seen at 100 microns carbachol and ibotenic acid in rats receiving 1.5-3.5 microgram colchicine/site. Compensatory increases in norepinephrine (100 microns) and N-methyl-D-aspartate (100 microns) stimulated PI were seen at 2.5-3.5 and 3.5 micrograms colchicine/site, respectively. Compensatory increases in PI hydrolysis were not seen in slices from animals receiving 0.5 microgram colchicine/site. These data support the hypothesis that the signal transduction system in the hippocampus undergoes a compensatory change following experimentally induced destruction of dentate gyrus granule cells. In addition, these changes occur for more than one neurotransmitter and the alterations vary as a function of the size of the lesion.

Animals↗

PubMed1991

Long-term behavioral and neurochemical effects of intradentate administration of colchicine in rats.

Previous work in our laboratory has shown that the intradentate administration of colchicine produces time-dependent behavioral and neurochemical changes. Deficits in learning and memory and alterations in the signal transduction process for the cholinergic muscarinic receptor have been observed up to 12 weeks after colchicine treatment. To study the long-term effects of colchicine administration on cognitive function and the cholinergic system, 6 month-old male, Fischer-344 rats were injected with 2.5 micrograms of colchicine bilaterally in the dorsal and ventral hippocampus. Twelve months later the animals were tested for the acquisition of a spatial reference memory task in the Morris water maze for 8 days, with 4 trials of 60 seconds each day. At the completion of the behavioral testing, one set of rats from each treatment group was used for histochemical studies. The remaining animals were sacrificed, the hippocampi removed and used for the estimation of receptor-stimulated turnover of phosphoinositides (Pl). [3H]-inositol was incorporated into the hippocampal slices, and various receptor agonists (carbachol, norepinephrine, serotonin) used to stimulate Pl turnover in the presence of lithium. A significant deficit in acquisition in the water maze was observed in animals 1 year after colchicine administration. Neurochemical studies showed an increase in carbachol-induced Pl metabolism in the rat hippocampus 1 year post-lesion with colchicine. However, in contrast to results obtained 12 weeks after lesioning, no significant changes were observed in norepinephrine or serotonin-induced Pl metabolism 1 year after lesioning. Pirenzepine, a M1 receptor antagonist, produced a greater degree of inhibition (62%) in lesioned animals as compared to the age-matched controls (20%). Increased staining for acetylcholinesterase was found in the hippocampus of treated rats. This effect is similar to that observed 12 weeks after lesioning. These data suggest that the effects of colchicine on the cholinergic system are long-lasting and can be observed a year after treatment.

Acetylcholine↗

PubMed1990

Alterations in acetylcholine-induced stimulation of inositol phospholipid hydrolysis in the dorsal hippocampus of kindled rats.

Agonist-induced turnover or release of inositolphosphates (IP) was studied in the dorsal and the ventral hippocampus 24 h, 1 month, and 3 months after the last electrical stimulus of kindled rats. A significant increase in acetylcholine (ACh)-stimulated IP turnover was observed in dorsal, but not ventral, hippocampus 24 h and 1 month after the last electrical stimulus. However, this effect was not evident 3 months after kindling. The excitatory amino acids (quisqualic acid and ibotenic acid) at the concentrations used, however, failed to produce any change in receptor-stimulated release or turnover of IP. Thus the changes in ACh-induced IP release, although long-term, are not permanent and do not appear to be released to the neurobiological alterations associated with the long-term maintenance of the kindling phenomenon.

Acetylcholine↗

PubMed1990

Granule cells in the ventral, but not dorsal, dentate gyrus are essential for kainic acid-induced wet dog shakes.

Intrahippocampal injections of colchicine selectively destroy dentate granule cells. Wet dog shaking elicited by systemic administration of kainic acid is eliminated by bilateral destruction of ventral dentate granule cells but unaffected by bilateral destruction of dorsal dentate granule cells. This implies that ventral dentate granule cells are essential for the generation of kainic acid-induced wet dog shakes.

Animals↗

PubMed1990

Neurotoxic lesions of the nucleus basalis induced by colchicine: effects on spatial navigation in the water maze.

Neuronal loss in the nucleus basalis magnocellularis (NBM) has been consistently associated with learning and memory impairments. Previous studies have used excitotoxicants such as kainic acid or ibotenic acid to examine the behavioral consequences of NBM lesions. In the present study, rats were given bilateral injections of the neurotoxicant colchicine (1.0 micrograms/site) into the NBM and examined for changes in learning and memory. Unlike excitotoxicants, which can produce extensive subcortical damage, colchicine produced a lesion limited to the site of injection. Histological studies demonstrated that colchicine decreased the number of choline acetyltransferase (ChAT)-positive cells in the NBM, and resulted in a marked loss of cortical acetylcholinesterase staining. Separate neurochemical analysis showed that colchicine lesions decreased ChAT activity in the neocortex but not the hippocampus or caudate nucleus. Similar to previous studies, rats with NBM lesions showed a large deficit in a passive avoidance task. Lesions of the NBM impaired acquisition of a reference memory task in the Morris water maze. However, the deficit was transient and with continued training lesioned rats performed as well as controls. In a reversal test in the water maze the learning deficit reappeared. These data suggest that colchicine may be useful in producing lesions of the NBM, which primarily affects the rate of acquisition of a spatial reference memory task.

Animals↗

PubMed1990

Kainate-induced functional deficits are not blocked by MK-801.

Male, Fischer-344 rats were pretreated with MK-801 (0.1, 1.0 or 10.0 mg/kg, i.p.) prior to bilateral injection of kainate (0.33 micrograms/site) into the dorsal and ventral hippocampus. Kainate impaired the acquisition of a water maze acquisition task 4 weeks after surgery, an effect not attenuated by pretreatment with MK-801. However, higher doses (1.0 and 10.0 mg/kg) of MK-801 reduced the amount of kainate-induced granule cell and to some extent CA1 pyramidal cell damage in the hippocampus. Kainate-induced CA3/CA4 damage was not affected by MK-801 pretreatment. MK-801 (10 mg/kg) also reduced the amount of thalamic damage produced by kainate. These data support the conclusion that intrahippocampal kainate-induced destruction of CA3/CA4 pyramidal cells is mediated by non-N-methyl-D-aspartate (non-NMDA) receptors and that kainate-induced loss of these cells is associated with the neurobehavioral effects of intrahippocampally administered kainate.

Animals↗

PubMed1990

Acute exposure to tris(2-chloroethyl)phosphate produces hippocampal neuronal loss and impairs learning in rats.

Adult female, Fischer-344 rats were exposed to 275 mg/kg of tris(2-chloroethyl)phosphate (TRCP) by gavage. TRCP produced consistent signs of convulsive activity within 60-90 min after dosing and extensive loss of CAT hippocampal pyramidal cells when examined 7 days after dosing. At the light microscopic level, toxic effects of TRCP on pyramidal cells in the CA3 and CA4 regions and on granule cells in the dentate gyrus were less severe than those on the CA1 cells. The seizure-related and neurohistological effects of TRCP were significantly attenuated by pretreatment with atropine or chlordizepoxide, suggesting that the hippocampal damage was related to the seizures produced by TRCP. In a second experiment designed to assess the potential health risk associated with TRCP, exposed rats were mildly impaired in the acquisition of a reference memory task in a water maze. However, TRCP-exposed rats were consistently impaired in performing a repeated acquisition task in the water maze. These data underscore the potential health risk associated with exposure to TRCP and support the conclusion that the hippocampus is intimately involved in spatial memory in rats.

Animals↗

PubMed1990

MK-801 impedes the acquisition of a spatial memory task in rats.

Several studies have reported that MK-801 impairs the acquisition of various learning and memory tasks, while others suggest that MK-801 may interfere with performance rather than having a specific effect on memory. To characterize further the effects of MK-801 on learning and memory, MK-801 (0.05 mg/kg, SC) was administered prior to or immediately after learning trials in a trial-independent water maze task. Since MK-801 may affect nonassociative variables that may influence learning and memory, motor activity and general reactivity measures were also determined for 0.0125, 0.025, or 0.05 mg/kg of MK-801 administered SC. Since MK-801 may also be used to treat children with epilepsy, we investigated the possible persistent cognitive effects on neonates. MK-801 (0.02 mg/kg, SC) was administered at postnatal days 9-15 and tested in the same task as above starting at day 36 of age. There were no persistent effects of neonatal treatment. However, in adult rats, MK-801 impaired the acquisition of the water maze task but did not affect performance during a recall task in the same apparatus. At doses affecting learning, there were no effects on motor activity or general reactivity in adult rats. These results are consistent with the conclusion that MK-801 interferes with acquisition of spatial learning in the rat.

Aging↗

PubMed1990

Microinjection of dynorphin into the hippocampus impairs spatial learning in rats.

The effect of hippocampal dynorphin administration on learning and memory was examined in spatial and nonspatial tasks. Bilateral infusion of dynorphin A(1-8) (DYN; 10 or 20 micrograms in one microliters) into the dorsal hippocampus resulted in a dose-related impairment of spatial working memory in a radial maze win-stay task. Subsequent experiments found that acquisition of a reference memory task in the water maze was impaired by DYN injections (20 micrograms/microliters) in the dorsal hippocampus, but not in the ventral hippocampus, and that this impairment could be blocked by naloxone. In a nonspatial task, posttraining DYN injections in the dorsal hippocampus had no effect on retention of step-through passive avoidance. These results suggest that dynorphin specifically interferes with spatial learning and memory, and that this effect is mediated by opioid receptors in the dorsal hippocampus.

Animals↗

PubMed1990

Influence of nigrostriatal dopaminergic tone on the biosynthesis of dynorphin and enkephalin in rat striatum.

The purpose of this study was to obtain direct evidence that the nigrostriatal dopamine (DA) pathway modulates the metabolism of striatal dynorphin and [Met5]-enkephalin. This was achieved by repeated injections of apomorphine (APO) or D-amphetamine (AMP) in unilateral nigral 6-hydroxydopamine (6-OHDA)-lesioned rats. Three weeks after a 6-OHDA lesion, dynorphin A(1-8)-like immunoreactivity (DN-LI) and the level of mRNA encoding prodynorphin in the striatum on the lesioned side were decreased compared with the contralateral control side. Activation of DA receptors by 7 daily injections of APO (5 mg/kg, Bid, s.c.), however, caused a large increase (3- to 4-fold of saline control) in striatal levels of DN-LI and prodynorphin mRNA on the 6-OHDA lesioned side, which is far greater than the increase on the contralateral side (2-fold of saline control). Presumably, the potentiated effect of APO in 6-OHDA lesioned rats is due to hypersensitivity of DA receptors resulting from DA denervation. Seven daily injections of AMP (5 mg/kg, Bid, s.c.), a DA-releasing agent, increased striatal DN-LI (187% of saline control) on the non-lesioned side, but not on the 6-OHDA-lesioned side. Taken together, the data indicate that the nigrostriatal pathway exerts a tonic excitatory influence over the biosynthesis of dynorphin and that this influence is not maximal since an additional increase in dopaminergic tone further increases the expression of dynorphin. In contrast, [Met5]-enkephalin-like immunoreactivity (ME-LI) in the striatum was increased by a 6-OHDA-lesion (145% of contralateral control), which was blocked by repeated administration of APO but not AMP.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1990

Neurochemical recovery in the neocortex after colchicine lesions of the nucleus basalis magnocellularis in rats.

Neurochemical recovery was investigated in male, Fischer-344 rats up to 3 months after lesions of the nucleus basalis. Bilateral injections of colchicine (1.0 micrograms/site) into the nucleus basalis magnocellularis (NBM) resulted in a 30% decrease in choline acetyltransferase (ChAT) activity in frontal cortex 4 weeks after surgery, compared to unlesioned controls. ChAT activity in the frontal cortex gradually recovered to control levels by 12 weeks. The loss of ChAT-immunoreactive neurons in the NBM observed 4 weeks after surgery was still evident 12 weeks after surgery. These results suggest that surviving cholinergic neurons in the NBM contribute to recovery of ChAT activity in the neocortex.

Animals↗

PubMed1990

Behavioral indices of neurotoxicity.

There are many classes of chemicals widely used in a number of commercial and industrial processes having a potential to affect adversely the nervous system. Because of their relative sensitivity to some agents and general noninvasive characteristics, functional measurements of neurotoxicity are being used with greater frequency, especially at the level of hazard identification. The neurobehavioral test battery used by the National Toxicology Program (NTP) includes motor activity, fore- and hindlimb grip strength, acoustic startle response, responsiveness to an adverse thermal stimulus and general health and clinical measures (body weight, autonomic signs, tremor, convulsions). These tests have been used in nearly 40 studies involving various dosing regimens with rats and mice. The NTP battery shows several salient features of an effective screen, including the ability to differentiate known neurotoxicants from nonneurotoxicants, identify certain types of neurological sequelae or profiles of neurotoxic effects and construct dose- and time-response data in a screening context. The extent to which the NTP battery has predictive validity is still being evaluated.

Animals↗

PubMed1990

Systemic administration of kainic acid increases GABA levels in perfusate from the hippocampus of rats in vivo.

The ventral hippocampi of male, Fischer-344 rats were implanted with microdialysis probes and the effects of systemically administered kainic acid (KA) (8 mg/kg, s.c.) on the in vivo release of amino acids were measured for four hours after administration. In order to measure GABA release in vivo, gamma-vinyl-GABA (GVG), an irreversible inhibitor of GABA transaminase, was injected intrahippocampally prior to perfusion. GVG pretreatment resulted in measurable levels of GABA in the perfusate without significant effects on the release of aspartate, glutamate, glutamine, glycine or taurine. Following GVG pretreatment systemic administration of KA produced a time-dependent increase in GABA, as well as all other amino acids except glutamine, which was initially decreased. These results show for the first time that systemically administered KA increases extracellular GABA levels, an effect previously reported only in vitro. These data suggest that prior to destruction of GABA-containing interneurons in the hippocampus, there is an increased activity of those GABA interneurons reflected as an increase in extracellular GABA levels.

Amino Acids↗