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Biomedical subjects

H A Tilson

Publications and source records attributed to H A Tilson.

At least 91 records · Page 5Linked to original sources
PubMed1990

Stereospecificity of N-MDA-induced functional deficits.

Male Fischer-344N rats were pretreated bilaterally with intrahippocampal (D) (-)-2-amino-7-phosphonoheptanoic acid [(D)-2-APH] (2.5, 5.0 and 10 micrograms/site), a competitive N-methyl-d-aspartate (NMDA) antagonist, prior to the administration of bilateral N-MDA (10 micrograms/site). (D)-2-APH completely attenuated NMDA-induced hyperactivity and water maze acquisition deficits. (D)-2-APH also attenuated hippocampal pyramidal and granule cell loss induced by NMDA. These effects were stereospecific since pretreatment of the isomer L-(+)-2-APH (10 micrograms/site) had no effect on hyperactivity and water maze acquisition deficits produced by NMDA. In addition, (L)-2-APH provided no protection from NMDA-induced hippocampal granule and pyramidal cell loss. Together, these results suggest that the intrahippocampal administration of NMDA might serve as a useful in vivo model for evaluating the effects associated with the overactivation of NMDA receptors.

2-Amino-5-phosphonovalerate↗
PubMed1990

Neurotoxic effects of colchicine.

Neurotoxicants have found increasing use as tools to study the structure and function of the central nervous system. One class of compounds which block mitosis and disrupt axoplasmic transport includes colchicine, a chemical which is highly toxic to certain neuronal populations. Colchicine administered directly into the hippocampus of rats results in the preferential destruction of dentate gyrus granule cells without affecting the surrounding pyramidal cells. Injection of colchicine into other brain areas also destroys neurons but with less selectivity than is observed in the hippocampus. The neurotoxicity of colchicine appears to be related to the ability to bind to tubulin, although its exact mechanism remains to be elucidated.

Animals↗
PubMed1989

Colchicine-induced alterations of reference memory in rats: role of spatial versus non-spatial task components.

Male, Fischer-344 rats received bilateral injections of 2.5 micrograms of colchicine per site in the dorsal and ventral hippocampus. Intradentate colchicine preferentially destroyed dentate granule cells. Subsequent behavioral studies showed that 3 weeks after dosing, colchicine impaired the acquisition of a spatial, reference memory task in the Morris water maze. In a second group of rats, which were trained in the water maze prior to dosing, intradentate colchicine impaired retention of this task when rats were tested 3 weeks later. The acquisition of non-spatial reference memory task, an autoshape of a lever touch response in an operant chamber, was facilitated by prior administration of colchicine. Facilitative effects of colchicine were seen if delays of 0, 4, or 6 s were interposed between response and presentation of food reinforcement. If rats were trained to lever-touch with either a 0- or 4-s delay between response and reinforcement, intradentate colchicine had no effect on retention of the response 3 weeks later. These data are in accord with the conclusion that the dentate gyrus plays an important role in the acquisition of new information and retrieval of previously learned material and is an integral neural substrate for reference memory involving a spatial component.

Animals↗
PubMed1989

Functional deficits after sustained stimulation of the perforant path.

Several reports have implicated the overactivity of hippocampal glutaminergic systems in neurodegenerative conditions including Senile dementia of the Alzheimer's type (SDAT). The neurobiological effects of hippocampal glutaminergic hyperactivity were studied by perforant pathway stimulation. Forty-five minutes of sustained perforant pathway stimulation produced a 50% or greater increase in motor activity 1, 2, and 3 weeks after stimulation. Robust retention deficits in a 48-h step-through passive avoidance task were evident 2 weeks post-stimulation. Furthermore, animals receiving stimulation were impaired in the acquisition of a spatial task in the Morris water maze. Stimulated animals exhibited little reduction in their escape latencies over the testing period. The learning and memory deficits were associated with a loss of CA1 and CA3 pyramidal cells and pretreatment with the N-methyl-D-aspartate antagonist MK-801 reduced this cell loss, particularly in the CA1 region of the hippocampus. These results suggest that sustained stimulation of the perforant pathway may be useful in studying neurological deficits associated with glutaminergic hyperfunction.

Animals↗
PubMed1989

Colchicine-induced alterations in receptor-stimulated phosphoinositide hydrolysis in the rat hippocampus.

Intradentate administration of colchicine has been reported to affect the cholinergic muscarinic system in the hippocampus, causing a reduction in quinclidinylbenzilate binding sites and an increase in choline acetyltransferase activity. Since the cholinergic muscarinic system is coupled to the formation of inositolphosphates in the brain, the effect of intradentate administration of colchicine on the agonist-induced turnover of inositollipid was studied in rats. The animals were sacrificed 12 weeks after injection, and the hippocampi removed and sliced. [3H]Inositol was incorporated into slices in the presence of lithium, and carbachol, a cholinergic muscarinic receptor agonist, was used to study the stimulated turnover of inositollipids. Hippocampal slices taken from colchicine-treated rats showed an increased carbachol-stimulated accumulation of inositolmonophosphate. Thus, intradentate colchicine appears to alter the signal transduction process for the muscarinic cholinergic receptor in the hippocampus, a change that may be associated with compensatory processes following damage to the hippocampus.

Animals↗
PubMed1989

The role of 5HT1A receptors in the modulation of the acoustic startle reflex in rats.

The modulatory role of serotonin (5-HT) on the acoustic startle reflex was studied using 5-HT receptor agonists and antagonists. 8-Hydroxy-2-(di-n-propylamino) tetralin (8-OHDPAT) (1,2 and 4 mg/kg, SC) and 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) (1,2 and 4 mg/kg, IP), putative 5-HT1a receptor agonists, increased the magnitude of the startle reflex, while quipazine (5, 10 and 20 mg/kg, SC), an agonist with mixed 5-HT2 and 5-HT1b receptor activity, decreased startle responsiveness. Pretreatment of rats with ketanserin (1, 2 and 4 mg/kg, SC), a 5-HT2 receptor antagonist, had no significant effect on the activity of 8-OHDPAT, 5-MeODMT, or quipazine. Metergoline (0.25, 0.5, 1 and 2 mg/kg, SC), a mixed 5-HT1/5-HT2 receptor antagonist attenuated the augmentation of the reflex by 8-OHDPAT and 5-MeODMT and the suppression produced by quipazine. At the doses used, metergoline produced a non-dose-dependent increase in startle, while ketanserin had no effect. None of the agents specifically affected the ability of a prepulse stimulus to inhibit the acoustic startle response. These data suggest that 5-HT1a and 5-HT1b receptors play opposite roles in the modulation of the acoustic startle response and that 5-HT plays little, if any, role in the prepulse inhibition of the acoustic startle response.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1989

Colchicine administered into the area of the nucleus basalis decreases cortical nicotinic cholinergic receptors labelled by [3H]-acetylcholine.

Lesions in the nucleus basalis in the rat are known to decrease presynaptic markers for acetylcholine, including levels of cholineacetyltransferase (CHAT), high affinity uptake of choline and levels of acetylcholinesterase. Effects of lesions of the nucleus basalis on populations of nicotinic and muscarinic receptors are less well understood. After bilateral injection of the neurotoxic agent, colchicine into the nucleus basalis in the rat, levels of CHAT in the cerebral cortex were reduced 44%. Muscarinic cholinergic [( 3H]QNB) and dopaminergic [( 3H]spiroperidol) binding was not changed in the cortex, hippocampus or striatum. However, significant decreases in nicotinic binding sites, labelled by [( 3H]acetylcholine), were observed in the frontal cortex of nucleus basalis treated animals; scatchard plot analysis indicated a significant decrease in the number, but not affinity, of nicotinic binding sites. Colchicine injected into the nucleus basalis had no effect on the binding of [3H]acetylcholine in the hippocampus, but decreased binding of [3H]acetylcholine in the striatum. Subsequent experiments, in which colchicine was administered into the striatum at a site above the nucleus basalis had no significant effect on nicotinic binding in the striatum or frontal cortex. These results support the hypothesis that degeneration of the nucleus-basalis-cortical cholinergic pathway results in a loss of presynaptic nicotinic binding sites in the cortex as well as in the striatum (through transsynaptic degeneration of the cortico-striatal pathway).

Acetylcholine↗
PubMed1989

MK-801 prevents cognitive and behavioral deficits produced by NMDA receptor overstimulation in the rat hippocampus.

The overstimulation of receptors for L-glutamate, particularly those of the N-methyl-D-aspartate (NMDA) type, has been suggested to play a role in mediating damage in a variety of neurodegenerative conditions or disorders ranging from ischemia/hypoxia to senile dementia of the Alzheimer's type (SDAT). We report here that the functional deficits and histological damage mediated by the overactivation of NMDA receptors in the Fischer 344 rat hippocampus can be blocked effectively by systemic administration of the noncompetitive NMDA antagonist, MK-801. These results suggest that MK-801 may be effective clinically in attenuating memory loss and hippocampal damage in disorders associated with the overstimulation of NMDA receptors.

Animals↗
PubMed1989

Blockade of only spinal alpha 1 adrenoceptors is insufficient to attenuate DDT-induced alterations in motor function.

Male Fischer 344N rats were chronically implanted with an intrathecal cannula and gavaged with p,p'-DDT (1,1,1-trichloro-2,2-bis[p-chlorophenyl]ethane; 30 or 45 mg/kg) or corn oil. Seven hours later, subjects were intrathecally infused with vehicle, 15, 30, 60, or 120 micrograms of prazosin (an alpha 1-adrenergic antagonist). Spectral analysis of bodily movements was performed 7.5, 8, and 10 hr after DDT administration. In control rats, 15 micrograms of prazosin reduced the spectral profiles of spontaneous movements. A 30-micrograms dose produced motor impairments, without significantly changing the spectral profiles. Tremulous movements induced by DDT were unaffected by 15 or 30 micrograms, whereas 60 or 120 micrograms of intrathecal prazosin significantly reduced the spectral profiles of rats pretreated with 45 mg/kg of DDT. Other subjects were administered vehicle or DDT (45 mg/kg), intrathecally infused with 15 or 60 micrograms of prazosin (7 hr), and sacrificed (7.5 hr). Noncannulated rats were gavaged with 60 mg/kg of DDT, injected subcutaneously (sc) with 0.5 mg/kg of prazosin (5.5 hr), and sacrificed (8 hr). Cortical and spinal tissues were used in ex vivo binding assay utilizing [3H]prazosin. Fifteen or sixty micrograms of intrathecal prazosin occupied similar percentages of spinal [3H]prazosin binding sites, but produced a dose-related increase in cortical prazosin equivalents. Sixty micrograms of intrathecal or 0.5 mg/kg of sc prazosin resulted in similar concentrations of cortical prazosin equivalents. Together, these data indicate that while intrathecal prazosin will attenuate DDT-induced motor dysfunction, this effect requires blockade of alpha 1 adrenoceptors in regions other than solely the spinal cord.

Analysis of Variance↗
PubMed1989

Characterization of receptor-coupled phosphoinositide hydrolysis in the rat hippocampus after intradentate colchicine.

Lesions produced by intradentate hippocampal administration of colchicine have been reported to produce several time-dependent behavioral and neurochemical changes, including a possible change in the signal transduction process for the cholinergic muscarinic receptor. To characterize further the effects of colchicine on receptor-coupled hydrolysis of phosphoinositides, colchicine was injected stereotaxically into the dentate gyrus of rats at a dose of 2.5 micrograms/site. The animals were killed 1, 3, or 12 weeks after injection and the hippocampi removed and sliced. [3H]Inositol was incorporated into slices, and various receptor agonists known to stimulate inositol phosphate (IP) metabolism were studied. Colchicine administration altered agonist-stimulated turnover in the hippocampus in a time-dependent manner. This hyperstimulation was receptor-mediated, because it was blocked by pirenzepine. The hyperstimulation of turnover was observed also with norepinephrine and serotonin. Colchicine had no effect on IP turnover in vitro. The effect of the colchicine lesion was observed only in the hippocampus, because no change in cholinergic muscarinic receptor-stimulated phosphatidylinositol turnover was observed in the cortex. These studies indicate that intradentate administration of colchicine produces a compensatory change in the signal transduction process in the hippocampus detectable 12 weeks after the lesion.

Animals↗
PubMed1989

Results of a United States and Soviet Union joint project on nervous system effects of microwave radiation.

During the course of a formal program of cooperation between the United States and the Soviet Union concerning the biological effects of physical factors in the environment, it was concluded that duplicate projects should be initiated with the general goal of determining the most sensitive and valid test procedures for evaluating the effects of microwave radiation on the central nervous system. This report details an initial step in this direction. Male rats of the Fischer 344 strain were exposed or sham exposed to 10 mW/cm2 continuous wave microwave radiation at 2.45 GHz for a period of 7 hr. Animals were subjected to behavioral, biochemical, or electrophysiological measurements during and/or immediately after exposure. Behavioral tests used were passive avoidance and activity in an open field. Biochemical measurements were ATPase (Na+, K+; Mg2+, Ca2+) and K+ alkaline phosphatase activities. Electrophysiological measurements consisted of EEG frequency analysis. Neither group observed a significant effect of microwave irradiation on open field activity. Both groups observed changes in variability of the data obtained using the passive avoidance procedure, but not in the same parameters. The U.S. group, but not the USSR group, found significantly less Na+,K+-ATPase activity in the microwave-exposed animals compared to the sham exposed animals. Both groups found incidences of statistically significant effects in the power spectral analysis of EEG frequency, but not at the same frequency. The failure of both groups to substantiate the results of the other reinforces our contention that such duplicate projects are important and necessary.

Adenosine Triphosphatases↗
PubMed1989

The neurobehavioral consequences of N-methyl-D-aspartate (N-MDA) administration in rats.

Evidence is accumulating which suggests that brain damage associated with certain neurodegenerative conditions may be at least partially produced by the overactivation of N-methyl-D-aspartate receptors (N-MDA). To systematically examine the overactivation of N-MDA receptors, N-MDA was administered directly to the frontal cortex and to the hippocampus in rats. It was found that cortical application (1, 2, or 4 mg) had no effect on motor activity 1, 2, or 3 wk after surgery. Four mg N-MDA failed to affect acquisition of a water maze task despite large decreases in cortical width at the site of application. In addition, no alterations in striatal, hippocampal, or cortical cholineacetyltransferase (CHAT) activity were detected after cortical application. Intrahippocampal N-MDA (0, 2.5, 5.0, 10.0, 20.0 micrograms/site) increased motor activity in a dose dependent manner 1, 2, and 3 wk post-surgery. Furthermore, 10 micrograms/site significantly impaired water maze acquisition. Intrahippocampal N-MDA also increased hippocampal CHAT activity and resulted in a loss of pyramidal and dentate granule cells. These results suggest that N-MDA may serve as a useful tool in studying the effects of glutaminergic hyperfunction and its role in neurodegenerative disorders which involve the overactivation of N-MDA receptors.

Animals↗
PubMed1989

Oral administration of aspartame is not proconvulsant in rats.

These experiments examined the potential for single or repeated doses of aspartame to exacerbate or facilitate the production of seizures in Fischer-344 rats. In adult animals, 1,000 mg/kg of aspartame given by gavage acutely or over a 14 day period had no significant effect on the rate of kindling induced by stimulation of the prepyriform cortex. A single dose of 1,000 mg/kg of aspartame had no effect on the number of animals developing tonic seizures after electroconvulsive shock, nor did aspartame affect the frequency or duration of seizure activity after pentylenetetrazol. In a second series of studies, young male and female rats were dosed with 1,000 mg/kg of aspartame on day 3-13 or 21-35 of age. Prior exposure to aspartame had no significant effect on the rate of kindling at 90 days of age. These experiments indicate that aspartame does not act a pro-convulsant in rats.

Administration, Oral↗
PubMed1988

Intradentate colchicine impairs acquisition of a two-way active avoidance response in a Y-maze.

Male, Fischer-344 rats received bilateral injections of colchicine (2.0 micrograms/site) into the dorsal and ventral hippocampus to destroy dentate gyrus granule cells. Colchicine impaired the ability of rats to learn a brightness discrimination, active avoidance task in a Y-maze. Acquisition was measured in 120-trial sessions given once weekly for 3 or 4 weeks. In a second experiment, colchicine-treated rats were tested in a modified procedure in which only the tone warning stimulus and a light directional cue were presented; shock was not presented. Colchicine-treated rats showed an enhanced response bias under these conditions, selecting to go to the unlighted arm with a greater frequency than the control rats whenever the tone and light were activated. These data are consistent with other reports indicating that rats with hippocampal lesions are impaired in the acquisition of a simultaneous discrimination if a response bias exists to one of the choices.

Animals↗
PubMed1988

Fetal hippocampal cell suspensions ameliorate behavioral effects of intradentate colchicine in the rat.

Colchicine, a neurotoxin that preferentially destroys dentate gyrus granule cells and mossy fibers, was injected into the hippocampus of adult rats. Three weeks later, the rats were tested for colchicine-induced hypermotility after which they received fetal hippocampal explants. Locomotor activity was retested three weeks later, after which the rats were trained over a period of four weeks on a food-reinforced, spatial, working memory task in an 8-arm radial maze. Fetal hippocampal explants were found to attenuate significantly the colchicine-induced hypermotility and spatial learning deficits. Histological observations showed the presence of surviving hippocampal explants in both the lesioned and the control rat brains, suggesting that the presence of viable implants facilitates the recovery of behavioral function in rats with spatial memory deficits.

Animals↗
PubMed1988

Increased dopamine release from striata of rats after unilateral nigrostriatal bundle damage.

Dopaminergic control of striatal neurons is retained in rats sustaining lesions of the nigrostriatal bundle (NSB) as long as 10% of the projection remains, suggesting that enhanced efficiency of dopamine (DA) transmission may compensate for the denervation of the striatum. To examine this hypothesis we have studied the extracellular concentration of striatal DA using brain dialysis. In control rats, haloperidol (1 mg/kg, i.p.) or depolarization of striatal tissue with 25 mM KCl increased, and gamma-butyrolactone (500 mg/kg, i.p.) decreased DA and homovanillic acid (HVA) levels in striatal dialysates. Three weeks after unilateral injection of 6-hydroxydopamine (6-OHDA) to substantia nigra, DA content in the ipsilateral striatum was decreased by 60-98%. Nevertheless, extracellular DA concentration in the lesioned striata remained unchanged in rats with 60-90% DA depletions. More extensive lesions (96% DA depletion) were accompanied by 60% reduction in DA release. In contrast, extracellular HVA levels in the lesioned striata decreased proportionally to the depletion of tissue DA, indicating decreased inactivation of extracellular DA. We propose that the capacity of the residual DA terminals to maintain normal levels of extracellular DA after 60-90% NSB lesions may serve to compensate for the partial denervation of the striatal tissue. Disruption of striatal DA functions and postsynaptic supersensitivity after more extensive lesions may be associated with the failure of the NSB to fully compensate for loss of DA terminals. In striata contralateral to the 6-OHDA lesions, increased DA release was also observed. In addition, 60-90% ipsilateral DA depletions were accompanied by 32% and 42% increases in DA and HVA content in contralateral tissue, respectively. The possibility of the contralateral sprouting of DA terminals is discussed.

4-Butyrolactone↗
PubMed1988

Radial-arm maze deficits produced by colchicine administered into the area of the nucleus basalis are ameliorated by cholinergic agents.

Rats were given bilateral injections of colchicine into the area of the nucleus basalis. Colchicine produced dose-dependent alterations in the acquisition of a food-reinforced working-memory task. Colchicine-induced deficits in maze performance were attenuated by cholinergic agents, including physostigmine, RS-86 (2-ethyl-8-methyl-2,8-diazospiro-(4,5)-decan-1,3-dione-hydro bromide) and nicotine. Naloxone and vasopressin did not affect radial-arm maze performance of colchicine-treated rats. Subsequent neurochemical analysis showed that colchicine decreased choline acetyltransferase (ChAT) activity and levels of norepinephrine, dopamine, 3,4-dihydroxyphenylacetic acid, serotonin and 5-hydroxyindoleacetic acid in the neocortex. However, ChAT activity and other neurochemical measures were not altered in the hippocampus or corpus striatum. Histological assessment indicated damage limited to the injection in the area of the nucleus basalis and enlarged cerebrolateral ventricles. These data suggest the possible utility of the colchicine model in the study of cognitive deficits associated with neurodegenerative diseases.

Animals↗