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H A Tilson

Publications and source records attributed to H A Tilson.

At least 145 records · Page 8Linked to original sources
PubMed1985

DDT-induced tremor in rats: effects of pharmacological agents.

Rats given a tremorigenic dose of DDT (75 mg/kg, PO) were treated with pharmacological agents either 30 min prior to DDT or 1-2 h prior to testing at the time of peak effect (12 h postdosing). The administration of mephenesin (a centrally acting muscle relaxant) or Dilantin (an anticonvulsant) prior to DDT significantly attenuated tremor. Pretreatment with pizotifen (a serotonergic receptor antagonist) had no significant effect on tremor. Administration of the same agents 1-2 h prior to measurement had minimal effects. Trihexyphenidyl (a muscarinic cholinergic receptor antagonist) exacerbated the tremor produced by DDT. These data suggest that cholinergic neurotransmitter systems may be involved in DDT-induced tremor. That DDT-induced tremor was significantly attenuated by mephenesin and Dilantin is in accord with the conclusion that DDT-induced tremor is a manifestation of repetitive discharge due to interference with ionic conductance.

Analysis of Variance↗
PubMed1985

Effect of chlordecone (Kepone) on the rat brain concentration of 3-methoxy-4-hydroxyphenylglycol: evidence for a possible involvement of the norepinephrine system in chlordecone-induced tremor.

3-Methoxy-4-hydroxyphenylglycol (MHPG) is the major metabolite of norepinephrine (NE) in the rat brain. A single injection of tremorigenic doses of chlordecone to adult male Fischer-344 rats resulted in significant increases in MHPG concentrations in hypothalamus, brain stem, cerebellum, and caudate nucleus. The increase in MHPG was accompanied by a decrease in NE in the hypothalamus, suggesting that chlordecone treatment caused an increase in the turnover of NE in the brain. There was a dose- and time-related correlation between the increases in the concentrations of MHPG in hypothalamus, brain stem, and cerebellum and tremor in rats. The increase in MHPG in hypothalamus and brain stem occurred as early as 1 hr postdosing; this preceded the earliest measurable sign of tremor and initial hypothermia. Whether the alterations in the brain NE system are involved in the expression of the tremor and the initial hypothermia induced by chlordecone or whether they are merely associated with these changes is not clear.

Animals↗
PubMed1985

Effects of triethyl lead on hot-plate responsiveness and biochemical properties of hippocampus.

Rats treated with a single dose of triethyl lead chloride (TEL) by subcutaneous injection (7.9 mg/kg) showed a transient increase in latencies to lick the hind paw during hot-plate testing. The time course of triethyl lead-induced antinociception was temporally associated with depressed binding capacity of benzodiazepine receptor sites and reduced levels of Substance P. Both of these changes appeared to be confined to the hippocampus and were not apparent in the cortex or striatum of treated rats. Met-enkephalin levels were not altered in any region studied at any time during the 21-day postdosing period. Lead levels within the brain were higher than blood levels 1 week after triethyl lead injection. Although changes in more than one factor may account for the antinociceptive effect of triethyl lead, the hippocampus seems especially vulnerable to this amphiphilic organometal.

Animals↗
PubMed1985

Effects of p,p'-DDT on the rat brain concentrations of biogenic amine and amino acid neurotransmitters and their association with p,p'-DDT-induced tremor and hyperthermia.

Male, Fischer strain 344 adult rats were given various doses (25-100 mg/kg) of p,p'-DDT by oral gavage, and levels of biogenic amines, their metabolites, and amino acid neurotransmitters, tremor activity, and rectal temperature were measured at several intervals (2, 5, 12, and 24 h) after dosing. Dose-related increases in rectal temperature and in tremor activity were observed at 50-100 mg/kg 12 h after dosing. Tremorigenic doses of DDT increased the 5-hydroxyindoleacetic acid (5-HIAA) level in hypothalamus, brainstem, and striatum, whereas doses of 75 and 100 mg/kg increased the 3-methoxy-4-hydroxyphenylglycol (MHPG) level in hypothalamus and brainstem and the 3,4-dihydroxyphenylacetic acid level in striatum. Six amino acids were assayed in the brainstem, hypothalamus, and striatum; aspartate and glutamate levels were increased only in brainstem at 25-100 mg/kg. No consistent changes in concentrations of taurine, glutamine, glycine, or gamma-aminobutyric acid were observed in any of the regions assayed. Time-related increases in rectal temperature were seen 2-12 h after dosing, and the presence of tremor was observed 5-12 h after dosing; for both the time of peak effect was at 12 h. The DDT-induced hyperthermia and tremor were associated with dose- and time-related increases in levels of 5-HIAA, MHPG, aspartate, and glutamate. It is suggested that an increase in the turnover rate of 5-hydroxytryptamine (5-HT) may be responsible for the DDT-induced hyperthermia, whereas increases in the metabolism of 5-HT and norepinephrine may be involved in the tremor.

Amino Acids↗
PubMed1985

AF64A produces long-term cognitive impairments following infusion into the lateral cerebral ventricles or the dorsal hippocampus: involvement of hippocampal cholinergic processes in learning and memory.

In summary, the data presented here suggest that depleting ACh in the HPC has long term consequences on cognitive behavior. It is suggested that HPC cholinergic processes are an important neurobiological substrate of cognitive behavior. Finally, AF64A seems a useful tool for elucidating the cholinergic mechanisms underlying the modulation of behavior.

Animals↗
PubMed1985

Studies on the mechanism of chlordecone-induced tremor in rats.

Organochlorine insecticides such as DDT and chlordecone produce tremor in exposed individuals. Using a spectral analysis technique, chlordecone-induced tremor in rats was found to be dose- and time-related and could be distinguished from pharmacological agents (i.e., harmine, oxotremorine, and apomorphine) that produce tremor or stereotypic behavior. Drugs with known pharmacological effects were used to study the possible mechanism of chlordecone-induced tremor. Although no one neurotransmitter system appears necessary for tremor, the serotonergic, gabaergic, and cholinergic systems appear to contribute to chlordecone-induced tremor. The role of the catecholaminergic system is uncertain. Subsequent experiments indicated that supraspinal processes, possibly located in the brain stem, are important contributors to chlordecone-induced tremor. Activation of the cerebellum via the olivocerebellar tract to produce tremor cannot explain chlordecone's tremorgenic effects.

Animals↗
PubMed1985

Effects of 5,5-diphenylhydantoin (phenytoin) on neurobehavioral toxicity of organochlorine insecticides and permethrin.

Rats were given various doses of chlordecone, 1,1,1-trichloro-2,2-bis(p-chloro-phenyl)ethane (DDT) and lindane and tested for neurobehavioral toxicity up to 24 hr postdosing. The organochlorines either had no effect or increased responsiveness to an acoustic stimulus at subconvulsant doses. Only chlordecone and p,p'-DDT produced tremor. For purposes of comparison, the neurobehavioral effects of permethrin were also studied; this pyrethroid insecticide produced tremor and hyperresponsiveness similar to that of p,p'-DDT. Pretreatment with phenytoin significantly reduced the tremor and hyperresponsiveness produced by p,p'-DDT and permethrin. On the other hand, pretreatment with phenytoin increased the responsiveness of animals dosed with chlordecone or lindane, suggesting that these agents differ in their mechanism of action from p,p'-DDT and permethrin. The results of our experiments also indicate that care should be taken in the choice of agents, particularly anticonvulsants, to be used to treat symptoms of insecticide toxicity.

Animals↗
PubMed1984

AF64A, a cholinergic neurotoxin, selectively depletes acetylcholine in hippocampus and cortex, and produces long-term passive avoidance and radial-arm maze deficits in the rat.

The behavioral and biochemical effects of AF64A, a presynaptic cholinergic neurotoxin, were investigated. Bilateral administration of this compound into the lateral cerebral ventricles produced transient and dose-related effects on sensorimotor function and long-term impairments of cognitive behavior. Male Fischer-F344 rats dosed with either 15 or 30 nmol of AF64A reacted 29-62% faster than CSF-injected controls in a hot-plate test 14 (but not 1, 7, 21 or 28) days following dosing. The group administered 15 nmol of AF64A was also significantly more active (41%) than controls 28 days following dosing. The activity level of this group was comparable to that of controls at other times and hyperactivity was never observed in the 30 nmol group. Retention of a step-through passive avoidance task, assessed 35 days after dosing, was impaired in both the 15 and the 30 nmol groups. Their step-through latencies were significantly shorter than the control latencies, and they exhibited more partial entries during the 24-h retention test. Radial-arm maze performance, measured 60-80 days following treatment, was markedly impaired in the treated groups. Animals treated with AF64A made fewer correct responses in their first 8 choices, required more total selections to complete the task, and had an altered pattern of spatial responding in the maze. The neurochemical changes produced by AF64A, determined 120 days after dosing, were specific to the cholinergic system and consisted of decreases of ACh in both the hippocampus (15 and 30 nmol groups) and the frontal cortex (30 nmol group). The concentrations of catecholamines, indoleamines, their metabolites and choline in various brain regions were not affected by AF64A. Furthermore, histological analysis revealed that the doses of AF64A used in the present study did not damage the hippocampus, the fimbria-fornix, the septum or the caudate nucleus. These data support the contention that cholinergic processes in the hippocampus and/or frontal cortex play an important role in learning and memory processes. Furthermore, based upon the behavioral and biochemical data presented, it is suggested that AF64A could be a useful pharmacological tool for examining the neurobiological substrates of putative cholinergic disorders such as senile dementia of the Alzheimer's type.

Acetylcholine↗
PubMed1984

Organometal-induced antinociception: a time- and dose-response comparison of triethyl and trimethyl lead and tin.

Recent reports have demonstrated that organolead and -tin compounds can alter behavioral reactivity to noxious stimuli. To further define the dose response and temporal characteristics of these neurobehavioral effects, male Fischer 344 rats were injected sc with either one-fourth, one-half, or three-fourths the acute LD50 of triethyl lead (TEL), triethyl tin (TET), trimethyl lead (TML), trimethyl tin (TMT), or distilled water and tested on a 57.5 degrees C hot plate 1, 7, 14, 21, and 28 days after dosing. All four organometals altered hot plate latencies, but the magnitude and time course of these effects differed among the compounds. TEL produced a dose-related increase in latencies which was maximal 1 and 7 days postdosing and had dissipated by 28 days. In contrast, the group administered TML (3/4 LD50) exhibited a late developing antinocioception which became evident 14 days after dosing and persisted throughout the period of testing. The intermediate dose of TMT (1/2 LD50) also produced a delayed increase in response times which was observed 21 and 28 days post-treatment. The 3/4 LD50 dose of TMT produced increased hot plate latencies on all post-treatment test days except Day 14. TET (1/2 LD50) produced increased hot plate latencies 1, 7, 14, and 21 days postdosing and also induced a reversible ataxia and akinesia. Higher doses of TET proved lethal to 80% of the animals and lower doses failed to alter response times in the hot plate. These data demonstrate that trialkyl lead and tin compounds can produce time- and dose-related increases in hot plate latencies.

Animals↗
PubMed1984

Effects of chlordecone exposure on brain neurotransmitters: possible involvement of the serotonin system in chlordecone-elicited tremor.

The purpose of this study was to correlate the chlordecone-elicited tremor activity with alterations of brain neurotransmitters. A single injection of chlordecone (80 mg/kg, ip) significantly increased the brain levels of 5-hydroxyindoleacetic acid (5-HIAA) but did not affect the concentrations of dopamine, dihydroxphenylacetic acid, aspartate, taurine, glutamate, glycine, and gamma-aminobutyric acid (GABA). There was a dose- and time-related correlation between the increases in striatal 5-HIAA levels and tremor after chlordecone treatment. A subsequent study with pargyline indicated that the increase in striatal 5-HIAA level represented an increase in the turnover of serotonin. This study plus the previous finding that pizotifen (BC-105), a serotonin receptor blocker, attenuated chlordecone-elicited tremor strongly suggests a possible involvement of the serotonin system in mediating the tremor elicited by this insecticide.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1984

Neurobehavioral toxicology of the organoleads.

Alkyl leads (R x Pb) are environmentally prevalent compounds which have been shown to produce a variety of neurological and behavioral deficits in both laboratory animals and man. Due to the increasing commercial use of these compounds, the episodes of human poisoning, and the limited understanding of their sites and mechanisms of toxicity, the organoleads, as a class, remain potentially important environmental health hazards. Recent data indicate that the constellation of behavioral effects produced by these compounds resembles the behavioral sequelae of limbic system damage. For example, alterations in sensory responsiveness and/or behavioral reactivity and task-dependent changes in avoidance learning are observed following organolead exposure and experimental disruption of the limbic system. Furthermore, neurochemical changes induced by organoleads are regionally-specific and restricted to the limbic forebrain and frontal cortex. The present review will summarize the toxic properties of organoleads, discuss their neurobehavioral effects, and suggest that these effects might be attributable to a disruption of the limbic forebrain.

Animals↗
PubMed1983

Studies on the possible sites of chlordecone-induced tremor in rats.

A series of psychopharmacological agents were administered to adult male Fischer-344 rats pretreated with a tremorigenic dose of chlordecone in an attempt to elucidate the involvement of spinal and supraspinal processes in the mediation and/or expression of chlordecone-induced tremor. Agents effective in attenuating the frequency of tremor were chlordiazepoxide, muscimol, and mecamylamine; quipazine exacerbated the tremor. Catecholaminergic agents including yohimbine, clonidine, propranolol, and haloperidol did not affect the frequency of chlordecone-induced tremor. Disinhibition of postsynaptic inhibitory sites in the spinal cord with strychnine and antagonism of spinal and supraspinal polysynaptic pathways with mephenesin exacerbated and attenuated the effects of chlordecone, respectively. Destruction of the climbing fibers with 3-acetylpyridine effectively blocked harmine, but not chlordecone-induced tremor, suggesting that chlordecone does not act through this pathway.

Animals↗
PubMed1983

Correlation of neurochemical and behavioral effects of triethyl lead chloride in rats.

Adult male Fischer-344 rats were dosed sc with 1 or 2.5 mg/kg of triethyl lead chloride (TEL) for 5 consecutive days. One week after the last dose, TEL-exposed rats had decreased Met-enkephalin in the hypothalamus, septum, and frontal cortex, while substance P was decreased in the hippocampus and frontal cortex. Dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) in the caudate nucleus were not altered by TEL nor were serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) in the caudate nucleus, hypothalamus, hippocampus, or frontal cortex. In a second experiment, rats were dosed with 1.75 mg/kg sc for 5 days. Subsequent assay of brain tissue indicated that TEL decreased met-enkephalin levels in the septum of rats one and seven days after cessation of dosing; effects on substance P were not observed. TEL-induced decreases in Met-enkephalin in the septum were temporally associated with increased hot plate latencies. One day after cessation of dosing with TEL, concentration of 5-HIAA in the caudate nucleus, hippocampus, frontal cortex, and brain stem, and 5-HT in the hippocampus and brain stem were increased. Biogenic amine concentrations were not affected in any other region or at any other time postdosing. A third experiment indicated that TEL-induced analgesia could be attenuated by 10 mg/kg chlordiazepoxide or 10 mg/kg of naloxone. The present results suggest that TEL-induced analgesia may be due to alterations in emotionality or reactivity to noxious stimuli, which may be associated with the alteration in delta opiate mechanism in the limbic system, such as the change of septal enkephalin neuronal activities.

Analgesia↗
PubMed1983

Effects of lithium and haloperidol administration on the rat brain levels of substance P.

In an attempt to obtain more biochemical information concerning the possible roles of substance P (SP) in the etiology of mental and neurological disorders, we studied the effects of long-term administration of lithium or haloperidol on the levels of this peptide in various rat brain regions. Daily injections of LiCl (5 mEq/kg/day for 6 days) increased the SP level in regions which are enriched in dopamine innervation such as striatum, nucleus accumbens or frontal cortex, but not in the other regions such as hypothalamus, hippocampus or brain stem. Subchronic oral administration of Li2CO3 through the diet also caused a time-dependent increase in striatal SP level which was prevented by coadministration with haloperidol. This result suggests that the dopaminergic system might mediate the change in SP level elicited by lithium.

Animals↗
PubMed1982

Behavioral toxicology in risk assessment: problems and research needs.

Behavioral methods are being used with increasing frequency in toxicology to assess the deleterious effects of chemicals to which we are exposed. The impetus for the use of behavioral techniques in risk assessment resulted from the presumption that they were more sensitive than other tests in detecting toxicity. A more logical reason for the use of behavioral tests is the fact that behavior is the functional indicator of the net sensory, motor, and integrative processes occurring in the central and peripheral nervous system. Thus, the functional capacity of the nervous system cannot be determined independent of behavioral analysis. Some of the problems confronting behavioral toxicology are (1) the translation of human subjective complaints into behavioral tests in animals; (2) determining subtle effects on the nervous system in the face of the well-known functional reserve and adaptability of the system; (3) dealing with the variety of statistical problems resulting from the use of multiple tests, multiple measurements using the same test and the (relatively) large variability inherent in some behavioral phenomena; and (4) selecting the proper tests. Three critical research needs in behavioral toxicology as they relate to risk assessment are (1) development and validation of methods, (2) determining subpopulations at greatest risk, and (3) developing a strategy for determining interactions between two or more agents.

Animals↗