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Essential tremor (ET) is the most frequent form of pathologic tremor and one of the most common adult-onset neurologic impairments. However, underlying mechanisms by which structural alterations within the tremor circuit generate the pathological state and how rhythmic neuronal activities propagate and drive tremor remains unclear. Harmaline (HA)-induced tremor model has been most frequently utilized animal model for ET studies, however, there is still a dearth of knowledge over the degree to whether HA-induced tremor mimics the actual underlying pathophysiology of ET, particularly the involvement of thalamo-cortical region. In this study, we investigated the electrophysiological response of the motor circuit including the ventrolateral thalamus (vlTh) and the primary motor cortex (M1), and the modulatory effect of thalamic deep brain stimulation (DBS) using a rat HA-induced tremor model. We found that the theta and high-frequency oscillation (HFO) band power significantly increased after HA administration in both vlTh and M1, and the activity was modulated by the tremor suppression drug (propranolol) and the thalamic DBS. The theta band phase synchronization between the vlTh and M1 was significantly enhanced during the HA-induced tremor, and the transition of cross-frequency coupling in vlTh was found to be associated with the state of HA-induced tremor. Our findings support that the HA tremor could be useful as a valid preclinical model of ET in the context of thalamo-cortical neural network interaction., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Su-Youne Chang reports financial support was provided by National Institute of Health., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The scarcity of studies on boron containing compounds (BCC) in the medicinal field is gradually being remedied. Efforts have been made to explore the effects of BCCs due to the properties that boron confers to molecules. Research has shown that the safety of some BCCs is similar to that found for boron-free compounds (judging from the acute toxicological evaluation). However, it has been observed that the administration of 3-thienylboronic acid (3TB) induced motor disruption in CD1 mice. In the current contribution we studied in deeper form the disruption of motor performance produced by the intraperitoneal administration of 3TB in mice from two strains (CD1 and C57BL6). Disruption of motor activity was dependent not only on the dose of 3TB administered, but also on the DMSO concentration in the vehicle. The ability of 3TB to enter the Central Nervous System (CNS) was evidenced by Raman spectroscopy as well as morphological effects on the CNS, such as loss of neurons yielding biased injury to the substantia nigra and striatum at doses ≥200mg/kg, and involving granular cell damage at doses of 400mg/kg but less injury in the motor cortex. Our work acquaints about the use of this compound in drug design, but the interesting profile as neurotoxic agent invite us to study it regarding the damage on the motor system., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Long-term therapy with L-3,4-dihydroxyphenylalanine (L-DOPA), still the most effective treatment in Parkinson's disease (PD), is associated with severe motor complications such as dyskinesia. Experimental and clinical data have indicated that adenosine A2A receptor antagonists can provide symptomatic improvement by potentiating L-DOPA efficacy and minimizing its side effects. It is known that the G-protein-coupled adenosine A2A, cannabinoid CB1 and dopamine D2 receptors may interact and form functional A2A-CB1-D2 receptor heteromers in co-transfected cells as well as in rat striatum. These data suggest that treatment with a combination of drugs or a single compound selectively acting on A2A-CB1-D2 heteromers may represent an alternative therapeutic treatment of PD. We investigated the expression of A2A-CB1-D2 receptor heteromers in the striatum of both naïve and hemiparkinsonian rats (HPD-rats) bearing a unilateral 6-hydroxydopamine (6-OHDA) lesion, and assessed how receptor heteromer expression and biochemical properties were affected by L-DOPA treatment. Radioligand binding data showed that A2A-CB1-D2 receptor heteromers are present in the striatum of both naïve and HPD-rats. However, behavioral results indicated that the combined administration of A2A (MSX-3 or SCH58261) and CB1 (rimonabant) receptor antagonists, in the presence of L-DOPA does not produce a response different from administration of the A2A receptor antagonist alone. These behavioral results prompted identification of heteromers in L-DOPA-treated animals. Interestingly, the radioligand binding results in samples from lesioned animals suggest that the heteromer is lost following acute or chronic treatment with L-DOPA., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Tremor is one of the most characteristic adverse effects following administration of β(2)-adrenergic agonists. It is reported by around 2-4% of patients with asthma taking a regular β(2)-adrenergic agonist and is induced by both short-acting and long-acting agents. Tremor associated with β(2)-adrenergic agonists is dose-related and may occur more commonly with oral dosing. The exact mechanism for tremor induction by β(2)-adrenergic agonists is still unknown, but there is some evidence that β(2)-adrenergic agonists act directly on muscle. An early explanation of the tremor was that β(2)-adrenoceptor stimulation shortens the active state of skeletal muscle, which leads to incomplete fusion and reduced tension of tetanic contractions. More recently, tremor has been correlated closely with hypokalaemia. A possible diverse impact of different modes of administration of β(2)-adrenergic agonists on tremorogenic responses has been suggested but solid evidence is still lacking. In any case, the desensitization of β(2)-adrenoceptors that occurs during the first few days of regular use of a β(2)-adrenergic agonist accounts for the commonly observed resolution of tremor after the first few doses. Therefore, tremor is not a really important adverse effect in patients under regular treatment with a β(2)-adrenergic agonist., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The default assumption that different pyrethroid insecticides, sharing a common mode of action, will show additivity of toxicity has not always been supported by in vitro measures, some of which have indicated antagonism. Our intention was to see whether the antagonism between pyrethroids of different classes seen in vitro could be reproduced in vivo. We therefore investigated the effects of single and combined exposures to two commonly used pyrethroids, deltamethrin (type II) and S-bioallethrin (type I) given intravenously to anaesthetised rats. We used two quantitative measures that are responsive to pyrethroids: the duration of prolongation of hippocampal dentate granule cell inhibition and the amplitude of the abnormal electromyogram discharge. At equi-toxic doses, S-bioallethrin extended the inter-stimulus interval evoking 50% inhibition in the hippocampus by 30+/-2.2 ms, and deltamethrin extended it by 199+/-21 ms. Combined administration of the same doses of deltamethrin and S-bioallethrin extended hippocampal inhibition by 164+/-14 ms, which did not differ significantly from the effect of deltamethrin alone. S-bioallethrin was without any effect on the electromyogram, and produced no significant change in the amplitude of the abnormal muscle discharges evoked by deltamethrin. The increase in arterial blood pressure evoked by the combination was significantly less than that evoked by either pyrethroid alone (p<0.001). In summary, although our electrophysiological indices provide no support for functional antagonism between these two pyrethroids, they also fail to indicate any summation of effect.

Unilateral intracarotid artery (ICA) MPTP infusion, along with sequential systemic doses of MPTP, produces near complete degeneration of the nigrostriatal pathway on the side of infusion (ipsilateral) and variable levels of damage in the contralateral hemisphere accompanied by varying levels of parkinsonism (overlesioned hemiparkinsonian model). Positron emission tomography and the dopamine (DA) metabolism tracer [(18)F]6-fluoro-l-m-tyrosine (FMT) were used to evaluate the relationship between DA metabolism and clinical features of parkinsonism in 14 overlesioned hemiparkinsonian monkeys. Monkeys were rated on a parkinsonian scale that included ratings of bradykinesia, fine motor skills (FMS), and rest tremor. Because the monkeys tended to show more severe clinical signs on the side of the body contralateral to ICA MPTP infusion, we calculated asymmetry scores for each of the clinical features as well as for FMT uptake (K(i)) in the caudate and putamen. Tremor asymmetry was associated with FMT uptake asymmetry in the putamen. No such relationship was observed for FMS or bradykinesia. The overall severity of tremor (mild, moderate/severe) was associated with FMT uptake in the caudate and putamen. Postmortem biochemical analysis for a subset of monkeys showed that the monkeys with moderate/severe tremor had significantly lower DA levels in both caudate and putamen than those with mild tremor. In addition, K(i) values were significantly correlated with DA levels in both caudate and putamen. These findings support the idea that nigrostriatal degeneration contributes to rest tremor., (Copyright 2000 Academic Press.)

Young organisms are often more sensitive to the toxic effects of pesticides, and this finding has spurred research on further characterization of this susceptibility. The neurotoxic effects of cholinesterase (ChE)-inhibiting pesticides are of particular concern for human health risk assessment due to the widespread exposure potential in children. This study evaluated age-related differences in susceptibility for a carbamate (aldicarb) and an organophosphorus pesticide (methamidophos). Comparisons were made between preweanling (Postnatal Day 17, PND17), postweanling (PND27), and adult (approximately PND70) male and female rats. All were acute studies using oral administration. Sensitivity was quantified by (1) determination of maximally-tolerated doses (MTDs); (2) measurement of brain and blood ChE inhibition; and (3) neurobehavioral evaluation using end points known to be sensitive indicators of exposure to anticholinesterases. MTD data showed that preweanling rats were twice as sensitive as adults to aldicarb, but there was no differential sensitivity to methamidophos. The dose-response data for brain ChE inhibition followed a similar pattern of age-related differences, and similar levels of inhibition were measured at the MTD regardless of age. Dose-response and time course studies of neurobehavioral end points indicated that differential effects due to age depend on the behavioral end point examined. Following aldicarb administration, the dose-response curves for a few end points overlapped; however, the young rats otherwise showed fewer signs of toxicity than did the adults despite similar levels of brain ChE inhibition. Motor activity assessment showed that aldicarb did not produce any activity depression in PND17 rats, whereas the data for the PND27 and adult rats overlapped. With methamidophos, the dose-response curves for most end points for preweanling and adult rats were quite similar. Aldicarb-induced ChE inhibition was readily reversible in all age groups, whereas with methamidophos, enzyme activity recovered more rapidly in the young. Most behavioral alterations had recovered by 24 h with either pesticide. The results of these studies indicate that (1) ChE-inhibiting pesticides are not all the same regarding relative sensitivity of the young; (2) age-related differences were reflected in both the MTDs and degree of ChE inhibition; and (3) age-related differences in neurobehavioral measures depended on the pesticide and on the end points examined.

The effects of hydroquinone (HQ) on reproductive performance and fertility were assessed in a two-generation study with CD Sprague-Dawley rats (one litter per generation). HQ was administered in an aqueous solution by gavage at doses of 0, 15, 50, and 150 mg/kg/day. F0 and F1 parental animals were dosed daily for at least 10 weeks prior to cohabitation, during cohabitation, and until scheduled termination. At all dose levels tested, no adverse effects were observed on feed consumption, survival, or reproductive parameters for the F0 or F1 parental animals. Mild, transient tremors were observed shortly after dosing at 150 mg/kg/day in several F0 and F1 parental animals and in a single F0 male at 50 mg/kg/day. These tremors occurred infrequently and were considered to be due to an acute stimulatory effect of HQ on the nervous system. Body weights for F0 and F1 parental females were similar between all dose groups throughout the study. Body weights for F0 parental males were also comparable to those of control throughout the study. Statistically significant differences in body weights were noted for the F1 parental males in the 50 and 150 mg/kg/day dose groups at several intervals during the premating, mating, and postmating periods. No treatment-related effects on pup weight, sex distribution, or survival were noted for pups of either generation. Upon postmortem examination, no treatment-related gross lesions were observed in either the F0 or F1 parental animals or their weanlings. Histopathologic examination of reproductive tissues and pituitary glands from high-dose F0 and F1 parental animals did not reveal any changes related to treatment with HQ.(ABSTRACT TRUNCATED AT 250 WORDS)

S-Adenosyl-L-methionine has been shown to cause Parkinson's disease-like effects that include hypokinesia, tremor, rigidity, and abnormal posture. S-Adenosyl-L-methionine is the rate-limiting endogenous methyl donor. Its biochemical role, which includes the metabolism of dopamine and the synthesis of acetylcholine, also resembles the changes that occur in Parkinson's disease. Therefore, S-adenosyl-L-methionine may play a role in Parkinson's disease-like motor impairments. In this study we manipulated the levels of S-adenosyl-L-methionine in the brain of rats and quantified the changes in hypokinetic type motor activity that seems to occur also in Parkinsonism. Male Sprague-Dawley rats were anesthetized with chloral hydrate (400 mg/kg/rat), cannulated, injected into the lateral ventricle with S-adenosyl-L-methionine or saline, and their motor activity was measured in a Digiscan Animal Activity Monitor. Other behaviors were also observed. S-Adenosyl-L-methionine caused hypokinesia, tremor, rigidity, and abnormal posture in rats. Motor activity was significantly decreased within 2 min postinjection. The hypokinesia was maximal at 60 min, at which time a 65, 75, and 90% decrease for total distance, number of movements, and the ratio of total distance to the number of movements occurred, respectively. The hypokinetic effect of S-adenosyl-L-methionine was dose dependent. A 65.0 and 51.3% decrease in total distance and number of movements, respectively, were observed following 9.38 x 10(-9) mol. The 5.0 x 10(-8) mol caused a reduction of 73.42 and 57.66% and 4.0 x 10(-7) mol/rat caused a 94.9 and 78.43% decrease, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Ten-day-old NMRI mice were given deltamethrin, bioallethrin, or the vehicle once daily for 7 days. The doses used were as follows: deltamethrin, 0.71 and 1.2 mg/kg body wt; bioallethrin, 0.72 and 72 mg/kg body wt; and 20% fat emulsion vehicle, 10 ml/kg body wt. The mice were killed 24 hr after the last administration, and crude synaptosomal fractions (P2) were prepared from the cerebral cortex and hippocampus. The densities of the muscarinic and nicotinic receptors were assayed by measuring the amounts of quinuclidinyl benzilate ([3H]QNB) and [3H]nicotine, respectively, specifically bound in the P2 fraction. The proportions of high- and low-affinity binding sites of the muscarinic receptors were assayed in a displacement study using [3H]QNB/carbachol. The two types of pyrethroids affected the cholinergic system in the neonatal mouse brain in two different ways. At the lower dose, which did not cause any neurotoxic symptoms, both pyrethroid types affected the muscarinic receptors in the cerebral cortex. Here deltamethrin caused an increase and decrease in the percentage of high- and low-affinity binding sites, respectively, whereas the reverse was observed after bioallethrin treatment. Deltamethrin treatment also caused an increase in the density of nicotinic receptors in the cerebral cortex. The higher doses revealed typical symptoms of pyrethroid poisoning, such as choreoathetosis and tremor for deltamethrin and bioallethrin, respectively. The symptoms declined gradually during each successive day of administration and had disappeared by Day 4. At this dose deltamethrin affected the muscarinic receptors in the hippocampus and the nicotinic receptors in the cerebral cortex, whereas bioallethrin had no apparent effect. This study further supports that the cholinergic system under rapid development in the neonatal mouse is sensitive to xenobiotics.

In exploratory studies aimed at elucidating CNS effects due to heavy metal toxicity, signs of compromised renal function were seen in rats. The studies reported here describe the sequential steps of the development of nephrotoxicity by trimethyltin chloride (TMT) in rats. Single doses of 12.25 mg/kg TMT administered orally to 150- to 175-g Long-Evans rats elicited overt signs of toxicity including behavioral abnormalities and marked weight loss. Concurrent with the development of these signs, nephrotoxicity was manifested as functional kidney compromise and associated histopathologic evidence of tubular damage. Pathological changes in the kidneys from treated rats were hyaline droplet inclusions, attenuated brush border, basolateral vacuolization, and eosinophilic granular casts in the proximal tubule cells. These lesions were detected as early as 2 days post-treatment and progressed with time in an orderly and sequential fashion. Renal lesions between 5 and 8 days were mild to severe cortical tubular dilatation, hydropic degeneration, and diffuse hyaline droplet deposition in the lower nephron tubules. Medullary edema and exfoliation of degenerated tubular epithelial cells with cast formation followed from 8 to 11 days. The morphological changes were accompanied by marked elevation of blood urea nitrogen, parallel with polyuria at Day 2 and oliguria by Day 14. Behavioral abnormalities as well as weight loss correlated well with the time course and severity of renal dysfunction and progression of morphological changes. A second experiment compared the effects of TMT in rats of different weights. Heavier rats were more sensitive than lighter rats to the nephrotoxic effects of TMT. These effects were independent of recognizable neurotoxic effects of TMT in the hippocampus.

Adult cynomolgus monkeys were administered trimethyltin (TMT) iv in dosages ranging from 0.75 to 4.0 mg TMT/kg and observed for behavioral changes. Animals were subsequently killed for light and electron microscopic examination. TMT showed a dose-related toxicity, with high dose animals (4.0 and 3.0 mg/kg) dying within 24 hr, and low dose animals (0.75 mg/kg) surviving without morphological effects. Animals given 1.10 mg TMT/kg displayed a reproducible clinical course, characterized by tremor, hyperactivity, and ataxia which progressed to stupor and finally unconsciousness. By light microscopy, neuropathology was most pronounced in the CA-3 and CA-4 regions of Ammon's horn. Degenerating pyramidal neurons, micro- and astrogliosis, and neuronophagia were commonly observed. Mild degenerative changes were identified in amygdala, medulla, spinal cord, and Purkinje cells. The fascia dentata remained intact. Ultrastructurally, injured neurons contained accumulations of lysosomes and lysosome-like structures within perikarya and neurites. Demyelination or vascular damage was not observed. Data indicate the monkey to be highly sensitive to TMT, with morphological injury most severe in limbic structures.

We recently found that glucose injections attenuate amnesia and hyperactivity produced by scopolamine, a muscarinic antagonist. The present study examined whether glucose would augment behavioral effects produced by a muscarinic agonist, physostigmine. In experiment I, doses were first determined for which neither glucose (10 mg/kg) nor physostigmine (0.05 mg/kg) altered scopolamine-induced hyperactivity. However, combined glucose-physostigmine injections significantly reduced scopolamine hyperactivity. Experiment II evaluated the effects of glucose on physostigmine-induced tremors. Glucose (10, 100, and 250 mg/kg) or saline injections were given 20 min before physostigmine injections (0.4 or 0.05 mg/kg). Observations of glucose effects on the severity of physostigmine-induced tremors were then obtained at 5-min intervals for 25 min after physostigmine injections. Glucose (100 mg/kg) significantly facilitated the onset of tremors when injected before either dose of physostigmine, and augmented (at 100 and 250 mg/kg) tremor severity when injected before the lower dose of physostigmine. These findings indicate that glucose can facilitate the actions of a cholinergic agonist on two behaviors, locomotor activity and tremors, adding support to the view that circulating glucose levels can modulate central cholinergic function. More generally, the results provide additional evidence that circulating glucose levels can influence brain function.

The putative neurotoxicity of the organophosphorus compound triphenyl phosphite (TPP) was examined in Long Evans, adult male rats. Animals were exposed to two 1.0 ml/kg (1184 mg/kg) injections (sc) of TPP spaced 1 week apart and sampled for biochemical and neuropathological examination. At the time of sampling, rats displayed dysfunctional changes including tail rigidity, circling, and hindlimb paralysis. Neuropathic damage was confined to the lateral and ventral columns of all spinal levels and consisted of myelin ellipsoids and giant axonal swellings filled with smooth endoplasmic reticulum. Wallerian-like degeneration was observed in the spinal roots, the sciatic nerve, and tibial branches. Biochemical assessment of brain acetylcholinesterase (AChE) and neurotoxic esterase (NTE) activity was determined 1, 4, 24, 48, and 72 hr after the second TPP treatment. Both enzyme activity concentrations were depressed maximally at 48 hr postexposure by 30 and 39%, respectively. Serum cholinesterase, sampled 48 hr after the second TPP exposure was depressed by 33%. Data from this study indicate that subchronic exposure to the organophosphite TPP results in severe neurotoxic consequences which differ from those previously described in rats with organophosphorus-induced delayed neuropathy.

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.

Six monkeys were trained to report detection of a vibratory or electrical stimulus applied to the fingertip. The vibratory stimuli were presented at two frequencies (40 and 150 Hz). Thresholds were determined with a tracking procedure before, during, and after dosing. Each monkey served as its own control. Four monkeys were dosed orally with 10 mg/kg of acrylamide 5 days a week until the appearance of toxic signs. The total administered dose varied between 320 and 450 mg/kg. The other two monkeys served as time-matched controls. All the monkeys were observed 5 days a week. They were also weighed and presented with a visuomotor task (pickup test) twice a week. Weight loss usually preceded the onset of gross behavioral disturbances, such as loss of balance, tremor, or decreased activity. Impaired coordination, as revealed with the pickup test, paralleled weight loss. Electrical sensitivity was not affected. Vibration sensitivity, however, fell during dosing and remained impaired for several months after dosing ceased, outlasting all the other effects. Recovery of the other indices occurred relatively soon after dosing ended. These data indicate that vibration sensitivity testing can trace the time course of intoxication and recovery in toxic peripheral neuropathies. Furthermore, the differential results obtained with vibratory and electrical stimulation are consonant with a primary effect on end-organ receptors.

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.

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.

Effects of 1-(o-chlorophenyl)-1-(p-chlorophenyl)-2,2-dichloroethane (o,p'-DDD) (Lysodren; Mitotane) (I) and 1-(o-chlorophenyl)-1-(p-chlorophenyl)-2, 2-dichloropropane (Mitometh) (II) were investigated. Ultrastructural and toxicity studies were conducted with male Hartley outbred guinea pigs given 300 mg/kg/day ip for 14 days. Profound mitochondrial damage in the guinea pig adrenal cortex, an index of Lysodren's action as a cancer chemotherapeutic, reversible necrosis of the zona fasciculata and zona reticularis with swelling, disrupted cristae, and organelles destroyed in the mitochondria from these areas. Yet guinea pigs given Mitometh tolerated the drug better than those given an equivalent amount of Lysodren. In general the animals treated with Mitometh showed less alopecia, diarrhea, and weakness. The only deaths recorded in our study were in the Lysodren group. In addition po administration of these two drugs to male Sprague-Dawley rats and male Hartley guinea pigs for 4 days allowed for a direct comparison of urinary metabolites. Metabolites were identified from urine extracts by computerized mass spectrometry interfaced with capillary gas chromatography. Both compounds were shown to undergo dehydrohalogenation and side-chain cleavage to a limited extent; however, only Lysodren afforded side-chain oxidation metabolites. In fact, the dominant metabolite from Lysodren biotransformation was the corresponding carboxylic acid o,p'-DDA (III). On the other hand, Mitometh resisted side-chain oxidative metabolism and was less toxic than Lysodren. Therefore, when given to guinea pigs and rats, Mitometh had Lysodren-like biologic activity, did not undergo rapid inactivation, and was less toxic than Lysodren. Mitometh represents a potential alternative to Lysodren which should be investigated further for its possible use in the treatment of adrenal cortical carcinoma and Cushing's syndrome.

Groups of Alpk:AP (Wistar-derived) rats were fed diets containing 0, 500, 1000 or 2500 ppm permethrin for 2 years and Swiss-derived mice were maintained for their lifetime (80% mortality) on diets containing 0, 250, 1000, or 2500 ppm permethrin. Changes of toxicological significance were confined to the top dose level of 2500 ppm permethrin in both species. Tremors and hypersensitivity to noise were noted in rats at this dose during the first 2 weeks of study but such signs were not seen in mice. Pathological examination of the central and peripheral nervous systems did not reveal abnormalities attributable to permethrin administration. The effect on mice at 2500 ppm permethrin was shown by decreased body weight gain. Liver hypertrophy, associated with increase in liver weight, microsomal enzyme activity, and proliferation of smooth endoplasmic reticulum occurred in the rat with similar but less marked changes in the mouse. This was considered to be an adaptive response of no toxicological significance. No evidence of a carcinogenic effect was seen in the rat study. In the mouse study a slight elevation in benign lung tumor incidence in males only at 2500 ppm permethrin was observed but was not considered to represent a carcinogenic effect.

Sixteen new compounds 2-methylamino substituted phenyl-3-substituted anilino 4 (3H) quinazolinones (3-18) were prepared. All the compounds were evaluated for their antiparkinsonian activity and compared with bromocriptine. Compounds 10,15 and 18 showed better activity. These compounds also bind with the dopamine receptors in striatal membrane preparations of rat brain.

Pretreatment of rats with atropine and the reversible esterase inhibitor physostigmine [-)PHY), prior to injection of a lethal dose of the irreversible organophosphate sarin (0.13 mg/kg), protects 100% of the animals from lethality. We have used quantitative light and qualitative electron microscopy to show that damage to the end plate region of voluntary muscles is also strikingly limited by the same pretreatment. Drug effects on soleus motor end plates detectable 1 hr after treatment were (1) a single sublethal dose of sarin (0.08 mg/kg) produced large, blistered, and severely disrupted subjucntional regions. Damage extended from the end plate, in the form of myofiber necrosis and subsequent phagocytosis; (2) (-)PHY (0.1 mg/kg) itself had a selective effect in inducing irregularities of the subjunctional sarcomere band without any gross vacuolization; (3) the morphometric analysis done with light microscopy indicated that the combination of atropine (0.5 mg/kg) and (-)PHY (0.1 mg/kg) prior to a lethal dose of sarin (0.13 mg/kg) offered 86% reduction in the average area of the lesions, relative to the dimensions of damage induced by atropine/sarin alone. In most lesions induced by (-)PHY, recognizable changes were markedly less severe in degree and extent than those seen in sarin myopathy; there were few instances of extensive muscle damage and myofiber necrosis. The relationship of the (-)PHY dose to the level of protection against sarin suggested that (-)PHY pretreatment almost completely prevents the characteristic sarin-induced myopathy and, instead, imposes the characteristic PHY-induced subjunctional swelling. In all three experimental groups examined, the myopathic changes located extrajuctionally were reversible. The mechanism by which (-)PHY acts as a protective agent is discussed.

The effect of cyanide on whole-brain calcium levels was determined in mice administered KCN and correlated with the neurotoxic signs manifested during acute cyanide poisoning. KCN (10mg/kg, sc) significantly increased whole-brain total calcium levels from 48.1 +/- 1.8 to 66.5 +/- 3.9 micrograms/g dry wt within 15 min after administration. The levels remained elevated for 3 hr and returned to control readings after 12 hr. Dose-response studies revealed KCN, at doses of 10-15 mg/kg, produced significant elevations of whole-brain calcium 30 min after administration. No measurable effect was obtained from lower doses which suggested a threshold effect. Pretreatment 15 min before KCN with diltiazem, a calcium channel blocker, prevented the cyanide-induced rise in whole-brain total calcium. Cyanide-induced tremors, which are centrally mediated symptoms of intoxication, were quantified and correlated with the observed changes in whole-brain calcium. Tremors were detected at 10 and 12 mg/kg KCN and peak intensity was observed at 15 min postcyanide. Pretreatment with diltiazem markedly attenuated the cyanide-induced tremors. It appears that a correlation exists between cyanide-induced change in whole-brain calcium and tremors. This study suggests that intraneuronal calcium may play an important role in mediating cyanide neurotoxicity and calcium channel blocking agents may be useful in limiting the severity of the centrally mediated symptoms of acute cyanide intoxication.

Acetaldehyde has been reported, but has not been proven, to be the toxic entity resulting from metaldehyde ingestion. To investigate this, male dogs were given a single dose of 600 mg metaldehyde or acetaldehyde/kg of body wt via stomach tube. Clinical signs were monitored, and plasma and urine were assayed for metaldehyde and acetaldehyde. Vomiting occurred less often and in a significantly lower number of metaldehyde-dosed dogs than in acetaldehyde-dosed dogs. Ataxia and tremors occurred significantly more often in metaldehyde-dosed dogs than in acetaldehyde-dosed dogs. Acetaldehyde was not detected in the plasma or urine of metaldehyde-dosed dogs, however, it was found in a sample of vomitus from one of the metaldehyde-dosed dogs. Metaldehyde was found in plasma and urine of metaldehyde-dosed dogs. Urinary excretion of metaldehyde from the metaldehyde-dosed dogs was less than 1%. Urinary excretion of acetaldehyde from acetaldehyde-dosed dogs was essentially nonexistent. Metaldehyde has a larger role in the mechanism of metaldehyde toxicity than previously thought. While acetaldehyde appeared to be of significantly lesser importance, we could not eliminate it as a factor in metaldehyde toxicity in dogs.

The effects of diazepam, dantrolene and atropine on drug-induced tremors were investigated in mice from the point of view of the tremor frequency. The study involved a power spectral analysis of the random current induced by movement of a magnet (attached to the mouse) on a wire coil. To induce tremor, tremorine and harmaline were subcutaneously injected. The power spectral density function defined the frequency composition of the tremor and its severity was determined quantitatively in terms of the mean square value of the data in any frequency range of concern. Diazepam markedly depressed the power spectral density of the tremorine- and harmaline-induced tremor and reduced the tremor frequency. With higher doses of diazepam, the peak frequency of the tremorine-induced tremor shifted to the lower frequency side as if the tremor components were taken into the component of the spontaneous motor activity. Dantrolene and atropine suppressed the power spectral density without affecting tremor frequency. The relationship between the change of tremor frequency and the site of action of antitremorgenic agents are discussed.

The paramagnetism of manganese was exploited to obtain proton nuclear magnetic resonance (MR) images of manganese-rich tissue in the central nervous system in vivo. One Macaca fascicularis monkey inhaled MnCl2 aerosol prior to imaging. A second M. fascicularis and two Cebus apellas were administered MnCl2 in various doses intravenously. The monkeys' brains were imaged before and after manganese administration in coronal and horizontal planes that included the basal ganglia and substantia nigra. A T1-weighted pulse sequence exploited manganese's reduction of spin-lattice relaxation times and clearly distinguished several separate and specific regions after manganese administration: the caudate nucleus, the lenticular nuclei, the substantia nigra, a region corresponding to subthalamic nucleus and ventromedial hypothalamus, and the pituitary gland. The kinetics of manganese accumulation were important in determining the imaged intensity of these regions but the route of parenteral administration was not. Spin-lattice relaxation times showed that T1 was shortened at lower doses of manganese and remained shortened longer in the globus pallidus and pituitary gland while little effect appeared in gray and white matter. T1 effects in caudate and putamen effects were intermediate. These data suggest selective affinity for manganese in globus pallidus and pituitary.

p,p'-DDT (1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane; 75 mg/kg) or corn oil was administered po to male Fischer 344N rats. Tremor was quantified 8 hr later by spectral analysis of whole body movements. The effect of sc injection of pharmacological challenges on the spectral profile of body movements was determined. The alpha antagonist phenoxybenzamine decreased the intensity of movements over most of the power spectra in animals exposed to DDT, but decreased spectral power only at lower frequencies in control subjects. The alpha-1 antagonist prazosin had similar effects in animals given DDT. The alpha-2 antagonist yohimbine and the beta antagonist propranolol produced lethality and increased the intensity of movements in animals administered DDT, without significantly affecting control animals. The alpha-2 agonist clonidine decreased the spectral profile over a wide range of frequencies in animals exposed to DDT, while depressing the spectral power of control animals only at higher frequencies. The dopamine antagonist haloperidol increased the intensity of movements in DDT-treated animals, without altering the spectral profile of controls. The dopamine agonist apomorphine induced stereotypy in control animals, but failed to significantly alter the power spectra in subjects given DDT. These data suggest a facilitatory and inhibitory role, respectively, for alpha-1 and alpha-2 receptors in the modulation of DDT-induced tremor. Dopamine and beta receptors may be involved in the tonic inhibition of tremor produced by DDT.

The effects on baseline ventilation as well as beta 2-receptor stimulant-induced bronchodilation and tremor of atenolol and dilevalol, a beta-blocking agent with non-selective beta-antagonistic properties and intrinsic activity on the beta 2-receptor were evaluated in 8 patients with stable asthma. Both atenolol and dilevalol were found to significantly decrease both forced expiratory volume during 1 s (FEV1) and forced vital capacity (FVC). This decrease was significantly more pronounced after atenolol. Both agents decreased systolic and diastolic blood pressure as well as heart rate to a similar degree. Increased activation of beta 2-adrenoceptors by terbutaline infusion resulted in increased FEV1 and FVC as well as beta 2-adrenoceptor mediated reflex tachycardia and skeletal muscle tremor. The dose response curves for all these parameters were significantly shifted to the right and a decrease of the maximum relative response was seen after atenolol pretreatment. This effect was more pronounced after treatment with dilevalol with a further shift to the right of the response curve and a decrease of the maximum relative response. The haemodynamic and ventilatory effects of dilevalol are consistent with a non-selective beta-adrenoceptor blockade combined with intrinsic activity on the beta 2-receptors.

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.

Thirty-seven patients with advanced malignancies, who received cis-platinum-based combination chemotherapy, were evaluated for the antiemetic efficacy of high-dose metoclopramide. Most of the patients suffered from ovarian carcinoma. The dose of metoclopramide was 7.5 or 10 mg/kg per course. A total of 69 courses were given to 37 patients and in 22% of the courses, nausea and vomiting were eliminated altogether. In an additional 48% of the courses, a partial protection from chemotherapy-induced emesis was evident. No serious side effects were observed. The administration of high-dose metoclopramide is recommended for prevention of cis-platinum chemotherapy-induced emesis.