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One of the main intoxications to livestock in the Patagonia region of Argentina is the tremorgenic disease "Mal de Huecú", attributed to the consumption of the native grasses Poa huecu and/or Festuca argentina. In this report, five outbreaks of spontaneous intoxications were investigated. Several indole-diterpene alkaloids were identified in Poa huecu and Festuca argentina including the known tremorgen terpendole C and are likely the cause of "Mal de Huecú" disease., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Cannabis is the most frequently used federally illicit substance in the United States. However, there are currently no FDA-approved pharmacotherapies to mitigate the withdrawal symptoms associated with cessation in heavy users. A promising, readily available, non-cannabinoid therapy are the gabapentinoids. Although currently approved for epilepsy and neuropathic pain, gabapentinoids are increasingly used for their "off-label" efficacy in treating various psychiatric conditions and substance abuse. Gabapentin (GBP) synergizes with cannabinoid agonism in neuropathic pain models, substitutes for Δ 9 -tetrahydrocannabinol (THC) in drug discrimination procedures, and reduced withdrawal symptoms in an outpatient clinical trial. However, there are limited data on the biological plausibility of the therapeutic action of gabapentinoids in cannabinoid withdrawal in preclinical models. The purpose of the current study was to determine the efficacy of GBP on attenuating THC withdrawal in mice, using an array of tests targeting withdrawal-induced and withdrawal-suppressed behaviors. Separate cohorts of male and female mice were administered THC (10 mg/kg, s.c.) or vehicle for 5.5 days, and withdrawal was precipitated by the CB 1 antagonist rimonabant (2 or 3 mg/kg, i.p.) on the sixth day. GBP (≥10 mg/kg) reduced somatic signs of withdrawal (i.e., paw tremors and head twitches), but had no effect in locomotor activity or conditioned place preference. GBP (50 mg/kg) also restored withdrawal-suppressed responding on a progressive ratio reinforcement schedule. However, GBP (50 mg/kg) had no effect in withdrawal-suppressed marble burying or tail suspension struggling and did not normalize the stress response induced by THC withdrawal, as indicated by plasma corticosterone. These data suggest gabapentin may be effective at treating cannabinoid withdrawal symptoms including somatic and affective symptoms but may act independently of endocrine stress activation., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The indole diterpenoid toxin lolitrem B is a tremorgenic agent found in the common grass species, perennial ryegrass (Lolium perenne). The toxin is produced by a symbiotic fungus Epichloë festucae (var. lolii) and ingestion of infested grass with sufficient toxin levels causes a movement disorder in grazing herbivores known as 'ryegrass staggers'. Beside ataxia, lolitrem B intoxicated animals frequently show indicators of cognitive dysfunction or exhibition of erratic and unpredictable behaviours during handling. Evidence from field cases in livestock and controlled feeding studies in horses have indicated that intoxication with lolitrem B may affect higher cortical or subcortical functioning. In order to define the role of lolitrem B in voluntary motor control, spatial learning and memory under controlled conditions, mice were exposed to a known dose of purified lolitrem B toxin and tremor, coordination, voluntary motor activity and spatial learning and memory assessed. Motor activity, coordination and spatial memory were compared to tremor intensity using a novel quantitative piezo-electronic tremor analysis. Peak tremor was observed as frequencies between 15 and 25Hz compared to normal movement at approximately 1.4-10Hz. A single exposure to a known tremorgenic dose of lolitrem B (2 mg/kg IP) induced measureable tremor for up to 72 h in some animals. Initially, intoxication with lolitrem B significantly decreased voluntary movement. By 25 h post exposure a return to normal voluntary movement was observed in this group, despite continuing evidence of tremor. This effect was not observed in animals exposed to the short-acting tremorgenic toxin paxilline. Lolitrem B intoxicated mice demonstrated a random search pattern and delayed latency to escape a 3 h post intoxication, however by 27 h post exposure latency to escape matched controls and mice had returned to normal searching behavior indicating normal spatial learning and memory. Together these data indicate that the tremor exhibited by lolitrem B intoxicated mice does not directly impair spatial learning and memory but that exposure does reduce voluntary motor activity in intoxicated animals. Management of acutely affected livestock suffering toxicosis should be considered in the context of their ability to spatially orientate with severe toxicity., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Ipomoea asarifolia has been associated with a tremorgenic syndrome in livestock. Recently indole diterpene compounds were identified in I. asarifolia, some of which have been shown to cause a tremorgenic syndrome. In this study, the tremorgenic nature of I. asarifolia was assessed using a mouse model. Adult mice were fed rodent chow containing 10, 15, 20 and 25% endophyte infected (E+), or 25% endophyte free (E-), I. asarifolia for 14 days. The mice fed E+ chow developed a tremorgenic syndrome as characterized by visually observed muscle tremors and an inability to traverse a balance beam, whereas the mice fed E- chow did not develop tremors and had similar muscle coordination to control mice. A lactating mouse model was also used to determine if the compounds can be transferred to nursing pups via the milk. Nursing pups were exposed via their mother's milk for 21 days, from post-natal day 0-21. The pups from dams exposed to E+ chow developed a similar tremorgenic syndrome. Data presented in this study demonstrate that the tremorgenic compounds in I. asarifolia are endophyte derived. Additionally, both adult mice and nursing pups are good models for studying the tremorgenic nature of I. asarifolia and related plants., (Published by Elsevier Ltd.)

MVIIA (ziconotide) is a specific inhibitor of N-type calcium channel, Cav2.2. It is derived from Cone snail and currently used for the treatment of severe chronic pains in patients unresponsive to opioid therapy. However, MVIIA produces severe side-effects, including dizziness, nystagmus, somnolence, abnormal gait, and ataxia, that limit its wider application. We previously identified a novel inhibitor of Cav2.2, ω-conopeptide SO-3, which possesses similar structure and analgesic activity to MVIIA's. To investigate the key residues for MVIIA toxicity, MVIIA/SO-3 hybrids and MVIIA variants carrying mutations in its loop 2 were synthesized. The substitution of MVIIA's loop 1 with the loop 1 of SO-3 resulted in significantly reduced Cav2.2 binding activity in vitro; the replacement of MVIIA loop 2 by the loop 2 of SO-3 not only enhanced the peptide/Cav2.2 binding but also decreased its toxicity on goldfish, attenuated mouse tremor symptom, spontaneous locomotor activity, and coordinated locomotion function. Further mutation analysis and molecular calculation revealed that the toxicity of MVIIA mainly arose from Met(12) in the loop 2, and this residue inserts into a hydrophobic hole (Ile(300), Phe(302) and Leu(305)) located between repeats II and III of Cav2.2. The combinative mutations of the loop 2 of MVIIA or other ω-conopeptides may be used for future development of more effective Cav2.2 inhibitors with lower side effects., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Two experiments, each with 10 pregnant ewes (8 treated and 2 controls) were performed to determine if nursing lambs of lactating ewes become intoxicated when the ewes ingest Ipomoea asarifolia but do not show clinical signs themselves. In the first experiment the sheep grazed I. asarifolia in the field while in the second, sheep were maintained in individual bays consuming dry I. asarifolia at 10% and 20% into their ration. In both experiments the lambs remained confined, consuming only their mother's milk. Four of 8 lambs in the grazing experiment and the 4 nursing lambs from the ewes given 20% I. asarifolia showed signs of I. asarifolia poisoning. These results confirm that the tremorgenic compound of I. asarifolia or its toxic metabolites are eliminated in milk and can intoxicate nursing lambs., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Harmaline induces tremor in animals resembling essential tremor which has been suggested to result from activation of the glutamatergic olivo-cerebellar projection. The aim of the present study was to examine the effects of systemic administration of Lu AF21934, a brain-penetrating positive allosteric modulator of the metabotropic glutamate receptor 4 (mGlu4), on the harmaline-induced tremor and other forms of motor activity in rats using fully automated Force Plate Actimeters. The influence of harmaline on the mGlu4 mRNA expression in the cerebellum and inferior olive was analysed by in situ hybridization. Harmaline at a dose of 15 mg/kg (ip) triggered tremor which was manifested by an increase in the power within 9-15 Hz band and in the tremor index (a difference in power between bands 9-15 Hz and 0-8 Hz). Harmaline induced a biphasic effect on mobility, initially inhibiting the exploratory locomotor activity of rats (0-30 min after administration), followed by an increase in their basic activity. Lu AF21934 (0.5-5 mg/kg sc) did not influence tremor but at doses of 0.5 and 2.5 mg/kg reversed harmaline-induced hyperactivity. MGlu4 mRNA expression was high in the cerebellar cortex and low in the inferior olive. Repeated harmaline (15 mg/kg ip once a day for 5 days] decreased mGlu4 mRNA in the cerebellum and inferior olive. The present study indicates that the mGlu4 stimulation counteracts hyperactivity induced by harmaline which suggests the involvement of cerebellar glutamatergic transmission in this process. In contrast, neuronal mechanisms involved in tremor seem to be insensitive to the stimulation of mGlu4., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Several cases of neurological disease in dogs after poisoning by food- and feed-borne Penicillium toxins in Norway during the last years have uncovered a lack of knowledge regarding the toxicity and mechanism of action of neuroactive mycotoxins. In the present study, the lowest tremor-inducing dose after single oral administration of penitrem A to mice was 0.50 mg/kg bw. The estimated half maximal effective dose (ED(50)) in respect to the visual tremor scale was 2.74 mg/kg bw. Mice receiving the maximum penitrem A dose (8 mg/kg bw) suffered severe spontaneous tremors and even convulsions. Thomitrem A and E are penitrem analogues lacking the C-16-C-18 ether linkage and possessing an olefin at C-18-C-19. Compared with penitrem A, the lowest tremor-inducing dose of thomitrem A was 16-times higher (8 mg/kg bw) and thomitrem E was found to be non-tremorgenic at the highest dose tested (16 mg/kg bw). During a recovery phase of two weeks post administration animals appeared restored and no changes in feeding and other biological processes were observed. An initial dose-related weight reduction was observed 2 days after penitrem A administration. Penitrem A was absorbed and distributed to gastrointestinal tract, liver, kidneys and brain in the mice. Elimination of penitrem A appeared to be mainly hepatic and the highest concentration levels were found 1 h post administration for all investigated organs. The relationship between liver and gastrointestinal tract concentration levels showed time-dependent linear correlation and a doubling within 1.5 h., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The effects of the fungal neurotoxin penitrem A on the GABAergic and glutamatergic systems in rat brain were evaluated. Penitrem A inhibited binding of the GABA(A)-receptor ligand [³H]TBOB to rat forebrain and cerebellar membrane preparations with IC₅₀ (half maximal inhibitory concentration) values of 11 and 9 μM, respectively. Furthermore, penitrem A caused a concentration-dependent increase of [³H]flunitrazepam and [³H]muscimol binding in rat forebrain, but not in cerebellar preparations. The stimulation of [³H]flunitrazepam binding by penitrem A was abolished by the addition of GABA. In cerebellar preparations, a different pharmacological profile was found, with penitrem A allosterically inhibiting [³H]TBOB binding by interacting with a bicuculline-sensitive site. Moreover, penitrem A inhibited the high affinity uptake of GABA and glutamate into cerebellar synaptosomes with IC₅₀ values of 20 and 47 μM, respectively. The toxin showed no effect on NMDA or AMPA glutamate receptor binding. In conclusion, our results suggest that penitrem A exerts region-specific effects in the brain, leading to positive modulation of GABA(A)-receptor function in forebrain. Conversely, penitrem A may act as a bicuculline-like convulsant in cerebellum., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Essential tremor (ET) is one of the most common and most disabling movement disorders among adults. The drug treatment of ET remains unsatisfactory. Additional therapies are required for patients with inadequate response or intolerable side effects. The current study aims to investigate the anti-tremogenic and neuroprotective effects of memantine (NMDA receptor antagonist) on the harmaline model of transient action tremor. The effects of memantine were further compared with ethanol. Three separate groups of male Wistar rats were injected either with saline, ethanol (1.5 gr/kg), or memantine (5 mg/kg) 15 min prior to a single intraperitoneal injection of harmaline (20 mg/kg). Tremor and locomotion were evaluated by a custom-built tremor and locomotion analysis system. After 24 h of harmaline injection, cellular viability, and apoptosis were assessed using crystal violet staining, and caspase-3 immunostaining, respectively. Harmaline caused neuronal cell loss and caspase-3 mediated apoptosis in cerebellar granular and purkinje cells as well as the inferior olivary neurons. Despite a reduction in tremor intensity and duration with ethanol, this compound resulted in cell loss in cerebellum and olivary nucleus. Memantine exhibited neuroprotective efficacy on cerebellar and inferior olivary neurons albeit weaker anti-tremor effect compared to ethanol. In conclusion, anti-tremogenic and neuroprotective effects do not necessarily overlap. Memantine is a potential treatment for ET particularly given its neuroprotective efficacy., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The effect of Bothrops antivenom on blocking the disturbances induced by Bothrops jararaca venom in leukocyte-endothelial interactions (LEI) at the microcirculation of the cremaster muscle in mice was evaluated using intravital microscopy. Our findings showed that an i.v. injection of Bothrops antivenom, per se, induced changes in LEI, similar to those induced by an s.c. injection of B. jararaca venom, and that Bothrops antivenom can also induce ephemeral symptoms, such as tremor and dyspnea in mice. These effects were mostly due to phenol used in Bothrops antivenom as a preservative, since animals injected i.v. with a phenol solution, but not with phenol-free Bothrops antivenom, presented those effects on LEI, and also tremor and dyspnea. In addition, phenol-free antivenom abrogated venom-induced changes in LEI parameters. The present data demonstrate that Bothrops antivenom contains antibodies that neutralize toxins of B. jararaca venom that impair LEI, and suggest that the phenol used as a preservative in it can originate some undesired effects.

Glutamate plays an important role in the psychotomimetic effects of both channel blocking N-methyl D-aspartate (NMDA) receptor antagonists and hallucinogenic drugs which activate 5-hydroxytryptamine2A (5-HT2A) receptors. Previous work suggested that activation of non-NMDA ionotropic glutamate receptors mediates the effects of 5-HT-induced excitatory post-synaptic potentials/currents (EPSPs/EPSCs) when recording from layer V pyramidal cells in the rat medial pre-frontal cortex (mPFC). However, those effects are mediated by either alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) or kainate receptors of the iGluk5 subtype. To test whether activation of AMPA receptors is sufficient to mediate 5-HT-induced EPSCs, a 2,3-benzodiazepine that selectively blocks AMPA receptors was assessed. This selective AMPA receptor antagonist potently suppressed 5-HT-induced EPSCs. Since phenethylamine hallucinogens induce head shakes by activating 5-HT2A receptors in the mPFC and this action is modulated by glutamate, we also examined whether selective blockade of AMPA receptors would suppress DOI-induced head shakes. As predicted, we found that selective blockade of AMPA receptors suppressed DOI-induced head shakes. Given evidence that activation of AMPA receptors is an important downstream effect for both channel blocking NMDA receptor antagonists and phenethylamine hallucinogens, we also tested multiple doses of DOI with a sub-anesthetic dose of MK-801. Synergistic action between these two classes of psychotomimetic drugs was demonstrated by MK-801 enhancing DOI-induced head shakes and locomotor activity. These findings expand the dependence of both channel blocking NMDA receptor antagonists and phenethylamine hallucinogens on enhancing extracellular glutamate.

Pyrethroids are pesticides with high insecticidal activity and relatively low potency in mammals. The influence of dosing volume on the neurobehavioral syndrome following oral acute exposure to the Type-I pyrethroid insecticide bifenthrin in corn oil was evaluated in adult male Long Evans rats. We tested bifenthrin effects at 1 and 5 ml/kg, two commonly used dose volumes in toxicological studies. Two testing times (4 and 7 h) were used in motor activity and functional observational battery (FOB) assessments. Four to eight doses were examined at either dosing condition (up to 20 or 26 mg/kg, at 1 and 5 ml/kg, respectively). Acute oral bifenthrin exposure produced toxic signs typical of Type I pyrethroids, with dose-related increases in fine tremor, decreased motor activity and grip strength, and increased pawing, head shaking, click response, and body temperature. Bifenthrin effects on motor activity and pyrethroid-specific clinical signs were approximately 2-fold more potent at 1 ml/kg than 5 ml/kg. This difference was clearly evident at 4 h and slightly attenuated at 7 h post-dosing. Benchmark dose (BMD) modeling estimated similar 2-fold potency differences in motor activity and pyrethroid-specific FOB data. These findings demonstrate that dose volume, in studies using corn oil as the vehicle influences bifenthrin potency. Further, these data suggest that inconsistent estimates of pyrethroid potency between laboratories are at least partially due to differences in dosing volume.

Measurement of tremor has been used in several occupational studies of workers with long-term exposure to mercury vapor (Hg(0)). Recent studies indicate an adverse effect even at relatively low exposure levels. In the present study, we used sensitive quantitative methods to assess tremor in chloralkali workers with current low exposure to Hg(0). Neurological examinations and recordings of tremor using both an accelerometer and a laser-based system were conducted in 43 mercury-exposed workers and 22 age-matched referents. The median urinary mercury concentration in exposed workers was 5.9 (1.3-25) microg/g creatinine (microg/gC), while it was 0.7 (0.2-4.1) microg/gC in referents. The mean exposure time was 15 years, and the median cumulative mercury index was 161 years x microg/gC in exposed workers. There were no differences between the exposed workers and the referents in the clinical evaluation of tremor. In the quantitative tremor tests, no associations were found with current or cumulative mercury exposure for the majority of tremor measures. There were indications that exposure to Hg(0) was associated with a lowering of tremor frequency in the non-dominant hand, and a possible interaction with smoking. The differences were small, however, and overall, this study indicates no significant adverse effects on tremor at these exposure levels.

The aim of this study was to examine the effects of prenatal and postnatal chronic exposure to mercury (Hg), polychlorinated biphenyls (PCBs) and lead (Pb) on the neuromotor development of preschool children. The study population consisted of 110 preschool Inuit children from Nunavik (Canada). Blood Hg, PCBs and Pb concentrations were measured at birth (cord blood) and at the time of testing. Gross motor functions were evaluated and a neurological examination was performed. Fine neuromotor performance was assessed using quantitative measures of postural hand tremor, reaction time, sway oscillations, as well as alternating and pointing movements. Potential covariates were documented including demographic and familial characteristics, other prenatal neurotoxicants (alcohol, tobacco) and nutrients (selenium (Se), Omega-3 polyunsaturated fatty acids (n-3 PUFA)). Hierarchical multivariate regression analyses were performed, controlling for significant covariates. Gross motor development was not linked to prenatal exposures. However, significant associations were observed between blood Pb concentration at testing time and changes in reaction time, sway oscillations, alternating arm movements and action tremor. For some of these outcomes, neuromotor effects of Pb exposure are observed at blood concentrations below 10 microg/dl. Negative effects of PCBs on neuromotor development were not clearly observed, neither were the potential beneficial effects of n-3 PUFA and selenium. Tremor amplitude was related to blood Hg concentrations at testing time, which corroborate an effect already reported among adults.

This work was performed to clarify the differences between a long or short development of morphine dependence as well as between a recently installed or a long-term dependence. Morphine withdrawal in rats is a well-characterized phenomenon but this is not so in mice. A study of the principal withdrawal signs have been performed in mice, evaluating their specificity and particular profile of appearance in each type of dependence. Mice were divided into two groups that received increasing doses of morphine every 24 h, three groups that received increasing doses of morphine twice a day for 3 days, and a control group that received saline. Naloxone-induced opiate withdrawal was evaluated following short-term exposition to morphine [Test 1 (T1)--saline and Test 2 (T2)--naloxone] and long-term exposition to morphine [Test 3 (T3)--naloxone and Test 4 (T4)--saline]. Morphine administration twice a day is more effective in inducing opiate dependence than once a day, and with the latter, the duration of morphine exposure increases the intensity of withdrawal signs. Weight loss, diarrhea, body shakes, jumping, paw tremor, ptosis, piloerection, and the modified Gellert-Holtzman scale for mice are specific patterns of naloxone-induced withdrawal. The first four signs allow the discrimination between different levels of opiate dependence. Body care, piloerection, and the modified Gellert-Holtzman scale could be useful to detect conditioned withdrawal.

Several pharmacological and neurochemical conditions in rats induce 'vacuous' or 'tremulous' jaw movements. Although the clinical significance of these movements has been a subject of some debate, considerable evidence indicates that the non-directed, chewing-like movements induced by cholinomimetics, dopamine antagonists and dopamine depletions have many of the characteristics of parkinsonian tremor. These movements occur within the 3-7 Hz peak frequency range that is characteristic of parkinsonian tremor. Tremulous jaw movements are induced by many of the conditions that are associated with parkinsonism, and suppressed by several different antiparkinsonian drugs, including scopolamine, benztropine, L-DOPA, apomorphine, bromocriptine, amantadine and clozapine. Striatal cholinergic and dopaminergic mechanisms are involved in the generation of tremulous jaw movements, and substantia nigra pars reticulata appears to be a major basal ganglia output region through which the jaw movements are regulated. Future research on the neurochemical and anatomical characteristics of tremulous jaw movements could yield important insights into the brain mechanisms that generate tremulous movements.

Rest, postural, and kinetic tremors were recorded in Cree subjects (n = 36) exposed to low levels of methylmercury (MeHg) and control subjects (n = 30) using lasers designed to measure displacement. Displacement and derived velocity and acceleration time series were analyzed using quantitative characteristics in time and frequency domains. We found: 1) relatively low agreement between our results and those of a clinical examination done at the time of testing (r = 0.31 for postural tremor); 2) best discrimination with velocity of static (postural with visual feedback) and kinetic tremors for which significant differences between the two groups are found in many of the characteristics examined; 3) myoclonic-like finger microdisplacements in tremor of Cree subjects; 4) significant changes in static tremor of Cree subjects following a kinetic task; 5) significant differences among three age-matched subgroups of six subjects each (Cree with higher and lower MeHg level, and a control group) in characteristics that reflect difficulty with tracking, myoclonic-like microdisplacements and change in frequency composition of tremor after the tracking task. The subtle differences detected in this preliminary study suggest that further work is warranted to determine whether they can be unambiguously associated with exposure to MeHg.

A Across-study design was used to evaluate the sensitivities of five psychomotor tasks previously used to assess preclinical effects of low-level Hg0 (urinary < or =55 microg/l). Pooling dental professional subject populations from six studies conducted over the last 6 years, a larger study population was obtained with a high degree of uniformity (N = 230). The five psychomotor tests were: Intentional Hand Steadiness Test (IHST); Finger Tapping: The One-Hole Test: NES Simple Reaction Time (SRT); and Hand Tremor. Multivariate analyses were conducted following the hierarchical analysis of multiple responses (HAMR) approach. First, multiple scores of each test were combined into a single-factor (or related summary) variable and its reliability was estimated. Second. multiple regression analyses were conducted including log-transformed [Hg0]U levels, age, gender, and alcohol consumption in each model. Computed were both B and bu, the magnitudes of the log-Hg0 standardized coefficient. respectively uncorrected and corrected for dependent variable attenuation due to unreliability. Results indicated remarkable differences in the effects of relative level of Hg0 on psychomotor performance. Significant associations were found for the IHST factor (B = 0.415, p < 10(-6)), followed by finger tapping, which was relatively meager and insignificant (B 0.141, p = 0.17). The IHST results hold the greatest occupational relevance for dental professionals who rely on manual dexterity in restorative dentistry. Further, this statistical approach is recommended in future studies for condensation of multiple scores into summary scores with enhanced reliabilities useful in correcting for attenuation relationships (B(u)s) with exposure levels.

1. Extrapyramidal adverse effects have been reported with the selective serotonin re-uptake inhibitor (SSRI) antidepressants, particularly fluoxetine and paroxetine. 2. Recently, the SSRI sertraline has also been associated with treatment-emergent extrapyramidal syndrome (EPS) side effects. A review of the literature identified thirteen published cases of sertraline-induced EPS, several of which were confounded by the presence of concomitant medications, and few reported quantitative data using rating scales. 3. We present another case of EPS associated with sertraline in which daily ratings were obtained using the Abnormal Involuntary Movement Scale. 4. This review and case report add to the small but growing literature suggesting that sertraline, like the other SSRI's may cause significant extrapyramidal side-effects. These movement disorders presumably occur through an interaction between serotonergic and dopaminergic pathways, providing an important clinical correlation of interactions between these neurotransmitter systems.

A cross-sectional study of 63 current and former aluminum potroom workers and 37 comparison workers was conducted to evaluate for evidence of neurological dysfunction, including tremor from long-term exposures to aluminum using sensitive quantitative measures of arm/hand and leg tremor. Signs of upper extremity tremor were also evaluated by neurological examination and compared with the quantitative measures of arm/hand tremor. Both arm/hand and leg tremor were measured using fatiguing test conditions, but no statistically significant differences due to exposure to aluminum were present between the potroom workers and the comparison workers. The neurological examination also showed no statistically significant differences between the groups on the evaluation of signs of tremor. These results do not support the findings of Best-Pettersen et al., who reported evidence of increased tremor in aluminum workers using the static steadiness test in the Halstead-Reitan battery. Differences between the studies that may have contributed to the contrasting results are discussed. In addition, techniques are presented for using microcomputer-controlled devices to evaluate tremor in both the visible (1-6 Hz) and nonvisible (7-18 Hz) frequencies of the tremor spectrum.

At a mercury spill, several workers were exposed to mercury vapour concentrations up to 0.15 mg/m3. Two weeks after, 38 exposed workers were examined. Fourteen had a Hg in urine concentration above 25 nmol/l. Two exposed groups (n = 7) and an unexposed control group (n = 15) were formed, based on Hg in urine: a HI group with mean = 106.5 nmol/l (range: 49.5-249); a LO group with mean = 35.2 nmol/l (range: 28.8-48.0), and control group with mean = 10.5 nmol/l (range: 4.5-14.1). The groups were reexamined 3 and 16 months later. The groups were examined with two computer-based portable test systems. CATSYS quantifies hand pronation/supination, finger tapping, and reaction time. TREMOR records and analyses tremor at the finger tips. The results showed reduced coordination ability in the HI group at the first examination compared to the control group. Tremor intensity was very high in the HI group and decreased only slightly during the follow-up period. The study indicates that quantification of coordination ability and tremor intensity can be used within occupational medicine for the assessment of the impact of acute mercury intoxication.

The relation between phenol-induced tremor and brain acetylcholine levels, and the effects of cholinergic drugs on the tremor were investigated, using male ddY mice weighing 28-35 g. The magnitude of phenol-induced tremor was graded on a 4-point scale: 0, normal; 1, slight; 2, moderate; 3, severe, and acetylcholine levels were measured by high-performance liquid chromatography with electrochemical detection. The magnitude of tremor and the decrease in acetylcholine levels in the striatum and cerebral cortex induced by s.c. injection of phenol (50, 100, 200 mg/kg) were dose-dependent, and both showed parallel time courses. Intracerebroventricular (i.c.v.) injection of phenol (100 micrograms/mouse) caused a decrease in acetylcholine levels in the striatum but did not induce tremor. Intraperitoneal injection of pentobarbital (10 mg/kg), which inhibits the release of acetylcholine, weakened both the magnitude of the tremor and the decrease in acetylcholine levels induced by phenol (200 mg/kg), whereas i.c.v. injection of pentobarbital (120 micrograms/mouse) attenuated the decrease in acetylcholine levels induced by phenol, but did not affect the magnitude of the tremor. Intraperitoneal (20 mg/kg) or i.c.v. (60 micrograms/mouse) injection of mecamylamine further strengthened the tremor. Intraperitoneal (0.3 mg/kg) injection of physostigmine strengthened the tremor, while i.c.v. injection (1 microgram/mouse) caused a reduction in its magnitude. These results suggest that the tremor is caused directly by the phenol-induced increase in acetylcholine release in the peripheral nervous system (motor nerve endings), that the decrease in brain acetylcholine levels may be due to phenol-induced increases in acetylcholine release within the central nervous system, and that the resultant reduction in brain acetylcholine levels indirectly suppresses the tremor.

1. Rats given a 10-% (v/v) alcohol liquid diet over long periods of time reach high blood alcohol levels of more than 200 mg/dl over several weeks. 2. Repeated discontinuation of the alcohol intake resulted, each time within 8 hr, in several withdrawal reactions including a reduction in exploratory behaviour and tremorogenic activity. 3. The inhibition of exploratory activity was measured in a neutral two-chamber model, both in terms of the number of transits into the open area as well as the time spent in the open space. The differences in exploration remained over the 4 successive withdrawal tests. 4. Rats in alcohol withdrawal were also consistently less active than control animals in the tremor cages equipped with a piezofilm floor, and this despite the presence of a clearly visible tremor in the hindpaws when lifted up. 5. Alcohol withdrawal rats revealed a more frequent tremor activity than controls after a challenge with 5 mg/kg harmine. This effect was independent of the length of the tremor bursts used to quantify harmine-induced tremor starting from the second withdrawal period onwards. 6. With a dose of 10 mg/kg harmine, ceiling effects were reached in both the alcohol withdrawal and control rats and differences between the two groups were only present during the first exposures. 7. Overall, these results indicate that it is possible to quantify some withdrawal reactions at repeated time intervals of alcohol cessation in rats chronically exposed to a 10-% alcohol liquid diet. As a consequence, these withdrawal reactions can be studied in a more systematic way.

Because of the claim that ibogaine suppresses the symptoms of "narcotic withdrawal" in humans, the effect of ibogaine on naltrexone-precipitated withdrawal signs in morphine-dependent rats was assessed. Morphine was administered subcutaneously through implanted silicone reservoirs for 5 days. Ibogaine (20, 40 or 80 mg/kg, i.p.) or saline was administered 30 min prior to challenge with naltrexone (1 mg/kg, i.p.) and withdrawal signs were counted for the following 2 hr. Ibogaine (40 and 80 mg/kg) significantly reduced the occurrence of four signs (wet-dog shakes, grooming, teeth chattering and diarrhea) during naltrexone-precipitated withdrawal; three other signs (weight loss, burying and flinching) were unaffected. Ibogaine induces head and body tremors lasting for 2-3 hr and the tremors might have interfered with the expression of opioid withdrawal. To examine this issue, another experiment was conducted in which ibogaine (40 mg/kg) or saline was administered 4 hr prior to challenge with naltrexone. Although there was a complete absence of tremors, ibogaine still significantly reduced the occurrence of the same four signs of withdrawal.

1. Male hooded Lister rats were fed a liquid diet containing 10% absolute ethanol for 4-5 weeks. Control rats received the liquid diet in amounts controlled to produce equal weight gain. 2. The rats were tested 7.5 h after withdrawal of ethanol and 30 min after i.p. injection with nitrendipine, chlordiazepoxide or baclofen or 20 min after i.p. injection with flumazenil. 3. Nitrendipine (25-100 mg/kg) was unable to reverse the anxiogenic responses detected on withdrawal from ethanol, but the highest dose did reduce withdrawal tremor. 4. Chlordiazepoxide (10 mg/kg), flumazenil (4 mg/kg) and baclofen (1.25 mg/kg) significantly reversed the anxiogenic response detected on withdrawal from ethanol. 5. These reversals of ethanol withdrawal responses are similar to the reversal of the increased anxiety detected on withdrawal from chronic treatment with benzodiazepines. 6. The mechanisms and clinical implications of these drug-induced reversals are discussed.

It has previously been reported that intracerebroventricular administration of neurotensin (30 micrograms) reduced muscular rigidity and tremors, induced by a neurochemical lesion with 6-hydroxydopamine in the posterolateral hypothalamus of rats. In the present study, the effects of two fragments (NT1-10 and NT8-13) and two analogues ([D-Tyr11]-NT and [Ala11]-NT) of neurotensin on the grasping time (index of muscle rigidity) and tremors in 6-hydroxydopamine-lesioned rats are reported. Intracerebroventricular administration with 120 micrograms of NT1-10 and [Ala11]-NT had no effect on the muscle rigidity and tremors induced by the neurochemical lesion. The administration of NT8-13 60 micrograms) significantly attenuated both behavioural responses. The analogue [D-Tyr11]-NT produced a much greater attenuation of the muscle rigidity and tremors. The dose of 1.8 micrograms of [D-Tyr11]-NT significantly reduced the grasping time, while the number of tremors was attenuated with the threshold dose of 0.9 micrograms. Together, these results suggest that the effects of neurotensin on muscle rigidity and tremors, induced by pretreatment with 6-hydroxydopamine injected into the posterolateral hypothalamus, were not caused by non-specific effects but largely depended on the carboxy terminal of the peptide. The tyrosine residue in position 11 of the molecule plays a critical role in the action of neurotensin, as shown with the high potency and duration of action of the analogue [D-Tyr11]-NT. As previously suggested, the greater effect with [D-Tyr11]-NT may be due to greater resistance of the analogue to enzymatic degradation because of the incorporation of the D-Tyr amino acid, in position 11 of neurotensin.

Histidine injected intraperitoneally into rats in doses from 400 to 800 mg/kg induced a dose-dependent bizarre behaviour. The behaviour after histidine was similar to that observed after L-DOPA and peripheral decarboxylase inhibition. The bizarre behaviour was antagonized by chloropyramine, ketotifen, clemastine and promethazine, antagonists of histamine H1 receptors, with ED50's of 13.9, 14.2, 21.6 and 22.2 mg/kg, respectively. Cimetidine, an antagonist of histamine H2 receptors, injected intraventricularly at a dose of 100 micrograms, was without effect. The bizarre behaviour after histidine was not changed by antagonists of dopamine, noradrenaline and serotonin receptors, but it was blocked by atropine, indicating involvement of central cholinergic systems.

Ontogenic evolution of behavioural and electrophysiological responses to the serotonergic agents, quipazine and harmaline, was studied in the maturing rabbit in normal and pretreated conditions. As regards behavioural effects, tremor induced by quipazine was present from the first postnatal day and was antagonized by methysergide, but not by p-chlorophenylalanine (PCPA) or pretreatment with 5,7-dihydroxytryptamine (5,7-DHT). In contrast, tremor induced by harmaline could not be elicited before the second postnatal week and was partially antagonized by methysergide and 5,7-DHT, but not by PCPA. Electrophysiological studies of cell activity in the inferior olivary nucleus revealed a similar dependency on age since rhythmic activation of the inferior olivary nucleus could be registered from the first postnatal day with quipazine and only from the 8th postnatal day with harmaline; drug interactions with methysergide, PCPA and 5,7-DHT were the same as for the behavioural observations. It is suggested that quipazine directly activates serotonin receptors which are already present at birth, whereas harmaline requires the presence of serotonergic fibres for such activation.

Cholecystokinin octapeptide (CCK-8), ceruletide (caerulein, CER) and 10 analogues of ceruletide, were studied in mice for antagonism of the tremors induced by harmine (5 mg/kg, s.c.), ibogaine (20 mg/kg, s.c.) and oxotremorine (0.2 mg/kg, s.c.). The following reference drugs were tested for comparison: prolyl-leucylglycine amide (MIF), atropine, haloperidol, biperiden, ethopropazine, trihexyphenidyl, methixene and clonazepam. All treatments were subcutaneous, the antagonists being given 10 min (in some trials 30 min) before the tremorogen. Tremorolytic potency (ED50) was calculated from dose-response curves. Against the tremors induced by either harmine or ibogaine, CCK-8 and ceruletide, as well as many of the analogues of ceruletide had greater tremorolytic potency than the reference drugs. Against oxotremorine, however, ceruletide and its most potent analogue, Nle8-CER (other analogues were not tested) were inactive and MIF showed very little effectiveness. Additional experiments on hypothermia and sedation as well as evaluation of previous studies on other central actions suggested that the tremorolytic effect of CCK-like peptides is independent of other central effects. The CCK-like peptides may play a physiological role in the regulation of extrapyramidal motor activity.

This case report describes a schizophrenic patient who developed akathisia and tremor following neuroleptic pharmacotherapy with fluphenazine decanoate. The patient also suffered from familial (benign essential) tremor. The patient's neuroleptic-induced extrapyramidal side effects were not relieved by anticholinergic antiparkinson drugs or by phenobarbital. The patient was started on propranolol 10 mg b.i.d. She was also started on diazepam 5 mg t.i.d. for anxiety. The diazepam dose was held constant and propranolol was gradually increased to 40 mg q.i.d. The patient's extrapyramidal symptomatology gradually resolved over the course of one month, during which time the propranolol dose was being steadily increased. Propranolol also effectively controlled her familial tremor. After nine months as an outpatient, during which time the patient was neuroleptic-free, she developed psychotic decompensation for which she was treated with thiothixene. Akathisia or tremor did not develop, possibly because the patient was taking propranolol simultaneously. Propranolol may be useful for treating neuroleptic-induced akathisia. This requires systematic investigation with open and controlled trials.

The effects of excitatory amino acids, kainic acid and quisqualic acid, on the tremorine- and harmaline-induced tremor were quantitatively examined in mice using the power spectral analyzing method. The severity of the tremor was determined quantitatively in terms of the cumulative sum of the mean square value of the data. Kainic acid enhanced the tremor induced by tremorine but depressed the tremor induced by harmaline. Quisqualic acid depressed the tremor induced by both tremorine and harmaline in a dose-dependent manner. Kainic acid shifted the frequency of each component of the tremor induced by tremorine to the high frequency side, but quisqualic acid did not affect the frequency of tremor of the tremor induced by tremorine. The frequency of tremor of the tremor induced by harmaline was shifted by both excitatory amino acids to the low frequency side, and another component of tremor in the power spectral densities developed, of which the mean square values were very small. The present results suggest that, at least in part, the glutamatergic system can take a role on the modification of drug-induced tremor.

The effects of lesioning monoamine pathways in the rat brain on tremorine-induced hind-limb tremor and rigidity were studied. Nigro-striatal and mesolimbic dopamine (DA) neurones were lesioned unilaterally by injecting 6-hydroxydopamine (6-OHDA) into the median forebrain bundle. Tremor was reduced in the contralateral leg and rigidity was prevented in the ipsilateral leg. Injection of 6-OHDA into the nucleus accumbens affected tremor but not rigidity. In general, nigral DA neurones may influence rigidity whilst mesolimbic DA neurones affect tremor. A unilateral locus coeruleus electrolesion which destroys noradrenaline (NA) fibres reduced both tremor and rigidity. A median raphe electrolytic lesion affecting 5-hydroxytryptamine (5-HT) neurones had no effect on tremor and rigidity, whereas lesioning the dorsal raphe electrolytically or by injecting 5,6-dihydroxytryptamine prevented rigidity without affecting tremor. Electrical stimulation of the dorsal raphe increased transiently the hindlimb tone of normal rats. The findings demonstrate that the monoamines, especially 5-HT, are differently involved in the mechanisms of tremor and rigidity produced by tremorine.

The experiments characterized the dose- and time-dependence of parkinsonian motor signs induced by reserpine in rats and a standardized system of manipulation of animals, evaluation of symptoms and analysis of data was devised. The assay procedure yielded no more than 0.5, 4.5 and 0.0% false positives with the evaluation of tremor, rigidity and hypokinesia, respectively. A dose-dependent and often complete blockade of all three signs was obtained with L-DOPA plus carbidopa (10:1) as well as with other classes of pharmacological agents that are used in the treatment of Parkinson's disease, i.e. direct or indirect dopamine (DA) agonists (amantadine, pergolide, lisuride) and inhibitors of monoamine oxidase (MAO) (clorgyline, pargyline, deprenyl, tranylcypromine). The inhibitor of the uptake of DA, nomifensine, and anticholinergics, 5-hydroxytryptamine (5-HT) antagonists, histamine antagonists and tricyclic antidepressants exerted little or no effect. The effects of putative agonists and antagonists at alpha 1- and alpha 2-adrenoceptors were also examined. Yohimbine blocked tremor and rigidity, but not hypokinesia, at 0.66 and 0.28 mg/kg, respectively. It is suggested that alpha-adrenergic mechanisms and, in particular, alpha 2-adrenoceptors, may be involved in reserpine-induced tremor and rigidity. Noradrenergic and dopaminergic systems can conceivably interact to progressively generate these different motor signs.

Imipramine hydrochloride shows effects in a battery of tests used for the screening of antidepressant drugs. The central origin of these pharmacological effects of imipramine has not been clearly established. Imipramine methiodide is a quaternary derivative of imipramine which does not cross the blood-brain barrier easily. The effects of the two forms of imipramine have been compared: on an effect known to have a central origin; on two effects known to have a peripheral origin; on a battery of tests used for the screening of antidepressant drugs. It has been demonstrated that imipramine methiodide is as active as imipramine hydrochloride on two effects of peripheral origin, less active than imipramine hydrochloride on an effect considered to have a central origin and less active than imipramine hydrochloride or inactive on the tests which are used for the screening of antidepressant drugs. Consequently, the tests used for the screening of antidepressant drugs represent, primarily or exclusively, effects of central origin.

Twenty male adult Wistar rats were unilaterally lesioned in the substantia nigra (SN) with 6-hydroxydopamine (6-OHDA), and prepared with chronic cortical (ECoG) and neck muscle (EMG) electrodes. Longitudinal study over a period of up to 18 months demonstrated the emergence, in about two-thirds of the rats, of spontaneous repetitive episodes of head and neck tremor during awake at rest, of up to 20 seconds duration each, that were associated with spike and wave-like ECoG activities. These episodes of tremor at rest disappeared during sleep and REM sleep episodes, and also following the i.p. administration of L-DOPA. It is assumed that these tremor at rest episodes are analogous to those reported to occur in primates after experimentally induced dysfunction of the nigro-striatal, extrapyramidal system.