harmine and Tremor

Topics: Alkaloids; Animals; Cats; Cerebellar Nuclei; Cerebellum; Cyclic GMP; Diazepam; Dopamine; Electroencephalography; gamma-Aminobutyric Acid; Harmaline; Harmine; Levodopa; Medulla Oblongata; Neural Pathways; Olivary Nucleus; Rabbits; Spinal Cord; Synaptic Transmission; Tremor

CYP2D6 metabolically inactivates several neurotoxins, including beta-carbolines, which are implicated in neurodegenerative diseases. Variation in CYP2D6 within the brain may alter local inactivation of neurotoxic beta-carbolines, thereby influencing neurotoxicity. The beta-carboline harmine, which induces hypothermia and tremor, is metabolized by CYP2D6 to the non-hypothermic/non-tremorgenic harmol. Transgenic mice (TG), expressing human CYP2D6 in addition to their endogenous mouse CYP2D, experience less harmine-induced hypothermia and tremor compared with wild-type mice (WT). We first sought to elucidate the role of CYP2D in general within the brain in harmine-induced hypothermia and tremor severity. A 4-h intracerebroventricular (ICV) pretreatment with the CYP2D inhibitor propranolol increased harmine-induced hypothermia and tremor in TG and increased harmine-induced hypothermia in WT. We next sought to specifically demonstrate that human CYP2D6 expressed in TG brain altered harmine response severity. A 24-h ICV propranolol pretreatment, which selectively and irreversibly inhibits human CYP2D6 in TG brain, increased harmine-induced hypothermia. This 24-h pretreatment had no impact on harmine response in WT, as propranolol is not an irreversible inhibitor of mouse CYP2D in the brain, thus confirming no off-target effects of ICV propranolol pretreatment. Human CYP2D6 activity in TG brain was sufficient in vivo to mitigate harmine-induced neurotoxicity. These findings suggest that human CYP2D6 in the brain is protective against beta-carboline-induced neurotoxicity and that the extensive interindividual variability in CYP2D6 expression in human brain may contribute to variation in susceptibility to certain neurotoxin-associated neurodegenerative disorders.

Topics: Animals; Brain; Cytochrome P-450 CYP2D6; Harmine; Humans; Hypothermia, Induced; Injections, Intraventricular; Liver; Mice, Transgenic; Neurotoxicity Syndromes; Propranolol; Tremor

Tremor is a widespread phenomenon in human populations. Environmental factors are likely to play an etiological role. Harmane (1-methyl-9H-pyrido[3,4-β]indole) is a potent tremor-producing β-carboline alkaloid. Lead is another tremor-producing neurotoxicant. The effects of harmane and lead with respect to tremor have been studied in isolation.. We tested the hypothesis that tremor would be particularly severe among individuals who had high blood concentrations of both of these toxicants.. Blood concentrations of harmane and lead were each quantified in 257 individuals (106 essential tremor cases and 151 controls) enrolled in an environmental epidemiological study. Total tremor score (range = 0-36) was a clinical measure of tremor severity.. The total tremor score ranged from 0 to 36, indicating that a full spectrum of tremor severities was captured in our sample. Blood harmane concentration correlated with total tremor score (p = 0.007), as did blood lead concentration (p = 0.045). The total tremor score was lowest in participants with both low blood harmane and lead concentrations (8.4 ± 8.2), intermediate in participants with high concentrations of either toxicant (10.5 ± 9.8), and highest in participants with high concentrations of both toxicants (13.7 ± 10.4) (p=0.01).. Blood harmane and lead concentrations separately correlated with total tremor scores. Participants with high blood concentrations of both toxicants had the highest tremor scores, suggesting an additive effect of these toxicants on tremor severity. Given the very high population prevalence of tremor disorders, identifying environmental determinants is important for primary disease prevention.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Drug Synergism; Environmental Exposure; Essential Tremor; Female; Hand; Harmine; Humans; Lead; Male; Middle Aged; Tremor; Young Adult

Cyclosporin A, a calcineurin inhibitor, produces neurotoxicity with relatively high frequency in organ-transplanted patients. The aim of the present study was to clarify whether acute liver failure (ALF) simulated to the transient liver dysfunction at an early phase after liver transplantation increases the susceptibility to cyclosporin A-induced neurotoxicity through the blood-brain barrier (BBB) dysfunction.. The right internal, left lateral and left internal lobes in male ddy mice were surgically excised under sodium pentobarbital anesthesia. Effect of cyclosporin A on harmine-induced tremors was examined and BBB permeability to (3)[H]cyclosporin A was assessed in partially (70%) hepatectomized mice at postoperative days 1, 3 and 7.. Patrial hepatectomy aggravated harmine-induced tremors. Cyclosporin A (50mg/kg, i.p.) markedly augmented harmine-induced tremors in partially hepatectomized mice at postoperative day 1. Consistent with these behavioral findings, the brain uptake of (3)[H]cyclosporin A in mice injected with (3)[H]cyclosporin A into the jugular vein at postoperative day 1 was significantly increased by partial hepatectomy compared with sham operation.. Our results indicate that ALF increases BBB permeability to cyclosporin A by lowering the function of P-glycoprotein and tight junctions, consequently leading to augmentation of cyclosporin A-induced neurotoxicity. The possibility that cyclosporin A increases the risk of neurotoxicity including tremors at an early phase of liver transplantation must be considered.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Behavior, Animal; Blood-Brain Barrier; Capillary Permeability; Cell Culture Techniques; Cell Line; Cyclosporine; Harmine; Hepatectomy; Immunosuppressive Agents; Liver Failure, Acute; Liver Function Tests; Liver Transplantation; Male; Mice; Mice, Inbred BALB C; Mice, Inbred Strains; Neurotoxicity Syndromes; Tremor

1. Tacrolimus, a potent immunosuppressant, induces impaired renal function and neurological complications. We investigated the influence of dosing time on the neurotoxicity, nephrotoxicity, and immunosuppressive effect of tacrolimus in rats. 2. The repeated injection of tacrolimus in the light phase (8:00) produced a significantly greater increase than that in the dark phase (20:00) in the duration of harmine-induced tremors and in the blood urea nitrogen (BUN) concentration in rats. An immunosuppressive effect of tacrolimus on the xenotransplantation of mouse-to-rat skin grafts was apparent in the dark phase but not in the light phase. 3. The dosing time-dependent pharmacokinetic results were not observed when tacrolimus concentrations in rat whole blood were measured after a single or repeated injection in the light or dark phase. 4. These findings suggest that treatment in the active phase of the diurnal cycle ameliorates neurotoxicity and nephrotoxicity while maintaining the immunosuppressive effect of tacrolimus. The present findings have important implications for therapeutic approaches to avoid tacrolimus-induced neurotoxicity and nephrotoxicity.

Topics: Animals; Blood Urea Nitrogen; Creatinine; Darkness; Graft Survival; Harmine; Kidney; Male; Mice; Mice, Inbred C57BL; Rats; Rats, Wistar; Skin Transplantation; Tacrolimus; Transplantation, Heterologous; Tremor

A single cyclosporine injection (50 mg/kg, i.p.) significantly enhanced harmine- but not oxotremorine-induced tremors in mice. This potentiation became more apparent when cyclosporine (50 mg/kg, i.p.) was administered once a day for seven days. These findings suggest an involvement of monoaminergic mechanisms in cyclosporine-induced tremors. The effects of cyclosporine were examined on the dynamics of noradrenaline, dopamine and serotonin in the mouse brain. Both single and repeated treatment with cyclosporine significantly facilitated the serotonin turnover as estimated from the probenecid-induced accumulation of 5-hydroxyindoleacetic acid, but either mode of treatment failed to change the contents of monoamines and their metabolites or the turnover of noradrenaline and dopamine. Therefore, the cyclosporine-enhanced activity of serotonin neurons may be interpreted as producing adverse central effects, including tremors.

Topics: Animals; Biogenic Monoamines; Brain; Cyclosporine; Hallucinogens; Harmine; Immunosuppressive Agents; Male; Mice; Motor Neurons; Muscarinic Agonists; Oxotremorine; Serotonin; Tremor

Rats given a liquid diet containing 10% (v/v) alcohol consume high quantities of alcohol. Within 8 hr after cessation of the alcohol intake, the animals will show alcohol-withdrawal reactions including a supersensitivity to harmine-induced tremor and an inhibition of exploratory behaviour in a neutral environment. Several drugs can overcome one or more of these alcohol-withdrawal reactions. A reduction of the alcohol withdrawal-induced inhibition of exploration, in terms of both the number of transits into the open field and the time spent in the open field, was obtained with chlordiazepoxide, ritanserin, mianserin and propranolol. Of these four compounds, propranolol and mianserin were also active against the supersensitivity to both 5.00 and 10.00 mg/kg harmine-induced tremor. Chlordiazepoxide and ritanserin were only active against 5.00 mg/kg harmine. Other compounds that reversed the supersensitivity to harmine-induced tremor during alcohol withdrawal included buspirone, fluoxetine, haloperidol, clonidine, flunarizine and baclofen. Very limited effects on both alcohol-withdrawal reactions were observed with ondansetron, nimodipine and MK-801. Risperidone and SCH 23390 were inactive. These results demonstrate that some alcohol withdrawal reactions can be studied in a systematic way and that various pharmacological agents can differentially interact with these alcohol withdrawal reactions.

Topics: Alcohol Withdrawal Delirium; Animals; Brain; Ethanol; Exploratory Behavior; Harmine; Male; Neural Inhibition; Neurotransmitter Agents; Psychotropic Drugs; Rats; Rats, Wistar; Receptors, Neurotransmitter; 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.

Topics: Alcoholism; Animals; Behavior, Animal; Diet; Ethanol; Exploratory Behavior; Harmine; Male; Rats; Rats, Wistar; Substance Withdrawal Syndrome; Tremor

Clonidine exhibited a dose-dependent protection against harmine-induced tremors in mice. This protective effect was not completely blocked by pretreatment with yohimbine. The serotoninergic (5-HT) agonist quipazine and the uptake inhibitor fluoxetine completely antagonized this effect. On the other hand, the 5-HT antagonist cyproheptadine potentiated the protective effect of sub-effective doses of clonidine. These observations suggest a serotonin-mediated action of clonidine in its antitremor action against harmine-induced tremors.

Topics: Alkaloids; Animals; Clonidine; Cyproheptadine; Fluoxetine; Harmine; Male; Mice; Quipazine; Serotonin; Tremor; Yohimbine

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

Topics: Animals; Apomorphine; Ataxia; Chlordecone; Dose-Response Relationship, Drug; Harmine; Insecticides; Male; Motor Neurons; Neural Pathways; Oxotremorine; Picrotoxin; Rats; Rats, Inbred F344; Time Factors; Tremor

The effects of neonatal exposure of rats to chlordecone, during the major postnatal period of neuroendocrine differentiation were assessed after the animals matured to 90 days of age. On day 4 postpartum, pups received a s.c. injection of either DMSO vehicle or chlordecone (1 mg/pup) dissolved in DMSO. The neonatal exposure produced a significant sex-dependent alteration in adult body weight; chlordecone-exposed males were lighter than vehicle-exposed controls and chlordecone-exposed females were heavier than vehicle-exposed controls. Behavioral tests sensitive to neonatal chlordecone exposure during preweaning development--i.e., spectral analysis of movement, activity, and auditory startle responsiveness--gave no statistically significant evidence for residual effects of the early organochlorine treatment. When challenged with harmine, a known tremorogen with putative effects on olivocerebellar pathways, chlordecone-exposed males were less responsive than vehicle-exposed littermates in a spectral analysis of movement. The movement spectrum of chlordecone-exposed females was not differentially sensitive to the harmine challenge. However, subsequent evaluation of the auditory startle reflex indicated that harmine interacted with the neonatal treatment and sex of the animal; chlordecone-exposed males were less responsive and chlordecone-exposed females more responsive than same sex vehicle-exposed littermates. The responsiveness to a d-amphetamine challenge, expressed as a ratio of baseline activity in a pre- and post-test design, suggested the chlordecone-exposed males gave an exaggerated response to the drug challenge. Collectively, these findings suggest that the neonatal chlordecone exposure had a significant organizational effect on the development of behavioral and/or neural function. These findings also suggest the predictive utility of early behavioral tests; that is, long-term alterations were noted in each component of the toxicological syndrome previously identified during preweaning development.

Topics: Animals; Animals, Newborn; Behavior, Animal; Body Weight; Chlordecone; Dextroamphetamine; Female; Habituation, Psychophysiologic; Harmine; Insecticides; Male; Motor Activity; Movement; Nervous System; Rats; Rats, Inbred F344; Reflex, Startle; Sex Factors; Synaptic Transmission; Time Factors; Tremor

The tremors induced by harmine, LON-954 (N-carbamoyl-2-(2,6-dichlorophenyl)acetamidine hydrochloride) and 5-hydroxytryptophan (5-HTP) were studied in control rats and in rats withdrawn for 16-48 hrs from 6 to 9 days' ethanol administration. The frequencies and the intensities of the tremors were determined electronically. In control rats the frequency spectra of the tremors induced by harmine (20 mg/kg) and LON-954 (10 mg/kg) showed a narrow peak frequency at about 10 Hz. Atropine (1.2 mg/kg) altered neither the frequency nor the intensity of these tremors. 5-HTP (50 mg/kg) when given 3.5 hrs after iproniazid (100 mg/kg) induced tremor with peak frequencies at 6-7 Hz and 12 Hz. In ethanol-withdrawn rats treated with harmine or LON-954 the frequency analysis of tremor revealed a narrow peak frequency at about 12 Hz, which was neither the characteristic frequency of ethanol withdrawal tremor (6 Hz) nor that of harmine or LON-954 (10 Hz). The intensity of both harmine- and LON-954-induced tremor was significantly increased in ethanol-withdrawn rats. The ethanol-withdrawn rats were markedly sensitized to the effect of iproniazid+ 5-HTP, shown by deaths. The peak frequencies of this tremor were the same as those in control rats. The results suggest that harmine-induced tremor involves a dopaminergic-5-HT'ergic imbalance and the tremor induced by LON-954 a dopaminergic-cholinergic imbalance in the brain. The tremor in ethanol-withdrawn rats seems to be mediated by alterations in the activity of the cerebral 5-HT'ergic system.

Topics: 5-Hydroxytryptophan; Alkaloids; Animals; Ethanol; Harmine; Male; Physostigmine; Rats; Rats, Inbred Strains; Substance Withdrawal Syndrome; Tremor; Urea

Fumitremorgin A (FTA), a neurotropic mycotoxin induced dose-dependent abnormal behaviors, including tremor, clonic convulsion, kangaroo posture and tonic extensor convulsion in the mouse. FTA-induced tonic extensor convulsion was markedly suppressed by anticonvulsant, e.g. phenobarbital, phenytoin. Phenobarbital, trimethadione, valproic acid and mephenesin decreased the occurrence of abnormal behaviors induced by FTA. Although pentylenetetrazol-induced tonic extensor convulsion was not affected by antipsychotic drugs (dopaminergic drugs) except chlorpromazine, FTA-induced abnormal behaviors were inhibited by antipsychotic drugs, e.g. chlorpromazine, haloperidol. Chlordiazepoxide, diazepam and muscimol inhibited FTA-induced abnormal behaviors. These findings suggest that both dopaminergic and gamma-aminobutyric acid (GABA)-ergic systems are involved in FTA-induced abnormal behaviors. FTA-induced abnormal behaviors may be useful as a common experimental model for the primary evaluation of anticonvulsants, antipsychotic drugs and anxiolytic drugs.

Topics: Animals; Anti-Anxiety Agents; Anticonvulsants; Antiparkinson Agents; Antipsychotic Agents; Behavior, Animal; Central Nervous System Stimulants; Harmine; Indenes; Male; Mice; Mycotoxins; Pentylenetetrazole; Psychotropic Drugs; Seizures; Tremor

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.

Topics: Alkaloids; Animals; Antiparkinson Agents; Benzodiazepinones; Ceruletide; Cholecystokinin; Clonazepam; Drug Antagonism; Harmine; Hypnotics and Sedatives; Ibogaine; Male; Mice; Mice, Inbred Strains; Oligopeptides; Oxotremorine; Peptide Fragments; Sincalide; Structure-Activity Relationship; Tremor

Tofizopam, an anxiolytic 3,4-benzodiazepine, increases the affinity of benzodiazepine receptors for 1,4-benzodiazepines. In this study we investigated whether this increased affinity of the receptors alters the sensitivity of mice to tremor and to convulsions. Convulsions induced by harmane were not affected by tofizopam (50-300 mg/kg), but diazepam (15 mg/kg) increased the ED50 of harmane from 9.9 to 25.1 mg/kg. Tofizopam did not alter the threshold for electroshock-induced convulsions, while a dose of 10 mg/kg diazepam protected mice from convulsions. Low doses of tofizopam (12.5-25 mg/kg) sensitized mice to the tremorogenic effect of harmaline. Diazepam inhibited tremor: the ED50 of harmaline increased by 153% after 50 mg/kg of diazepam. In contrast to 1,4-benzodiazepines, tofizopam has no anticonvulsive effect. It sensitises mice to the tremor induced by harmaline. In combination with diazepam, however, tofizopam enhanced the anticonvulsive and antitremorogenic actions of this 1,4-benzodiazepine by 12-65%. This effect probably results from a tofizopam-induced increase in the occupation of benzodiazepine receptors.

Topics: Animals; Anti-Anxiety Agents; Benzodiazepines; Diazepam; Drug Interactions; Electroshock; Harmine; Male; Mice; Seizures; Tremor

Topics: Analysis of Variance; Animals; Apomorphine; Chlordecone; Dose-Response Relationship, Drug; Harmine; Insecticides; Male; Rats; Rats, Inbred F344; Serotonin; Time Factors; Tremor

Compounds from both the beta-carboline (BC) and xanthine groups have been suggested to be the natural ligands for benzodiazepine (BZ) receptors. In this study we examined the effects of several BC's and caffeine, 1,3,7-trimethylxanthine, on the binding of 3H-flunitrazepam (3H-FZ) and beta-3H-carboline-3-carboxylic acid ethyl ester (3H-BCCE) to the BZ receptors of rat and mouse brain. In mice, convulsion-producing doses of caffeine (120 mg/kg intravenously) and harmane (30 mg/kg intravenously) lowered the specific binding of 3H-FZ in vivo by 12-31%. A tremorogenic dose of harmaline (30 mg/kg intravenously) increased binding by 31%. Caffeine and harmane also slightly decreased the in vivo binding of 3H-BCCE, a compound that binds preferentially to the cerebellar type of BZ receptors. Harmaline stimulated the binding of 3H-BCCE only in the forebrain. Both harmaline and harmane increased by 41-111% the amount of 3H-BCCE that was distributed to the brain. In vitro BC's and caffeine displaced 3H-FZ from receptors in the rat brain with various Ki values (4.7 to 206.9 microM). The antagonism for BZ binding was competitive and in Scatchard analysis produced linear plots. Exceptions were harmaline and caffeine in the forebrain: both exhibited curvilinear plots for 3H-FZ binding. Harmaline increased the binding, and caffeine decreased it by altering the affinity of a subgroup of BZ receptors. In the hindbrain both harmaline and caffeine inhibited binding and produced linear plots. BC-induced tremor and convulsions unveil a large number of spare receptors in the brain, and these seem to be of the cerebellar type of BZ receptors. In addition, our results show that tremorogenic and convulsive BC's act differently on BZ receptors: during harmaline-induced tremor the affinity of some BZ receptors is increased, while harmane-induced convulsions are connected to direct occupation of BZ receptors.

Topics: Animals; Brain; Caffeine; Carbolines; Flunitrazepam; Harmaline; Harmine; Indoles; Male; Rats; Rats, Inbred Strains; Receptors, Cell Surface; Receptors, GABA-A; Seizures; Tremor

Harmine, a hallucinogen with potent monoamine oxidase inhibitory properties, induced abnormal behavior, including tremor, scratching, head twitch and cage biting, in the mouse. A dose-dependent tremor was produced by all routes of administration of harmine. Although oxotremorine tremor was markedly suppressed by atropine, harmine tremor was unaffected by cholinergic drugs, remarkably inhibited by dopaminergic drugs, antidepressants and diazepam, mildly diminished by p-chlorophenylalanine, markedly augmented by 5-hydroxytryptophan and mildly increased by alpha-methyl-p-tyrosine. These findings suggest that a catecholaminergic (particularly dopaminergic) and serotonergic system imbalance plays an important role in the manifestation of harmine tremor. In view of these characteristics, harmine tremor may be useful as an effective experimental model for the evaluation of antiparkinsonism drugs, along with oxotremorine tremor because of the different mechanism of occurrence. In addition, harmine tremor appears to be useful in characterizing the properties of antidepressant drugs.

Topics: 5-Hydroxytryptophan; Alkaloids; Animals; Antidepressive Agents; Behavior, Animal; Diazepam; Disease Models, Animal; Dopamine; Dose-Response Relationship, Drug; Harmine; Male; Mice; Oxotremorine; Tremor

Administration of perphenazine, tremorine, nicotine and harmine induced Parkinson-like symptoms in rats and mice. The efficacy of quipazine, a serotonin agonist, in antagonizing these drug-induced Parkinsonian symptoms was assessed. Combinations of this drug with other antiparkinsonian agents such as scopolamine, diphenhydramine and amantadine were also studied in the manifestation of Parkinson-like symptoms in the animal models. The results indicate that quipazine, a central serotonergic agent, counteracted some of the drug-induced symptoms of pseudoparkinsonism in laboratory animals. Cholinergic, dopaminergic and histaminergic receptors play an important role in the manifestations of these symptoms.

Topics: Animals; Antiparkinson Agents; Catatonia; Drug Combinations; Drug Interactions; Harmine; Humans; Male; Mice; Nicotine; Perphenazine; Quinolines; Quipazine; Rats; Tremor; Tremorine

Topics: Alkaloids; Animals; Atropine; Female; Harmine; Male; Neuromuscular Junction; Rats; Tremor; Trihexyphenidyl

It has been recently reported that the levo isomer of propranolol possesses anti-serotonin properties in animals. Since harmine-induced behavioural changes in mice are reported to be mediated through central serotonergic receptors, an attempt was made to test whether 1-propranolol would also modify harmine-induced responses by virtue of its anti-serotonergic or anti-adrenergic property. The results indicated that l- and dl-propranolol inhibited central serotonin receptor mediated responses to harmine in mice, a finding that is analogous to other recent observations.

Topics: Animals; Cyproheptadine; Dose-Response Relationship, Drug; Harmine; Male; Mice; Phenoxybenzamine; Practolol; Propranolol; Stereoisomerism; Structure-Activity Relationship; Tremor

Topics: Alkaloids; Animals; Cerebellum; Diazepam; Dopamine; Electroencephalography; Female; Harmine; Levodopa; Male; Rabbits; Spinal Cord; Time Factors; Tremor

In rats with lymphostatic encephalopathy the duration of harmine tremor was lengthened, and the brain concentrations of harmine decreased more slowly than in sham-operated controls. The tremor began simultaneously in both rat groups at coinciding brain concentrations of harmine. In rats with lymphostatic encephalopathy harmine concentrations in brain at the termination of tremor lay in the same range as in sham-operated controls. The plasma concentrations of harmine were not changed by the disease. It is concluded that during lymphostatic encephalopathy the lymphatic drug elimination from brain is impaired whereas--at least for harmine--the blood-brain barrier functions as normal.

Topics: Alkaloids; Animals; Blood-Brain Barrier; Brain; Brain Diseases; Harmine; Lymphatic System; Male; Rats; Tremor

Topics: Alkaloids; Animals; Apomorphine; Caudate Nucleus; Corpus Striatum; Dopamine; Globus Pallidus; Harmine; Injections; Male; Norepinephrine; Rats; Serotonin; Tremor

In rats, pretreatment with caffeine or ethanol shortens the duration of the harmine tremor and decreases the brain concentrations of this alkaloid. Caffeine and ethanol do not influence the plasma concentration of harmine, its plasma protein binding and its cerebral concentration at the termination of the tremor. The findings are regarded as indicative of a reduction by caffeine and ethanol of the blood-brain barrier permeability to harmine.

Topics: Animals; Blood-Brain Barrier; Brain; Caffeine; Ethanol; Harmine; Male; Protein Binding; Rats; Tremor

The brain lesion technique was used to destroy the ascending 5-hydroxytryptamine (5-HT) system at its cell bodies in the dorsal and medial raphe nuclei in order to assess the importance of 5-HT for the induction of harmine tremor and its antagonism by the dopaminergic agonists, L-DOPA, apomorphine and d-amphetamine. Lesions of the medial or dorsal raphe nucleus reduced the intensity of harmine tremor. The remaining tremor was generally resistant to further reduction by the dopaminergic agonists. 5-hydroxytryptophan was shown to enhance tremor: this effect was reduced both by the raphe lesions and by treatment with L-DOPA. The data are discussed in terms of the possible relationship between 5-HT and dopamine.

Topics: Alkaloids; Animals; Apomorphine; Dextroamphetamine; Harmine; Levodopa; Male; Mesencephalon; Nervous System Physiological Phenomena; Neural Pathways; Rats; Serotonin; Serotonin Antagonists; Tremor

The brain lesion technique was used to investigate the role of the paleostriatum and the nigro-neostriatum in harmine-induced tremor and in its antagonism by dopaminergic agonists, apomorphine, 1-dopa, piribedil, d- and l-amphetamine. Bilateral lesions of the caudate--putamen or substantia nigra failed to modify the intensity of tremor or its antagonism by dopaminergic agonists. Bilateral lesions of the globus pallidus markedly reduced the intensity of tremor and the results indicated that such lesions were also able to reduce the effectiveness of dopaminergic agonists as tremor antagonists. The data suggest that the integrity of the paleostriatum is more important than that of the neostriatum for the mediation of harmine tremor and its antagonism by dopaminergic agonists. The results are discussed in relation to the proposed clinical relationship between paleostriatal dopamine dysfunction and tremor mechanisms.

Topics: Alkaloids; Animals; Brain; Caudate Nucleus; Dihydroxyphenylalanine; Extrapyramidal Tracts; Globus Pallidus; Harmine; Male; Putamen; Rats; Substantia Nigra; Tremor

Injection of the tremorigenic alkaloid harmine into lymphostatic encephalopathic rats leads to a longer duration of tremor and higher brain concentrations than in sham-operated controls. In lymphostatic encephalopathic as well as in normal rats different antiphlogistics shorten the tremor duration and decrease harmine concentration in brain. The antiphlogistics do not influence the plasma concentration of harmine, its protein binding and its tremorend concentration in brain. The effect of antiphlogistics in lymphostatic encephalopathic rats is considered as a consequence of the reduced blood-brain barrier permeability. Obviously in sick animals the blood-brain barrier permeability for harmine is not increased; the prolonged harmine tremor and the increased alkaloid concentration in the brain are consequences of the impaired cerebral lymphatic drainage only.

Topics: Alkaloids; Animals; Anti-Inflammatory Agents; Blood-Brain Barrier; Brain Chemistry; Brain Diseases; Harmine; Male; Rats; Time Factors; Tremor

In rats transections of the brain have been carried out to localize tremorigenic centres. Ablation of cortical and diencephalic brain areas caused moderate reduction of oxotremorine induced tremor. A makred decrease of tremor intensity has been observed after transections eliminating the tegmental parts of the formation reticularis. We found in caudal sites of transections a shift of the tremor frequency to lower values including changes of distribution as well as the appearance of spontaneous tremor. Both the intensity of oxotremorine induced tremor and the appearance of spontaneous tremor was found to depend on body temperature. Harmine-induced tremor was influenced in opposite direction by ablation of the rostral brain areas.

Topics: Animals; Body Temperature; Brain Mapping; Harmine; Rats; Reticular Formation; Tremor; Tremorine

Topics: Alkaloids; Animals; Blood Proteins; Chromatography, Thin Layer; Erythrocytes; Half-Life; Harmaline; Harmine; Heart Rate; Kinetics; Male; Organ Specificity; Protein Binding; Rats; Structure-Activity Relationship; Time Factors; Tremor