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PubMed2000

Effect of lidocaine on harmaline-induced tremors in the rat.

The present study was undertaken to investigate the effect of lidocaine on harmaline-induced tremors in the rat. Four groups of Wistar rats weighing 45-50 g were injected with harmaline (50 mg/kg i.p.) for inducing experimental tremors. The rats in group 1 served as control, whereas the animals in groups 2, 3, and 4 were also given lidocaine i.p. at doses of 12.5, 25, and 50 mg/kg, respectively, 10 min after the onset of tremors (therapeutic study). In a separate four groups of animals intraperitoneal lidocaine injection was given 10 min before harmaline (prophylactic study) in the same dose regimen as mentioned above. The latency of onset, intensity, and duration of tremor and electromyographic responses were recorded. Lidocaine dose dependently attenuated harmaline-induced tremors in rats. The latency period was increased, and duration and intensity of harmaline-induced tremors was reduced by lidocaine. Our electromyography (EMG) study also revealed a decrease in the amplitude of harmaline-induced tremors in lidocaine-treated rats. In conclusion, the results of this study clearly suggest beneficial effects of lidocaine in harmaline-induced tremors.

Animals↗
PubMed1998

At low doses, harmaline increases forelimb tremor in the rat.

A behavioral preparation especially sensitive to low-dose drug effects on fine motor behavior in rats was used to assess the tremorogenic effects of harmaline, an indole alkaloid and beta-carboline derivative. Rats that were trained to press downward on a force transducer for water reinforcement were initially administered harmaline (0.5 and 1.0 mg/kg) in an acute dosing regime. Immediately following the day of initial acute exposure to 1 mg/kg, 3 consecutive days at this dose ensued, providing for a 4-day, repeated-dosing analysis. Harmaline did not significantly suppress task engagement during either acute or repeated dosing. Acute administration of harmaline dose-dependently increased power in the high-frequency (10-25 Hz) band of the power spectrum (tremor) without affecting overall forelimb force output. Upon continued administration, tremor remained significantly elevated above vehicle values. Harmaline also slowed the rats' licking frequency, an effect that did not diminish with repeated dosing. Harmaline increased the durations of individual responses during acute dosing and continued to exert this effect with repeated dosing. The effects reported in the present study may represent low-dose harmaline-induced alterations in the olivo-cerebellar system.

Animals↗
PubMed1996

Facilitatory and inhibitory effects of harmaline on the tryptophan-induced 5-hydroxytryptamine syndrome and body temperature changes in pargyline-pretreated rats.

The effects of harmaline on tryptophan-induced 5-hydroxytryptamine (5HT) syndrome and body temperature changes in pargyline-pretreated rats were investigated. When administered i.p. 60 min after pargyline treatment (50 mg/kg, i.p.), tryptophan, at 100 mg/kg but not 10 mg/kg, induced the 5-HT syndrome. Tryptophan at 100 mg/kg also produced hypothermia followed by hyperthermia in pargyline-pretreated rats. Administration of harmaline (10 mg/kg, i.p.) 30 min after pargyline not only potentiated the 100 mg/kg tryptophan-induced 5-HT syndrome and body temperature changes, but also produced the syndrome following administration of 10 mg/kg tryptophan in pargyline-pretreated rats. In contrast, when administered 30 min before parygline, 10 mg/kg harmaline completely suppressed the syndrome and body temperature changes caused by mg/kg tryptophan. Tryptophan (100 mg/kg, i.p.) administration significantly increased 5-HT levels and decreased 5-hydroxyindole acetic and levels and 5-HT turnover in the brain of pargyline-pretreated rats. Harmaline administration 30 min after pargyline did not significantly affect the tryptophan-induced changes in 5-HT levels and 5-HT turnover, whereas when administered 30 min before pargyline, harmaline significantly blocked the effect of tryptophan. These results suggest that mechanisms underlying the inhibitory action of harmaline on the tryptophan-induced 5-HT syndrome and body temperature changes in pargyline-pretreated rats differ from those by which harmaline potentiates the effects of tryptophan.

Analysis of Variance↗
PubMed1977

The mechanism of action of harmaline on renal solute transport.

The effect of the hallucinogenic drug harmaline was tested on rat kidney proximal tubular solute and water transport, using in vivo micropuncture and electrophysiological techniques as well as in vitro biochemical techniques. During peritubular application harmaline (5 mmol/l) was found to block net tubular volume absorption reversibly (by 85%) through inhibition of active Na+ transport and possibly active HCO-3 transport. The inhibition was accompanied by a rapid strong depolarization of the tubular cell membranes. As a biochemical equivalent harmaline inhibited the Na+-K+-ATPase and the Mg2+-ATPase of peritubular cell membrane fractions as well as the HCO-3-stimulated ATPase of a brush border membrane fraction with similar kinetics. By studying glucose tracer efflux and by measuring cell membrane potential and conductance changes in response to glucose perfusions, no evidence for a direct effect of harmaline on Na+-glucose (or amino acid) cotransport mechanisms in the brush border could be obtained. The data suggest that harmaline does not specifically compete with Na+ for transport sites. Neither are the cotransport systems in the brush border membrane specifically inhibited, nor could the inhibition of the Na+ pump in the peritubular cell membrane simply result from a competition between harmaline and Na+.

Adenosine Triphosphatases↗
PubMed1978

Vasopressin-like effects of a hallucinogenic drug--harmaline--on sodium and water transport.

To determine if harmala alkaloids affect transport systems other than (Na +K)-ATPase, effects of harmaline on Na and water fluxes were studied in amphibian skins. Net Na flux was evaluated from short-circuit current, and water flux monitored with automatic, volumetric methods. At 2 to 5 mM, harmaline consistently inhibited SCC and prevented the natriferic effects of oxytocin and norepinephrine. However, at 0.1 to 0.5 mM, harmaline produced an increase in SCC inhibitable with amiloride. The stimulatory effects of harmaline and oxytocin were either nonadditive or additive depending on whether the hallucinogen was present in the inner solution or in the outer solution bathing the skin, respectively. Water flow was not modified by harmaline on the outer medium. In contrast, addition of the drug to the inner medium elicited a conspicuous, sustained, vasopressin-like, hydrosmotic effect, comparable to and competive with those of vasopressin and norepinephrine. The ensemble of these results suggests that harmaline may affect three distinct transport systems: (i) the Na pump; (ii) the cyclic nucleotide system; (iii) the Na entry pathway at the outer membrane of the skin that is also activated by agents such as diphenylhydantoin, lanthanides and propranolol.

Alkaloids↗
PubMed1977

The indolaminergic innervation of the inferior olive. 2. Relation to harmaline induced tremor.

The possible involvement of serotoninergic mechanisms in the induction of harmaline generated tremor in the inferior olive has been investigated electrophysiologically in the cat and rat. Mass recordings of Purkinje cell activity in the cat showed that harmaline induces strong, synchronous and rhythmic activity in those parts of the climbing fibre system originating in the caudal part of the medial accessory olive and the caudolateral parts of the dorsal accessory nucleus. These are the areas of the cat olive shown to receive a dense serotoninergic innervation. In the rat, the selective removal of the serotoninergic innervation--produced by an intraventricular injection of 5,6-dihydroxytryptamine, or 5,7-dihydroxytryptamine in combination with desipramine--caused a significant attenuation of both the tremor and the climbing fibre activity induced by an intravenous harmaline injection. In the 5,6-dihydroxytryptamine-treated animals the reappearance of the harmaline tremor seemed to parallel the regrowth of new serotoninergic axon sprouts in the inferior olive. On the basis of the present results it is proposed that the serotoninergic afferents to the accessory olivary nuclei are of critical importance for the tremor induction of harmaline in the inferior olive. It is suggested that harmaline, rather than acting directly on the olivary neurones, exerts its effect through an interference with a serotoninergic (possibly inhibitory) innervation of these cells.

5,6-Dihydroxytryptamine↗
PubMed1988

Tolerance to the tremorogenic effects of harmaline: evidence for altered olivo-cerebellar function.

Administration of the beta-carboline alkaloid, harmaline, causes the neurons of the inferior olive to fire synchronously and to act as a pacemaker for the generation of tremor. Rats treated daily with harmaline showed a progressive loss of drug-induced tremor. This tolerance was long-lasting and specific. No cross-tolerance was noted to the drug oxotremorine. Prevention or attenuation of tremor by pretreatment with diazepam or morphine preserved the tremorogenic capacity of harmaline when administered alone. These results suggest a relatively permanent change in the olivo-cerebello-bulbar pathway that underlies the generation of tremor induced by harmaline. Treatment with harmaline also increased cyclic 3',5'-guanosine monophosphate (cGMP) in the cerebellum, presumably through activation of the climbing fiber pathway from the inferior olive to the cerebellar cortex. These increases were attenuated after repeated treatment. These results suggest that the site of tolerance to the tremogenic effects of harmaline lies within the olivo-cerebellar system.

Alkaloids↗
PubMed2002

Effect of acute caffeine on severity of harmaline induced tremor in rats.

Recent studies suggest an association between caffeine consumption and tremor. However, the available literature is scanty and inconclusive. The present study was undertaken to investigate the effect of acute caffeine treatment on harmaline induced tremors in the rat. Four groups of male Sprague-Dawley rats (six animals in each group) weighing 88+/-2 g were administered harmaline (10 mg/kg, intraperitoneally (i.p.)) for inducing experimental tremors. The rats in group 1 served as controls and received normal saline, whereas the animals in groups 2, 3 and 4 were given caffeine (i.p.) at doses of 50, 100 and 150 mg/kg, respectively 60 min after harmaline administration. The latency of onset, intensity and duration of tremor and electromyographic (EMG) responses were recorded. Treatment of rats with caffeine resulted in a significant increase in the intensity and duration of harmaline induced tremors. Caffeine also enhanced the EMG amplitude in harmaline treated animals. In conclusion, the results of this study suggest that acute treatment with caffeine significantly potentiates the severity of harmaline induced tremors in rats.

Animals↗
PubMed2002

Effect of R-(-)-deprenyl and harmaline on dopamine- and peroxynitrite-induced membrane permeability transition in brain mitochondria.

The present study examined the effect of MAO inhibitors, deprenyl and harmaline, on the membrane permeability transition in brain mitochondria. Deprenyl, harmaline, and antioxidant enzymes (SOD and catalase) attenuated alteration of the swelling, membrane potential, cytochrome c release, and Ca2+ transport in mitochondria treated with dopamine. In contrast, deprenyl and harmaline did not reduce the peroxynitrite-induced change in membrane permeability. Deprenyl and harmaline inhibited the decrease in thioredoxin reductase activity and the thiol oxidation in mitochondria treated with dopamine but did not decrease the effect of peroxynitrite. Deprenyl and harmaline significantly decreased the formation of melanin from dopamine. The results suggest that deprenyl and harmaline may protect brain mitochondria against the toxic action of dopamine oxidation by the maintenance of thioredoxin reductase activity, inhibition of thiol oxidation, and inhibition of dopamine oxidation product formation. In contrast, MAO inhibitors may not defend brain mitochondria against damaging action of peroxynitrite.

Animals↗
PubMed2003

Contribution of individual cytochrome P450 isozymes to the O-demethylation of the psychotropic beta-carboline alkaloids harmaline and harmine.

The psychotropic beta-carboline alkaloids, showing high affinity for 5-hydroxytryptamine, dopamine, benzodiazepine, and imidazoline receptors and the stimulation of locus coeruleus neurons, are formed endogenously from tryptophan-derived indolealkylamines through the Pictet-Spengler condensation with aldehydes in both plants and mammals. Cytochromes P450 1A1 (18.5), 1A2 (20), and 2D6 (100) catalyzed the O-demethylation of harmaline, and CYP1A1 (98.5), CYP1A2 (35), CYP2C9 (16), CYP2C19 (30), and CYP2D6 (115) catalyzed that of harmine (relative activities). The dehydrogenation/aromatization of harmaline to harmine was not carried out by aromatase (CYP19), CYP1A2, CYP2C9, CYP2D6, CYP3A4, pooled recombinant cytochromes P450, or human liver microsomes (HLMs). Kinetic parameters were calculated for the O-demethylations mediated by each isozyme and by pooled HLMs. K(cat) (min(-1)) and K(m) Awake M) values for harmaline were: CYP1A1, 10.8 and 11.8; CYP1A2, 12.3 and 13.3; CYP2C9, 5.3 and 175; CYP2C19, 10.3 and 160; and CYP2D6, 39.9 and 1.4. Values for harmine were: CYP1A1, 45.2 and 52.2; CYP1A2, 9.2 and 14.7; CYP2C9, 11.9 and 117; CYP2C19, 21.4 and 121; and CYP2D6, 29.7 and 7.4. Inhibition studies using monoclonal antibodies confirmed that CYP1A2 and CYP2D6 were the major isozymes contributing to both harmaline (20% and 50%, respectively) and harmine (20% and 30%) O-demethylations in pooled HLMs. The turnover numbers for CYP2D6 are among the highest ever reported for a CYP2D6 substrate. Finally, CYP2D6-transgenic mice were found to have increased harmaline and harmine O-demethylase activities as compared with wild-type mice. These findings suggest a role for polymorphic CYP2D6 in the pharmacology and toxicology of harmine and harmaline.

Animals↗
PubMed1980

Harmaline inhibition of Na-dependent transport in renal microvillus membrane vesicles.

The effects of the hallucinogen harmaline on D-glucose, L-alanine, and Na+ transport were studied in microvillus membrane vesicles isolated from the rabbit renal cortex. Harmaline had no effect on glucose transport in the absence of Na+, but reversibly inhibited sugar flux in the presence of NaCl. Inhibition of Na+-dependent glucose transport was inversely related to the Na+ concentrations. The hallucinogen competitively inhibited the Na+ activation of phlorizin binding to the membranes but did not inhibit phlorizin binding in the absence of Na+. Harmaline inhibited Na+-dependent alanine transport and, at higher drug concentrations, the amino acid flux in the absence of NaCl. Harmaline competitively inhibited the rate of Na+ uptake which, in the absence of glucose and alanine, is known to occur via Na+-H+ exchange. The hallucinogen trans-inhibited the efflux of glucoe and Na+ from membrane vesicles preloaded with the solutes. These findings suggest that harmaline is a direct inhibitor of microvillus membrane transport processes and acts as a competitive inhibitor of Na+ transport sites. Harmaline may therefore be a useful investigative tool for studying mechanisms of Na+-coupled transport in the luminal membrane of the proximal tubular cell.

Alanine↗
PubMed1976

[Inhibition of harmaline induced tremor by L-threo-3, 4-dihydroxyphenylserine, an L-norepinephrine precursor].

Effect of 3, 4-dihydroxyphenylserine (DOPS), a norepinephrine precurosr, on harmaline tremor was investigated in mice to elucidate the role of norepinephrine in the genesis of tremor. 1) Spontaneous motor activity was inhibited by L-threo-DOPS (200 mg/kg i.p.). 2) Tremor induced by harmaline (5 and 7 mg/kg i.p.) was enhanced by alpha-methyl-p-tyrosone (200 mg/kg i.p.). 3) The development and duration of tremor induced by harmaline (10 mg/kg i.p.) were inhibited significantly in a dose dependent manner by L-threo-DOPS (50, 70, 100, 150 and 200 mg/kg i.p.), but neither by D-threo-DOPS (200 mg/kg i.p.) nor DL-erythro-DOPS (200 mg/kg i.p.). 4) L-threo-DOPS (200 mg/kg i.-.) had no effect on the development of tremor induced by tremorine (5 and 10 mg/kg i.p.), while lacrimation and diarrhea caused by tremorine was markedly inhibited. 5) Administration of harmaline (10 mg/kg i.p.) produced an increase in brain 5-hydroxytryptamine content but not in that of norepinephrine. Administration of L-threo-DOPS (100 mg/kg i.p.) increased the norepinephrine content but not the 5-hydroxytryptamine content in the brain. Inhibition of harmaline tremor induced by L-threo-DOPS is attributed to the L-norepinephrine converted from L-threo-DOPS and the involvement of a noradrenergic mechanism in harmaline tremor has to be considered.

Alkaloids↗
PubMed1986

Differential effects of harmaline and ouabain on intestinal glucose transport in the pigeon.

Effects of harmaline and ouabain on intestinal transport in vitro of D-glucose in the pigeon are investigated. Harmaline inhibits glucose influx and affects intestinal Na+-K+-ATPase activity though the substrate uptake is more sensitive than the enzyme activity. Low concentration of harmaline while drastically inhibiting glucose uptake, does not affect intracellular concentration of Na+ and K+. In contrast, ouabain, though has no significant effect on glucose uptake, alters substantially the ionic balance of cells. Harmaline also affects that component of nutrient influx which is left unaffected by ouabain. Mucosal-serosal flux of glucose is reduced by harmaline when it is present only on the mucosal side of everted intestinal sacs. On the contrary, similar effect is produced by ouabain when it is placed only on the serosal side. It appears that harmaline possibly inhibits glucose transport in the pigeon intestine by two ways: first, by irreversible binding Na+-K+-ATPase - a feature shared by ouabain, and second, by reversible binding Na+-binding sites of enterocyte membrane - an effect not shared by ouabain.

Alkaloids↗
PubMed1988

Topographical similarities between harmaline inhibition sites on Na+-dependent amino acid transport system ASC in human erythrocytes and Na+-independent system asc in horse erythrocytes.

Na+-dependent system ASC and Na+-independent system asc are characterized by a common selectivity for neutral amino acids of intermediate size such as L-alanine and by their interactions with dibasic amino acids. For system ASC, the positive charge on the dibasic amino acid side chain is considered to occupy the Na+-binding site on the transporter. We report here the use of harmaline (a Na+-site inhibitor in some systems) as a probe of possible structural homology between these two classes of amino acid transporter. Harmaline was found to inhibit human erythrocyte system ASC noncompetitively with respect to L-alanine concentration, but approximated competitive inhibition with respect to Na+ concentration (apparent Ki = 2.0 and 0.9 mM, respectively). Similarly, harmaline noncompetitively inhibited L-alanine uptake by horse erythrocyte systems asc1 and asc2 (apparent Ki = 2.0 and 1.9 mM, respectively). In contrast, harmaline functioned as a competitive inhibitor of L-lysine uptake by system asc1 (apparent Ki = 2.6 mM). It is concluded that harmaline competes with Na+ for binding to system ASC and that a topographically similar harmaline inhibition site is present on system asc. This site does not however bind Na+, the asc1 transporter exhibiting normal L-alanine and L-lysine influx kinetics in the total absence of extracellular cations.

Alanine↗
PubMed1988

Spontaneous and harmaline-stimulated Purkinje cell activity in rats with a genetic movement disorder.

The genetically dystonic rat (dt) displays a complex movement disorder in the absence of morphological defects in the nervous system. This mutant is also insensitive to the tremorogenic effects of harmaline. Because harmaline is known to act on the cells of the inferior olive to induce activity at the tremor frequency in the olivocerebellobulbar pathway, this pathway has been investigated as a possible site of a defect in the dt rat. Biochemical studies suggested the presence of abnormalities at the level of the Purkinje cell or its afferent input. Thus, the present study investigated the harmaline response of Purkinje cells in dt rats and unaffected littermate controls with extracellular single-unit recording techniques. The spontaneous, simple spike and complex spike firing rates of dt rats were significantly lower than those of normal littermate controls. In normal rats, 2 responses to systemic harmaline injection were seen. Simple spikes were either completely suppressed for periods of 30-180 min, or were intermittently suppressed, pausing repeatedly for periods of 1-18 sec. Cells that showed complete suppression of simple spike activity also showed increased frequency and rhythmicity of complex spikes. In dt rats, intermittent simple spike responses were seen in a proportion (41%) similar to that in normal rats (53%). However, the proportion of cells showing high-frequency, rhythmic, complex spikes and complete suppression of simple spikes was low in the dt rats in comparison with littermate controls (18 versus 47%). In addition, 41% of the cells from dt rats displayed no change, or an anomalous change, in firing patterns in response to harmaline. Since the rhythmic activation of olivary neurons that results in the rhythmic, complex spike discharge of Purkinje cells is assumed to be responsible for the appearance of harmaline tremor, the failure of the dt rat to display tremor is most likely due to a failure at the olivocerebellar level, rather than at a site efferent to the cerebellum.

Action Potentials↗
PubMed1993

Harmaline-induced impairment of Pavlovian conditioning in the rabbit.

In this study we examined the effects of harmaline on Pavlovian conditioning of the rabbit's nictitating membrane response. The acquisition of conditioned responses was determined during a single session consisting of 120 pairings of a tone-conditioned stimulus with a corneal air puff unconditioned stimulus. Harmaline severely retarded (5 mg/kg) or completely blocked (10 and 20 mg/kg) acquisition of conditioned responses. The blocked or retarded acquisition of conditioned responses could still be detected when the rabbits were tested 2 d after cessation of drug injections, suggesting that harmaline was affecting acquisition and not the motoric expression of conditioned responses. Control experiments established that harmaline (5 mg/kg) did not affect (1) baseline levels of responding, (2) the level of non-associative responding to the conditioned stimulus, (3) the amplitude or any of the temporal characteristics of the unconditioned response, (4) the development of habituation to the unconditioned stimulus, and (5) the threshold of the unconditioned stimulus for eliciting the unconditioned response. However, harmaline did produce a 12 dB increase in the intensity threshold of the conditioned stimulus for eliciting conditioned responses. We concluded that the primary effect of harmaline was to impair stimulus processing within brainstem circuits such as to reduce the excitatory properties of the conditioned stimulus, thus retarding its entry into associative learning. The results were discussed with respect to the possible role of the inferior olive in associative learning.

Acoustic Stimulation↗
PubMed2006

Carbenoxolone and mefloquine suppress tremor in the harmaline mouse model of essential tremor.

Excessive olivo-cerebellar synchrony is implicated in essential tremor. Because synchrony in some networks is mediated by gap junctions, we examined whether the gap junction blockers heptanol, octanol, carbenoxolone, and mefloquine suppress tremor in the mouse harmaline model, and performed an open-treatment clinical study of mefloquine for essential tremor. Digitized motion was used to quantify tremor in mice administered harmaline, 20 mg/kg s.c. In mice the broad-spectrum gap junction blockers heptanol, octanol (350 mg/kg i.p. each), and carbenoxolone (20 mg/kg) suppressed harmaline tremor. Mefloquine (50 mg/kg), which blocks gap junctions containing connexin 36, robustly suppressed harmaline tremor. Glycyrrhizic acid (related to carbenoxolone) and chloroquine (related to mefloquine), which do not block gap junctions, failed to suppress harmaline tremor in mice. Clinically, tremor was assessed with standard rating scales, and subjects asked to take 62.5, 125, and 250 mg mefloquine weekly for 12 weeks at each dose. None of the four human subjects showed a meaningful tremor reduction with mefloquine, likely because clinical levels were below those required for efficacy. In view of recent genetic evidence, the anti-tremor mechanism of these compounds is uncertain but may represent a novel therapeutic target, possibly involving gap junctions other than those containing connexin 36.

1-Octanol↗
PubMed1981

Harmaline-induced tremor. II. Unit activity correlation in the interposito-rubral and oculomotor systems of cat.

Units were recorded extracellularly in the cat brainstem under the effect of tremogenic doses of harmaline. They were localized post mortem and the units discharging at the harmaline tremor frequency were mapped. Harmaline-sensitive neurons were found in the bulbo-pontine reticular formation, in particular, in the lateral reticular nucleus and the nucleus reticularis tegmenti pontis. The nucleus interpositus as well as the red nucleus also displayed numerous units discharging at the tremor frequency, indicating that the cerebello-interposito-rubro-spinal system controlling the flexor muscles participate in harmaline tremor. Participation of the oculomotor system in the harmaline-induced tremor was tested at the level of the vestibular neurons relaying the vestibulo-ocular reflex, the motoneurons, the eye muscles and the eye movements. No rhythmic discharge at the tremor frequency nor eye movements could be detected, indicating that harmalie tremor does not affect the oculomotor system.

Alkaloids↗