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At least 19 recordsLinked to original sources
PubMed1991

Effect of harmaline on cells of the inferior olive in the absence of tremor: differential response of genetically dystonic and harmaline-tolerant rats.

The genetically dystonic rat is insensitive to the tremorogenic effects of harmaline. This behavioral deficit has been linked to a defect in the olivocerebellar pathway, since few Purkinje cells of dystonic rats show a normal increase in rhythmic complex spike activity following harmaline. In normal rats, the Purkinje cell response to harmaline and tremor are initiated by a rhythmic increase in neuronal firing in the caudal inferior olive. The present single unit recording study was conducted, therefore, to determine if the inferior olive of the dystonic rat is activated by harmaline. Olivary unit responses to harmaline were also examined in normal rats made tolerant to harmaline tremor. These rats are behaviorally insensitive to harmaline and also fail to display rhythmic complex spike activity but do not have the motor deficits of the mutant rats. The spontaneous firing rate of neurons in the caudal and rostral inferior olive of the dystonic rat was significantly slower than that of phenotypically normal littermates. Despite this, all cells recorded in the caudal portion of the medial accessory olive of both dystonic and normal rats showed increased rhythmic activity following harmaline injection. Thus, the failure of the mutants to show harmaline tremor is not due to a failure of the drug to activate cells in the olive. Rather, the data suggest a defect in the subsequent transmission of this information. Unlike the control and dystonic rats, harmaline-tolerant rats failed to show sustained rhythmic activity in the inferior olive. These findings suggest that chronic treatment with harmaline may interfere with harmaline tremor at the level of the inferior olive.

Animals↗
PubMed1979

The effect of harmaline on intestinal sodium transport and on sodium-dependent D-glucose transport in brush-border membrane vesicles from rabbit jejunum.

Harmaline inhibition of sodium uptake and of sodium-dependent D-glucose transport was investigated using brush-border membrane vesicles from frozen rabbit jejunum. Under sodium-gradient conditions, "initial" D-glucose uptake (20 s) was inhibited by harmaline at concentrations above 0.5 mM, but at lower harmaline concentrations D-glucose uptake was stimulated by 10--15%. When a similar potassium gradient was used, harmaline had no effect. At concentrations up to 2 mM, harmaline did not alter the equilibrium uptake of D-glucose or D-mannitol. After pre-equilibration with sodium (25 mM), G-glucose uptake was inhibited at harmaline concentrations ranging from 0.1 to 2 mM. Sodium (10 mM) uptake was also inhibited by harmaline. Increasing the sodium concentration reduced the inhibitory effect of harmaline on tracer sodium uptake as well as on sodium-dependent D-glucose uptake. Similar to phlorizin, harmaline (1 mM) was able to prevent glucose-induced sodium influx across the brush-border membrane. Sodium uptake into brush-border membrane vesicles seems to be inhibited at lower harmaline concentrations than sodium-dependent D-glucose uptake. At high (2 mM) inhibitor concentrations, however, sodium-dependent glucose uptake is more strongly inhibited than sodium uptake. These results suggest that harmaline inhibits both sodium and sodium-dependent transport across intestinal brush-border membranes by interacting with specific sodium-binding sites.

Alkaloids↗
PubMed1981

Harmaline distribution in single muscle fibres and the inhibition of sodium efflux.

Harmaline, a known inhibitor of the (Na+ + K+)-ATPase in cell membranes, inhibited 50% of the 22Na efflux from barnacle muscle fibres at an extracellular concentration of 2.4 mM. Injected harmaline inhibited 50% of the efflux at an estimated intracellular concentration of about 8 mM . kg-1, assuming complete equilibration with no binding. Total fibre harmaline was measured in separate fibres by ultraviolet spectrophotometry. Fibres in 3 mM harmaline saline accumulated harmaline with a half-time of 17 min and a final total fibre concentration of 6-12 mM . kg-1. In harmaline-free saline this accumulated harmaline was lost exponentially with a half-time of 35 min; injected harmaline was lost exponentially from fibres with a half-time of 50 min. It is proposed that harmaline crosses the fibre membrane as the uncharged base and that its apparent accumulation against a concentration gradient is mainly due to intracellular binding with an additional contribution from a transmembrane ph gradient. It is concluded that, in fibres exposed to harmaline saline, the intracellular concentration can reach a sufficiently high value, as judged from the results of the injection experiments, to inhibit Na+ efflux at an interior-facing site on the fibre membrane. In contrast, harmaline appears to inhibit the Na+-dependent uptake of L-glutamate at an extracellular site.

Alkaloids↗
PubMed1997

Harmaline-induced tremor and impairment of learning are both blocked by dizocilpine in the rabbit.

Harmaline is known to produce tremors and retard acquisition of the rabbit's nictitating membrane response. These actions have been demonstrated to depend on the ability of harmaline to activate the inferior olive which gives rise to climbing fibers that project directly onto Purkinje cells in cerebellar cortex. However, the precise receptor systems involved in harmaline's actions remains unknown. This study examined the role of the NMDA receptor in harmaline's actions. Harmaline (10 mg/kg, s.c.) produced intense tremors and impaired the acquisition of conditioned responses. Both of these effects of harmaline were significantly blocked by the prior administration of the noncompetitive NMDA channel blocker, dizocilpine (0.01 mg/kg, s.c. given 20 min prior to the administration of harmaline). This dose od dizocilpine had no effect on acquisition of conditioned responses when given alone. A higher dose of dizocilpine (0.1 mg/kg s.c.) completely blocked the tremorogenic effects of harmaline (10 mg/kg, s.c.). Dizocilpine had no effect on motor behavior when given alone. It was suggested that the blockade of harmaline's actions by dizocilpine may be occurring at NMDA channels within the inferior olive. Regardless of the site of action, these data demonstrate that harmaline's ability to activate the interior olivary nucleus depends on the normal activity of the NMDA receptor.

Animals↗
PubMed1997

Harmaline competitively inhibits [3H]MK-801 binding to the NMDA receptor in rabbit brain.

Harmaline, a beta-carboline derivative, is known to produce tremor through a direct activation of cells in the inferior olive. However, the receptor(s) through which harmaline acts remains unknown. It was recently reported that the tremorogenic actions of harmaline could be blocked by the noncompetitive NMDA channel blocker, MK-801. This study examined whether the blockade of harmaline's action, in the rabbit, by MK-801 was due to a pharmacological antagonism at the MK-801 binding site. This was accomplished by measurement of [3H]MK-801 binding in membrane fractions derived from tissue containing the inferior olivary nucleus and from cerebral cortex. Harmaline completely displaced saturable [3H]MK-801 binding in both the inferior olive and cortex with apparent IC50 values of 60 and 170 microM, respectively. These IC50 values are consistent with the high doses of harmaline required to produce tremor, e.g., 10-30 mg/kg. Non-linear curve fitting analysis of [3H]MK-801 saturation experiments indicated that [3H]MK-801 bound to a single site and that harmaline's displacement of [3H]MK-801 binding to the NMDA receptor was competitive as indicated by a shift in Kd but not in Bmax. In addition, a Schild plot gave a slope that was not significantly different from 1 indicating that harmaline was producing a displacement of [3H]MK-801 from its binding site within the NMDA cation channel and not through an action at the glutamate or other allosteric sites on the NMDA receptor. These findings provide in vitro evidence that the competitive blockade of harmaline-induced tremor by MK-801 occurs within the calcium channel coupled to the NMDA receptor. Our hypothesis is that harmaline produces tremor by acting as an inverse agonist at the MK-801 binding site and thus opening the cation channel.

Animals↗
PubMed1978

Kinetics of the co-transport of sodium and phenylalanine in the guinea-pig samll intestine. III - Influence of harmaline on sodium and phenylalanine fluxes.

The effect of harmaline on sodium and phenylalanine influxes in guinea-pig small intestine has been examined kinetically. Harmaline behaves as a fully competitive inhibitor of the saturable component of sodium influx; this property has been revealed from experiments in which the sodium concentration was varied and the harmaline concentration maintained constant, and from a second series in which sodium was constant and harmaline levels were altered. A Ki-value for harmaline of 1.61 mM was deduced from these experiments. The effect of harmaline on phenylalanine influx is more complex, since only that component of entry which occurs in the form of the ternary complex is sensitive to the drug. Within the framework of a non-compulsory model for co-transport which appears to describe phenylalanine influx in this tissue, equations were derived to calculate the different components of influx under given experimental conditions. tJøala, the influx to phenylalanine in the form of the ternary complex, was found to be a Michaelis-Menten function of the sodium concentration. Assuming that the component in the form of the binary complex is unchanged by harmaline, that occurring in the ternary form in the presence of the drug can be evaluated by subtraction. This fraction is also a Michaelis-Menten function of the sodium concentration; the inhibition by harmaline is released on raising the sodium concentration. From these expressions, a Ki for harmaline under these conditions of 1.66 mM was derived. These observations support the proposal that harmaline interferes with the interaction of sodium with its specific sites on the carrier in the intestinal brush-border membrane.

Alkaloids↗
PubMed1986

Inhibition of calcium channels by harmaline and other harmala alkaloids in vascular and intestinal smooth muscles.

Effects of harmaline and other harmala alkaloids on the contractions induced in the vascular smooth muscle of rabbit aorta and intestinal smooth muscle of taenia isolated from guinea-pig caecum were examined. In rabbit isolated aorta, harmaline inhibited the sustained contraction induced by 65.4 mM K+ with an IC50 (concentration needed for 50% inhibition) of 4.6 X 10(-5) M. This inhibitory effect on high K+-induced contraction was antagonized by raising the concentration of external Ca2+ but not by Bay K 8644, a Ca2+ channel facilitator. Harmaline also inhibited the sustained contraction induced by noradrenaline (10(-6) M) with an IC50 of 7.6 X 10(-5) M. The inhibitory effects on noradrenaline-induced contractions were not antagonized by raising the external Ca2+ concentrations or by Bay K 8644. In guinea-pig taenia, harmaline inhibited the 45.4 mM K+-induced contraction with an IC50 of 6.8 X 10(-5) M and the carbachol (10(-6) M)-induced contraction with an IC50 of 7.0 X 10(-5) M. The inhibitory effects on both high K+- and carbachol-induced contractions were antagonized by raising the external Ca2+ concentrations but not by Bay K 8644. Harmaline, at the concentrations needed to inhibit the muscle contraction, inhibited the increase in 45Ca2+ uptake induced by high K+, noradrenaline and carbachol in aorta and taenia. Harmaline did not change the cellular Na+ and ATP contents in resting and high K+ stimulated taenia. Other harmala alkaloids also inhibited the contractions in these smooth muscles. The order of the inhibitory potency was 6-methoxyharman = harmine > harmaline = 2-methylharmine = harmane > 6-methoxyharmalan > harmalol = harmol for the contractions induced by high K+ in aorta and taenia and by carbachol in taenia, and 2-methylharmine >6-methoxyharman >6-methoxyharmalan = harmol = harmalol = harmane > harmine> harmaline for the contraction induced by noradrenaline in aorta. 7 These results suggest that harmaline inhibits the contractile response ofrabbit aorta and guinea-pig taenia by inhibiting different types of Ca2 channel. The structure-activity relationship indicates that the potency and selectivity of the inhibitory effects on these channels are varied by modification of the structure of this alkaloid.

Adenosine Triphosphate↗
PubMedDate not supplied

Effect of harmaline on organic ion transport in rabbit renal cortical slices.

The effect of harmaline on the transport of organic ions was determined in rabbit kidney cortical slices. Harmaline inhibited p-aminohippurate (PAH) uptake noncompetitively in a dose-dependent manner over the concentration range of 0.1 and 10 mM, with the 50% inhibition at 0.65 mM. Harmaline also inhibited the microsomal Na-K-ATPase activity and the tissue oxygen consumption and altered cellular Na and K contents, the effective dose being similar to that on PAH uptake. Under anaerobic conditions, harmaline inhibited Na-dependent PAH uptake in Na, K-depleted slices. Harmaline was a strong competitive inhibitor of TEA transport, showing the 50% inhibition at 8 microM. Amiloride (0.5 mM) and choline (1 mM) inhibited TEA uptake by 74 and 75%, respectively. Harmaline did not inhibit additively the TEA uptake in the presence of amiloride or choline. These results suggest that harmaline affects PAH uptake across the basolateral membrane by inhibiting Na-K-ATPase in aerobic slices, and probably by interacting with the Na sensitive site on the PAH carrier in anaerobic slices. Harmaline inhibits TEA uptake by direct action on the organic cation transport system in the basolateral membrane of the rabbit renal proximal tubule.

Alkaloids↗
PubMed1984

Harmaline induced tremor. III. A combined simple units, horseradish peroxidase, and 2-deoxyglucose study of the olivocerebellar system in the rat.

Purkinje cells were recorded extracellularly and mapped in the cerebellar cortex of the rat under tremogenic doses of harmaline. Four different types of responses were encountered, of which two were considered as being responsible for the harmaline tremor. The latter had a regular firing pattern of complex spikes at 5 to 10 Hz and were mostly found in the vermis. Their number decreased in the more lateral region of the cerebellar cortex until they eventually disappeared. Horseradish peroxidase was injected into all the areas of the cerebellar cortex containing Purkinje cells with harmaline-induced activity. Labeled neurons were in all cases traced to the medial accessory olive. The metabolic activity of the inferior olive under harmaline was measured with 2-deoxyglucose. Increased labeling was only found in the medial accessory olive. Such an increase was demonstrated as being due to a direct effect of the drug on the inferior olivary neurons, indicating that the medial accessory olive is responsible for the harmaline tremor in the rat. Our results point out that, in the rat, there is an inverse relationship between serotoninergic innervation of a region in the inferior olivary nucleus and that with harmaline sensitivity, therefore a serotoninergic mechanism hypothesis for the harmaline tremor needs further investigation.

Alkaloids↗
PubMed1975

New characteristics of harmaline inhibition of intestinal transport systems.

Harmaline strongly inhibits the uptake of phenylalanine by slices of guinea-pig intestine in vitro. The lowest concentration having a significant effect is 0.1 mM. The drug also inhibits the unidirectional flux of phenylalanine from the mucosal to serosal face of the tissue provided it is added to the solution bathing the mucosal surface. The unidirectional flux of sodium from the mucosa to the serosa was similarly reduced. Ion and water absorption in the perfused dog intestine in vivo is also diminished in the presence of harmaline. These results support the hypothesis, previously proposed in view of the rapid onset of harmaline inhibition of sodium-dependent uptake mechanisms in a variety of tissues, that harmaline interacts with the sodium-site of non-electrolyte carrier complexes. The effect of harmaline on phenylalanine uptake by the intesting is duplicated by other psychotropic indole analogues. The actions of harmine and harnalol are similar to that of harmaline, despite great differences in the liposolubility of the different compounds. N:N-dimethyl-tryptamine is equally inhibitory, but serotonin is inactive. Mescaline and lysergic acid diethylamide also inhibit phenylalanine transport, but to a much lesser extent than harmaline.

Alkaloids↗
PubMed1983

Apparent inhibition of Na+/H+ exchange by amiloride and harmaline in acridine orange studies.

Amiloride and harmaline were tested as inhibitors of proton movements in brush-border membrane vesicles from rat kidney cortex. Transmembrane pH differences were visualized using acridine orange. Fluorescence quenching due to Na+ gradient-driven intravesicular acidification was inhibited by amiloride and harmaline. However, a similar inhibition was observed for the Na+ gradient-driven electrogenic proton movements in the presence of gramicidin. Moreover, amiloride and harmaline decreased the fluorescence signal of electrogenic proton movements driven by a K+ gradient in the presence of valinomycin. The degree of inhibition of intravesicular acidification by both drugs was concentration dependent. Half-maximal inhibition (I50) of Na+/H+ exchange and K+ gradient-driven proton movements occurred at 0.21 and 0.6 amiloride, respectively. The I50 for harmaline was 0.21 mM in both cases. Amiloride also decreased the initial quenching of acridine orange fluorescence due to a preset pH gradient without affecting the rate of dissipation of the pH gradient. This effect was independent of the buffer capacity. In contrast, harmaline seemed to dissipate pH gradient in the same way as a permeant buffer. Amiloride and harmaline led to a concentration-dependent fluorescence decrease even in aqueous solution. The results suggest an interaction of amiloride and harmaline with acridine orange which overlaps a possible specific inhibition of Na+/H+ exchange by these drugs.

Acridine Orange↗
PubMed1988

Purkinje cell activity in rats following chronic treatment with harmaline.

Harmaline and related alkaloids produce a fine, generalized motor tremor with a frequency of 8-14 Hz in many mammalian species. The tremor is though to be initiated by the synchronous activation of cells in the inferior olive. Repeated administration of the drug at tremorogenic doses results in the rapid development of tolerance in the rat. Since the generation of cerebellar cyclic 3',5'-guanosine monophosphate by harmaline or apomorphine is reduced in harmaline-tolerant rats, it is possible that the site of tolerance is the olivocerebellar system. The present study used extracellular single unit recording techniques to determine whether harmaline tolerance was associated with changes in the firing patterns of Purkinje cells in the cerebellar vermis of the rat. In non-tolerant animals, the majority (8/13) of Purkinje cells recorded in the vermis responded to harmaline with a rhythmic increase in complex spike rate and a prolonged suppression of simple spikes. In harmaline-tolerant animals, only one cell in 14 could be identified that showed this response. In these animals, a variety of responses not encountered in experimentally naive animals were observed. Since the complex spike activity of Purkinje cells is presumed to reflect the activity of climbing fibers originating in the cells of the inferior olive, the results of the studies reported here support the conclusion that a reduction in the synchronous activation of cells at the olivocerebellar level blocks the appearance of tremor in harmaline-tolerant animals.

Action Potentials↗
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↗