Injection Of Harmaline Research Articles

Cerebellar control of vestibulo-ocular reflex (VOR) studied with injection of harmaline in the trained baboon.

Cerebellar control of vestibulo-ocular reflex (VOR) studied with injection of harmaline in the trained baboon.

Cerebellar control of eye movements studied with injection of harmaline in the trained baboon.

1. The alteration of the cortical cerebellar mechanisms resulting from the activation of the olivo-cerebellar pathway by Harmaline (H) administered at doses which were subthreshold for skeletomotor tremor (5 mg/kg, IM) yields, in the trained Baboon (Papio papio), a marked decrease of oculomotor system performance. 2. The mean angular excursion of the spontaneous eye movements produced in the dark over a given period of time is increased by 50%. The increase is basically due to an increase of the number of saccades in the 0-20 degrees amplitude range. 3. The eye movements in response to a slow target displacement are altered as evidenced by a decrease of the smooth pursuit gain, a 60% increase in latency, and by intrusive saccades. The effects are dose dependent so that around 8 mg/kg of H, smooth pursuit is totally suppressed. 4. The saccadic system is also altered, Stepping target tracking shows dysmetria and increase of the amplitude of the fixation eye movements. The velocity-amplitude relationship of the saccades is not modified but the saccadic reaction time is increased by 50%. The observed alterations are in no way similar to the tremor commonly induced by the drug, at skeletal level. In fact, no ocular tremor at 8 to 10 Hz was recorded. 5. In conclusion, administration of H alters considerably the control and the stability of the oculomotor system in a way similar to that resulting from partial or total cerebellectomy. It may thus be possible to use the drug to simulate, in a reversible manner, cerebellar dysfunctions and study the involvement of the cerebellum in oculomotor control.

Thermoregulatory effects of intracerebroventricular injection of serotonin and a monoamine oxidase inhibitor in a hibernator, Spermophilus richardsonii

1. 1.|The present study investigated the endogenous changes in thermoregulatory responses (heat production [HP], heat loss [HL], and rectal temperature [Tb]) at an ambient temperature of 5°C, following intracerebroventricular injections of serotonin (5-HT) and harmaline (to enhance endogenous 5-HT) in an unanesthetized, restrained hibernator ( Spermophilus [ Citellus] richardsonii) which was maintained under constant conditions (LD 12:12, Ta = 22°C). 2. 2.|In the non-hibernating phase, 5-HT caused an initial activation of HL followed by a compensatory increase of HP resulting in a maximal decrease of Tb of 0.40°C. In the hibernating phase, 5-HT increased HL with concurrent suppression of HP resulting in a maximal decrease of Tb of 1.65°C. 3. 3.|Injection of harmaline in the non-hibernating phase caused an increase in HP with a slight increase of HL resulting in a maximal increase of Tb of 0.80°C. In the hibernating phase, harmaline caused a marked decrease in HP with a slight decrease in HL resulting in a maximal decrease of Tb of 0.74°C. 4. 4.|It is concluded that (a) both exogenous and endogenous 5-HT suppress HP in cold during the hibernating phase; (b) since the animals were kept under constant conditions, the observed differential thermoregulatory responses following 5-HT and harmaline injections suggest an endogenous adjustment of thermoregulatory mechanisms incumbent with the circannual rhythm of hibernation.

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.

Post-natal development and regulation of cerebellar cyclic guanosine monophosphate system

Recent investigations suggest a role for cyclic GMP in cerebellum as an important factor involved in the regulation of Purkinje cells activity. Since the formation of synapses in cerebellar Purkinje cell body of rat is complete only after the first 15 days of life, cGMP levels have been measured during development. Young adult and three day old rats have been used. The animals were killed by a beam of focused microwave radiation on the skull for 3 seconds. In the new born rat cerebellum the levels of cGMP are much lower than in adult animals. Harmaline, a potent and selective activator of the climbing fibers, a pathway which activates the onset of burst discharges in the Purkinje cells when injected in adult rats,induces, as it has been-previously shown, a 5 fold increase of the level of cerebellar cGMP. In contrast in new born rats harmaline does not increase cGMP concentrations. Moreover diazepam, which has been shown to decrease cerebellar cGMP levels in adult rats, does not appear to have such effect in new borns. On the other hand guanylate-cyclase activity is significantly higher in the new born rats in comparison with adults. Furthermore Harmaline injection in adult animals induces a stimulation of cerebellar guanylate-cyclase, as measured in vitro.

Neuronal activity in the lateral vestibular nucleus of the cat. II. EPSPs in deiters neurones mediated by fast conducting fibres of the spinal cord.

Intracellular records from 203 neurones located in Deiter's nucleus were evaluated in respect to IPSPs evoked by stimulation of the spinal cord. In 85% of the cells, short latency IPSPs were observed (less than 4.5 ms from C2-level), attributable to fast conducting pathways. The majority of them (3–4.5 ms) includes activity transmitted via the cerebellar cortex, while latencies between 1.0 and 2.9 ms as observed for roughly 10% of the early IPSPs, are too short to include cerebellum. IPSPs with longer latencies (mean 7.3 ms from C2-level) were found in 75% of the cells. Low conduction velocity of their spinal pathways and other criteria suggest that spino-olivo-climbing fibre systems including the cerebellar cortex are involved. The latter type of IPSP often shows a complex configuration, expainable by reflex discharges of olivary neurones and disinhibitory phenomena coupled to climbing fibre activation. Clean, rhythmic IPSPs were seen after injection of harmaline.

Reduced binding of 3H-reserpine to the hearts of 6-hydroxydopamine-pretreated rats

6-Hydroxydopamine (6-OH-DA) pretreatment of rats resulted in a consistent reduction of the small amounts of reserpine residual in the heart, 24 hr after its injection. This finding presumably depends on the destruction of sympathetic nerve terminals currently ascribed to 6-OH-DA and it indicates that reserpine in the heart is at least in part bound to adrenergic structures. The injection of harmaline and of 3H-inuline did not result in lower harmaline and tritium concentration in the hearts of 6-OH-DA pretreated rats.

Effect of brain lesions and of harmaline on the DOPA decarboxylase activity in the striatum of the cat

The activity of DOPA decarboxylase in the striatum of the cat is not altered 1 or 3 h after the injection of harmaline (15 mg/kg). In cats with a unilateral lesion which interrupts the nigrostriatal pathway at the level of the midbrain or with a lesion of the rostral part of the medial forebrain bundle, this enzyme is considerably diminished in activity in the ipsilateral striatum. These results suggest that the previously-described depletion of dopamine induced by administration of harmaline does not occur as a result of a diminution in the activity of DOPA decarboxylase. Furthermore, it is shown that the integrity of the nigrostriatal pathway is essential for the maintenance of DOPA decarboxylase activity at the level of the striatum. This fact explains the deficient synthesis of dopamine from its immediate precursor l-DOPA in animals whose nigral neurones have degenerated as a result of a specific lesion. The implications of these findings for the use of DOPA in the treatment of Parkinson's disease are briefly discussed.

The rubro-olivo-cerebello-rubral loop and postural tremor in the monkey

The interruption of the rubro-olivary (from the small-celled red nucleus) or olivocerebellar fibres or of the superior cerebellar peduncle or destruction in the area of the lateral cerebellar nuclei did not result in any important and sustained motor impairment. The injection of harmaline following the interruption of the olivocerebellar (before their crossing) or rubro-olivary fibres induces postural tremor in the contralateral limbs. The injection of harmaline following lesions of the superior cerebellar peduncle or the interruption of the olivocerebellar fibres (after their crossing) or lesions in the area of the lateral cerebellar nuclei induces postural tremor in the ipsilateral limbs. It is concluded that the interruption of the rubro-olivo-cerebello-rubral loop and its interconnections represents an important feature in the appearance of postural tremor. Sustained postural tremor, however, will appear only after the concomitant involvement of certain upper brain stem monoaminergic mechanisms, a disturbance which is apparently duplicated by the effect of harmaline.

Influence of drugs on the temperature-lowering effect of harmaline

Harmaline (30 mg/kg), injected intraperitoneally into rats, causes a decrease in body temperature. Treatment with either α-methyl-dopa (200 mg/kg, i.p.) or with a-methyltyrosine (200 mg/kg, i.p.) 24 hr before, or with p-chlorophenylalanine (315 mg/kg, i.p.) 72 hr before injection of haarmaline, did not influence the decrease in temperature. Reserpine (5 mg/kg, i.p.) given 24 hr before harmaline did not affect the temperature fall caused by the latter drug. However, administration of Ro-4-4602 (693 mg/kg, i.p.), an inhibitor of dopa decarboxylase, or sodium diethyldithiocarbamate (360 mg/kg, i.p.) 24 hr after reserpine and 1 hr before the injection of harmaline prevented the fall in temperature ( p <0.05). Administration of harman (25 mg/kg), and harmalol (28 mg/kg), two derivatives of harmaline, also caused a fail in body temperature. The compounds harmaline, harman and harmalol, all antagonized the action of serotonin on the rat uterus. Distribution between free and bound serotonin and free and bound noradrenaline in rat brain (omitting the cerebellum), 1or 2 hr after the administration of harmaline, did not differ significantly from that observed in brains of saline-teeated controls. The results suggest that the decrease in body temperature after the administration of harmaline may be the consequence of a disturbance of monoamine relationship at brain thermoreceptor sites.

Opposite effect of harmaline on seotonin and on dopamine and its metabolites, homovanillic acid and norepinephrine, in the brain of the cat.

A comparison between the effects of a single injection and of several injections (24 h) of harmaline on the concentrations of serotonin, dopamine, homovanillic acid (HVA), and norepinephrine in different structures of the brains of normal cats gave the following results. Treatment during a 24-h period caused a somewhat higher increase of serotonin in the thalamus and in the striatum than after a single injection but neither treatment affected the concentration of norepinephrine in the hypothalamus. Under the same conditions, a single injection of harmaline produced a slight decrease of HVA but not of dopamine in the striatum whereas the 24-h treatment caused a significant decrease of dopamine and almost complete depletion of HVA in the same structure. A single dose of harmaline (15 mg/kg) injected before L-DOPA (30 mg/kg) prevented the marked increase of dopamine and HVA that normally occurs in the striatum after the injection of L-DOPA alone. Harmaline injected before 5-HTP did not prevent the marked increase of serotonin in the thalamus and in the striatum. Harmaline appears to have a trapping effect on dopamine in the striatum by inhibiting its conversion to homovanillic acid and by simultaneously preventing its formation from L-DOPA This peculiar effect of harmaline is considered in relation to its effect on extrapyramidal syndromes which are known to be associated with a metabolic imbalance of the monoamines in extrapyramidal structures.

The effect of harmaline on the concentration of noradrenaline and adrenaline in the heart

A single injection of harmaline increases the noradrenaline and adrenaline concentration in the rat heart. The maximum effect is obtained after about 40 min.