The effect of physostigmine and tetrabenazine on spinal motor control and its inhibition by drugs which influence reserpine rigidity

Summary The effect of monoaminergic (DOPA, metamphetamine, propylhexedrine) and cholinolytic agents (atropine, biperiden, caramiphen, trihexyphenidyl) on spinal motor control disturbed by physostigmine and tetrabenazine was studied in the rat. In addition the anticonvulsant agent phenytoin was included in the investigation. Physostigmine and tetrabenazine produced rigidity, increased reflex discharge, shortened the latency of reflex discharge and decreased reflex discharge. Rigidity as well as the action of physostigmine and tetrabenazine on motor activity were inhibited by the drugs. The results are in accordance with the hypothesis that parkinsonlike rigidity in the rat results from hyperactivity of the motor system, which is due to an imbalance between monoaminergic and cholinergic mechanisms in the brain.Supported by a grant of the Deutsche Forschungsgemeinschaft.     

Depression by antiparkinson drugs of reserpine rigidity

Summary The effect of metamphetamine, propylhexedrine and biperiden on reserpine rigidity in the rat was assessed in an electromyographical study. For comparison the anticonvulsant agent phenytoin was also included in the investigation. Tonic electromyographical activity during stretch of the calf muscles served as an indicator of rigidity. All drugs tested and their combinations depressed the rigidity elicited by an intravenous injection of a high dose of reserpine.Supported by a grant of the Deutsche Forschungsgemeinschaft.     

The evaluation of anti-parkinson drugs on reserpine-induced rigidity in rats.

The effect of anti-parkinson drugs on reserpine-induced rigidity was examined using a technique which measured rigidity by hind limb palpation. Centrally acting dopaminergic and anti-cholinergic drugs were able to antagonize reserpine-induced rigidity, whereas peripherally acting drugs had no effect. Results are discussed in terms of possible modes of action. Relative potencies of the drugs studied in this model were well correlated with the dose ranges of clinically established anti-parkinson drugs. It is concluded that measurement of reserpine-induced rigidity by hind limb palpation is a rapid and sensitive technique to evaluate potential anti-parkinson drugs.     

The effect of antiparkinson drugs on the liguomandibular reflex in cats

The linguomandibular reflex (LMR) is a polysynaptic reflex involving interneurons within the brain stem. Electrical stimulation of areas in the basal ganglia have been shown to influence this reflex. The effect of known antiparkinson drugs on the linguomandibular reflex in cats investigated. 1-Dopa and apomorphine poduced dose-related inhibition of the LMR whereas amantadine and benztropine were ineffective. Apomorphine-induced inhibition of the LMR was antagonized surmountably by haloperidol, a relatively specific dopamine antagonist but not by phenoxybenzamine, an α-adrenergic blocking agent. 1-Dopa-induced inhibition of the LMR was not antagonized by either haloperidol or phenoxybenzamine. Known metabolites of 1-dopa, dopamine and norepinephrine were tested for their effects on the LMR and none was more potent than 1-dopa. These results suggest that 1-dopa might inhibit the LMR via a direct effect of its own.     

Antiparkinson drugs used as prophylactics for nerve agents: studies of cognitive side effects in rats

Antiparkinson agents possess excellent anticonvulsant properties against nerve agent-induced seizures by exerting both cholinergic and glutamatergic antagonisms. It is important, however, that drugs used as prophylactics not by themselves cause impairment of cognitive capability. The purpose of the present study was to make a comparative assessment of potential cognitive effects of benactyzine (0.3 mg/kg), biperiden (0.11 mg/kg), caramiphen (10 mg/kg), procyclidine (3 mg/kg), and trihexyphenidyl (0.12 mg/kg) separately and each in combination with physostigmine (0.1 mg/kg). The results showed that benactyzine, caramiphen, and trihexyphenidyl reduced rats' innate preference for novelty, whereas biperiden and procyclidine did not. When benactyzine, caramiphen, and trihexyphenidyl were combined with physostigmine the cognitive impairment disappeared. This counteracting effect, however, caused changes in locomotor and rearing activities not seen by each drug alone. Acetylcholinesterase inhibitors and anticholinergics used as prophylactics can offset each other, but exceptions are observed in a previous study when a very potent anticholinergic (scopolamine) or a high dose of procyclidine still results in cognitive deficits in spite of coadministration with physostigmine. Among the present drugs tested, procyclidine appears to be a robust anticonvulsant with few cognitive side effects.     

The effect of phenytoin and metamphetamine on spinal motor activity

Summary The investigation was initiated by the idea that reserpine might exert its action on spinal motor activity through facilitatory impulses in descending pathways to the spinal motoneurones. Therefore, the effect of conditioning by repetitive stimulation of descending and segmental pathways on and reflex discharges was studied in the rat. Conditioning by stimulation of the dorsolateral funiculus increased a and decreased reflex discharge. Conditioning by stimulation of the dorsal funiculus increased reflex discharge without changing reflex activity. In partially or totally spinalized preparations, conditioning by repetitive stimulation of the same dorsal root to which the test stimulus was applied, produced an increase in a reflex activity which was associated with a decrease in motor activity. In the preparations with an intact neuraxis, repetitive stimulation of the dorsal root facilitating reflex discharge did not change motor activity. motor activity also remained unchanged when reflex discharge was inhibited by repetitive stimulation of the dorsal root in the intact or totally spinalized preparation.Phenytoin 50 mg/kg increased the unconditioned response in all types of preparations, apart from that in which the dorsal funiculus was isolated. Facilitation of reflex discharge elicited by repetitive stimulation of segmental and descending pathways was depressed by phenytoin, whereas inhibition remained unchanged.Metamphetamine 2 mg/kg increased the unconditioned reflex discharge in all types of preparations, and decreased the response in the preparations with an intact neuraxis and also in those in which the dorsal funiculus was isolated. Metamphetamine did not depress the facilitatory or inhibitory effects produced by repetitive stimulation of descending or segmental pathways.From the results obtained it is concluded that reserpine rigidity in the rat may be mediated by an increased facilitatory impulse input reaching the a motoneurones by way of descending pathways in the dorsolateral column of the spinal cord, and that phenytoin may antagonize, at least in part, the effect of reserpine by a depressant action on facilitatory processes at the spinal level, whereas abolition of reserpine rigidity produced by metamphetamine must be due to a supraspinal site of action of this drug.Supported by a grant of the Deutsche Forschungsgemeinschaft.     

The influence of hypothalamically administered reserpine on the sexual behavior of the female cat

Ovariectomized cats with intracerebral implants of reserpine, a monoamine depletor, were tested for sexual behavior by introducing them to sexually vigorous males and by artificial stimulation. Approximately a third of the animals mated in response to reserpine and another third exhibited some components of sexual behavior. The behavior exhibited by these animals had none of the frenzy of normal estrous behavior. Some components of the normal pattern were missing while all others were curtailed in duration and vigor. These animals responded with normal sexual behavior to intracerebrally and systemically administered estrogen. It is suggested that the unusual sexual behavior in response to reserpine was due to the release of these behavioral patterns from a monoamine system, inhibitory to sexual behavior.     

The anti-nociceptive effect of reserpine and haloperidol mediated by the nigro-striatal system: Antagonism by naloxone

Summary Reserpine (10 mg/kg) and haloperidol (2 mg/kg) injected intraperitoneally increased the reaction time of the tail-flick response in intact but not in pre-nigrally decerebrate or spinal rats. The anti-nociceptive effect of both drugs was antagonized by intraperitoneal injections of dopa (100 mg/kg), apomorphine (2mg/kg) or naloxone (1 mg/kg) as well as by bilateral micro-injections into the caudate nuclei of apomorphine (100 g and 20 g) and naloxone (10 g). It is concluded that the nigrostriatal feedback system is involved in the anti-nociceptive effect of reserpine and haloperidol.     

Facilitation of opiate-and enkephalin-induced motor activity in the mouse by phenytoin sodium and carbamazepine

In the first experiment, adult male Swiss-Webster mice were systemically injected with a standard dose of morphine. Compared to the influence of vehicle, the motor activity of morphine-injected mice was increased. Neither phenytoin sodium nor carbamazepine alone facilitated motor activity, but pretreatment with both drugs further facilitated the increased motor activity produced by morphine. In a second experiment, mice were injected centrally with a long-acting analog of leu-enkephalin. It also increased motor activity in comparison with vehicle. Again, both phenytoin sodium and carbamazepine further facilitated this response. Both experiments suggest a facilitatory interaction between some aspects of these anticonvulsants and opiate-induced motor activity.     

The effect of immunosympathectomy on the responses of the mouse to reserpine and various

The technique of immunosympathectomy was used to investigate the relative importance of sympathetically mediated processes in the body temperature responses of mice to reserpine treatment and the thermogenic effects of subsequently administered anti-depressant and CNS stimulant drugs.It was found that immunosympathectomized mice were less sensitive to the temperature lowering effects of reserpine but exhibited, unexpectedly, an enhanced thermogenic response to each of the representative antidepressant and stimulant drugs tested.These findings appear to exclude the sympathetic division of the autonomic nervous system as an essential prerequisite for the thermogenic effects of anti-depressant and stimulant drugs in reserpine treated mice. It is suggested that the observed effects could be accounted for in terms of a possible hyperfunctional adrenal gland.The findings reported above were presented, in part, at the 7th International Congress of C.I.N.P., Prague, Czechoslovakia, August 1970.     

Effect of anticholinergic drugs on gastro-intestinal absorption of L-dopa in rats and in man.

Plasma L-DOPA levels in rats receiving L-DOPA by the oral route were decreased by the concomitant administration of trihexyphenidyl. Following systemic L-DOPA administration no differences were observed between control and trihexyphenidyl-treated rats. Effects similar to those of trihexyphenidyl were observed with atropine. These results indicate that trihexyphenidyl decreases L-DOPA gastrointestinal absorption probably by delaying gastric emptying. The presence in humans of this interaction between the two antiparkinsonian drugs was suggested by similar findings made either in a group of normal volunteers or in a group of parkinsonian patients. These observations suggest that at the clinical level in selected cases the concomitant administration of trihexyphenidyl to patients receiving L-DOPA may decrease the therapeutic efficacy of L-DOPA by reducing its gastrointestinal absorption.     

Comparison of the long-term cumulative effects of reserpine and syrosingopine on general activity.

Reserpine, but not syrosingopine, produced a cumulative decrease in general motor activity when administered once every 10 days for a total of 8 drug treatments. The maximum depression of activity was evident following the second reserpine administration. Following a 30 day drug-free period animals previously treated with reserpine still exhibited decreased motor activity. The data suggest that chronic reserpine treatment may result in long term, and perhaps permanent behavioral effects.     

The effect of some hallucinogenic and other drugs on the temperature of reserpinized mice

Seven hallucinogenic and 9 centrally acting non-hallucinogenic drugs were studied for their calorigenic effects on reserpine pre-treated mice. With the exception of Ditran and mescaline, all the hallucinogens had a significant calorigenic effect. Of the other drugs studied, methylamphetamine and amphetamine, dimethoxyphenylethylamine, desmethylimipramine, amitryptyline and chlorpromizine also had a marked calorigenic action. Both -methyl-m-tyrosine, and its active metabolite metaraminol, had a significant calorigenic action in reserpinized mice even though they did not significantly affect the body temperature of otherwise untreated animals. The calorigenic effect of -methyl-m-tyrosine was significantly antagonized by phencyclidine, ketamine, LSD and mescaline; the other hallucinogens (harmine, Ditran and p-bromethylamphetamine) were without effect. Of the other drugs tested, only propranolol, desmethylimipramine and amitriptyline significantly antagonized the calorigenic effect of -methyl-m-tyrosine in reserpinized mice. The possible mechanism of action of the drugs studied is tentatively discussed.     

The effect of α-methyl-p-tyrosine and substantia nigra lesions on spinal motor activity in the rat

The effects of α-methyl-p-tyrosine (αMT) and of bilateral lesioning the substantia nigra on spinal motor activity were studied in rats and compared with reserpine rigidity. αMT, as well as the lesions produced by electrocoagulation or microinjection of 6-hydroxydopamine (6-OH-DA) produced rigidity signalled by tonic activity in the electromyogram during sustained muscle stretch, high α- and low γ-reflex activity, and a short latency of α-reflex discharges. The effect on spinal motor activity of αMT and of bilateral electrocoagulation of the substantia nigra was antagonized by DOPA. Motor disturbances following microinjection of 6-OH-DA into both substantiae nigrae were not influenced by DOPA, metamphetamine or amantadine. Atropine abolished the effect of substantia nigra lesioning by electrocoagulation or by microinjection of 6-OH-DA. On the basis of the results it is concluded that the rigidity produced by reserpine is due to dopamine depletion in the striatum.     

Inhibition of heat-induced denaturation of albumin by nonsteroidal antiinflammatory drugs (NSAIDs): Pharmacological implications

The activity of nonsteroidal antiinflammatory drugs (NSAIDs) in rheumatoid arthritis is not only due to the inhibition of the production of prostaglandins, which can even have beneficial immunosuppressive effects in chronic inflammatory processes. Since we speculated that these drugs could also act by protecting endogenous proteins against denaturation, we evaluated their effect on heat-induced denaturation human serum albumin (HSA) in comparison with several fatty acids which are known to be potent stabilizers of this protein. By the Mizushimas assay and a recently developed HPLC assay, we observed that NSAIDs were slightly less active [EC50 to approximately 10(-5)-10(-4) M] than FA and that the HPLC method was less sensitive but more selective than the turbidimetric assay, i.e. it was capable of distinguishing true antiaggregant agents like FA and NSAIDs from substances capable of inhibiting the precipitation of denatured protein aggregates. In conclusion, this survey could be useful for the development of more effective agents in protein condensation diseases like rheumatic disorders, cataract and Alzheimers disease.     

The acute effects of reserpine on the sleep-wakefulness cycle in rabbits

Summary The acute effects of reserpine on the sleep-wakefulness cycle were systematically studied in five male rabbits with chronically implanted electrodes for recording the EEG, the EMG of the neck muscles, and the oculogram. After careful control studies during which the rabbits became accustomed to the experimental situation and attained stable sleep-wakefulness patterns, various doses of reserpine (1.0, 0.5, 0.25, 0.1, 0.05 mg/kg) were injected intravenously and 5-hr polygraphic recordings were made. Twenty-four hours after administration, 2-hr recordings were made for all doses studied; for the dose of 1.0 mg/kg 2-hr recordings were also made 48 hours after administration. The percent times of the three stages, alert, slow wave sleep and paradoxical sleep, were calculated for the total recording time. In the unmedicated animals the percentages during 2-hr recordings were: alert, 32.9±5.7; slow wave sleep, 61.5±5.9; and paradoxical sleep, 5.6±1.1. Paradoxical sleep was also calculated for the first hour and the remaining 4 hours of the 5-hr recording period both as to percent time and the duration of single episodes. Some behavioral and polygraphic characteristics of paradoxical sleep were described. Reserpine, in doses of 1.0 to 0.25 mg/kg, caused a biphasic response; an initial alert period of 1 1/2 to 2 hours followed by a slow-wave-sleep period which endured until the end of the 5-hr recording. Suppression of paradoxical sleep was observed with doses of 1.0 to 0.1 mg/kg, although the doses of 0.25 and 0.1 mg/kg did not suppress it during the first hour after injection. The percent time of paradoxical sleep in total recording time showed a dose-dependent decrease: 0.2% for 1.0 mg/kg, 0.1% for 0.5 mg/kg, (both significant,p<0.001), 0.6% for 0.25 mg/kg (p<0.01), 2.4% for 0.1 mg/kg (p<0.05), 3.5% for 0.05 mg/kg (not significant) and 5.1% for the saline control. The duration of single episodes of paradoxical sleep was not changed by reserpine. In the 2-hr recordings made one and two days after reserpine administration the percent time of paradoxical sleep did not differ significantly from the normal level.     

Enhancement by a single dose of reserpine (plus alpha methyl-p-tyrosine) of the central stimulatory effects evoked by dopamine D-1 and D-2 agonists in the mouse

Summary With the advent of selective dopamine D-1 and D-2 agonists such as SKF38393 (2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine HCl) and quinpirole (LY171555, trans-4,4a,5,6,7,8a,9-octahydro-5-propyl-2H-pyrazolo [3,4-g]-quinoline), it has become possible to examine the functional role of the two dopamine receptor subtypes as well as their interrelationship. In the present study, we pretreated mice with the granule-depleting agent reserpine (5 mg/kg sc) and tested the mice from 4 h to 10 days later. In all the studies, each mouse also received an injection of the dopamine synthesis inhibitor alpha methyl-p-tyrosine (200 mg/kg ip) 1 h before agonist challenge. Where the reserpine was given 2 or more days before testing, a second dose of reserpine was given 4 h before agonist challenge. While producing no significant locomotor stimulation 4 h after reserpine, SKF38393 produced a dose-dependent increase in coordinated locomotion 24 h and 3 days after the reserpine. Likewise, quinpirole itself produced no significant alteration in activity at 4 h, but significantly increased activity at 24 h and 3 days. The new selective D-1 agonist CY208-243 ((–)-4,6,6a,7,8,12b-hexahydro-7-methyl-indolo [4,3-ab] phenanthridine), unlike SKF38393, produced some increase in activity 4 h after reserpine, but much greater activity was seen 1 and 3 days after reserpine. The enhancement with SKF38393, CY208-243 and quinpirole was most marked 3 days after the reserpine. The behavioural stimulation produced by the mixed D-1/D-2 agonist apomorphine was also greater 3 days after reserpine pretreatment than after 4 h. The combination of SKF38393 and quinpirole produced greater locomotor stimulation than either drug alone, and the increased response, while evident 4 h after reserpine, was most marked 3 days after, and had essentially disappeared by 10 days. A similar interaction was seen between CY208243 and quinpirole. At 3 days, there was also a supersensitive response of the mice to the rearing and sniffing produced by SKF38393 plus quinpirole. Striatal binding studies with the D-1 selective ligand [³H]-SCH23390 (R-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7ol) and with the D-2 selective ligand [³H]-spiperone indicated that there were no changes in K _d or B _max of the D-1 or D-2 receptors at the time of maximum behavioural supersensitivity (3 days). Thus, the behavioural supersensitivity to apomorphine, SKF38393, CY208-243 and to quinpirole was not accompanied by any change in D-1 or D-2 binding in the striatum indicating that the biochemical modulation of the supersensitivity is either outside the striatum and/or associated with neurochemical alterations in the striatum other than changes in the D-1 and D-2 recognition sites. Send offprint requests to D. M. Jackson at the above address     

Influence of naloxone upon motor activity induced by psychomotor stimulant drugs

Naloxone, an opioid receptor antagonist, attenuates a wide range of behavioral effects ofd-amphetamine, such as the stimulation of motor activity. To investigate the pharmacological selectivity of the naloxone/amphetamine interaction, we assessed the effects of naloxone (5.0 mg/kg SC) upon motor activity induced in rats by a range of psychomotor stimulant drugs with a mechanism of action either similar to or different from that ofd-amphetamine. Each of the drugs tested caused dose-dependent increases in both gross and fine activity. Naloxone attenuated the gross but not the fine activity response tod- andl-amphetamine, but had no influence upon the other catecholamine-releasing drugs, methamphetamine and phendimetrazine. In contrast, naloxone increased the gross but not the fine activity response to the catecholamine uptake inhibitors cocaine and mazindol, but had no effects upon the motor response to methylphenidate. The responses to other stimulant drugs (apomorphine, caffeine, scopolamine) were unaffected by naloxone pretreatment. The present findings extend the range of conditions under which naloxone and, by inference, endogenous opioid systems, modulate the behavioral response to psychomotor stimulants. However, the differential effects of naloxone upon the motor response to individual stimulant drugs support previous suggestions of fundamental differences in mechanisms of action among these compounds.     

The effect of reserpine treatment on the chronotropic and inotropic sensitivities of the perfused guinea-pig heart to norepinephrine and calcium

The chronotropic and inotropic responses of the isolated perfused guinea-pig heart to norepinephrine and calcium were measured in preparations obtained from untreated and reserpinetreated animals. Dose-response curves were obtained in spontaneously beating as well as electrically paced perfused hearts. The dose-response curve for the chronotropic effect of both norepinephrine and calcium was shifted to the left of control in spontaneously beating preparations from animals pretreated with reserpine (0.1 mg/kg/day) for seven days. However, in these same preparations the dose-response curve for the inotropic effect of only norepinephrine was shifted to the left. This may be reflection of the enhanced sensitivity to the chronotropic action of the agonist since a changing rate is known to influence inotropic response. This conclusion is supported by the finding that, in electrically paced perfused hearts, no postjunctional supersensitivity to the inotropic effects of norepinephrine was demonstrable. Since no supersensitivity was observed to the inotropic effects of calcium, it is concuded that true postjunctional supersensitivity develops to the chronotropic but not to the inotropic effects of drugs.     

Depression by amantadine of tremor induced by reserpine and oxotremorine in the rat

Summary Reserpine and oxotremorine tremor as well as the effect of amantadine on the tremor activity produced by both drugs were studied in rats with respect to changes in alpha and gamma motor activity.The tremor activity elicited by reserpine (10 mg/kg i.v.) is maintained by the alpha motoneurones, whereas the tremor activity developing during an infusion of oxotremorine (40 g/kg·min) is triggered by the gamma motoneurones. Amantadine (50 mg/kg i.v.), which itself elicited tremor activity, abolished the tremor produced by oxotremorine. The tremor activity resulting from an administration of reserpine was inhibited by amantadine in rats with their dorsal roots cut; in rats with intact dorsal roots, tremor activity persisted after reserpine and amantadine.It is concluded that the tremor resulting from reserpine and oxotremorine is brought about by an action of the two drugs on different structures of the central nervous system. The anti-tremor effect of amantadine is discussed.