Inhibition of the effect of reserpine on motor control by drugs which influence reserpine rigidity

Summary The effect of monoaminergic (DOPA, metamphetamine, propylhexedrine) and cholinolytic agents (atropine, biperiden, caramiphen, trihexyphenidyl) on and reflex discharge from the spinal cord was studied in the rat. For comparison, the anticonvulsant phenytoin was included in the investigation. All drugs antagonized the action of a high dose of reserpine on motor control by reducing the increased and increasing the diminished reflex activity. The latency of reflex discharge shortened by reserpine was increased by the drugs. The results provide further support of the view that disturbance of motor control caused by reserpine in the rat derives from an imbalance between monoaminergic and cholinergic systems in the brain.Supported by a grant of the Deutsche Forschungsgemeinschaft.     

Prevention of reserpine rigidity by alpha-2 adrenergic antagonists

Since alpha adrenergic antagonists are known to protect rats from the extrapyramidal effects of reserpine, the purpose of this study was to examie the relative contribution of alpha-2 receptors in modifying the reserpine-induced syndrome. Rats were pretreated with either clonidine, yohimbine, phentolamine, methysergide or SKF-7265. Thirty minutes later they were given reserpine (20 mg/kg) and evaluated using eleven categories of behavioral responses for three hours. Yohimbine, an alpha-2-antagonists, was the most effective agent in protecting against the reserpine effects. Phentolamine and SKF-7265, which block both alpha-1 and alpha-2 receptors, were also effective. Clonidine, an alpha-2 agonist, and methysergide a serotonin antagonist, were not. In all cases the alpha blocking drugs prevented the motor responses but did not alter the automatic responses induced by reserpine. The results show not only the efficacy of alpha adrenergic antagonists in protecting against reserpine rigidity but more importantly that the blockade of alpha-2 receptors may be the functionally important action. These results are consistent with the view that some descending motor pathways are controlled by an adrenergic mechanism and suggest that alpha-2 receptors are an important component.     

Differences in the effects of post-trial chlorpromazine,reserpine, and amphetamine on discrimination learning in rats

Rats were trained to perform in discrimination learning reinforced by water for 6 days, and were intraperitoneally injected with chlorpromazine, reserpine, or d-amphetamine after each training session. Although chlorpromazine at the dose levels of 0.5 mg/kg or more injected immediately after training impaired learning, the drug did not affect learning when it was injected 60 min after training. Reserpine and amphetamine also impaired learning, but delaying the time intervals between training and injection to 60 min or more had no influence on this learning impairment. Post-trial chlorpromazine and amphetamine had no effect on, but reserpine decreased, motility in the subsequent training session. Chlorpromazine had no effect on water intake in the subsequent session, but reserpine and amphetamine decreased water intake at the dose levels that impaired learning.It was concluded that all three drugs impaired learning, but differed in their effects on learning; chlorpromazine impaired learning by a specific effect on learning itself; reserpine, by a non-specific effect on behavior due to a long acting sedation; and amphetamine, by an effect to decrease the motivation to drink water. The specific effect of chlorpromazine could be related to the hypothesis of memory trace synthesis.     

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.     

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.     

über die Wirkung einiger Phenothiacine auf das Verhalten von freilebenden Silbermöwen (Larus a. argentatus Pontopp)

Zusammenfassung Die Wirkung einiger Phenothiacine auf das Verhalten von freilebenden Silbermöwen wurde in einer gro\en Brutkolonie untersucht. Chlorpromacin (12–75 mg/kg) rief eine zunehmende motorische Unruhe hervor, die Tiere hörten auf zu brüten und liefen wÄhrend mehreren Stunden ziellos in ihrem Brutrevier umher. Die geduckte Haltung sowie das in der Literatur beschriebene depressive Verhalten von Tauben in Dressurversuchen lassen vermuten, da\ beim Vogel durch Chlorpromacin neben der Aktivierung motorischer Systeme eine DÄmpfung psychischer VorgÄnge erfolgt. Nach Levomepromacin (25–50 mg/kg) verlie\en die Möwen das Nest nur kurzfristig und brüteten nach einigen Würgebewegungen wieder normal weiter. 4 mg/kg Fluphenacin und 2,5–7,5 mg/kg Butyrylperacin riefen keine VerhaltensÄnderungen hervor.

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The effects of some phenothiazine derivatives on the behaviour of free living Herring Gulls (Larus a. argentatus Pontopp)

The effects of some phenothiazines on the behaviour of free-living Herring Gulls were studied in a large breeding colony. Motor activity increased after chlorpromazine (12–75 mg/kg), the birds left their nests and walked around in their territories for some hours. The increased locomotor activity, hunched posture of the gulls and the depressed behaviour of pigeons in learned discriminative test situations mentioned in the literature, suggests that chlorpromazine both activates motor systems and depresses psychic activity in birds. After levomepromazine (25–50 mg/kg) the gulls left their nests only for a few minutes, tried to spittle something and continued to brood normally later on. 4 mg/kg fluphenazine and 2.5–7.5 mg/kg butyrylperazine had no effect at all on free behaviour of the gulls.

     

The action of reserpine on teleost melanophores

Reserpine caused darkening of both pencil fish and angelfish, this effect lasted for at least 10 and 25 days respectively.The aggregation of pigment granules within the melanophores evoked by stimulation of the nerves supplying the melanophores was inhibited by reserpine in both species. Reserpine caused a lowering of the catecholamine content of pencil fish skin. The time course both these effects paralleled the time course of darkening. The response of the melanophores of the angelfish to adrenaline, noradrenaline, dopamine, and melatonin was not affected by treatment with reserpine for 3 days. However, reserpine treatment for 14 days induced a marked sensitivity to noradrenaline. Reserpine partially abolished the response to tyramine in both pencil fish and angelfish. Small doses of noradrenaline and adrenaline given to reserpine-treated angelfish partially restored the response of the melanophores to nerve stimulation. No action of ACTH, MSH, nor direct effect of reserpine could be demonstrated on melanophores of either species. It was concluded that reserpine acts on the melanophores of pencil fish and angelfish in an indirect way by depletion of catecholamines from the sympathetic nerves supplying the melanophores.     

Mechanism of ulcerogenic activity of reserpine in albino rats

Reserpine-induced gastric ulceration was significantly prevented by α-adrenoceptor blockers but not by propanolol or by bilateral adrenalectomy. Intracerebroventricular (i.c.v.) administration of reserpine as well as tetrabenazine failed to induce ulceration in albino rats. Pretreatment with 6-hydroxydopamine or atropine methyl nitrate protected the animals from the ulcerogenic activity of reserpine.     

Effect of chlorpromazine and some of its metabolites on synthesis and turnover of catecholamines formed from 14C-tyrosine in mouse brain

Rates of accumulation and disappearance of labelled catecholamines formed from ¹⁴C-tyrosine in mouse brain in vivo were determined. The effects of chlorpromazine (CPZ) and the following metabolites were studied: desmethyl-CPZ, didesmethyl-CPZ, 7-hydroxy-CPZ, CPZ-sulphoxide and CPZ-N-oxide. As we have found previously CPZ accelerated both accumulation and disappearance of ¹⁴C-dopamine indicating that synthesis and turnover of brain dopamine are accelerated. All the metabolites, with the exception of CPZ-sulphoxide, accelerated accumulation and disappearance of ¹⁴C-dopamine to about the same extent as did the parent compound. Neither CPZ nor the metabolites significantly affected the accumulation and disappearance of ¹⁴C-noradrenaline. The accelerated turnover of brain dopamine is probably a consequence of a central receptor blockade, which by a compensatory feed-back mechanism activates the presynaptic neurons. The results indicate that sulphoxidation of CPZ interferes with the action of CPZ on brain dopamine receptors, and that the clinical effects of CPZ may be mediated at least partly by its metabolites.     

Behavior “recovery” during chronic reserpine treatment: Effect of dose of reserpine

Summary Various doses of reserpine were administered chronically to rats which were tested for rotarod performance and spontaneous locomotor activity. Doses of 0.0625, 0.125 and 0.25 mg/kg/day produced depression of rotarod performance after varying periods of treatment. No evidence of recovery of performance was observed during treatment with any dose. Doses of 0.125, 0.25 and 0.5 mg/kg/ day produced depression of spontaneous locomotor activity after varying periods of treatment. “Recovery” of activity was observed after the initial depression. A subsequent phase of hyperactivity occurred during treatment with 0.5 and 0.25 mg/kg while activity of the animals treated with 0.125 mg/kg became depressed and remained depressed during another 32 days of treatment. It is suggested that more than one action of reserpine should be considered in the explanation of these results. Supported by USPHS Grant MH 15490-01. Supported by USPHS Grant FR 05404.     

Evaluation of Defined Daily Dose,percentage of British National Formulary maximum and chlorpromazine equivalents in antipsychotic drug utilization

Objective

The present study was carried out to investigate and compare the three methods for calculating total antipsychotic dose among outpatients with schizophrenia attending primary psychiatric health care centers. The three methods were: Defined Daily Doses (DDDs), chlorpromazine equivalents (CPZeq) and percentages of the British National Formulary (BNF) maximum.

Methodology

Antipsychotic drug dosing data for 250 patients with schizophrenia were investigated by calculating Spearman’s rank correlation coefficients. Factors associated with antipsychotic dose, expressed as DDDs, CPZeq and percentages of the BNF maximum recommended daily dose, were investigated by means of linear regression analysis.

Results

Spearman’s correlation showed that there is a significant relationship between all pairs of the three dosing methods. In all three methods, coherence was strongest when dealing with first generation antipsychotics (FGA). Linear regression analyses showed a high degree of coherence between antipsychotic doses expressed as DDDs, CPZeq and percentages of the BNF maximum recommended daily dose.

Conclusion

All three tested methods are reliable and coherent for calculating antipsychotic dosing.Abbreviations: %BNFmax, percentage of British National Formulary maximum; CPZeq, chlorpromazine equivalents; DDD, Defined Daily Dose (DDD); FGA, first generation antipsychotics; SGA, second generation antipsychotics     

Effects of denervation and reserpine on nexuses in the rat vas deferens

Permanganate-fixed vasa deferentia from rats were examined for the presence of nexal-like contacts by electron microscopy. There was a significantly greater incidence of nexuses (2×) in chronically denervated tissues (5–7 days) but not in tissues from reserpine-pretreated animals (1.0 mg/kg/day for 5–7 days). The results suggest that an increase in nexal regions may not be a general feature of postjunctional supersensitivity but rather may contribute to other denervation-induced changes in contractile response.     

GABAergic effects of reserpine following chronic treatment

Reserpine-induced depression has been used as an animal model to screen for antidepressant agents. Chronic (14-day) tretment with reserpine resulted in a significant increase in -adrenergic receptor binding in the cerebral cortex and the hippocampus, which was partially prevented by chronic treatment with either the antidepressant imipramine, the GABA-A agonist THIP or, the GABA-B agonist baclofen. Chronic treatment with reserpine also significant increased ³H-GABA receptor binding, which was partially prevented by chronic treatment with either imipramine or THIP. Both subchronic and chronic administration of reserpine resulted in a decrease in GABA concentrations in the cerebral cortex and hippocampus. These data demonstrate the effect of reserpine treatment on the GABA-ergic system, and add further support for a functional coupling between the noradrenergic and GABA-ergic systems, which may be important for the mechanism of action of antidepressant agents.     

Time-dependent effects of reserpine on retention of passive avoidance

Reserpine produced amnesia for a one-trial passive avoidance task when given 2, 3, 4, 5 hr before but not when given 1, 8, 12, 24 hr or 30 min before, immediately, 90 min or 2, 4, 5, 6, 8, 9, 12, 24 hr following training. The results were discussed in terms of the reserpine effect on biogenic amines and their possible role in memory formation.     

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.     

Effect of combined reserpine and ECS on electroshock seizure thresholds in mice

Recent evidence has suggested that electroshock seizure threshold is correlated with levels of brain biogenic amines. Reserpine, a drug that depletes serotonin and norepinephrine, has been shown to decrease seizure thresholds. ECS treatment has been shown to increase amine levels as well as seizure thresholds. Combined reserpine and ECS have been shown to produce an intermediate level of serotonin and norepinephrine, but seizure threshold data for this group is absent. It was the purpose of this study to examine the seizure thresholds for combined treatment and compare then with groups treated with reserpine alone, ECS alone, and a placebo control group. The results suggest that, if only maximal seizures are considered, the seizure threshold is lowest for the reserpine and highest for the ECS alone or control groups, with the combined treatment group falling intermediate. If both minimal and maximal seizures are considered, the reserpine and combined treatment groups do not differ from one another, but do show a lower threshold as compared to ECS or control groups.     

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.     

Central effects of thyrotropin-releasing factor (TRF) : Interaction with some antipsychotic drugs

The behavioral effects (tremors, tail erection, increased motility) of intracerebrally injected TRF are enhanced pretreatment with chlorpromazine, reserpine and sulpiride; haloperidol does not exert appreciable effects. L-Dopa attenuates or abolishes the potentiation.     

Blockade of reserpine emesis in pigeons by metoclopramide.

Reserpine (0.5 mg/kg i.m.) produced emesis in pigeons with 60% of the animals responding. Metoclopramide HCl at 10, 20 and 40 mg/kg p.o. administered 30 min before or after reserpine injection was effective in blocking reserpine emesis. Metoclopramide was unable to antagonize reserpine-induced sedation and hypotension in rats, thus inviting discussion of its possible mechanism in blocking reserpine emesis.     

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.