Cataleptic Effects Research Articles

A study of the sites of interaction between dopamine and 5-hydroxytryptamine for the production of fluphenazine-induced catalepsy.

The effect of reducing 5-hydroxytryptamine (5-HT) concentration within various areas of the central dopamine (DA) system on catalepsy has been investigated. The neurotoxin 5,7-dihydroxytryptamine was used to selectively deplete 5-HT in the striatum, nucleus accumbens septi, tuberculum olfactorium or substantia nigra. Localised depletion of 5-HT within the nucleus accumbens septi and substantia nigra reduced the cataleptic effects of the neuroleptic agent fluphenazine, while lesions of the striatum or tuberculum olfactorium were without effect. Each injection of neurotoxin resulted in a 38--47% depletion of 5-HT in the target site: DA levels were not significantly altered. The results suggest that varied dopamine/5-hydroxytryptamine interactions within the nucleus accumbens may contribute to the action of the neuroleptic. The reduction of fluphenazine-induced catalepsy produced by 5-HT depletion within the substantia nigra supports the concept of a controlling influence of 5-HT on nigro-striatal DA function.

Failure of vasopressin and oxytocin to antagonize acute morphine antinociception or facilitate narcotic tolerance development

The effects of vasopressin and oxytocin on acute morphine antinociception and on tolerance development were examined in mice and rats. The studies failed to demonstrate any alteration of chronic morphine effects using two separate models of tolerance development in the mouse. Adrenalectomy enhanced the antinociceptive, hyperthermic, and cataleptic effects of acute morphine treatment, but vasopressin was without additional effect in either adrenalectomized or sham-control rats. Furthermore, neither vasopressin nor oxytocin pretreatment altered brain concentrations of acutely injected morphine. It is concluded that the role of vasopressin and oxytocin as endogenous mediators of opiate analgesia or tolerance/dependence is minimal at best.

Effect of mecamylamine on the fate of dopamine in striatal and mesolimbic areas of rat brain; interaction with morphine and haloperidol.

1 The effects of the nicotinic cholinoceptor blocking drug, mecamylamine (alone or in combination with morphine or haloperidol) were investigated on the striatal homovanillic acid (HVA) concentration and on the alpha-methyl-p-tyrosine (AMPT)-induced depletion of striatal or mesolimbic dopamine content in the brain of rats. 2 Mecamylamine (2 mg/kg) alone did not alter the striatal HVA concentration, but it reduced the probenecid-induced accumulation of HVA. Mecamylamine pretreatment reduced the morphine- and haloperidol-induced elevation of striatal HVA concentrations. Hexamethonium did not alter the striatal HVA concentration when given alone or in probenecid- or morphine-treated rats, whereas pempidine (8 mg/kg) clearly reduced the probenecid-induced accumulation of HVA in the striatum. 3 Mecamylamine (2 and 8 mg/kg) slowed the rate of AMPT-induced depletion of dopamine from the striatum and mesolimbic area both in the brain of control rats treated with morphine or haloperidol. 4 Mecamylamine slightly prolonged the cataleptic effect of morphine. 5 The results indicate that mecamylamine inhibits the release of dopamine both from the striatal and mesolimbic dopaminergic neurones.

Cataleptic Effect of 61-91 Beta-Lipotropic Hormone in Rat

Intraventricular administration of a peptide from ovine pituitaries whose structure is identical to the 61-91 C-terminal portion of beta-lipotropic hormone (61-91 beta-LPH) induced catalepsy, muscular hypertonus and analgesia in rats. Naloxone inhibited both the analgesic and cataleptic effects. 1-dihydroxyphenylalanine (1-DOPA) completely prevented the cataleptic effect. The cataleptic effect of 61-91 beta-LPH was potentiated by 1-5-hydroxytryptophan (5-HTP).

Effect of muscarinic cholinergic drugs on morphine-induced catalepsy, antinociception and changes in brain dopamine metabolism

The effects of drugs acting on muscarinic cholinergic receptors on the catalepsy, antinociception and changes in rectal temperature and in brain dopamine metabolism induced by morphine were studied in Wistar rats. Scopolamine (0.3 - 30 mg/kg) was about three times as potent as atropine (1 - 30 mg/kg) in potentiating the cataleptic effect of morphine. Methylscopolamine and methylatropine did not alter the cataleptic effect of morphine. Pilocarpine (100 mg/kg) and arecoline (10 mg/kg) slightly but significantly and RS86 (20 - 40 mg/kg) clearly antagonized the morphine-catalepsy. RS86 antagonized the atropine-induced potentiation of morphine catalepsy. The antinociceptive effect of pilocarpine was additive and that of RS86 less than additive with morphine. The antimuscarinic compounds did not alter the antinociceptive effect of morphine. Antimuscarinic compounds enhanced the hypothermic effect of morphine, but none of the compounds studied altered the hyperthermic effect of morphine. The antimuscarinic drugs reduced the concentration of striatal homovanillic acid (HVA) in about same proportion in control and morphine-treated rats. Both the muscarinic compounds and morphine increased the concentration of striatal HVA, but when combined their effects were not significantly different from those of morphine alone. Scopolamine antagonized and pilocarpine accelerated the morphine-induced increase in the rate of depletion of cerebral dopamine content. The present results show that the effects of muscarinic aand antimuscarinic cholinergic drugs on the cataleptic effect of morphine were opposite to their effects on the catalepsy induced by neuroleptic compounds.

The interaction of clonidine with dopamine-dependent behaviour in rodents.

The effect of clonidine on a number of behavioural parameters believed to be expressed through central dopaminergic mechanisms has been studied in rodents. 1. Clonidine (0.06-2 mg/kg) potentiated the circling response to standard doses of both apomorphine (0.25 mg/kg) and amphetamine (3 mg/kg) in mice with unilateral destruction of nigro-neostriatal dopamine nerve terminals. Similarly, clonidine (0.06-2 mg/kg) enhanced the locomotor effect of apomorphine in reserpinised mice. 2. Clonidine (0.5 mg/kg) was without effect on the patterns of stereotypyd behaviours induced by the dopamine agonist apomorphine (0.1-5 mg/kg) in the rat. Unilateral intrastriatal injections of clonidine (5-100 microng) caused no discernable behavioural effects in rats. 3. Injection of apomorphine (10 microng) bilaterally into the region of the nucleus accumbens of the rat resulted in a hyperactive response, while bilateral injection of clonidine (50 microng) into this region caused marked sedation, thus mimicking the effects of these drugs on motor activity when administered systemically. Combinations of systemic or nucleus accumbens apomorphine and clonidine resulted in potentiated stereotype and prolonged hyperactivity responses. 4. Clonidine (0.5 mg/kg) potentiated the cataleptic effect of the dopamine antagonist haloperidol (0.1-2 mg/kg) in rats. Clonidine therefore potentiated those behavioural responses exhibiting a locomotor component (viz. circling and hyperactivity), but was without effect on stereotypy. The potentiation of catalepsy induced by clonidine may be explained in non-specific sedatory terms. It is apparent that clonidine acts through a secondary neurone system which modifies the effects of dopamine receptor stimulation, although the exact site of this interaction is not clear. The tentative conclusion might be that clonidine inhibits 5-HT neuronal activity, and the possible relationships between 5-HT and NA and dopamine are discussed.

Effect of cholinergic drugs on methadone-induced catalepsy and stereotypies in rats treated chronically with methadone

The effects of antimuscarinic (atropine, scopolamine, methylscopolamine), muscarinic (RS86, pilocarpine), antinicotinic (mecamylamine, hexamethonium) and nicotinic (nicotine) cholinergic drugs on the catalepsy and stereotypies induced by acute methadone in rats treated chronically with methadone were studied. The antimuscarinic drugs potentiated and the muscarinic drugs antagonized the cataleptic effect of methadone, whereas the antimuscarinic drugs tended to antagonize and the muscarinic drugs potentiated the methadone-induced stereotypies. Nicotine initially slightly potentiated, and mecamylamine antagonized the cataleptic effect of methadone. The actions of the cholinergic drugs on the extrapyramidal motor effects of methadone were most probably central, because methylscopolamine and hexamethonium had only very weak actions. These results show that the effects of antimuscarinic and muscarinic drugs on the catalepsy and stereotypies induced by methadone are opposite to their effects on the catalepsy and stereotypiesproduced by drugs which are thought to act on the postsynaptic dopaminergic receptors.

Interaction of benzodiazepines with neuroleptics at central dopamine neurons.

Several benzodiazepines (chlordiazepoxide, clonazepam, diazepam and flunitrazepam) markedly counteracted the elevation of the homovanillic acid (HVA) content of the rat brain induced by neuroleptics (haloperidol, pimozide, chlorpromazine, and clozapine). A similar effect was obtained with the inhibitor of GABA transaminase, aminooxyacetic acid (AOAA). The interaction of benzodiazepines with the neuroleptic-induced HVA increase was similar in the striatum and in the limbic forebrain and was antagonized by the GABA receptor-blocking agent, picrotoxin. Both the benzodiazepines used and AOAA potentiated the cataleptic effect of the four neuroleptics. It is concluded that benzodiazepines, by intensifying GABA-ergic transmission, enhance the ongoing inhibition of mesencephalic dopamine neurons exerted by the striatonigral GABA system. As a consequence, the feedback activation of dopamine neurons induced by the neuroleptic blockade of dopamine receptors in the striatum and the limbic system is attenuated. This results in a reduction of the neuroleptic-induced increase of HVA and in the potentiation of the cataleptic effect of neuroleptics.

Serotonergic involvement with neuroleptic catalepsy

The electrolytic brain lesion technique was used to interrupt the ascending serotonergic pathways at the level of the midbrain raphé nuclei in order to determine the role of 5-hydroxytryptamine in the mediation of neuroleptic catalepsy. Lesions of either the medial or dorsal raphé nuclei were shown to reduce the 5-hydroxytryptamine content of the cerebral cortex, striatum and limbic forebrain but had no significant effect on limbic and striatal dopamine levels or on cortical and limbic noradrenaline levels. A differential innervation from the raphé nuclei could not be demonstrated. Lesions of the medial or dorsal raphe nuclei were shown to significantly reduce the cataleptic actions of the neuroleptic agents haloperidol, fluphenazine, oxiperomide and spiroxatrine but had no consistent effect on the cataleptic actions of the dibenzazepine neuroleptics, loxapine and clothiapine. The weak cataleptic action of thioridazine tended to be reduced similarly to that of the classical neuroleptics. The weak effect of clozapine was significantly potentiated by lesions of the dorsal raphé nucleus. The cataleptic effect of the non-neuroleptic agent metoclopramide could not be differentiated from either group of neuroleptics: its actions were reduced by the medial raphé lesions (similarly to the classical neuroleptics), but were not reduced by the dorsal lesions (similarly to the dibenzazepines). The results indicate that 5-hydroxytryptamine function may be important, but not necessarily essential, for the cataleptic action of some neuroleptic agents.

Inhibition by apomorphine of the metoclopramide-induced catalepsy and increase in striatal homovanillic acid content.

1 The mechanism of the cataleptic effect of metoclopramide was analyzed by using drugs which alter the activity of dopaminergic or cholinergic neurones or the content of psi-aminobutyric acid in the central nervous system of rats. 2 The cataleptic effect of metoclopramide (20 mg/kg) was antagonized by apomorphine (10 mg/kg) and by atropine (50 mg/kg). Aminoxyacete acid (AOAA, 25-50 mg/kg) potentiated the catalepsy induced by metoclopramide (5 mg/kg). 3 Metoclopramide alone did not alter the rectal temperature of rats. It did not alter the AOAA-induced hypothermia, but it partially antagonized apomorphine-induced hypothermia. 4 Metoclopramide induced a six-fold increase in striatal homovanillic acid (HVA) concentration, but it did not change the dopamine or noradrenaline content in the brain of rats. Apomorphine decreased the striatal HVA concentration in control and in metoclopramide-treated rats. Atropine and AOAA did not alter the metoclopramide-induced increase in striatal HVA concentration. 5 The results suggest that metoclopramide produces catalepsy by blocking striatal dopamine receptors.

KETAMINE CATALEPSY AND ANESTHESIA IN DOGS PRETREATED WITH ANTISEROTONERGIC OR ANTIDOPAMINERGIC NEUROLEPTICS OR WITH ANTICHOLINERGIC AGENTS

Summary Pretreatment with methiothepin or chlorpromazine prevents catalepsy, prolongs duration of anesthesia and recovery, prevents apneustic respiration, and favors disappearance of limb-withdrawal and jaw reflexes in dogs injected intramuscularly with a minimum anesthetic dose of ketamine. These effects relate to degree of sedation produced by the neuroleptics, and therefore may be nonspecific. A subsedative dose of pimozide antagonizes ketamine anesthesia and potentiates catalepsy, respiratory apneusis, and emergent delirium. Sedative doses of pimozide are less effective in these regards. Mecamylamine enhances ketamine catalepsy and respiratory apneusis, and lightens (but does not shorten) anesthesia. Atropine prevents ketamine catalepsy and antagonizes respiratory apneusis, but potentiates muscle jerking, prolongs recovery time, and greatly prolongs emergent delirium. The results seem to implicate dopaminergic, nicotinic cholinoceptive, and muscarinic cholinoceptive mechanisms in a complex system of mediation and modulation of canine responses to ketamine. This system is different from one previously proposed for the cat. Weingarten (1972) postulated that ketamine catalepsy might be due to stimulation of the monoaminergic component of a balanced cholinergic-monoaminergic system in the brain. In rabbits, the anticholinergic agent procyclidine enhanced ketamine catalepsy ( Authier & others, 1972 ). In cats, the antiserotonergic neuroleptic agent methiothepin ( Monachon & others, 1972 ) prevented ketamine catalepsy, but pimozide 9an antidopaminergic neuroleptic, Anden & others, 1970 ) and chlorpromazine 9a neuroleptic of mixed antimonoamine activity) did not affect ketamine catalepsy ( Hatch, 1973 ). Thus, it appeared that ketamine catalepsy may indeed relate to a cholinergic-monoaminergic imbalance, and that the monoamine of interest in this regard might be serotonin. The purpose of the present study was to examine the validity of the proposed cholinergic-serotonergic mechanism of ketamine catalepsy in dogs. This species is particularly susceptible to the cataleptic and deliriant effects of ketamine.

Haloperidol catalepsy in grouped and isolated mice.

A method was worked out to assess in a quantitative and dose-dependent way the development of catalepsy of mice after low doses of haloperidol. This method was also capable of detecting the anticataleptic effect of phenytoin and the catalepsy-enhancing effect of nikethamide. After 4 weeks' isolation, the mice became aggressive and revealed increased susceptibility to the cataleptic effect of haloperidol. The analysis of the data indicates that in these experiments altered central mechanisms were more important than changes of the peripheral pharmacokinetics of haloperidol.

Catalepsy and stereotypies in rats treated with methadone; Relation to striatal dopamine

To study methadone-induced catalepsy and stereotyped behaviour, rats were treated for 8 weeks with (±)-methadone. Acute administration of 10 mg/kg of methadone produced catalepsy but no stereotypies in control rats. After 5 weeks of chronic administration methadone still produced dose-dependent catalepsy, the degree of which gradually decreased with continuing treatment. However, all rats showed stereotypies which appeared after 4–5 days and were at their maximum after 5–6 weeks of chronic administration. Naloxone administered before methadone completely prevented the appearance of catalepsy and stereotypy; naloxone administered 0.5–1 hr after methadone abolished the catalepsy and stereotyped symptoms. Reserpine pretreatment prevented the appearance of stereotypies. 2 hr after methadone, 10 mg/kg, the striatal homovanillic acid (HVA) concentration of rats receiving methadone for 8 weeks was increased to about the same degree as in control (saline) rats receiving the same dose of methadone as a single injection; however, 19 hr after the last injection of methadone the striatal HVA concentrations of rats receiving methadone for 8 weeks was decreased to 55% of that of untreated control rats. The results suggest that the primary effect of methadone is catalepsy which causes increased dopamine production as a compensatory mechanism. The additional dopamine is a probable cause of stereotyped behaviour in rats which are partially tolerant to the cataleptic effect of methadone.

The importance of the ascending dopaminergic systems to the extrapyramidal and mesolimbic brain areas for the cataleptic action of the neuroleptic and cholinergic agents

The relative roles of the extrapyramidal and mesolimbic areas in the catecholaminergic-cholinergic control of catalepsy were investigated by assessment of the effects of disruption to catecholaminergic systems using α-methylparatyrosine and by surgical lesion of the ascending dopaminergic pathways to the extrapyramidal and/or mesolimbic brain areas upon neuroleptic and cholinergic catalepsy. α-Methylparatyrosine pretreatment was shown to enhance both neuroleptic (haloperidol, fluphenazine, clothiapine, oxypertine and clozapine) and cholinergic (arecoline and RS86) catalepsy. Lesions placed either to interrupt both extrapyramidal and mesolimbic dopaminergic afferents or to interrupt only the innervation to the mesolimbic nuclei caused an initial potentiation followed by a reduction in the cataleptic effects of the neuroleptic agents but caused potentiation of cholinergic catalepsy at all times of testing. The results are interpreted as supporting a dopaminergic-cholinergic balanced control of catalepsy which involves not only the extrapyramidal but also the mesolimbic dopaminergic systems.

The nucleus amygdaloideus centralis and neuroleptic activity in the rat

The bilateral electrolytic brain lesion technique was used to determine the role of the nucleus amygdaloideus centralis (ACE) in the mediation of the cataleptic and antistereotypic (amphetamine) effects of the neuroleptic agents (antipsychotic) and metoclopramide (non-antipsycotic). The cataleptic effects of haloperidol, fluphenazine, AHR2277, clothiapine and oxypertine were markedly reduced or abolished at the lower dose levels by the ACE lesions. The reducion in the clothiapine effect was readily overcome by increasing the dosage whilst the reduction in the effects of haloperidol, fluphenazine and AHR2277 were only partially overcome at high doses. The marked reduction in the cataleptic effect of oxypertine was apparent at all doses. ACE lesions failed to modify clozapine whilst this effect of metoclopramide was markedly reduced at all doses used. The antistereotypic activities of haloperidol, fluphenazine, oxypertine and clothiapine were not significantly modified by ACE lesions although the abilities of AHR2277, clozapine and metoclopramide to antagonise stereotypy were significantly reduced. The results indicate an involvement of the ACE with both neuroleptic- and metoclopramide-induced cataleptic behaviour and, to varying degrees, with the antistereotypic activity of these agents. Differences in the sites and modes of action of the neuroleptics are considered and results are discussed in relation to the use of the catalepsy and antistereotypy tests as indicators of antipsycotic activity.

Effects of orotic acid on the development of morphine tolerance.

A marked tolerance to both analgesic and cataleptic effects of 20 mg/kg morphine hydrochloride was developed in rats during treatment with daily doses increasing from 20 to 120mg/kg s.c. within 11 days. Daily administration of 100 mg/kg sodium orotate i. p. 14 days before and during treatment with morphine significantly accelerated the development of tolerance for cataleptic as well as analgesic effects of morphine. The disappearance of the tolerance phenomena was delayed in the orotate-treated animals. No influence of orotate, however, could be observed on the formation of stereotyped behaviour and disappearance of stereotype.

A role for the amygdala in the development of the cataleptic and stereotypic actions of the narcotic agonists and antagonists in the rat.

The electrolytic brain lesion technique was used to assess the role of the nucleus amygdaloideus centralis in the mediation of the catalepsy and stereotyped behaviour induced in the rat by the narcotic agonists and antagonists. M6029 and M6007 exhibited a biphasic action in the rat consisting initially of catalepsy induction followed by the development of stereotyped gnawing, biting and licking responses with a transition period when both behaviours were apparent. Morphine and M320 produced a cataleptic response in the rat but stereotyped behaviour did not develop. Bilateral ablation of the nucleus amygdaloideus centralis was found to abolish the cataleptic phase of the effects of M6029 and M6007 and to markedly enhance the stereotypic phase. The lesions were similarly shown to markedly reduce or abolish the cataleptic effects of morphine and M320 and, in contrast to the actions of these drugs in normal animals, a periodic stereotyped behaviour developed. A role is suggested for the nucleus amygdaloideus centralis in the genesis of the cataleptic action of the narcotic agonists and antagonists. An amygdaloid-cataleptic: striatal-stereotypic balance is hypothesised for the action of these agents in the rat.

The role of dopamine in pilocarpine-induced catalepsy.

The cataleptic effect of the cholinomimetic compound, pilocarpine, was compared to the pilocarpine-induced changes in striatal dopamine metabolism in rats.

Is there a relationship between the involvement of extrapyramidal and mesolimbic brain areas with the cataleptic action of neuroleptic agents and their clinical antipsychotic effect?

The electrolytic brain lesion technique was used in the rat to disrupt the ascending dopaminergic pathways to the extrapyramidal (striatal) and mesolimbic brain areas in the lateral hypothalamus and the pathways to the mesolimbic areas only in the rostral hypothalamus. The cataleptic effects of the neuroleptic agents spiroperidol and perphenazine were enhanced in the acute stage following the lateral hypothalamic lesions but were unmodifield or reduced by the rostral hypothalamic lesions. The cataleptic effects of the neuroleptic agents AHR 2277 and thioridazine were not significantly modified in the acute stage by either lesions. Both lateral and rostral hypothalamic lesions markedly reduced or abolished the cataleptic ability of all neuroleptics tested in the chronic stage. The cataleptic activities of the non-neuroleptic agents metoclopramide and bulbocapnine were unmodified or potentiated by lesions in the lateral hypothalamus and potentiated or unmodified by lesions in the rostral hypothalamus respectively during the acute stage. In the chronic stage the cataleptic effects of both agents were markedly reduced or abolished in animals with lateral or rostral hypothalamic lesions.

Catalepsy and circling behaviour after intracerebral injections of neuroleptic, cholinergic and anticholinergic agents into the caudate-putamen, globus pallidus and substantia nigra of rat brain

Haloperidol, arecoline and atropine were injected in various combinations into the caudate-putamen, globus pallidus and substantia nigra. Unilateral injections of haloperidol or arecoline into the caudate-putamen, globus pallidus or substantia nigra induced an ipsilateral circling behaviour, the globus pallidus being the most sensitive and the substantia nigra the least sensitive to this effect. Atropine induced a contralateral circling behaviour after injection into the caudate-putamen or globus pallidus and in each case potentiated the ipsilateral circling of haloperidol and arecoline when injected into the opposite nucleus. The injection of atropine into the same caudate-putamen as haloperidol or arecoline inhibited the ipsilateral circling induced by the latter drugs. Catalepsy was observed after haloperidol injections into the caudate-putamen and globus pallidus, the latter nucleus being the most sensitive. Catalepsy was not observed after arecoline injection into any of the nuclei considered. The bilateral injection of atropine into the caudate-putamen and globus pallidus did not modify the catalepsy induced by peripheral administration of haloperidol or arecoline but intranigral atropine markedly potentiated the cataleptic effects of these drugs. Results are discussed in terms of cholinergic and dopaminergic mechanisms within the extrapyramidal system.