Kainic acid injections in the striatum alter the cataleptic and locomotor effects of drugs influencing dopaminerig and cholinergic systems

Rats with bilateral injections of kainic acid into the striatum were tested for their motor responsiveness to drugs influencing dopaminergic and cholinergic systems. The kainic acid-induced lesions potentiated the locomotor response to both the dopaminergic agonist, d-amphetamine, and the cholinergic antagonist, scopolamine, attenuated the cataleptic response to the dopaminergic antagonist, haloperidol, and potentiated the cataleptic and convulsive responses to the cholinergic agonist, pilocarpine. The analogy of these pharmacological effects with those induced by similar drugs in patients with Huntington's disease supports the view that this animal preparation is a useful model of Huntington's disease. The opposite effects of haloperidol and pilocarpine on catalepsy in kainic acid-lesioned rats suggest that more work should be done to elucidate the mechanism behind this conflict before full support can be given to its use as a model system for evaluating possible pharmacotherapy in Huntington's disease.     

Noradrenergic influences on catalepsy

Widespread depletion of forebrain noradrenaline, produced by the intracerebral injection of 4 g of 6-hydroxydopamine into the fibres of the dorsal noradrenergic bundle, potentiated the catalepsy induced by 20 mg/kg of morphine and severely attenuated the catalepsy induced by two separate cholinergic agonists, arecoline and pilocarpine. It did not, however, affect haloperidol catalepsy at any of the four doses tested. These results suggest that cholinergic catalepsy may be critically dependent on an intact noradrenergic substrate, perhaps through cholinergic receptors located either presynaptically on noradrenergic terminals or on the cell bodies of origin in the locus coeruleus. Noradrenaline appears to play a modulatory role in morphine catalepsy, although other sites of action must also be involved. Ascending noradrenergic systems do not appear to influence haloperidol catalepsy.     

The role of dopamine in pilocarpine-induced catalepsy

Summary The cataleptic effect of the cholinomimetic compound, pilocarpine, was compared to the pilocarpine-induced changes in striatal dopamine metabolism in rats.Pilocarpine induced catalepsy, the intensity of which increased with increasing dosage, but it did not make rats maximally cataleptic in the doses studied here. Doses higher than 200 mg/kg i.p. could not be studied because of toxicity. Pilocarpine increased the striatal homovanillic acid (HVA) content up to three times the original concentration. The greatest increase was found 2 h after 50 mg/kg of pilocarpine. Atropine (50 mg/kg) antagonized both the catalepsy and HVA increase produced by pilocarpine (200 mg/kg). Apomorphine (10 mg/kg) lowered the striatal HVA content by about 85%. This decrease had disappeared after 4 h. Apomorphine antagonized the HVA increase caused by 50 mg/kg of pilocarpine, but after an initial decrease apomorphine potentiated the HVA increase produced by 200 mg/kg of pilocarpine. Apomorphine did not modify the slight cataleptic effect of 50 mg/kg of pilocarpine but potentiated and prolonged the catalepsy produced by 200 mg/kg of pilocarpine. Pilocarpine-catalepsy was potentiated by -methyl-p-tyrosine (MPT 250 mg/kg) and pilocarpine accelerated the dopamine decrease caused by MPT. Pilocarpine alone in doses up to 200 mg/kg did not statistically significantly change the brain dopamine concentration.These results show that when the striatal cholinergic mechanisms are disturbed changes are induced in striatal dopamine metabolism. The striatal cholinergic and dopaminergic systems are antagonistic but the dopaminergic system can compensate for the overactivity of the striatal cholinergic system only to a certain extent.This study was supported by the National Research Council for Medical Sciences Finland, and the Finnish Medical Society, Duodecim.     

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.     

Radiation-induced increases in sensitivity of cataleptic behavior to haloperidol: possible involvement of prostaglandins

The effects of radiation exposure on haloperidol-induced catalepsy were examined in order to determine whether elevated prostaglandins, through an action on dopaminergic autoreceptors, could be involved in the radiation-induced increase in the potency of this neuroleptic. Cataleptic behavior was examined in animals irradiated with various doses of gamma photons (1-150 Gy) and pretreated with a subthreshold dose of haloperidol (0.1 mg/kg). This approach was chosen to maximize any synergistic effects of radiation and haloperidol. After irradiation with doses less than or equal to 30 Gy, the combined treatment of haloperidol and radiation produced catalepsy, whereas neither treatment alone had an effect. This observed catalepsy could be blocked with prior administration of indomethacin, a prostaglandin synthesis inhibitor. Animals exposed to doses of radiation less than or equal to 50 Gy and no haloperidol, however, displayed apparent catalepsy. This effect was also antagonized by indomethacin. Prostaglandins can induce catalepsy and when administered in subthreshold doses along with subthreshold doses of haloperidol, catalepsy was observed. In order to assess a possible action of prostaglandins and radiation on dopaminergic activity, the functioning of striatal dopaminergic autoreceptors was examined by determining the effects of varying concentrations of haloperidol on the K+-evoked release of dopamine from striatal slices obtained from parallel groups of animals treated as above. Results indicated that sensitivity to haloperidol increased (higher K+-evoked dopamine release) in slices from irradiated or prostaglandin-treated animals and that this increase in sensitivity was blocked by indomethacin. Results from both experiments suggest that radiation-induced increases in endogenous neuronal mediators, such as prostaglandins, can induce catalepsy through an action on dopaminergic autoreceptors.     

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.     

Altered pilocarpine- or chlorpromazine-induced catalepsy after long-term treatment with cholinergic drugs

Long-term administration of the cholinergic drug pilocarpine attenuates the catalepsy induced by an acute injection of pilocarpine or the dopamine antagonist chlorpromazine. Similar results (i.e., tolerance to pilocarpine and cross-tolerance to chlorpromazine) were noted in mice chronically treated with the cholinesterase inhibitor physostigmine but not in mice chronically treated with neostigmine, a cholinesterase inhibitor which does not penetrate the central nervous system. Mice maintained on the anticholinergic scopolamine showed the opposite effect; there was an increase in the sensitivity to the catalepsy induced by pilocarpine or chlorpromazine. The results suggest that long-term changes in cholinergic receptors may indirectly alter the behavioral effects of drugs which act via dopamine.     

Mutually potentiating effects of mecamylamine and haloperidol in producing catalepsy in rats

Haloperidol and other dopaminergic (DA) blockers have long been known to induce catalepsy. Recently, it has been reported that nicotine potentiates the cataleptic effect of haloperidol. However, this presents a quandary in terms of neural interactions between nicotinic and DA systems. Nicotine promotes the release of DA in the striatum, which should attenuate haloperidol‐induced catalepsy. To resolve this quandary, we assessed haloperidol interactions with nicotine and its antagonist mecamylamine in five studies. With low to moderate doses, we did not find that nicotine potentiated haloperidol‐induced catalepsy. However, in two different studies we found that mecamylamine, a nicotinic antagonist, significantly potentiated the haloperidol‐induced catalepsy. This effect was seen with a dose of mecamylamine which, by itself, did not have any cataleptic effect. These results demonstrate that nicotinic receptor blockade effectively potentiates catalepsy caused by DA blockade. This suggests that previously seen nicotine‐induced potentiation of catalepsy may have been due to its desensitizing effect. Perhaps the use of nicotinic antagonists such as mecamylamine or nicotine + mecamylamine combinations would provide a useful adjunct to DA antagonist therapy in motor disorders such as Tourette's syndrome. Drug Dev. Res. 47:90–96, 1999. © 1999 Wiley‐Liss, Inc.     

Experimental catalepsy is both enhanced and disrupted by apomorphine

In mice that were scored for the length of time they remained immobile in awkward postures (cataleptic) on an inclined wire grid, a large IP dose of pilocarpine (80 mg/kg) caused a clear catalepsy, which was prevented by both dopamine agonists that were tested, apomorphine (4 or 8 mg/kg, IP) and bromocriptine (8 mg/kg, IP). In other experiments, haloperidol (2.5 mg/kg) caused mild catalepsy. As expected, neither 4 nor 8 mg/kg apomorphine caused much effect when given alone, but both doses produced profound and long-lasting catalepsy in the haloperidol-treated animals. Bromocriptine also had little effect when given alone, and neither 4 nor 8 mg/kg enhanced the haloperidol catalepsy. Apomorphine alone produced catalepsy at low doses. Repeated testing after a low (0.3 mg/kg) dose of apomorphine showed that catalepsy was most profound at 5 min postinjection, with progressive decline thereafter. Apomorphine, but not bromocriptine, thus can produce catalepsy under certain conditions of DA receptor blockade or in low dose. Catalepsy, and perhaps other forms of hypomotility, appear to be differentially mediated by a sublcass of dopaminergic receptors.     

Catalepsy induced by intrastriatal injections of delta9-THC and 11-OH-delta9-THC in the rat

Intrastriatal injections of Δ⁹-THC and 1 l-hydroxy-Δ⁹-THC induced dose-dependent catalepsy in the rat, the parent compound being more potent than the metabolite. Catalepsy was not induced following intrapallidal injection of either drug. The results suggest that the caudate-putamen could be a “specific site” in the mediation of catalepsy induced by Δ⁹-THC.Intrastriatal amphetamine attenuated Δ⁹-THC-induced catalepsy whereas intrapallidal amphetamine potentiated the effect indicating a complex interaction with dopaminergic systems in the basal ganglia.Δ⁹-THC and the central cholinergic stimulant, RS-86 synergize on administration to either area indicating a possible cholinergic involvement in the phenomenon.     

Role of brain monoamine systems in the jumping behavior induced in rats by the combination of harmine and apomorphine

The role of brain monoamine systems in the jumping behavior induced by the combination of harmine and apomorphine was studied by using a MT pick-up to assess jumping behavior in rats. The jumping induced by the combination of harmine 10 mg/kg and apomorphine 2 mg/kg was enhanced by pretreatment with p-chlorophenylalanine, methysergide and by treatment with clonidine, while, it was reduced by pretreatment with 5-hydroxytryptophan, haloperidol, perphenazine, atropine and pilocarpine. The combination of harmaline or harmane and apomorphine also induced jumping with the aid of p-chlorophenylalanine. The combination of benserazide, L-DOPA and harmine induced jumping similar to that induced by harmine and apomorphine. Despite pretreatment with p-chlorophenylalanine the combination of apomorphine and benzylhydrazine, iproniazid, tranylcypromine or pargyline failed to induce jumping. These results suggest that this jumping behavior is induced not by the monoamine oxidase inhibitory effect of harmine but probably by the specific central action of harmine and on condition that the dopaminergic system is activated. The activation of this system appears to be essential, the noradrenergic system plays a facilitatory role, the serotonergic system an inhibitory role and the cholinergic system probably a specific role.     

Pilocarpine: Noradrenergic mechanism of a cholinergic drug

Pilocarpine, usually regarded as a cholinergic agonist, induces a state of catalepsy or tonic immobility. Depletion of forebrain noradrenaline using the selective neurotoxin 6-hydroxydopamine was found almost completely to abolish the cateleptic action of the drug. Following higher doses of pilocarpine, a rebound hyperactivity is seen after the initial catelepsy, and this effect too was blocked by noradrenergic depletion. It is suggested that pilocarpine may act to stimulate cholinergic receptors located on noradrenergic neurones and its action may be critically dependent on the integrity of these noradrenergic systems.     

Clip-induced analgesia and immobility in the mouse: pharmacological characterization

A pinch to the nape of the neck of mice, by application of a noxious clip, produces analgesia and immobility. Because both opiate and dopaminergic systems are usually implicated in analgesia and immobility, the pharmacological profile of clip-induced effects was compared to those elicited by the dopamine antagonist haloperidol, and by morphine. In addition, the effects of a series of pharmacological agents on clip-induced effects was examined. Haloperidol, but not morphine, produced immobility similar to that seen after application of the clip to the neck. Application of clip completely inhibited righting in all tests utilized. Haloperidol inhibited righting in all tests, except for inversion from a supine position. Righting from this position could also be inhibited in mice treated with haloperidol when a mild pinch, ineffective in a naive animal, was applied. Clip-induced immobility, but not analgesia, was reversed by amphetamine. Administration of the cholinergic antagonist scopolamine, but not methylscopolamine, reversed both the analgesia and immobility. Pinch-induced analgesia was as marked as that elicited by morphine but could not be reversed by the opiate antagonist naloxone. It is proposed that pinch-induced immobility is mediated by both dopaminergic and cholinergic systems. Additional unidentified systems are also involved. Analgesia, induced by a noxious pinch, can be dissociated pharmacologically from the immobilizing effect, is non-opiate in nature, and involves activation of central cholinergic synapses.     

Cataleptic and anticataleptic effects of muscimol and gabaculine injected into globus pallidus and substantia nigra,and interactions with haloperidol or benzodiazepines

Summary Intranigral injection of muscimol induced hyperactivity in rats and antagonized haloperidol-induced catalepsy. Intranigral injection of gabaculine, an inhibitor of GABA transaminase, induced similar effects 5 h after injection, when the nigral GABA content was increased 7-fold. On the other hand, injections of muscimol (30 ng) into the globus pallidus potentiated the cataleptic effect of haloperidol, and muscimol alone in high doses (100 and 200 ng) induced catalepsy. Gabaculine also induced catalepsy of medium intensity and potentiated the effect of haloperidol 24 h after injection, when GABA was increased in the globus pallidus as well as in the substantia nigra. Injections of muscimol into either the globus pallidus or substantia nigra increased striatal HVA and enhanced haloperidol-induced elevation of HVA.Three benzodiazepines, nitrazepam, diazepam and chlordiazepoxide administered orally, potentiated the effect of muscimol (30 ng) injected into the globus pallidus and induced catalepsy. A similar effect was not obtained with phenobarbital.It is suggested that stimulation of GABA receptor or increase of GABA content in the sustantia nigra antagonize haloperidol-induced catalepsy by activation of nigral dopaminergic system, and that enhancement of pallidal GABA function induces catalepsy by non-dopaminergic mechanisms. Potentiation of haloperidol-induced catalepsy by benzodiazepines may be due to enhancement of GABA-ergic transmission within the globus pallidus.     

Cholinergic influences on opioids activity in rats

The influence of cholinergic and anticholinergic agents on the catalepsy and antinociceptive action of morphine, codeine, fentanyl and pentazocine was studied in rats. Anticholinergic drugs scopolamine (3 and 6 mg/kg) and slightly atropine (1 mg/kg) enhanced morphine-induced catalepsy. Benztropine did not change this action of morphine. Cholinergic physostigmine (0.2 and 0.4 mg/kg) showed marked and dose-dependent antagonism toward morphine catalepsy, but pilocarpine, in doses of 2 and 4 mg/kg, failed to influence it. Catalepsy induced by codeine and fentanyl was nearly not influenced by cholinergic and anticholinergic agents. In the hot plate test, cholinergic influences on antinociceptive activity of analgesics are slight, but sometimes it may be observed the similar interaction as in morphine catalepsy: anticholinergic agents enhance, and cholinergic agents antagonize these effects. Present results indicate that some cholinergic and anticholinergic agents influence morphine catalepsy, and this influence is opposite to that observed in neuroleptic-induced catalepsy. Failure of the cholinergic influences on fentanyl- and codeine-induced catalepsy suggests that the mechanisms of cataleptogenic activity of morphine and other analgesics are not the same.     

On catalepsy and catatonia and the predictability of the catalepsy test for neuroleptic activity

The neuroleptic agents peromide and spiroxatrine induced an immobility in the rat which, in appearance, more resembled morphine catatonia than haloperidol catalepsy. Therefore, in a attempt to differentiate the behavioural states termed catalepsy and catatonia, haloperidol and morphine were closely compared using drug interaction and brain lesion studies.Atropine abolished or reduced the effects of haloperidol, peromide and spiroxatrine but not morphine, whilst morphine and spiroxatrine were similarly modified by nalorphine. The spiroxatrine effect was completely abolished by atropine and nalorphine combined. The cholinergic agent RS 86 synergised with haloperidol, peromide and spiroxatrine but not with morphine.Lesion of the dopaminergic extrapyramidal and/or mesolimbic innervation, of the caudate-putamen, globus pallidus and nucleus amygdaloideus centralis each reduced or abolished haloperidol, peromide and spiroxatrine catalepsy/catatonia. In contrast, morphine catatonia was only partially reduced by ablating the mesolimbic input, and was potentiated by lesions destroying the extrapyramidal/mesolimbic innervation, caudate-putamen and globus pallidus. Morphine catatonia was more susceptible to inhibition by the amygdaloid lesions than the catalepsy/catatonia induced by the other agents tested.     

Effects of pharmacological manipulation of dopaminergic and cholinergic neurotransmission in genetically dystonic hamsters.

In an inbred line of Syrian hamsters, attacks of sustained dystonic postures of the limbs and trunk can be initiated by handling or mild environmental stimuli (e.g. new cage). The severity of the dystonic syndrome in these mutant hamsters (gene symbol dtSZ) is age-dependent, with a peak at about 30-40 days of age. A scoring system for grading the type and severity of the dystonic attacks can be used to study the activity of drugs against dystonic movements with individual pre- and post-drug vehicle trials as control. The effects of drugs which alter dopaminergic or cholinergic functions in the brain were studied in selectively bred dystonic hamsters and age-matched non-dystonic controls. The dopamine precursor levodopa (injected together with carbidopa) and the dopamine receptor agonist apomorphine increased the severity of dystonia in hamsters when administered prior to the age of maximum severity of dystonia. A very similar effect was observed with the cholinomimetic pilocarpine. In contrast, the dopamine receptor antagonist haloperidol caused a marked overall reduction in dystonic movements. Anticholinergic drugs, i.e. trihexyphenidyl and biperiden, increased the latency to onset of the dystonic attack, but did not reduce its severity. No differences were observed between dystonic and non-dystonic hamsters with respect to extent and duration of stereotypies induced by dopaminergic and cholinergic drugs or hypolocomotion and catalepsy produced by haloperidol. The data suggest that dopaminergic hyperactivity might be involved in the pathophysiology of dystonia in dtSZ mutant hamsters.     

Effects of receptor blockers on ACTH-induced changes in extinction of active avoidance reflex in rat

The actions of blockers of dopaminergic receptors (haloperidol), alpha-receptors (phenoxybenzamine), beta-receptors (propranolol) and muscarinic cholinergic receptor (atropine) on the ACTH-induced delay of the extinction of active avoidance behavior were studied in rats. In the doses used, none of the receptor blockers modified the extinction of active avoidance behavior. ACTH delayed the extinction. However, the dopamine receptor blocker (haloperidol) and the muscarinic cholinergic receptor blocker (atropine) did prevent the action of ACTH in delaying the extinction of active avoidance behavior, whereas the alpha-(phenoxybenzamine) and beta- (propranolol) receptor blockers were ineffective. The results suggest that mainly dopaminergic and cholinergic mediations are involved in the delaying action of ACTH on the extinction of active avoidance behavior.     

Nicotine potentiates sulpiride-induced catalepsy in mice

The effects of nicotine on sulpiride-induced catalepsy in mice were investigated. Sulpiride (12.5-100 mg/kg) induced a low degree of catalepsy in mice which was dose dependent. Nicotine (0.0001-1 mg/kg) caused an even lower degree of catalepsy. When the drugs were co-administered a much higher cataleptogenic response was obtained. The potentiation of the effect of sulpiride by nicotine was elicited by 0.5 mg/kg or higher doses of the drug. The central nicotinic receptor antagonist mecamylamine (1-3 mg/kg) and the peripheral antagonist hexamethonium (5 and 10 mg/kg) decreased the response induced by the combination of nicotine and sulpiride. Higher doses of the cholinoceptor antagonist atropine (10 mg/kg) also reduced the catalepsy induced by the drug combination. It is concluded that nicotine potentiates sulpiride-induced catalepsy through activation of cholinergic mechanism(s) and that the central nicotinic mechanism mediates nicotine's action.     

Pharmacological characteristics of catalepsy induced by intracerebroventricular administration of histamine in mice: the importance of muscarinic step in central cholinergic neurons

Histamine-induced catalepsy was antagonized potently by scopolamine, an antimuscarinic drug, and partially blocked by sparteine. Neither methylatropine nor antinicotinic drugs could reverse histamine-induced catalepsy. These results indicate the greater importance of muscarinic receptors rather than their nicotinic counterparts in histamine-induced catalepsy. Various antiparkinson drugs, i.e. biperiden and trihexyphenidyl, which have antimuscarinic activity or dopamine agonists, i.e. L-dopa, amantadine and bromocriptine, could antagonize the histamine-induced catalepsy to various degrees. Thus, catalepsy induced by icv histamine can be evoked not only by an activation of the histamine receptor, but also indirectly due to cholinergic and dopaminergic imbalance.