Anticataleptic Effect Research Articles

Clozapine inhibits catalepsy induced by olanzapine and loxapine, but prolongs catalepsy induced by SCH 23390 in rats.

Loxapine (0.3 mg/kg s.c.), olanzapine (10 mg/kg s.c.) and SCH 23390 (R-(+)-chloro-2, 3, 4, 5-tetrahydro-3-methyl-5-phenyl-1-H-3-benzazepine; 1 mg/kg, s.c.), but not clozapine (10 mg/kg, s.c.), induced catalepsy in rats. Co-administration of clozapine (1, 3 and 10 mg/kg s.c.) dose-dependently inhibited loxapine-induced catalepsy. Clozapine (10 mg/kg s.c.) also prevented the induction of catalepsy by olanzapine. In addition, clozapine abolished the catalepsy induced by loxapine when it was administered after the response had fully developed. In contrast, the duration of SCH 23390-induced catalepsy was prolonged by clozapine, indicating that its anti-catalepsy effects against olanzapine and loxapine are unlikely to be caused by muscle relaxation, sedation or stimulation. Since SCH 23390-induced catalepsy is reported to be blocked by scopolamine, dizocilpine (MK-801) or 8-hydroxy-dipropylamino-tetralin, it is unlikely that muscarinic blockade, NMDA ion channel blockade and 5-HT1A receptor agonism, respectively, are involved in clozapine's action, but the mechanism by which clozapine exerts this anti-cataleptic effect remains unknown.

Dose-dependent suppression of haloperidol-induced catalepsy by potentized Agaricus muscarius

Agaricus muscarius 30c, a potentized homoeopathic drug prepared by successive dilution with 90% alcohol followed by sonication, suppressed haloperidol-induced catalepsy in Swiss albino mice significantly. This anticataleptic effect was dose-dependent being greatest with the undiluted Agaricus 30c and least if diluted 1:20,000. Higher dilutions like 1:40,000 and 1:50,000 did not produce an anticataleptic effect. The effect reappeared when the 1:50,000 dilution was sonicated. The anticataleptic effect of potentized Agaricus was observed with the drug administered both before and after haloperidol. However, the pre-treatment effect was more pronounced than the post-treatment effect. It is thought that potentized Agaricus contains an active principle that can be attenuated by dilution and multiplied by mechanical agitation or sonication.

The adenosine receptor antagonist theophylline induces a monoamine-dependent increase of the anticataleptic effects of NMDA receptor antagonists.

Previous work revealed that adenosine antagonists as theophylline reversed neuroleptic-induced catalepsy and potentiated anticataleptic effects of dopamine agonists reflecting specific adenosine-dopamine receptor interactions in the central nervous system. We tested whether similar functional interactions exist between adenosine receptors and glutamate receptors of the N-methyl-D-asparte (NMDA) subtype. The present study demonstrates that the anticataleptic effects of the competitive NMDA receptor antagonist CGP37849 and the non-competitive NMDA receptor antagonist dizocilpine can be potentiated by coadministration of a threshold dose of the adenosine receptor antagonist theophylline (2.5 mg/kg, i.p.) in haloperidol (0.5 mg/kg, i.p.)-pretreated rats. This potentiation was elicited only with higher doses of CGP37849 (4 and 8 mg/kg, i.p.) or dizocilpine (0.16 mg/kg, i.p.) in haloperidol (0.5 mg/kg, i.p.), but not in reserpine (5 mg/kg, i.p.) plus alpha-methyl-p-tyrosine (100 mg/kg, i.p.)-pretreated animals. Therefore, these synergistic interactions seem to be brought about by indirect monoamine-dependent mechanisms rather than direct functional interrelationships between NMDA and adenosine A2a receptors.

Stimulation of adenosine A 2a receptors in the rat striatum induces catalepsy that is reversed by antagonists of N-methyl- D-aspartate receptors

Bilateral infusion of the selective adenosine A 2a agonist CGS 21680C (1 μg per side) into the anterodorsal striatum of rats produced profound catalepsy. Intraperitoneal coadministration of the non-competitive N-methyl- D-aspartate (NMDA) antagonist dizocilpine (0.16 mg/kg) or the competitive NMDA antagonist CGP 37849 (4 mg/kg) completely reversed CGS 21680C-induced catalepsy, while lower doses of both NMDA antagonists induced no or only weak anticataleptic effects. The adenosine A 2a receptor localization to striatopallidal neurons suggests that a selective activation of the striatopallidal efferent pathway is involved in the expression of catalepsy induced by intrastriatal infusion of CGS 21680C. In addition, striatopallidal neurons seem to be an important neuronal substrate of the anticataleptic effects of NMDA antagonists.

Glucocorticoids attenuate haloperidol-induced catalepsy through adrenal catecholamines.

To examine the influence of adrenal secretions on neuroleptic induced catalepsy, we studied the effect of adrenocorticoids, noradrenaline (NA) or adrenaline (AD) on haloperidol (HAL) induced catalepsy in adrenalectomised (ADX) and sham-adrenalectomised (sham-ADX) rats. HAL (1 mg/kg, i.p.) induced a greater degree of catalepsy in ADX rats as compared to sham-ADX rats. Corticosterone (CORT, 1-2 mg/kg, s.c.) or dexamethasone (1-2 mg/kg, s.c.) attenuated the HAL catalepsy in sham-ADX but not in ADX rats. Further, when the HAL (1 mg/kg) catalepsy score was maximal (at 120 min), the rats were subjected to cold stress (3 degrees C for 10 min) or treated with NA, AD (2 micrograms/kg, i.v.) or CORT (2 mg/kg, s.c.). After cold stress procedure or CORT treatment, the catalepsy was significantly reduced in sham-ADX but not in ADX rats, whereas NA or AD infusion caused an immediate but short lasting significant decrease in HAL catalepsy in both sham-ADX and ADX rats. The anticataleptic effect of NA or glucocorticoids was blocked by an alpha 1 adrenoceptor blocker, prazosin. These findings suggest that peripheral noradrenergic and adrenergic mechanisms play an important role in the neuroleptic induced catalepsy. Such mechanisms may mediate the anticataleptic action of glucocorticoids.

Haloperidol-induced catalepsy in mice and rats suppressed by orally pre-administered potentized Agaricus

Agaricus muscarius 30s, a potentized homoeopathic drug prepared by successive dilution and sonication from the alcoholic extract of the fungus of the same name, significantly reduced haloperidol-induced catalepsy in mice and rats. The drug produced the anticataleptic effect when administered orally and no such effect when administered intraperitoneally. Open field activity of the mice was suppressed more with haloperidol (hal) alone than with the combination of Agaricus 30s (oral) and hal. Agaricus 30s, given intraperitoneally, did not alter hal-induced suppression of the spontaneous activity of mice. Based on the previously reported results with Agaricus in combination with apomorphine, D1 and D2 agonists, it was thought that Agaricus might have served as a D1 blocker. It was further assumed that the effect of Agaricus was mediated through the oral taste receptors.

Effect of dizocilpine (MK-801) on the catalepsy induced by delta 9-tetrahydrocannabinol in mice.

Mice treated with delta 9-tetrahydrocannabinol (THC; 5 and 10 mg/kg i.v.) showed the catalepsy in high bar test, and median descent latencies of catalepsy were about 150 sec. Dizocilpine (MK-801, 0.05 and 0.1 mg/kg), non-competitive N-methyl-D-aspartate (NMDA) antagonist, significantly attenuated THC-induced catalepsy. Furthermore, the anticataleptic effect of MK-801 on THC-induced catalepsy was blocked by acetylcholine agonist oxotremorine (0.005 mg/kg) and dopamine antagonist haloperidol (0.01 mg/kg), but not by NMDA. Oxotremorine, haloperidol, and NMDA themselves did not affect THC-induced catalepsy at the doses used. These results suggest that the anticataleptic effect of MK-801 on THC-induced catalepsy may be developed through dopaminergic and acetylcholinergic neuronal systems.

Lesions of the entopeduncular nucleus and the subthalamic nucleus reduce dopamine receptor antagonist-induced catalepsy in the rat

The role of the entopeduncular nucleus (EP) and the subthalamic nucleus (STN) in mediating dopamine receptor antagonist-induced catalepsy in the rat was investigated. Five days after bilateral lesions of EP and STN respectively with the excitotoxin quinolinic acid (15, 30 nmol/0.5 μl/side and 24 nmol/0.5 μl/side, respectively) rats were injected intraperitoneally with the dopamine D1 receptor antagonist SCH 23390 (0.5 mg/kg) or the dopamine D2 receptor antagonist haloperidol (0.5 mg/kg). Complete EP lesions prevented both SCH 23390- and haloperidol-induced catalepsy. STN lesions exerted pronounced anticataleptic effects in case of haloperidol-induced catalepsy, but less pronounced in case of SCH 233390-induced catalepsy. Further characterization of these anticataleptic effects in an open field demonstrated, that neither EP- nor STN lesions reversed bradykinesia, which occurred after selective dopamine receptor blockade. In conclusion, both EP and STN participate in the mediation of catalepsy induced by dopamine D1- and dopamine D2 receptor antagonists. Thereby these nuclei preferentially mediate rigidity and akinesia, but to a lesser extent bradykinesia.

KF17837: A novel selective adenosine A 2A receptor antagonist with anticataleptic activity

KF17837 is a novel selective adenosine A 2A receptor antagonist. Oral administration of KF17837 (2.5, 10.0 and 30.0 mg/kg) significantly ameliorated the cataleptic responses induced by intracerebroventricular administration of an adenosine A 2A receptor agonist, CGS 21680 (10 μg), in a dose-dependent manner. KF17837 also reduced the catalepsy induced by haloperidol (1 mg/kg i.p.) and by reserpine (5 mg/kg i.p.). These anticataleptic effects were exhibited dose dependently at doses from 0.625 and 2.5 mg/kg p.o., respectively. Moreover, KF17837 (0.625 mg/kg p.o.) potentiated the anticataleptic effects of a subthreshold dose of L-3,4-dihydroxyphenylalanine (L-DOPA; 25 mg/kg i.p.) plus benserazide (6.25 mg/kg i.p.). These results suggested that KF17837 is a centrally active adenosine A 2A receptor antagonist and that the dopaminergic function of the nigrostriatal pathway is potentiated by adenosine A 2A receptor antagonists. Furthermore, KF17837 may be a useful drug in the treatment of parkinsonism.

The AMPA receptor antagonist GYKI 52466 reverses the anti-cataleptic effects of the competitive NMDA receptor antagonist CGP 37849

The effects of the AMPA receptor antagonist GYKI 52466 (1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5 H-2,3-benzodiazepine HCl) on haloperidol-induced catalepsy were tested in drug-naive rats and in rats pretreated with the competitive NMDA receptor antagonist CGP 37849 ( DL-(E)-2- amino-4- methyl-5- phosphono-3- pentenoic acid ). CGP 37849 (4 mg/kg i.p.) given alone significantly reversed haloperidol-induced catalepsy (0.5 mg/kg i.p.) while GYKI 52466 (4.8 mg/kg i.p.) given alone was without effect. Administration of GYKI 52466 to rats pretreated with CGP 37849 abolished the anticataleptic effects of the competitive NMDA receptor antagonist seen following single administration. Thus the AMPA receptor antagonist prevents behavioural effects induced by a NMDA receptor antagonist in this behavioral model.

Distinct sites of dopaminergic and glutamatergic regulation of haloperidol-induced catalepsy within the rat caudate-putamen

Previous studies have indicated that corticostriatal glutamatergic pathways are implicated in the regulation of neuroleptic catalepsy. To obtain a better understanding of the way in which dopamine (DA) and glutamate interact within the caudate-putamen (CP) in the development of catalepsy, we investigated the regional distribution within the rat CP of the cataleptogenic effect of haloperidol and its antagonism by d(−)-2-amino-5-phosphonopentanoic acid ( d(−)AP5), a selective antagonist of the N-methyl- d-aspartate (NMDA) glutamate receptor subtype. Bilateral injections of haloperidol (3 μg/side) into the rostral ventromedial (VM) CP induced potent catalepsy with a short latency after the injection. In contrast, only a weak cataleptic response, of slower onset, was observed after haloperidol injections into the rostral ventrolateral (VL), rostral dorsomedial (DM), or rostral dorsolateral (DL) CP, or into the nucleus accumbens. d(−)AP5 (5 μg/side) injected bilaterally into the dorsorostral CP (DM and DL) strongly inhibited the catalepsy induced by systemic haloperidol (1 mg/kg, i.p.), and this effect lasted longer when the drug was injected into the DM than when it was injected into the DL. d(−)AP5 did not affect haloperidol-induced catalepsy when injected into the ventrorostral (VM and VL) or intermediate dorsal CP. d(−)AP5 injected into the DM, the region most sensitive to the anticataleptic effect of the drug, had no effect on basal levels of DA and its metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, or on the modification of these levels by haloperidol in either the DM or VM. These findings suggest that, while the catalepsy resulting from DA receptor blockade by haloperidol originates mainly from the VM, the expression of this phenomenon depends on an intact glutamatergic transmission within the dorsorostral CP. In the development of neuroleptic catalepsy, the mesencephalostriatal DAergic and corticostriatal glutamatergic pathways seem to be functionally linked through an indirect, rather than a direct, interaction.

The AMPA antagonists NBQX and GYKI 52466 do not counteract neuroleptic-induced catalepsy.

The AMPA antagonists NBQX (2.5, 5, 10 mg/kg) and GYKI 52466 (4.8, 8 mg/kg) were investigated in haloperidol (0.5 mg/kg)-induced catalepsy in the rat. The effects of AMPA antagonists administered either alone or in combination with the noncompetitive NMDA antagonist dizocilpine (0.02 mg/kg), with the dopamine D-2 agonist quinpirole (1 mg/kg) or with L-DOPA (50, 100 mg/kg plus benserazide) were tested. NBQX or GYKI 52466 did not exert anticataleptic effects, neither alone nor in combination with dizocilpine, quinpirole or L-DOPA. Thus, in the rat inhibition of AMPA receptors with NBQX or GYKI 52466 does not have effects predictive for an antiparkinsonian potential.

The non-NMDA glutamate receptor antagonist GYKI 52466 counteracts locomotor stimulation and anticataleptic activity induced by the NMDA antagonist dizocilpine

The effects of the non-NMDA glutamate receptor antagonist GYKI 52466 (2.4 and 4.8 mg/kg, i.p.) on spontaneous locomotor activity and haloperidol-induced catalepsy (0.5 mg/kg, i.p.) were assessed in naive rats and in rats pretreated with the NMDA antagonist dizocilpine (0.08 mg/kg, i.p.). GYKI 52466 given alone did not alter locomotor activity and haloperidol-induced catalepsy, but significantly antagonized the dizocilpine-induced locomotor stimulation and counteracted the anti-cataleptic effects of dizocilpine on haloperidol-induced catalepsy. Thus blockade of non-NMDA glutamate receptors antagonized the behavioural stimulant effects of a NMDA receptor blockade.

The effect of NMDA receptor antagonists on the neuroleptics‐induced catalepsy in mice

AbstractThe effect of non‐competitive (MK‐801:/+/‐5‐methy‐10,11‐dihydro‐5H‐dibenzo [a, d] cyclohepten‐5,10‐imine hydrogen maleate) and competitive (CGP 37849: DL‐/E/‐2‐amino‐4‐methyl‐5‐phosphono‐3‐pentenoic acid) NMDA receptor antagonists on the catalepsy induced by neuroleptics in mice was studied. MK‐801 and CGP 37849 antagonized the catalepsy induced by haloperidol, spiperone and fluphenazine. (+)‐Cycloserine, a partial glycine agonist, reversed the anticataleptic effect of CGP 37849, but not that of MK‐801. The above results indicate that the anticataleptic activity of both these NMDA receptor antagonists is induced by an indirect activation of the dopamine system. The results provide further evidence that competitive NMDA receptor antagonists may be a new class of antiparkinsonian drugs.

NMDA receptor antagonists inhibit catalepsy induced by either dopamine D 1 or D 2 receptor antagonists

In the present study, we investigated the ability of NMDA receptor antagonists to inhibit catelepsy induced by haloperidol, or SCH23390 and clebopride, selective dopamine D 1 and D 2 receptor antagonists respectively. Catalepsy was measured by recording the time the animal remained with its forepaws placed over a rod 6cm above the bench. Pretreatment with either the non-competitive NMDA receptor antagonist, MK-801 (0.25–0.5 mg/kg i.p.) or the competitive antagonist, LY274614 (10–20 mg/kg i.p.) reduced the cataleptic response produced by haloperidol (1.0 mg/kg), SCH23390 (2.5–10 mg/kg i.p.) or clebopride (5–20 mg/kg i.p.). This demonstrates that NMDA receptor antagonists will reduce both dopamine D 1 and D 2 receptor antagonist-induced catelepsy. Muscle relaxant doses of chlordiazepoxide (10 mg/kg i.p.) failed to reduce the catalepsy induced by haloperidol, suggesting that the anticataleptic effect of the NMDA receptor antagonists was not due to a non-specific action. There results support the hypothesis that NMDA receptor antagonists may have beneficial effects in disorders involving reduced dopaminergic function, such as Parkinson's disease.

Attenuation of haloperidol-induced catalepsy by noradrenaline and L-threo-DOPS.

In addition to impaired dopaminergic neurotransmission a dysfunctional noradrenergic system has been demonstrated in Parkinson's disease. L-threo-3,4-dihydroxyphenylserine (DOPS), a synthetic precursor of noradrenaline (NA), appears to be effective in the treatment of some akinetic symptoms in parkinsonian patients. In the present study the possible effect of DOPS was studied in rats, in which catalepsy was induced with haloperidol as a model for parkinsonian akinesia. Intravenous infusion of NA (1.5 and 15 micrograms/kg) or DOPS (2 and 4 mg/kg) in male Wistar rats (240-290 g) significantly decreased catalepsy. The effect of DOPS was abolished by pretreatment with the peripheral decarboxylase inhibitor benserazide (2 mg/kg). Pretreatment with Ro 40-7592, a catechol-O-methyltransferase inhibitor, potentiated and prolonged the anticataleptic effect of DOPS. The findings suggest a peripheral site of NA mediated anticataleptic action. Therapy with DOPS may be successful only without a peripheral decarboxylase inhibitor. Moreover, the therapeutic effect of DOPS may be potentiated by COMT inhibition.

D1/D2 dopamine and N-methyl-D-aspartate (NMDA) receptor participation in experimental catalepsy in rats.

Mixed D1/D2 dopamine (DA) antagonists, perphenazine (5 mg/kg) and haloperidol (2 mg/kg) induced catalepsy in rats. SCH 23390 (1 mg/kg), a D1 DA antagonist, also produced catalepsy. Co-administration of perphenazine (0.5 mg/kg) and SCH 23390 (0.1 mg/kg), at low doses, produced a marked increase in cataleptic response. B-HT 920, a D2 agonist, reversed the cataleptogenic effects of perphenazine, haloperidol and SCH 23390. SKF 38893 (5 mg/kg) reduced the cataleptogenic effect of SCH 23390 but failed to reverse haloperidol- or perphenazine-induced catalepsy. SKF 38393 (10 mg/kg), however, protected the animals against perphenazine- induced catalepsy. Combined administration of B-HT 920 (0.1 mg/kg) and SKF 38393 (5 mg/kg) enhanced the protective effect of B-HT 920 in SCH 23390-treated animals but not in animals treated with haloperidol or perphenazine. MK-801 (0.025-0.5 mg/kg), a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, reduced the cataleptogenic effects of perphenazine, haloperidol as well as SCH 23390. The anticataleptic action of MK-801 was enhanced by scopolamine (0.1 mg/kg) but not by bromocriptine (1 mg/kg) or clonidine (0.05 mg/kg) in perphenazine-treated rats. Unlike B-HT 920 (0.1 mg/kg), SKF 38393 (5 mg/kg) potentiated the anticataleptic effect of MK-801 (0.01 mg/kg) against SCH 23390-induced catalepsy. The above data suggests D1/D2 interdependence in catalepsy and a modulatory role of D1 and D2 DA receptor stimulation on the anticataleptic effect of MK-801.

Competitive and non-competitive NMDA receptor antagonists in spatial learning tasks

The effects of the competitive N-methyl-D-aspartate (NMDA) receptor antagonists, CGP37849 (3 or 6 mg/kg i.p.) and its ethyl ester CGP39551 (5 or 15 mg/kg i.p.) and of the non-competitive NMDA receptor antagonist, dizocilpine (0.16 mg/kg; i.p.) on acquisition by rats of different spatial orientation tasks in an 8-arm radial maze were evaluated. Neither of the CGP compounds influenced locomotor activity during spontaneous alternation, only dizocilpine increased the number of arm entries (locomotion). Preferred angles between consecutive arm entries were changed by the high doses of CGP37849 (6 mg/kg), CGP39551 (15 mg/kg) and dizocilpine (0.16 mg/kg). The high doses of both CGP compounds as well as dizocilpine produced impairments in the acquisition of an egocentric orientation task and an allocentric reversal task indicated by an increased number of arm entries and re-entries. Such amnesic effects did not occur after administration of low doses of CGP37849 (3 mb/kg) and CGP39551 (5 mg/kg), doses which are sufficient to produce anticonvulsant and anticataleptic effects. In contrast, the non-competitive NMDA receptor antagonist, dizocilpine, produced amnesic effects over the entire behaviourally effective dose range.

Anticataleptic potencies of glutamate-antagonists

The anticataleptic effects of non-competitive and competitive NMDA antagonists as well as those of an agonist at the allosteric glycine binding site of the NMDA receptor were tested in the catalepsy model. Some of these drugs were further tested in a reaction time task demanding rapid locomotor initiation. The results show that the non-competitive NMDA antagonists dizocilpine and memantine as well as the competitive antagonists CGP 39551, CGP 37849 and CPPene antagonized dopamine D2 receptor mediated catalepsy induced by haloperidol. D-cycloserine, a partial glycine agonist per se had no effects, but it enhanced the anticataleptic effects of dizocilpine when coadministered. However, the effects of CGP 37849 were abolished. Dopamine D1 receptor mediated catalepsy induced by SCH 23390 was antagonized by dizocilpine, memantine, CPPene, but not by CGP 37849. In the reaction time task dizocilpine, memantine and CGP 37849 were tested for their anti-akinetic and anti-bradykinetic potencies. All these compounds improved haloperidolinduced slowing of reaction time. However, they acted differentially on haloperidol-induced slowing of movement execution and decreased initial acceleration. Thus, antagonists at the NMDA receptor may have a therapeutic potential in the treatment of Parkinson's disease. Their potency can be manipulated specifically at the glycine binding site.

Behavioural effects of serotonin agonists and antagonists in the rat and marmoset

The present study was conducted to investigate the effects of various 5-hydroxytryptamine (5-HT) agonists and antagonists on motor behaviour in rats and marmosets. Various motor-based responses were assessed after central or peripheral administration of 5-HT agents to rats and marmosets. Drugs acting as agonists at the 5-HT 1A receptor (8-OHDPAT, gepirone, BMY-7378, NAN-190, PAPP (LY165163) and flesinoxan) and 5-HT 2/1C receptors (DOI) were found to reverse neuroleptic-induced catalepsy in the rat whereas 5-HT 2/1C antagonists (mianserin, ritanserin and ICI-170,809) and the 5-HT 1 antagonist ((±)pindolol) increased catalepsy. Agonists acting at 5-HT 3 receptors (phenylbiguanide and 2-methyl-5-HT) had no effect on catalepsy. The putative 5-HT 1A antagonist, (±) pindolol, attenuated the reversal of catalepsy by 8-OHDPAT. Although both 8-OHDPAT and BMY-7378 were tested, only the latter was found to reduce apomorphine-induced stereotypy. Bilateral or unilateral infusions of 8-OHDPAT, BMY-7378 or pindolol into the substantia nigra of non-lesioned rats had no effect on spontaneous locomotor or rotational activity, respectively. However, 8-OHDPAT and BMY-7378 were found to increase or decrease motor activity, after injection into the median or dorsal raphe nuclei, respectively. Finally, 8-OHDPAT and BMY-7378 were found to be inactive against MPTP-induced bradykinesia in the marmoset. It is concluded that both 5-HT 1A and 5-HT 2/1C receptors are involved in the anti-cataleptic effects of 5-HT agents. The 5-HT 1A receptors are probably situated within the raphe, whereas the location of the 5-HT 2/1C receptors remains undetermined.