SCH 23390-induced Catalepsy Research Articles

Conditioning to Injection Procedures and Repeated Testing Increase SCH 23390-Induced Catalepsy in Mice

The cataleptic behavior induced by the dopamine D1 antagonist SCH 23390 (SCH) has proven to be a useful assay for investigating the sensitivity of D1-like dopamine receptor-mediated effects during chronic drug administration. A fundamental flaw in most of these studies may be the involvement of the “repeated measures effect,” a behavioral phenomenon well demonstrated for neuroleptic-induced catalepsy but not yet investigated for dopamine D1 antagonists. In this study, mice exposed for various sessions to the bar test presented a strong sensitization to the cataleptic behavior induced by repeated SCH treatment. Conversely, single tested animals exhibited a trend toward decreased catalepsy after repeated SCH treatment, which was in line with the development of a D1-like dopamine receptor supersensitivity suggested by an increase in SKF 38393-induced grooming behavior. Surprisingly, a challenge intraperitoneal saline injection increased the cataleptic behavior of single tested mice after long-term SCH treatment. This “injection-conditioned catalepsy” was also observed after repeated treatment with the dopamine D2 antagonists, haloperidol and metoclopramide. While these findings seem to explain some important contradictory data in the literature, they provide a new and simple animal model of the placebo effect.

Involvement of 5-HT6 receptors in nigro-striatal function in rodents.

4-Amino-N-(2,4 bis-methylamino-pyrimidin-4-yl) benzene sulphonamide (Ro 04-6790) is a potent, selective and competitive antagonist for the 5-HT6 receptor which can be detected in the cerebro-spinal fluid (CSF) of rats following intraperitoneal administration. Since 5-HT6 receptor mRNA and 5-HT6 receptor-like immunoreactivity have been shown to be present in the striatum, the purpose of the present study was to evaluate the effect of 5-HT6 receptor antagonism on haloperidol- and SCH 23390-induced catalepsy in mice and on the turning behaviour of rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the medial forebrain bundle. Ro 04-6790 (3, 10 and 30 mg kg(-1) i.p.) did not induce catalepsy and had no effect on catalepsy induced by either haloperidol or SCH 23390. Ro 04-6790 (3, 10 and 30 mg kg(-1) i.p.) did not itself induce rotational behaviour in rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the medial forebrain bundle nor did it affect the rotational behaviour induced by either L-Dopa or amphetamine. 5-HT6 receptor antagonism inhibited the rotational behaviour of 6-OHDA lesioned rats induced by treatment with the muscarinic antagonists scopolamine and atropine. The data support earlier conclusions from experiments with antisense oligonucleotides that the 5-HT6 receptor is involved in the control of acetylcholine neurotransmission in the rat brain.

Dopaminergic and Cholinergic Interaction in Cataleptic Responses in Mice

The cataleptogenic effects of haloperidol, a dopamine D2 receptor antagonist; SCH23390, a D1 receptor antagonist; physostigmine, a cholinesterase inhibitor; and pilocarpine, a muscarinic M1 receptor agonist, were challenged by pretreatment of mice with SKF38393, a dopamine D1 receptor agonist; apomorphine, a dopamine D1/D2 receptor agonist (mainly D2 receptor); pirenzepine, a muscarinic M1 receptor antagonist; and scopolamine, a muscarinic M1/M2 receptor antagonist. The effect of physostigmine and pilocarpine on haloperidol and SCH23390 cataleptic responses was also examined. Each of the challenging agents blocked one or more of the cataleptogenic agents, but only scopolamine blocked all four. Pirenzepine blocked cataleptic responses induced by SCH23390 and pilocarpine, but not those by haloperidol and physostigmine. The results of this study suggest that the action of physostigmine (endogenous acetylcholine) on M2 receptors might be more potent than that on muscarinic M1 receptors. A further interesting observation was that the haloperidol-induced catalepsy was enhanced by physostigmine pretreatment, but not by pilocarpine pretreatment, whereas the SCH23390-induced catalepsy showed the opposite spectrum of enhancement by the two cholinergic agonists. We conclude that, although the four cataleptogenic agents act via the dopaminergic-cholinergic systems, their pharmacological differences may be due largely to the different receptor subtypes that are involved in the mediation of catalepsy produced by each agent. Thus, dopamine receptors not only influence the cholinergic muscarinic receptors, but muscarinic M1 and M2 receptors also might mediate dopamine D1 and D2 receptor responses, respectively. The results suggest that there are, at the least, relationships between muscarinic M1 receptors and dopaminergic D1 receptors, and between muscarinic M2 receptors and dopaminergic D2 receptors. Dopamine D1 and D2 receptors may interact in a synergistic fashion on dopaminergic systems, but act independently of each other in influencing other system such as cholinergic neurons.

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.

Behavioral effects mediated by the modulatory glycine site of the NMDA receptor in the anterodorsal striatum and nucleus accumbens

The striatum and the nucleus accumbens are the main input structures of the basal ganglia (BG). They contribute differently to motor behavior controlled by the BG in rats, e.g., stereo-typed behavior, catalepsy, and locomotion. Whereas the striatum is predominantly involved in the control of sniffing behavior and catalepsy, the nucleus accumbens contributes to control of locomotion. To test whether the allosteric glycine site of the NMDA receptor complex modulates these behavioral variables, we injected the glycine-site antagonist 7-chlorokynurenate and the glycine-site agonist D-serine into the anterodorsal striatum and the nucleus accumbens and studied their influence on stereotypical snout contacts and locomotion. Additionally, the effects of intrastriatal injections of 7-chlorokynurenate on haloperidol- and SCH 23390-induced catalepsy were investigated. 7-Chlorokynurenate enhanced stereotypical snout contacts in the anterodorsal striatum and in the nucleus accumbens but did not change spontaneous locomotion in either of these structures. Haloperidol- but not SCH 23390-induced catalepsy was attenuated by intrastriatally administered 7-chlorokynurenate. The glycine-site agonist D-serine had no effect on stereotypical snout contacts and locomotion. The results suggest that motor behavior mediated by the striatopallidal output pathway is modulated by the glycine site, whereas motor behavior mediated by the accumbopallidal and striatonigral output pathway is not.

Opposite effects of NMDA and AMPA receptor blockade on catalepsy induced by dopamine receptor antagonists

Excitatory amino acid antagonists have been proposed as novel therapeutic agents for Parkinson's disease due to their ability to reverse akinesia in animal models of this disorder. To further evaluate this therapeutic potential, we examined the effects of a N-methyl-D-aspartate (NMDA) and an α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor antagonist on catalepsy produced by dopamine D 1 or D 2 receptor antagonists in rats. Male Sprague-Dawley rats were injected with dizocilpine (MK-801 0.025, 0.05 or 0.1 mg/kg i.p.), 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX 12.5 mg/kg i.p.) or saline prior to administration of either raclopride (2.5 mg/kg i.p.) or SCH 23390 (0.5 mg/kg i.p.). Catalepsy was evaluated with both grid and bar tests every 20 min for 2.7 h. MK-801 (0.1 mg/kg) reversed the catalepsy produced by either raclopride or SCH 23390 but did not stimulate locomotion when given alone at this dose. At 0.05 mg/kg, MK-801 markedly decreased SCH 23390-induced catalepsy, but did not affect the catalepsy produced by raclopride. In contrast, NBQX increased raclopride-induced catalepsy, but had no effect on catalepsy elicited by SCH 23390. These findings suggest that blockade of NMDA receptors, but not non-NMDA receptors, may reverse the catalepsy produced by dopamine receptor antagonists.

Tyr-MIF-1 attenuates development of tolerance to spiperone-induced catalepsy in rats

Because the tripeptide MIF-1 (Pro-Leu-Gly-NH 2) is known to attenuate the effects of neuroleptic-induced catalepsy as well as neuroleptic-induced proliferation of dopamine (DA) receptors, we studied the related naturally occurring peptide, Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH 2) for similar properties. Male rats were treated SC for 11 consecutive days with either the DA D 1 receptor antagonist SCH 23390 HC1 (0.50 mg/kg per day), the DA D 2 receptor antagonist spiperone HCl (0.30 mg/kg per day), or vehicle. Half the rats were cotreated daily with Tyr-MIF-1 (1.0 mg/kg per day). The cataleptic effects of SCH 23390 were not altered by Tyr-MIF-1. Tolerance to SCH 23390-induced catalepsy did not develop during the 11-day treatment, and Tyr-MIF-1 had no effect on SCH 23390-induced catalepsy. However, tolerance developed to spiperone-induced catalepsy, and Tyr-MIF-1 attenuated this development of tolerance ( p < 0.001). Locomotor and stereotyped activities of the DA D 1 and D 2 agonists, SKF 39393 (3.0 mg/kg) and quinpirole (3.0 mg/kg) were not affected by Tyr-MIF-1 after treatment with the DA antagonists was discontinued. Tyr-MIF-1 did not alter the B max or K d for in vitro binding of [ 3H]SCH 23390 and [ 3H]spiperone to homogenates of the striatum. These findings indicate that Tyr-MIF-1 is able to selectively affect the development of receptor tolerance to a DA D 2 receptor antagonist, and that this effect is unrelated to changes in affinity or numbers of D 2 receptors.

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.

The ontogeny of SCH 23390-induced catalepsy in male and female rats exposed to ethanol in utero

The maturation of sensitivity to the cataleptic actions of selective D1 dopamine receptor blockade was assessed in rats exposed prenatally to ethanol, Pregnant rats received an average of 12.68 g/kg body weight of ethanol per day through a liquid diet. Control dams were either pair-fed an isocaloric liquid diet without ethanol or given ad lib lab chow. Separate groups of male and female offspring of these dams were administered either 0.33 or 1.00 mg/kg of the selective dopamine D1 receptor antagonist SCH 23390 at postnatal days 13, 17 or 21, and catalepsy was measured 0, 15 and 30 min later. The results are consistent with a hypothesis that prenatal ethanol exposure alters behaviors mediated by nigrostriatal dopamine systems. Overall, prenatal ethanol-exposed animals showed less catalepsy than control rats. Further, there is a gender effect in that dopamine antagonist-induced catalepsy matures earlier in normal male than in normal female controls. Prenatal alcohol exposure appears to delay the emergence of mature behavioral responses to dopamine blockade in male but not female rats.

Cholinergic maturation and SCH 23390-induced catalepsy in the male rat pup

The cataleptogenic effects of the selective dopamine D 1 receptor antagonist, SCH 23390, increased between 13 and 17 days of age in male pups. Seventeen- and 21-day-old pups showed equivalent catalepsy. Scopolamine blocked SCH 23390-induced catalepsy in 21-day-old pups but had little effect in 13-day-old pups. The development and cholinergic sensitivity of SCH 23390-induced catalepsy are similar to those seen after D 2 or mixed D 1/D 2 receptor blockade. Cholinergic maturation appears to be an important component in the development of adult-like catalepsy, and the nature of a D 1-acetylcholine interaction mediating catalepsy remains to be determined.

Intracerebral SCH 23390 and catalepsy in the rat

Stereotaxic injection of SCH 23390 (D-1 antagonist), but not water or ritanserin (5-HT antagonist), into all parts of the caudate-putamen, elicited an immediate and often long-lasting catalepsy in 79% of rats. Similar results were obtained with SCH 23390 delivered into the nucleus accumbens and globus pallidus, but not into a variety of other brain sites. The results support the idea that SCH 23390-induced catalepsy is related to the occlusion of dopamine D-1 receptors in the forebrain, particularly the striatum, although the topography of the catalepsy evoked by intrastriatal SCH 23390 did not match the distribution of D-1 sites labelled in autoradiographic studies.

D-1 and D-2 receptor blockade have additive cataleptic effects in mice, but receptor effects may interact in opposite ways

The dopaminergic role of D-1 and D-2 receptors in catalepsy was evaluated using drugs with preferential receptor affinities. The D-1 antagonist, SCH 23390, caused distinct catalepsy in mice at 1, 2, and 10 mg/kg, IP, but not at two lower doses. The selective D-1 blocker, molindone, also caused catalepsy at 5 and 10 mg/kg; and blockade of both receptor types produced additive cataleptogenic effects. Apomorphine (4 mg/kg), which is an agonist for both receptors, potentiated SCH 23390-induced catalepsy much more than it did the catalepsy induced by molindone; the potentiation was produced by higher, not lower, doses of apomorphine. To determine if the apomorphine potentiation was mediated by D-1 or D-2 receptors, we tested selective agonists in mice that were concurrently injected with selective blockers. SCH 23390-induced catalepsy was potentiated by a large dose of the D-2 agonist, bromocriptine. The catalepsy of D-2 blockade with molindone was not potentiated by the D-1 agonist, SKF 38393, which slightly disrupted the catalepsy of D-2 blockade. We conclude that catalepsy is not a simple D-2 blockade phenomenon and that preferential antagonism of either receptor type can cause catalepsy. Catalepsy is most profound when both receptor types are blocked. Dopamine agonists, in large concentrations, are known to promote movements, and thus it is not surprising that they tend to disrupt catalepsy. What is surprising is that the results suggest that the D-1 and D-2 systems interact in rather complex and seemingly opposite ways in the presence of large amounts of agonist with regard to mediation of catalepsy.