Catalepsy induced by morphine or haloperidol: effects of apomorphine and anticholinergic drugs.

To investigate the extent of cholinergic involvement in opiate-induced catalepsy, the effects of three anticholinergic drugs were studied on morphine-induced catalepsy. Haloperidol-induced catalepsy was also examined. Maximum catalepsy in rats was obtained with 30 mg/kg morphine or 3 mg/kg haloperidol. The anticholinergic drugs atropine, benztropine, and scopolamine were unable to antagonize morphine-induced catalepsy, yet readily antagonized haloperidol-induced catalepsy. Low doses of apomorphine (7.5 mg/kg), on the other hand, readily antagonized morphine catalepsy, but 13-fold higher doses of apomorphine were needed to block haloperidol-induced catalepsy. The results are compatible with the idea that catalepsy can be mediated via the striatum or the amygdala; morphine-dopamine antagonism may occur in the amygdala, whereas morphine-dopamine-cholinergic interactions occur in the striatum.     

Effects of dextromethorphan on dopamine dependent behaviours in rats

Dextromethorphan, a noncompetitive blocker of N-methyl-D- aspartate (NMDA) type of glutamate receptor, at 7.5-75 mg/kg, ip did not induce oral stereotypies or catalepsy and did not antagonize apomorphine stereotypy in rats. These results indicate that dextromethorphan at 7.5-75 mg/kg does not stimulate or block postsynaptic striatal D2 and D1 dopamine (DA) receptors. Pretreatment with 15 and 30 mg/kg dextromethorphan potentiated dexamphetamine stereotypy and antagonised haloperidol catalepsy. Pretreatment with 45, 60 and 75 mg/kg dextromethorphan, which release 5-hydroxytryptamine (5-HT), however, antagonised dexamphetamine stereotypy and potentiated haloperidol catalepsy. Apomorphine stereotypy was not potentiated or antagonised by pretreatment with 7.5-75 mg/kg dextromethorphan. This respectively indicates that at 7.5-75 mg/kg dextromethorphan does not exert facilitatory or inhibitory effect at or beyond the postsynaptic striatal D2 and D1 DA receptors. The results are explained on the basis of dextromethorphan (15-75 mg/kg)-induced blockade of NMDA receptors in striatum and substantia nigra pars compacta. Dextromethorphan at 15 and 30 mg/kg, by blocking NMDA receptors, activates nigrostriatal dopaminergic neurons and thereby potentiates dexampetamine stereotypy and antagonizes haloperidol catalepsy. Dextromethorphan at 45, 60 and 75 mg/kg, by blocking NMDA receptors, releases 5-HT and through the released 5-HT exerts an inhibitory influence on the nigrostriatal dopaminergic neurons with resultant antagonism of dexampetamine stereotypy and potentiation of haloperidol catalepsy.     

Effect of haloperidol on cyclic AMP and inositol trisphosphate in rat striatum in vivo.

To investigate the effect of haloperidol (HAL) on second messengers in the brain striatum, the concentrations of cAMP and inositol trisphosphate (IP-3) were measured in the striatum of rats in vivo after intravenous administration of HAL, and their concentrations were compared with the severity of catalepsy and changes in dopamine (DA) metabolism in the striatum. Catalepsy developed both in the animals treated with 5 mg/kg and those with 0.5 mg/kg of HAL, but it appeared earlier, and the period of severe catalepsy was longer in the former than in the latter. In the animals treated with 5 mg/kg of HAL, DOPAC and HVA began to increase at 20 min after administration, and their percent increases were correlated with the severity of catalepsy. In the 5 mg/kg animals, both cAMP and IP-3 increased. The IP-3 showed a delayed peak but a greater increase as compared with the cAMP. In the 0.5 mg/kg animals, only IP-3 increased. These findings suggest that HAL might affect not only the adenylate cyclase system but also the phosphoinositide response in the striatum. Moreover, the changes in the phosphoinositide response might be secondarily induced by the blocking of D-2 receptors by HAL.     

Studies on the mechanism of postetorphine catalepsy. Effects of clotiapine, haloperidol and rompun on postetorphine changes in concentrations of dopamine and noradrenaline in central nervous system of rats

Changes in dopamine (DA) and noradrenaline (NA) concentrations in various central nervous system structures were compared in rats after administration of haloperidol, clotiapine and rompun with changes in these concentrations during etorphine-induced catalepsy. Besides that, these changes were compared with changes in DA and NA concentrations after etorphine administration during full action of haloperidol, clotiapine and rompun. Haloperidol, clotiapine and rompun prolonged the duration of etorphine-induced catalepsy in rats and modified significantly postetorphine changes in DA and NA concentrations in the investigated central nervous system structures. The action of haloperidol, clotiapine and rompun increasing the intensity of postetorphine catalepsy and the previously demonstrated anticataleptic and antietorphine action of agents stimulating the postsynaptic adrenergic structures in the central nervous system in rats may suggest that DA release from presynaptic structures is inhibited after etorphine.     

Involvement of striatum serotonergic system in the expression of genetically defined catalepsy

The activity of the rate-limiting enzyme of serotonin biosynthesis, tryptophan hydroxylase, and specific binding of [3H]ketanserin to 5-HT2A receptors and [3H]8-OH-DPAT to 5-HT1A receptors in the striatum of genetically predisposed to catalepsy rats and mice have been studied. The activity of tryptophan hydroxylase in the striatum of rats bred for many generations for predisposition to catalepsy was higher than in nonselected rats. Mice of highly susceptible to pinch-induced catalepsy CBA strain also differed from noncataleptic AKR and C57BL mouse strains by higher activity of tryptophan hydroxylase in striatum. Inhibition of tryptophan hydroxylase with p-chlorophenylalanine or p-chloromethamphetamine significantly decreased immobility time in genetically predisposed to catalepsy rats and mice. A decrease in the [3H]ketanserin specific binding in the striatum of cataleptic rats and CBA mice was found indicating a decrease in 5-HT2A receptor density. A decrease in [3H]8-OH-DPAT binding in striatum of cataleptic rats but not in CBA mice was shown. These results indicate that serotonergic system of striatum is involved in the expression of hereditary catalepsy and suggest that hereditary catalepsy may result from genetic changes in the regulation of serotonin metabolism and reception in striatum.     

Comparative study of sulpiride and haloperidol on dopamine turnover in the rat brain

The effects of the neuroleptics, sulpiride and haloperidol, on dopamine (DA) turnover were compared following the acute and chronic administration of these drugs alone or in combination with levodopa or apomorphine. In the acute treatment, the increase in DA metabolites in the striatum and nucleus accumbens was more marked in the haloperidol-treated rats than in the sulpiridetreated rats. Following the additional administration of levodopa, however, the potency of the neuroleptics in elevating DA metabolites was reversed. A low dose of apomorphine induced a marked reduction in the striatal DA metabolite levels by approximately 50%. When rats were pretreated with the neuroleptics, haloperidol was more effective in preventing an apomorphine-induced reduction in DA metabolites. On repeated administration of the neuroleptics, a tolerance occurred in the striatum and nucleus accumbens, but not in the prefrontal cortex. This differential development of tolerance was observed in the different brain regions and with the different drugs administered. These results suggests that the pharmacological mechanism of sulpiride on DA turnover differs from that of haloperidol.     

Effect of chronic treatment with neuroleptics on the content of 3',5'-cyclic guanosine monophosphate in cerebellar cortex of rats.

Chronic treatment with haloperidol is associated with complete tolerance to the decreasing effect of the neuroleptic on cerebellar cGMP content, vice versa chronic haloperidol causes hypersensitivity to the enhancing effect of apomorphine on cerebellar cGMP. Thus, the administration of 0.5 mg/Kg of haloperidol decreases cerebellar cGMP by 80% in control rats but fails to alter this nucleotide in rats chronically treated with haloperidol (0.5 mg/Kg twice daily for 20 days). A dose of 0.5 mg/Kg of apomorphine enhances cGMP by approximately 25 and 60 percent in control rats and in rats chronically treated with haloperidol, respectively. The results suggest that: a) There is a functional link between striatum and cerebellum; b) Cerebellar cGMP is a sensitive index of the state of activation of striatal dopamine receptors.     

Effect of an imidazobenzodiazepine (RO 15-1788) on aggressive behavior in mice

Imidazobenzodiazepine (Ro 15-1788, 5 mg/kg) similarly to a lose dose of apomorphine (0.1 mg/kg) decreased the intensity of footshock aggression in male rats. Ro 15-1788 significantly potentiated the antiaggressive action of apomorphine. Pirenperone (0.01 mg/kg) potentiated the effect of both drugs, whereas haloperidol (0.01 mg/kg) had an opposite action. After long-term treatment with apomorphine and Ro 15-1788 the tolerance to their antiaggressive action developed. This change was in agreement with increased serotonin metabolism in the forebrain. Unlike the action on aggressive behavior, Ro 15-1788 similarly to haloperidol (0.05 mg/kg) decreased the motor depressant effect of apomorphine (0.01 mg/kg) in mice. This effect correlated with the lowered serotonin metabolism after Ro 15-1788 administration. Unlike apomorphine, Ro 15-1788 reversed catalepsy induced by haloperidol (0.25 mg/kg). Administration of pirenperone (0.03 mg/kg) and destruction of serotoninergic terminals by p-chloroamphetamine (2 X 15 mg/kg) significantly potentiated the sedative action of apomorphine. It appears that different action of Ro 15-1788 on behavioral effects of apomorphine is related to different influence of Ro-1788 on serotoninergic processes in the striatum and limbic structures.     

Sulpiride: a study of the effects on dopamine receptors in rat neostriatum and limbic forebrain.

Sulpiride is a new neuroleptic which does not produce extrapyramidal side effects in humans nor catalepsy in experimental animals. Sulpiride in rat striatum and nucleus accumbens homogenates fails to block adenylate cyclase activation induced by both dopamine and apomorphine. Moreover the in vivo cyclic adenosine monophosphate accumulation induced by apomorphine in the striatum of rats is not blocked by sulpiride as haloperidol and other classic neuroleptic do. Sulpiride appears to be unique in respect to other neuroleptic since according to the experiments reported in this paper it does not block dopamine receptors either in vitro or in vivo.     

Effects of haloperidol on rat behavior and density of dopaminergic D2-like receptors

The present work shows the effects of a typical neuroleptic drug (haloperidol, HAL) on rat behavior (catalepsy and locomotor activity) and dopaminergic D2-like receptor densities in the hippocampus and striatum. Male Wistar rats (2-3 months old) were treated daily for 30 days with HAL (0.2 or 1mg/kg, intraperitoneally (i.p.)). At the end of treatment and 1h or 1, 3, 7 and 15 days after drug withdrawal, animals were subjected to behavioral tests and sacrificed afterwards for binding assays. The results showed that behavioral effects with both doses were significant only 1h and 1 day after withdrawal, and similar to controls at the third day. An up-regulation of D2 receptors was observed in the striatum (28% increase) but not in the hippocampus after 24h HAL (1mg/kg) withdrawal. However, an up-regulation was seen in both areas (1mg/kg) 3 days after drug withdrawal (58 and 42% increases in the hippocampus and striatum, respectively), and continued after 7 days of withdrawal only in the striatum (43 and 49% for the doses of 0.2 and 1mg/kg, respectively), suggesting the influence of dose, age, and time of drug withdrawal on these parameters. The up-regulation disappeared after 15 days of haloperidol withdrawal. Increases (72 and 140%) in constant dissociation values (K(d)) values were also observed 7 days after withdrawal. Results show differences on a time-basis between behavioral alterations and dopaminergic D2 receptors up-regulation.     

Further evaluation of the tropane analogs of haloperidol

Previous work from our labs has indicated that a tropane analog of haloperidol with potent D₂ binding but designed to avoid the formation of MPP⁺-like metabolites, such as 4-(4-chlorophenyl)-1-(4-(4-fluorophenyl)-4-oxobutyl)pyridin-1-ium (BCPP⁺) still produced catalepsy, suggesting a strong role for the D₂ receptor in the production of catalepsy in rats, and hence EPS in humans. This study tested the hypothesis that further modifications of the tropane analog to produce compounds with less potent binding to the D₂ receptor than haloperidol, would produce less catalepsy. These tests have now revealed that while haloperidol produced maximum catalepsy, these compounds produced moderate to low levels of catalepsy. Compound 9, with the least binding affinity to the D₂R, produced the least catalepsy and highest Minimum Adverse Effective Dose (MAED) of the analogs tested regardless of their affinities at other receptors including the 5-HT_1AR. These observations support the hypothesis that moderation of the D₂ binding of the tropane analogs could reduce catalepsy potential in rats and consequently EPS in man.     

Central antidopaminergic properties of 2-bromolisuride, an analogue of the ergot dopamine agonist lisuride

2-Bromolisuride (2-Br-LIS), a derivative of the ergot dopamine (DA) agonist lisuride, was investigated in rodents in comparison with the DA antagonist haloperidol with regard to its influence on DA related behaviour, cerebral DA metabolism and prolactin (PRL) secretion. 2-Br-LIS produced catalepsy in mice (ED50 3.3 mg/kg i.p.), antagonized apomorphine-induced stereotypies in mice (ED50 0.4 mg/kg i.p.), antagonized DA agonist-induced stereotypies in rats (0.1-1.56 mg/kg i.p.), inhibited locomotor activity in rats (0.025-6.25 mg/kg i.p.), antagonized the hyperactivity produced by various DA agonists in rats (0.025-6.25 mg/kg i.p.) and inhibited the apomorphine-induced hypothermia in mice (0.05-0.78 mg/kg i.p.). 2-Br-LIS (0.03-10 mg/kg i.p.) stimulated DA biosynthesis and DOPAC formation in the striatum and DA rich limbic system of rats, but had no effect on serotonin turnover. In striatum and limbic forebrain of gamma-butyrolactone-pretreated rats 2-Br-LIS reversed the apomorphine-induced inhibition of DOPA accumulation. 2-Br-LIS (0.03 - 3 mg/kg) enhanced PRL secretion in intact male rats. These findings indicate DA antagonistic properties of 2-Br-LIS presumably due to blockade of central pre- and postsynaptic DA receptors being of approximately the same order of potency as haloperidol. 2-Br-LIS is the first ergot compound with definite antidopaminergic properties suggesting its potential usefulness as a neuroleptic.     

高频电刺激下丘脑后核对氟哌啶醇致大鼠运动不能的影响

目的：利用氟哌啶醇致僵直大鼠模拟帕金森病（PD）的运动不能,通过高频电刺激下丘脑后核（PH）,观察大鼠僵直和运动能力的变化,从而探讨PH在PD治疗中潜在的应用价值。方法：将成年雄性SD大鼠随机分为PH刺激组、假刺激组和对照组,对PH刺激组和假刺激组大鼠双侧PH置入双极刺激电极,腹腔注射氟哌啶醇30min后,PH刺激组给予持续高频电刺激（130Hz,60μs,100μA）,分别利用爬杆实验和跑步机实验评价大鼠僵直程度和运动能力。结果：腹腔注射氟哌啶醇1．0mg／kg后,①大鼠呈僵直状态,其潜伏期为167．88±17．88S,给予双侧PH高频电刺激后潜伏期显著缩短至77．5±21．27s（P〈0．01）。②跑步机试验显示大鼠跑动速度和跑动距离显著下降,分别为5．78±0．90cm／s和8．06±4．35m（P〈0．01）,给予双侧PH高频电刺激后显著提高跑动速度和跑动距离,分别为12．72±3．66cm／s和98．61±96．75m（P〈0．01）。结论：腹腔注射氟哌啶醇可模拟帕金森病的僵直和运动不能症状,双侧高频电刺激PH可显著拮抗氟哌啶醇对大鼠僵直和运动不能的作用,提示PH为DBS治疗帕金森病运动不能的有效刺激靶点,为临床DBS刺激PH治疗PD提供实验依据。     

Inhibitory effect of ceruletide on haloperidol-induced catalepsy in rats

Ceruletide (CLT: 160 micrograms/kg, SC) produced a relatively long-lasting inhibition of haloperidol (HPD: 2 mg/kg, PO) catalepsy in rats. Neither bilateral vagotomies nor hypophysectomy abolished the anticataleptic effect of CLT. However, (-)-L-364,718 and proglumide blocked the effect of CLT. CLT (160 micrograms/kg) significantly inhibited HPD (2 mg/kg)-induced increase in dopamine (DA) release from the rat striatum. This effect of CLT was also antagonized by proglumide. These results suggest that CLT (160 micrograms/kg) primarily acts on cholecystokinin-A receptor in the brain, exerts some modulatory influence on HPD binding to striatal DA receptors via unknown neural pathways and, consequently, inhibits HPD catalepsy.     

Differential effects of acute and chronic haloperidol treatment on striatal and nigral 3, 4-dihydroxyphenylacetic acid (DOPAC) levels

Chronic treatment of rats with haloperidol (4 weeks, 0.5 or 1 mg/kg) resulted in a significant attenuation of the large DOPAC rise seen in the corpus striatum after acute treatment. This tolerance effect was observed both shortly following termination of chronic treatment and on challenge with a low dose (0.1 mg/kg) of the drug 6–8 days later. In contrast, acute haloperidol treatment resulted in only a small and nonsignificant elevation of DOPAC levels in the substantia nigra, while chronic treatment caused a larger and significant increase in levels of the metabolite. Moreover, the latter effect was also observed in response to haloperidol challenge 6–8 days after discontinuation of drug treatment. The differential pattern of response in these two brain regions is discussed in relation to possible mechanisms mediating striatal tolerance and to recent observations regarding changes in nigral dopamine cell firing after chronic haloperidol treatment.     

An influence of ligands of metabotropic glutamate receptor subtypes on parkinsonian-like symptoms and the striatopallidal pathway in rats

Summary. Several data indicate that inhibition of glutamatergic transmission may be important to alleviate of parkinsonian symptoms. Therefore, the aim of the present paper is to review recent studies on the search for putative antiparkinsonian-like effects of mGluR ligands and their brain targets. In order to inhibit glutamatergic transmission, the group I mGluRs (mGluR1 and mGluR5) were blocked, and group II (mGluR2/3) or III (mGluR4/7/8) mGluRs were activated. Systemic or intrastriatal administration of group I mGluR antagonists (mGluR5 – MPEP, MTEP; mGluR1 – AIDA) was found to inhibit parkinsonian-like symptoms (catalepsy, muscle rigidity) in rats. MPEP administered systemically and mGluR1 antagonists (AIDA, CPCCOEt, LY367385) injected intrastriatally reversed also the haloperidol-increased proenkephalin (PENK) mRNA expression in the striatopallidal pathway. Similarly, ACPT-1, a group III mGluR agonist, administered into the striatum, globus pallidus or substantia nigra inhibited the catalepsy. Intrastriatal injection of this compound reduced the striatal PENK expression induced by haloperidol. In contrast, a group II mGluR agonist (2R,4R-APDC) administered intrastriatally reduced neither PENK expression nor the above-mentioned parkinsonian-like symptoms. Moreover, a mixed mGluR8 agonist/AMPA antagonist, (R,S)-3,4-DCPG, administered systemically evoked catalepsy and enhanced both the catalepsy and PENK expression induced by haloperidol. The results reviewed in this article seem to indicate that group I mGluR antagonists or some agonists of group III may possess antiparkinsonian properties, and point at the striatopallidal pathway as a potential target of therapeutic intervention.     

Effects of iptakalim on extracellular glutamate and dopamine levels in the striatum of unilateral 6-hydroxydopamine-lesioned rats: a microdialysis study

In a previous study, we demonstrated that iptakalim (Ipt) significantly ameliorated hypolocomotion and catalepsy induced by haloperidol and rotenone in rats. In order to further understand the mechanism(s), using a rat model of Parkinson's disease (PD) established by unilateral 6-hydroxydopamine (6-OHDA) administration to the substantia nigra pars compacta (SNpc) and reverse microdialysis techniques with high performance liquid chromatography (HPLC), we investigated the effects of Ipt on extracellular levels of glutamate, dopamine (DA) and its metabolite dihydroxyphenylacetic acid (DOPAC) in the striatum of conscious and freely moving rats. The results indicated that unilateral 6-OHDA-lesioned rats have a significantly higher level of extracellular glutamate and a lower level of extracellular DOPAC in the lesioned-side of the striatum, and a lower level of extracellular DA in both sides of the striatum compared to the striatum of control rats. Ipt reduced extracellular glutamate levels in both sides of striatum of the lesioned and control rats in a concentration-dependent manner. Ipt, at lower concentrations (0.01, 0.1, 1 microM), enhanced extracellular DA levels in the lesioned-side striatum of the unilateral 6-OHDA-lesioned rats, while causing no significant changes in the intact side striatum, and even a significant decline in striatum of control rats at higher concentrations of Ipt (10, 100 microM). In addition, Ipt also caused a significant decline in the extracellular DOPAC levels in the lesioned-side striatum of unilateral 6-OHDA-lesioned rats. These data suggest that the major mechanism underlying the ameliorative effects of Ipt on the behavior in 6-OHDA-lesioned rats is the alteration of levels of extracellular neurotransmitters, such as glutamate and DA in the striatum of unilateral 6-OHDA-lesioned rats.     

Fyn is required for haloperidol-induced catalepsy in mice

Fyn-mediated tyrosine phosphorylation of N-methyl-D-aspartate (NMDA) receptor subunits has been implicated in various brain functions, including ethanol tolerance, learning, and seizure susceptibility. In this study, we explored the role of Fyn in haloperidol-induced catalepsy, an animal model of the extrapyramidal side effects of antipsychotics. Haloperidol induced catalepsy and muscle rigidity in the control mice, but these responses were significantly reduced in Fyn-deficient mice. Expression of the striatal dopamine D(2) receptor, the main site of haloperidol action, did not differ between the two genotypes. Fyn activation and enhanced tyrosine phosphorylation of the NMDA receptor NR2B subunit, as measured by Western blotting, were induced after haloperidol injection of the control mice, but both responses were significantly reduced in Fyn-deficient mice. Dopamine D(2) receptor blockade was shown to increase both NR2B phosphorylation and the NMDA-induced calcium responses in control cultured striatal neurons but not in Fyn-deficient neurons. Based on these findings, we proposed a new molecular mechanism underlying haloperidol-induced catalepsy, in which the dopamine D(2) receptor antagonist induces striatal Fyn activation and the subsequent tyrosine phosphorylation of NR2B alters striatal neuronal activity, thereby inducing the behavioral changes that are manifested as a cataleptic response.     

Pro-Leu-Gly-NH2 and pareptide inhibit development of tolerance to haloperidol catalepsy in the mouse

Single doses of MIF-1 (0.03-2.0 mg/kg, SC) and chronic pretreatments with MIF-1 (0.03-2.0 mg/kg, SC, BID, 3 1/2 days) or pareptide (0.25 mg/kg, SC, BID, 3 1/2 days) did not affect the acute cataleptic response to haloperidol in the mouse. Chronic pretreatment with haloperidol (8.0 mg/kg, IP, BID, 3 days) decreased the duration of catalepsy in mice given smaller challenge dose of haloperidol (2.0 or 3.0 mg/kg, IP) 15 hours after the last pretreatment injections. Administration of either MIF-1 or pareptide to mice also chronically pretreated with haloperidol antagonized the development of tolerance.     

Changes in the serotonin system of the brains of rats genetically predisposed to catalepsy

Some changes in the brain serotonergic system were found in rats bred for predisposition to catalepsy, and in those bred for its absence. The genetic predisposition for catalepsy was found to be characterized by an increased tryptophan hydroxylase activity in the striatum, and an increased serotonin content in the midbrain. No changes in 5-hydroxyindoleacetic acid level were found. A selection for predisposition to catalepsy turned out to entail a decrease in the sensitivity of postsynaptic serotonin receptors as estimated by the "head twitch" test after 5-hydroxytryptophan administration, while a selection for the absence of catalepsy increased the sensitivity of serotonin receptors.