Neuroendocrine modulation of haloperidol-induced catalepsy

Evidence has been accumulated implicating sex hormones as possible modulators of extrapyramidal motor function. In the present study we have investigated the effects of estrogens, progesterone, testosterone, prolactin and calcitonin on behavioral parameters related to nigro-striatal dopaminergic system, such as haloperidol-induced catalepsy in male rats. It was found that 7-days estradiol benzoate treatment (5 micrograms/rat/day) significantly increases haloperidol-induced catalepsy, suggesting a possible antidopaminergic activity of estrogens. On the other hand, prolactin facilitates nigro-striatal dopaminergic transmission. Interestingly, 7 day treatment with medroxy-acetate progesterone (MAP, 5 mg/Kg, i.p.) brings about a trend to a decrease in haloperidol-induced catalepsy, while no significantly effect was observed following acute MAP administration at the same dose. So, it is tempting to speculate that chronic progestinic treatment may result in an increase in dopaminergic tonus. Testosterone, acutely administered (5mg/kg.s.c.) induces changes similar to those observed following progesterone administration. Finally, also calcitonin is able to influence haloperidol-induced catalepsy by markedly increasing it.     

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.     

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.     

The neurochemical mechanisms of the formation and consolidation of haloperidol-induced catalepsy

In rat brain cortex, haloperidol initiates the long-term potentiation of K(+)-induced Ca(2+)-dependent noradrenaline (NA) and dopamine (DA) secretion in vitro and in vivo. In both cases, the long-term potentiation is caused by the long-term increase in catecholamine content in the NA and DA terminals, as it has been shown in cortical tangential slices. Acute intraperitoneal haloperidol injection (2.5 mg/kg) evokes catalepsy and increases the content of NA and DA in the brain structures with localization of catecholamine receptors on terminals. This increase appears to be caused, predominantly, by modification of the terminal DA receptors, since only a trend to catecholamine increase is observed in the brain structures with a mixed type of NA and DA receptor localization (on somata and terminals). It is suggested that the long-term and diffuse action of haloperidol after its acute administration consists in the anxiogenic reaction and consolidation of catalepsy without an additional procedure of training and in the absence of unconditioned stimulus.     

Enhancement of haloperidol-induced catalepsy by nicotine: an investigation of possible mechanisms

Nicotine has been reported to potentiate the cataleptic effect of the dopamine receptor antagonist haloperidol in rats. This effect is paradoxical, since nicotine alone tends to increase nigrostriatal dopamine release. In the present experiments, a pro-cataleptic effect of nicotine was confirmed statistically but was small and variable. Three potential mechanisms underlying this effect were investigated. (i) Desensitization of brain nicotinic receptors appears to make little if any contribution to the pro-cataleptic effect of nicotine, insofar as the latter was not mimicked by two centrally active nicotinic antagonists (mecamylamine and chlorisondamine). (ii) Depolarization inactivation resulting from combined treatment with haloperidol and nicotine does not appear to be critical, since the pro-cataleptic effect of nicotine was not enhanced by chronic haloperidol administration, a treatment designed to enhance depolarization inactivation. (iii) The slow emergence and persistence of the acute pro-cataleptic effect of nicotine suggested possible mediation by a nicotine metabolite. However, neither cotinine nor nornicotine, the principal pharmacologically-active metabolites of nicotine, exerted a significant pro-cataleptic effect. In conclusion, the pro-cataleptic effect of nicotine was weak and variable in the present study, and its mechanism remains obscure.     

Modulatory effects of PLG and its peptidomimetics on haloperidol-induced catalepsy in rats.

A behavioral model of dopaminergic function in the rat was used to examine the anticataleptic effects of L-prolyl-L-leucyl-glycinamide (PLG) and peptidomimetic analogs of PLG. Administration of 1 mg/kg PLG intraperitoneally significantly attenuated haloperidol (1 mg/kg)-induced catalepsy (as measured by the standard horizontal bar test), whereas doses of 0.1 and 10 mg/kg PLG did not. Eight synthetic PLG peptidomimetics (Calpha, alpha-dialkylated glycyl residues with lactam bridge constraint [1-4] and without [5-8]) were tested in the same manner (at a dose of 1 microg/kg) and categorized according to their activity, i.e. very active (5), moderately active (2, 3, 4, and 6), and inactive (1, 7, and 8). The catalepsy-reversal action of the diethylglycine-substituted peptidomimetic 5 was examined further and found to exhibit a U-shaped dose-response effect with an optimal dose of 1 microg/kg. The similarity between the effects of PLG and the synthetic peptidomimetics suggests a common mechanism of action. Finally, the synthetic peptidomimetics examined here, particularly peptidomimetic 5, were more effective than PLG in attenuating haloperidol-induced catalepsy.     

Glucose stimulates and potentiates islet amyloid polypeptide secretion by the B-cell.

Islet amyloid polypeptide (IAPP) has been shown to be actively secreted by the pancreatic B-cell along with insulin. To determine whether the modulation of B-cell IAPP secretion is similar to that of insulin, we assessed IAPP release in response to glucose at 4 different concentrations (1.67, 5.5, 8.8 and 16.7 mM) and to non-glucose secretagogues at different glucose concentrations in a neonatal rat islet monolayer culture preparation. Glucose alone stimulated IAPP and insulin secretion in a dose dependent fashion with maximal release for both peptides occurring at 8.8 mM. B-cell secretion of IAPP in response to arginine, isobutylmethylxanthine or both together was potentiated by increasing glucose concentrations from 1.67 to 16.7 mM. This same pattern of glucose potentiation was observed for insulin secretion. The data indicate that the pattern of peptide responses of cultured neonatal B-cells to glucose is similar for both IAPP and insulin release. Furthermore, the data suggest that glucose is capable of potentiating B-cell secretion of both IAPP and insulin.     

Synthesis of 61-bis(1-adamantylcarbamoyl)-1,2-methano[60]fullerene and its antagonistic effect on haloperidol-induced catalepsy in mice

The 61-bis(1-adamantylcarbamoyl)-1,2-methano[60]fullerene was synthesized from N,N'-di(1-adamantyl)malondiamide and C(60) in the presence of 1,8-diazabicyclo[5,4,0]-7-undecene. The intraperitoneal administration of this fullerene derivative (10mg/kg) caused an antagonistic effect on haloperidol-induced catalepsy in mice.     

Mechanism of haloperidol-induced miosis

Haloperidol administration (iv) has been shown to produce miosis in dogs. In the present study on rabbits, haloperidol administration (iv) produced dose-related miosis but when administered intracerebroventricularly, it failed to produce any change in pupillary size. Higher degree of miosis was observed when haloperidol was administered directly into the anterior chamber of eye. Haloperidol pretreatment failed to significantly modify the mydriasis produced by phenylephrine or atropine. These observations suggest that the miosis produced by haloperidol is a peripheral effect, and also that the miosis is not mediated through the blockade of alpha adrenoceptors of radial muscles or stimulation of cholinoceptors of circular muscles of iris.     

The characteristics of the minute fluctuations in haloperidol-induced catalepsy and the contribution of different sections of the striatum to their formation in rats]

After constant recording of haloperidol catalepsy in rats a rhythmic structure with waves of minute range was observed. On the basis of individual pharmacological sensitivity all rats may be divided in animals with strong rhythmic fluctuations but rapid tolerance (hyperkinetic type) and with weak rhythmicity but delayed adaptation to haloperidol (hypokinetic type). Oscillatory pattern of catalepsy increased after bilateral lesions of dorsal striatum and decreased after ventral striatectomy. As suggested, ventral striatum has a rhythmogenic function which conditions a more easy neuroleptic tolerance.     

Hereditary catalepsy: genetic and molecular mechanisms of catalepsy in mice

The results of experiments on the inheritance and neurobiological mechanism of high predisposition to tonic immobility (catalepsy) in CBA mice are discussed. Genetic analysis has demonstrated a monogenic inheritance of the predisposition to catalepsy. A set of polymorphic microsatellite markers has been used to demonstrate that the predisposition to catalepsy is linked to the distal fragment of mouse chromosome 13, which contains the gene of the 5-HT1A-serotonin receptor. Pharmacological and biochemical evidence for the association between hereditary catalepsy and 5-HT1A-receptor dysfunction are presented. The use of CBA mice for studying the mechanisms of depression and the effects of antidepressants is discussed.     

Genetic control of catalepsy in mice

Pinch-induced immobility (catalepsy) was studied in mice of 9 inbred strains. CBA mice were found to be different from those of other strains both by the highest percent of cataleptics (56%) and by the highest duration of immobility. The Mendelian analysis of predisposition to catalepsy was performed on CBA and AKR mice strains contrasting in this feature. Reciprocal F1 hybrids did not display any catalepsy. Manifestation of cataleptics in the F2 and in CBA x F2 backcrosses suggested that catalepsy was inherited as a recessive, monogenic, autosomal feature.     

Minute rhythms of haloperidol catalepsy in rats

Haloperidol-induced (0.25-1.0 mg/kg) catalepsy in rats is characterized by rhythmic time fluctuations. Marked catalepsy was accompanied by slow regular waves at 2-4 and 5-7 min period. Natural or L-dopa-induced inhibition of the process involves the phase of irregular and frequent fluctuations. The study of time fluctuations of the muscular tone are believed important for predicting the development of drug-induced Parkinson's disease.     

Reversal of haloperidol-induced orofacial dyskinesia and neuroinflammation by isoflavones

Molecular Biology Reports - Schizophrenia is a mental illness and its pharmacological treatment consists in the administration of antipsychotics like haloperidol. However, haloperidol often causes...     

Selection of Wistar rats for predisposition to catalepsy

Non-inbred Wistar rats were bred for predisposition to catalepsy for 14 generations. The percentage of cataleptic rats, beginning from the F1, was about 50%, while in the control population it was about 9%. This, together with the data obtained after comparison of the proportion of cataleptic animals in the progeny from homogeneous crossings between rats of normal and cataleptic phenotypes from the group selected for catalepsy (16 and 48%, respectively), makes one suppose predisposition to catalepsy to be an oligogenic character. The later onset of stereotype-like reactions to administrations of methylphenidate, and their longer persistence in cataleptic animals points to inertness of dopaminergic systems. At the same time, the increased frequency of "hyperactivity"-like reactions to methylphenidate, as well as higher arterial pressure and lower frequency of defecations seem to reflect an increased excitability of noradrenergic brain systems in rats predisposed to catalepsy.     

Glutamate receptor antagonists attenuate experimental catalepsy in rats

A long-term akinesia induced by haloperidol used as an experimental model of catalepsy helped to reveal that a dicationic derivatives adamantane (IEM-1754) and phenylcyclohexyl (IEM-1925) exerted different degrees of inhibition of the haloperidol effect: the IEM-1754 proved to be not inferior to the most effective NMDA antagonist MK-801. A relatively low potency of the IEM-1925 may be due to its obvious equal effects both on the NMDA and the AMPA receptor channels. A good correlation between the anticataleptic effects of the glutamate antagonists and the NMDA receptor blocking activity, were found. The AMPA receptor blockade might negatively affect the anticataleptic potency of the drugs under study.     

Neurophysiology and analysis of the phenomenon of catalepsy

Neurophysiological mechanisms of the photogenic catalepsy (the "animal hypnosis"), genetic catalepsy, and cataplexy are discussed. The data obtained demonstrates a significance of the brainstem structures suppressing motor activity and the muscle tone in these conditions. Motor disorders associated with the general immobility are discussed from the standpoint of the evolutionary theory.     

Simultaneous catalepsy and apomorphine-induced stereotypic behavior in mice

Intraventricular administration of haloperidol or chlorpromazine produces catalepsy and blocks apomorphine-induced stereotypic behavior. Low intraventricular doses of domperidone, sulpiride and spiperone, equally cataleptogenic as haloperidol or chlorpromazine, augment rather than diminish stereotypic behavior produced by subsequent apomorphine treatment. The resultant stereotypic behavior continues even while the animal is in a rigid cataleptic posture and is marked by persistent gnawing and licking. Prior to the induction of catalepsy and after recovery from it, mice display the entire range of typical apomorphine-induced behavior including sniffing, climbing, gnawing, and licking. This animal model may be related to the clinical observation of the coexistence of tardive dyskinesia and drug-induced Parkinsonism in individual patients.     

The ECoG of rats with genetic catalepsy]

Electrographic study was carried out in Wistar rats and the rats of genetical catalepsy (GC) strain. In contrast to Wistar rats epileptiform activity was observed in ECoG of GC rats being enhanced at the transition to a cataleptic state. Analysis of spectra and coherence of EEG revealed the presence of interhemispheric brain asymmetry in all the rats. In some frequency bands in GC rats inversion of interhemispheric asymmetry was found, which had been characteristic for Wistar strain. The highest interhemispheric synchronization of biopotentials was observed in the frontal cortical areas in GC rats and in the occipital areas in those of Wistar strain.