Cataleptic Effects Of Haloperidol Research Articles

Immunohistochemical evidence for the involvement of gonadotropin releasing hormone in neuroleptic and cataleptic effects of haloperidol in mice

Blockade of dopamine D2 receptor by haloperidol is attributed for neuroleptic and cataleptic effects; and also for the release of gonadotropin releasing hormone (GnRH) from the hypothalamus. GnRH agonist is reported to exhibit similar behavioural effects as that of haloperidol, and pre-treatment with GnRH antagonist is shown to attenuate the effects of haloperidol, suggesting a possibility that GnRH might mediate the effects of haloperidol. To substantiate such possibility, the influence of haloperidol on GnRH immunoreactivity (GnRH-ir) in the brain was studied in vehicle/antide pre-treated mice by peroxidase–antiperoxidase method. Initially, an earlier reported antide–haloperidol interaction in rat was confirmed in mice, wherein haloperidol (250μg/kg, i.p.) exhibited suppression of conditioned avoidance response (CAR) on two-way shuttle box, and induced catalepsy in bar test; and pre-treatment with antide (50μg/kg, s.c., GnRH antagonist) attenuated both effects of haloperidol. Immunohistochemical study was carried out to identify GnRH-ir in the brain, isolated 1h after haloperidol treatment to mice pre-treated with vehicle/antide. The morphometric analysis of microphotographs of brain sections revealed that haloperidol treatment increased integrated density units of GnRH-ir in various regions of the limbic system. Considering basal GnRH-ir in vehicle treated group as 100%, the increase in GnRH-ir after haloperidol treatment was by 100.98% in the medial septum; 54.26% in the bed nucleus of the stria terminalis; 1152.85% in the anteroventral periventricular nucleus; 120.79% in the preoptic area–organum vasculosum of the lamina terminalis and 138.82% in the arcuate nucleus. Antide did not influence basal and haloperidol induced increase in GnRH-ir in any of the regions.As significant increase in GnRH-ir after haloperidol treatment was observed in such regions of the brain which are reported to directly or indirectly communicate with the hippocampus and basal ganglia, the regions respectively responsible for neuroleptic and cataleptic effects; and as GnRH antagonist eliminated the effects of haloperidol without affecting GnRH-ir, it appears that GnRH released by haloperidol mediates its neuroleptic and cataleptic effects.

Contribution of the central histaminergic transmission in the cataleptic and neuroleptic effects of haloperidol

The antipsychotic properties of haloperidol are primarily attributed to its ability to block dopamine D2 receptors. Histaminergic transmission modulates some of the behavioral effects of haloperidol. Hence, the present study investigated the contribution of central histaminergic transmission in the cataleptic and neuroleptic effect of haloperidol respectively, using bar test and conditioned avoidance response (CAR) in a two-way shuttle box. The studies revealed that haloperidol (0.50 or 1mg/kg, i.p.) exhibited cataleptic behavior and inhibited conditioned avoidance response (CAR) in the doses 0.25 or 0.50mg in rats. The rats, pretreated centrally (i.c.v.) with histamine precursor, l-histidine (1, 2.5μg) or histamine neuronal inducer (H3 receptor antagonist), thioperamide (20, 50μg/rat), showed an enhanced cataleptic effect with sub-maximal dose of haloperidol (0.5mg/kg, i.p.). Similarly, the neuroleptic effect of haloperidol (0.25mg/kg, i.p.) in CAR was also potentiated in the rats pretreated with l-histidine (2.5μg) or thioperamide (50μg/rat). Further, the cataleptic effect of haloperidol (1mg/kg, i.p.) was attenuated in rats pretreated with the H1 receptor antagonist, chlorpheniramine (60, 80μg/rat, i.c.v.) or H2 receptor antagonist, ranitidine (60μg/rat, i.c.v.). However, the neuroleptic effect of haloperidol (0.5mg/kg, i.p.) was completely reversed by pretreatment with ranitidine (60μg/rat, i.c.v.), and partially attenuated by chlorpheniramine (80μg/rat, i.c.v.). These findings suggest the possible involvement of histaminergic transmission in the cataleptic and neuroleptic effects of haloperidol probably via H1 or H2 receptor stimulation.

A possible participation of gonadotropin-releasing hormone in the neuroleptic and cataleptic effect of haloperidol

Haloperidol, an antipsychotic agent, stimulates the release of gonadotropin-releasing hormone (GnRH), and this hormone is known to mimic some of the behavioral effects of haloperidol. Hence, the present study was carried out to find out the contribution of GnRH in the behavioral effects of haloperidol. The studies revealed that haloperidol (0.15, 0.25 and 0.5 mg/kg, i.p.) and leuprolide (GnRH agonist; 50, 100, 200 and 400 microg/kg, s.c.) dose-dependently inhibited conditioned avoidance response (CAR) in male Sprague-Dawley rats. In higher doses, haloperidol (0.5, 1 mg/kg, i.p.) and leuprolide (200, 400 microg/kg, s.c.) produced catalepsy in rats. Co-administration of sub-effective dose of leuprolide (50 or 100 microg/kg, s.c.) and haloperidol (0.15 or 0.5 mg/kg, i.p.) similarly inhibited CAR and induced catalepsy. Pre-treatment of rats with antide (GnRH antagonist; 10 microg/rat, s.c.), attenuated the inhibitory effect of both the agents on CAR; blocked leuprolide-induced catalepsy; and attenuated the intensity and reduced the duration of haloperidol-induced catalepsy. In conclusion, the studies suggest a possible role of GnRH in the neuroleptic and cataleptic effect of haloperidol.

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.

Alteration of cataleptic responses induced by dopamine receptor antagonists after chronic cocaine administration in mice

The influence of chronic treatment of mice with cocaine, an indirect dopamine receptor agonist, on the cataleptic effects of R-(+)-chloro-2,3,4,5,-tetrahydro-3-methyl-5-phenyl-1 H-3-benzazepin-7ol hydrochloride (SCH23390), a dopamine D 1 receptor antagonist, or haloperidol, mainly a dopamine D 2 receptor antagonist, was investigated. Mice were given cocaine (10 mg/kg s.c.) once every other day for 7 (4 injections), 15 (8 injections) or 21 (11 injections) days. The cataleptic effects of SCH23390 (0.3 mg/kg i.p.) were significantly reduced when it was given 1–7 days after the last dose of a 7- or 15-day pretreatment course of cocaine. When SCH23390 was given 14–21 days after the cocaine the cataleptic effect was increased in the 15-day, but not the 7-day, cocaine-pretreated mice. However, after a 21-day treatment with cocaine, a challenge dose of SCH23390 given 1–3 days thereafter produced a decreased cataleptic response, but an increased response after 7–21 days. The cataleptic effects of haloperidol (0.3 mg/kg i.p.) were reduced when it was given 1–7 days after the last dose of a 7-day pretreatment, but increased 1–3 days after that of a 15-day pretreatment with cocaine (10 mg/kg s.c.). The pretreatment with cocaine for 21 days did not affect the haloperidol catalepsy during a 1- to 3-day withdrawal period. However, haloperidol catalepsy was decreased only 7 days, then reversed 14 days and gradually increased 21 days after the last injection of a 15- or 21-day pretreatment course of cocaine. These results suggest that chronic treatment with the indirect dopamine receptor agonist, cocaine, caused supersensitivity of dopamine D 1 receptors (a decrease in SCH23390 catalepsy) during the early withdrawal period and subsensitivity (an increase in SCH23390 catalepsy) after a longer period of withdrawal. It was apparent that the longer the period and the higher the dose of pretreatment with cocaine, the less were the alterations in initial responses and the greater were the alterations in subsequent responses to the dopamine D 1 receptor antagonists.

Development of tolerance and reverse tolerance to haloperidol- and SCH23390-induced cataleptic effects during withdrawal periods after long-term treatment

The development of tolerance and reverse tolerance and reverse tolerance to the cataleptic effects of selective D 1 antagonist, SCH23390, and the mainly D 2 antagonist, haloperidol, was investigated in mice that had been chronically treated (7 or 30 days) with haloperidol (l mg/kg SC), SCH23390 (0.5 mg/kg SC), or saline (5 ml/kg SC). In control animals, SCH23390 (0.1–1.0 mg/kg IP) and haloperidol (0.1–1.0 mg/kg IP) produced cataleptic responses in a dose-dependent manner, although the responses had different time course profiles. SCH23390 catalepsy had a rapid onset but a short duration, whereas haloperidol catalepsy had a slower onset and longer duration. This could be due to differences in lipid solubility of the drugs, or at least pertly to an action of the drugs on different neuronal pathways. The cataleptic effects of SCH23390 (0.3 mg/kg IP) and haloperidol (0.3 mg/kg IP) were significantly reduced in mice when given 24 h, but not 72 h, after the last dose of a 7 day-pretreatment course (short-term treatment) of SCH23390. However, after long-term treatment (30 days) with SCH23390, a challenge dose of SCH23390 exhibited reverse tolerance (i.e., increased catalepsy) when given 7–21 days, but not 1–3 days, after the last injection of the SCH23390 pretreatment course. In contrast, haloperidol catalepsy was not affected by long-term SCH23390 treatment. However, after the last dose of long-term haloperidol treatment both SCH23390 and haloperidol exhibited tolerance to their cataleptic effects at 1–3 days, a normal response at 7 days, and an exaggerated response (reverse tolerance) at 15–21 days. These results suggest that a prolonged withdrawal period after chronic D 1 antagonist treatment is necessary for the development of reverse tolerance to a D 1 antagonist (an increase in catalepsy), which may be a reflection of a long-lasting subsensitivity of D 1 receptors. Long-term treatment with a D 2 receptor antagonist caused supersensitivity of D 1 and D 2 receptors during the early withdrawal period and subsensitivity after a longer period of withdrawal. These results also provide evidence that the cataleptic effects of SCH23390 may be mediated by indirect blockade of D 2 receptor function through its D 1 blocking action, whereas the cataleptic effects of haloperidol may be affected by supersensitivity of D 1 receptors, but not by their subsensitivity.

Dopaminergic behavior in frontal decorticated rats

Decortication of the frontal neocortex in rats enhanced the increased general activity caused by methamphetamine, 0.15 mg/kg, SC. However, the low, 0.1 mg/kg, SC, and high, 0.5 mg/kg, SC, dose effects of apomorphine were not affected by the decortication. The cataleptic effect of haloperidol, 2 mg/kg, SC, was decreased. The data suggest that the frontal cortex may inhibit dopamine release in mesolimbic and nigrostriatal areas. However, the sensitivity of presynaptic or postsynaptic dopamine receptor systems in the nucleus accumbens area appears to be unaltered by frontal decortication.

Modification of the behavioural effects of haloperidol and of dopamine receptor regulation by altered thyroid status.

Rats made hypothyroid by the chronic oral administration of 200 mg/kg propylthiouracil were less sensitive to the cataleptic effects of haloperidol (0.1 mg/kg) treatment than were euthyroid rats chronically treated with isotonic saline. However, rats made hyperthyroid by the chronic injection of 200 micrograms/kg thyroxine were not more sensitive to the cataleptic suppressant effects of haloperidol (0.1 mg/kg). Higher doses of haloperidol (1 and 5 mg/kg) produced significantly greater catalepsy in the hyperthyroid rats and significantly reduced catalepsy in the hypothyroid rats. Receptor binding studies carried out on the striata from rats sacrificed 48 h after a 6-day course of chronic haloperidol (0.1 mg/kg once daily) treatment revealed a significant upregulation (increase) of dopamine receptors in the hypothyroid rats only. These findings are consistent with the hypothesis that altered thyroid status can modify the sensitivity of dopamine receptors.

Haloperidol-induced catalepsy is mediated by postsynaptic dopamine receptors.

Antipsychotic or neuroleptic drugs, which block central dopamine receptors, produce a behavioural state in animals in which they fail to correct externally imposed postures. This is referred to as catalepsy. Previous lesion studies have shown that the dopamine receptors in the striatum are involved in this neuroleptic-induced catalepsy. Dopamine receptors, identified by the specific, high-affinity binding of the potent neuroleptic haloperiodol, have been shown to be equally distributed postsynaptically on striatal neurones and presynaptically on cortico-striatal terminals. Because the electrolytic lesioning studies have unavoidably damaged both pre- and postsynaptic striatal dopamine receptors, it is not known whether these two receptors are separately involved in neuroleptic-induced catalepsy. Using kainic acid and cortical ablation to destroy postsynaptic and presynaptic dopamine receptors, respectively, the present study demonstrates that the cataleptic effects of haloperidol are apparently mediated by dopamine receptors localised postsynaptically on striatal neurones.

The nucleus amygdaloideus centralis and neuroleptic activity in the rat

The bilateral electrolytic brain lesion technique was used to determine the role of the nucleus amygdaloideus centralis (ACE) in the mediation of the cataleptic and antistereotypic (amphetamine) effects of the neuroleptic agents (antipsychotic) and metoclopramide (non-antipsycotic). The cataleptic effects of haloperidol, fluphenazine, AHR2277, clothiapine and oxypertine were markedly reduced or abolished at the lower dose levels by the ACE lesions. The reducion in the clothiapine effect was readily overcome by increasing the dosage whilst the reduction in the effects of haloperidol, fluphenazine and AHR2277 were only partially overcome at high doses. The marked reduction in the cataleptic effect of oxypertine was apparent at all doses. ACE lesions failed to modify clozapine whilst this effect of metoclopramide was markedly reduced at all doses used. The antistereotypic activities of haloperidol, fluphenazine, oxypertine and clothiapine were not significantly modified by ACE lesions although the abilities of AHR2277, clozapine and metoclopramide to antagonise stereotypy were significantly reduced. The results indicate an involvement of the ACE with both neuroleptic- and metoclopramide-induced cataleptic behaviour and, to varying degrees, with the antistereotypic activity of these agents. Differences in the sites and modes of action of the neuroleptics are considered and results are discussed in relation to the use of the catalepsy and antistereotypy tests as indicators of antipsycotic activity.