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PubMed2006

Translocation of AIF in the human and rat striatum following protracted haloperidol, but not clozapine treatment.

Loss of mitochondrial membrane integrity and consequent release of apoptogenic factors may be involved in mediating striatal neurodegeneration after prolonged treatment with the typical antipsychotic drug haloperidol. Apoptosis-inducing factor (AIF), an intramitochondrial protein, may have a large influence on mediating haloperidol-induced striatal neuron destruction. Translocation of this protein from mitochondria to the nucleus promotes cell death independently of the caspase cascade. To examine how AIF may contribute to haloperidol-induced apoptosis, AIF translocation was observed in three haloperidol treatment paradigms. SH-SY5Y cells were treated with both haloperidol and clozapine and examined for AIF immunofluorescence. Immunohistochemistry was also performed on human striatal sections obtained from the Stanley Foundation Neuropathology Consortium and on rat brain sections following 28 days of antipsychotic drug treatment. In the cellular model haloperidol, but not clozapine treatment increased the nuclear AIF immunofluorescent signal and decreased cell viability. Corollary to these findings, striatal sections from patients who had taken haloperidol and rats who were administered haloperidol both had an elevated nuclear AIF signal. The results provide novel evidence implicating the involvement of AIF in haloperidol-associated apoptosis and its relevance to the development of typical antipsychotic drug-related adverse effects such as tardive dyskinesia.

Animals↗
PubMed1982

Tyrosine hydroxylase activation. Comparison of in vitro phosphorylation and in vivo administration of haloperidol.

Rat striatal tyrosine hydroxylase (TH) was assayed 2 hr following treatment with 1 mg/kg haloperidol. TH activity in striata from haloperidol-treated rats (haloperidol TH) was increased significantly relative to control when assayed at pH 7.0, but not at pH 6.0, in the presence of 175 muM tetrahydrobiopterin (BH4). TH was also phosphorylated in vitro, catalyzed by sufficient quantities of the catalytic subunit of bovine heart protein kinase to cause greater than 90% activation after 10 min. TH was activated by phosphorylation at both pH 6.0 and pH 7.0, but the activation was greater at pH 7.0. Haloperidol TH, activated relative to control TH at pH 7.0, was activated by phosphorylation, but there was no difference between haloperidol TH and control TH activity at either pH 6.0 or 7.0 following phosphorylation. Comparison of Lineweaver-Burk plots of nonphosphorylated and phosphorylated TH indicated that activation by phosphorylation was due to a 5-fold change in Km for BH4 and a 2-fold change in Vmax at pH 7.0. Haloperidol TH kinetics were intermediate between those of nonphosphorylated and phosphorylated TH at pH 7.0. Analysis by Lineweaver-Burk, Hanes-Woolf, and Eadie-Scatchard plots suggested that the haloperidol TH kinetic data were the result of a mixture of two forms of the enzyme, with different affinities for cofactor. Theoretical calculations of TH activity of mixtures of nonphosphorylated and phosphorylated TH suggested that the haloperidol data could be explained by postulating a mixture of 25-35% phosphorylated TH molecules with 65-75% nonphosphorylated TH molecules. An hypothesis of the role of TH phosphorylation during conditions of increased neuronal firing rate, such as may occur with haloperidol treatment, is presented.

Animals↗
PubMed1987

Conditioning and the delayed onset of a haloperidol-induced behavioral effect.

In a series of experiments, rats were given daily injections of 0.3 mg/kg haloperidol or vehicle 1 hr prior to behavioral testing. In these experiments, when rats were placed in an illuminated compartment and given the opportunity to enter a darkened compartment, haloperidol- and vehicle-treated rats initially entered the dark compartment with similar latencies. With repeated treatments, however, the haloperidol group gradually took increasingly longer times to enter the dark compartment. Furthermore, when the drug treatments of the groups were reversed, behavioral performance was dissociated from the drug state of the animal. Vehicle rats switched to haloperidol entered the dark compartment much more rapidly than haloperidol rats switched to vehicle. As additional control procedures, rats were given haloperidol 1 hr posttrial or were given haloperidol and only placed in the dark compartment. These haloperidol treatments did not differ from vehicle treatments. The gradual development of long latencies to initiate behavior and the persistence of this behavior during withdrawal from the haloperidol are consistent with the establishment of a conditioned drug response. This observation suggests that conditioning may contribute to the delayed onset of response in the clinical use of neuroleptic drugs.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1989

Chronic haloperidol treatment with low doses may enhance the increase of homovanillic acid in rat brain.

Homovanillic acid (HVA) levels were determined by high performance liquid chromatography with electrochemical detection in the striatum and prefrontal cortex of rats that had received single or repeated injections of various doses of haloperidol. Haloperidol increased the HVA concentrations in both brain regions after both acute and chronic treatment with doses of 0.01-1 mg/kg. The increase in the HVA concentrations in the striatum was blunted after repeated haloperidol injections with doses of 0.5-1 mg/kg, suggesting that haloperidol pretreatment results in a decreased responsiveness to the drug at high doses (tolerance). Tolerance also developed to the effect of long-term haloperidol treatment on the HVA concentrations in the prefrontal cortex at the highest dose used (1 mg/kg). This suggests that the differences in the development of tolerance between the striatum and prefrontal cortex are not qualitative but quantitative. However, repeated haloperidol injections at doses of 0.01-0.05 mg/kg enhanced the increase in HVA concentrations. This suggests that tolerance does not develop after chronic haloperidol treatment with low doses. Decreased HVA concentrations were also found after withdrawal from chronic haloperidol treatment (rebound decrease). However, this rebound decrease was much smaller than the decrease in response of the HVA concentrations to repeated haloperidol injections, suggesting that different mechanisms are involved.

Animals↗
PubMed1990

Metabolites of haloperidol display preferential activity at sigma receptors compared to dopamine D-2 receptors.

Haloperidol bound with equal affinity to sigma and dopamine D-2 receptors (KI = 2.8 nM). Compared to haloperidol, its carbonyl-reduced metabolite bound to sigma receptors with nearly equal affinity. However, reduced haloperidol bound to dopamine receptors with 85-fold lower affinity compared to haloperidol (KI = 239 nM). The chlorophenyl-hydroxy-piperidine metabolite of haloperidol lacked affinity for dopamine receptors, but bound with moderate affinity to sigma receptors (KI = 326 nM). The carboxylic acid metabolite lacked affinity for either receptor. Like haloperidol, (+)-pentazocine, and 1,3-di-o-tolylguanidine, reduced haloperidol potently inhibited the phosphoinositide response to muscarinic agonists in rat brain synaptoneurosomes, an assay which monitors sigma agonist activity. This metabolite also produced a dystonic alteration of head position in rats when microinjected into the red nucleus. However, unlike observations with haloperidol and other sigma ligands, this effect was associated with pathological changes in the red nucleus. Therefore, it cannot be attributed to sigma receptor interactions with certainty. These findings suggest that administration of haloperidol results initially in effects mediated through both dopamine and sigma receptors, but as metabolism proceeds the sigma actions would be expected to decline at a significantly slower rate than the dopaminergic actions.

Animals↗
PubMed1986

Increased sensitivity of adenylate cyclase activity in the striatum of the rat to calmodulin and GppNHp after chronic treatment with haloperidol.

Chronic treatment of rats with haloperidol causes behavioral supersensitivity to dopaminergic agonists and an increase in the sensitivity of adenylate cyclase activity in the striatum to stimulation by dopamine. In this study the authors examined whether chronic treatment with haloperidol could elicit a change in sensitivity of adenylate cyclase in the striatum of the rat for guanyl nucleotides and the endogenous Ca2+-binding protein, calmodulin. These agents increase the activation of adenylate cyclase activity by dopamine but act beyond the level of the dopamine receptor. Male, Sprague-Dawley rats were injected subcutaneously with either 0.6 mg/kg haloperidol or vehicle for 14 days. Four days after the last injection, the animals were sacrificed and the activity of adenylate cyclase was measured in a EGTA-washed particulate preparation of the striatum. There was an increase in the activation of adenylate cyclase activity by calmodulin and GppNHp but not by guanosine triphosphate (GTP) in particulate fractions of the striatum from rats treated with haloperidol as compared to controls. The sensitivity of adenylate cyclase to calmodulin was increased 5-fold in particulate fractions from rats treated with haloperidol as opposed to vehicle-treated rats. The lack of change in activation by GTP was not due to an altered activity of GTPase in rats treated with haloperidol. In animals treated for 14 days but not withdrawn from haloperidol there was no statistically significant increase in the sensitivity of adenylate cyclase to calmodulin. There was no change in activation of the enzyme by GppNHp or GTP as compared to control. The activation of adenylate cyclase by calmodulin was not affected when haloperidol was added in vitro to the assay or after the acute injection of rats with haloperidol.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗
PubMed1984

Salivary secretion induced by L-DOPA in haloperidol-treated rats.

The effect of chronic haloperidol treatment on salivary secretion induced by L-dopa, was studied in male Sprague-Dawley rats. Dose-response relationships for L-dopa, obtained 24 h after haloperidol treatment, showed that salivary secretion was greater in rats that had been injected with haloperidol (2 mg/kg/day, i.p.) for 7 days than in controls. The threshold doses requirements were significantly reduced in that group. Pretreatment with carbidopa suppressed the salivary secretion produced by L-dopa in haloperidol-treated and control rats whose glands had been denervated. The secretory response in innervated glands was higher in haloperidol-treated animals than in controls. Haloperidol treatment also increased salivation induced by L-noradrenaline as determined by dose-response relationships. This was associated with a decrease in the threshold doses requirement. In controls and in rats chronically treated with haloperidol, the salivary responses to L-noradrenaline were temporarily depressed by 80-90% by a prior acute injection of haloperidol (2 mg/kg, i.v.) presumably acting as an alpha blocker. A similar reduction was observed after acute treatment with phentolamine (3 mg/kg, i.v.). The data obtained in this study, i.e. that chronic administration of haloperidol increases the salivary response to L-dopa and L-noradrenaline, suggests that such an affect could be due to the development of supersensitivity of striatal dopamine receptors as well as of peripheral alpha-adrenergic receptors.

Animals↗
PubMed1991

Chronic ascorbate potentiates the effects of chronic haloperidol on behavioral supersensitivity but not D2 dopamine receptor binding.

Ample behavioral evidence suggests that ascorbate parallels the action of haloperidol, a widely used neuroleptic. To determine the extent to which this parallel extends to chronic treatment, 21 days of exposure to ascorbate (100 or 500 mg/kg) alone or combined with haloperidol (0.5 mg/kg) were assessed on stereotyped behavior and neostriatal D2 dopamine receptor binding in rats. Our results indicate that when challenged with the dopamine agonist, apomorphine (0.5 mg/kg), animals chronically treated with haloperidol or high-dose ascorbate alone display a supersensitive sniffing response relative to controls, while animals chronically treated with the combination of haloperidol and high-dose ascorbate display a further potentiation of sniffing relative to the haloperidol groups. In addition, [3H]spiperone saturation studies showed, as expected, an up-regulation of striatal D2 dopamine receptors in rats treated with haloperidol as reflected by a change in receptor density (Bmax) but not affinity (KD). Ascorbate treatment, however, had no effect on D2 receptor density or the distribution of [3H]apomorphine in whole brain. Even though chronic treatment with the haloperidol-high-dose-ascorbate combination produced an up-regulation of striatal D2 dopamine receptors, this treatment did not cause a further up-regulation relative to haloperidol alone nor did it have any effect on [3H]apomorphine distribution. Taken together, these findings indicate that although chronic ascorbate produces behavioral supersensitivity to apomorphine through central mechanisms, they appear to differ from those induced by chronic haloperidol.

Amphetamines↗
PubMed2006

Correlation of haloperidol levels between submandibular saliva and brain in the rat.

OBJECTIVE: The clinical usefulness of therapeutic drug monitoring (TDM) for haloperidol using blood samples has to be validated. Despite the potential advantage of TDM using saliva, there are few reports comparing drug levels in saliva and blood. Additionally, the relation between haloperidol levels in saliva and brain, the target organ of this drug, has not been reported. We compared haloperidol levels in rat submandibular saliva, plasma and brain. DESIGN: Haloperidol was administered through the femoral vein (0.25 mg/kg). Submandibular saliva was collected 30 min after drug administration. To stimulate secretion, the chorda (parasympathetic) and superior cervical ganglion (sympathetic) were electrically stimulated, and pilocarpine was administered. The concentration of haloperidol in saliva, plasma and brain homogenate was determined. RESULTS: Haloperidol levels in saliva elicited by any stimuli significantly correlated with levels in the brain and plasma. The correlation of haloperidol between saliva and brain was higher than that between plasma and brain. Immunohistochemistry showed that haloperidol was secreted from striated duct cells within the submandibular gland. CONCLUSION: These results suggested that haloperidol was specifically secreted from the striated duct system, and that salivary drug levels reflect the levels in the brain more precisely than plasma.

Animals↗
PubMed2004

Role of NMDA receptor subtypes in the induction of catalepsy and increase in Fos protein expression after administration of haloperidol.

The increase of Fos expression in the striatum induced by haloperidol, an antagonist of the dopamine D2 receptor, might be related to the activation of glutamatergic neurotransmission, especially that of N-methyl-D-aspartate (NMDA) receptors. In this study, using behavioral and immunohistochemical techniques, we examined the effects of a noncompetitive NMDA antagonist, (+)-MK-801, and an NMDA receptor NR2B subunit antagonist, ifenprodil, on catalepsy, an extrapyramidal symptom; in this context, we also considered the expression of Fos protein in the forebrain after the administration of haloperidol. Catalepsy in mice, induced by the administration of haloperidol (1 mg/kg), was inhibited by pretreatment with (+)-MK-801 (0.2 mg/kg) or ifenprodil (10 mg/kg). Furthermore, pretreatment with (+)-MK-801 (0.2 mg/kg) significantly attenuated the induction of Fos-immunoreactive (IR) cells in the dorsomedial, dorsolateral, and ventrolateral striatum, but not in the shell region of the nucleus accumbens after the administration of haloperidol, whereas pretreatment with ifenprodil (10 mg/kg) significantly attenuated the induction of Fos-IR cells in all of these areas. It is known that ifenprodil binds sigma receptors and alpha-1 adrenergic receptors with high affinity. Pretreatment with the sigma receptor antagonist BD-1407 (3 mg/kg) or the alpha-1 adrenergic receptor antagonist prazosin (3 mg/kg) affected neither catalepsy nor the expression of Fos-IR cells after the administration of haloperidol. However, pretreatment with CP-101,606 (1 mg/kg), a selective antagonist for the NR2B subunit of the NMDA receptor, significantly attenuated catalepsy and the expression of Fos-IR cells in the forebrain after the administration of haloperidol. These results suggest that the NMDA receptor antagonists attenuated the induction of catalepsy and Fos-IR cells in forebrain after the administration of haloperidol. It was also suggested that haloperidol-induced expression of Fos-IR cells in the shell region of the nucleus accumbens might be differentially regulated by NMDA receptor subunits. Therefore, it appears that selective antagonists for the NR2B subunit of the NMDA receptor (e.g., CP-101,606) might be useful drugs for the treatment of extrapyramidal side effects (EPS) associated with the chronic use of typical antipsychotics such as haloperidol.

Adrenergic alpha-Antagonists↗
PubMed2005

Haloperidol treatments increased macrophage activity in male and female rats: influence of corticosterone and prolactin serum levels.

Haloperidol is a receptor D2 antagonist frequently used in the treatment of schizophrenic patients. Haloperidol increased prolactin release from anterior pituitary gland, and prolactin modulates immune system activity. Groups of six male and female rats received an acute 2 mg/kg haloperidol treatment (E1), or a long-term (E2) haloperidol treatments (2 mg/kg/day for 21 days); control rats were treated similarly, but with control solution (groups C1 and C2, respectively). In this work long-term haloperidol treatment (E2) increased macrophage spreading, phagocytosis and NO release in male and female rats. However, acute haloperidol treatment (E1) did not change macrophage activity. Corticosterone and prolactin serum levels were increased after acute (E1) and long-term (E2) haloperidol treatments in male and female rats, being this increment higher in female. Macrophage of male and female rats presented the same pattern of alterations after acute and long-term haloperidol treatments. Haloperidol-induced macrophage activation was discussed in the light of a possible indirect effect through prolactin increments in rats, or, alternatively, as a consequence of a direct action of macrophage dopamine receptor.

Animals↗
PubMed2003

Role of NR2B-containing N-methyl-D-aspartate receptors in haloperidol-induced c-Fos expression in the striatum and nucleus accumbens.

Administration of haloperidol in rats leads to a robust induction of immediate-early genes including c-Fos throughout the striatum, which is significantly attenuated by pretreatment with the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801. The striatum expresses mainly NR1/NR2A and NR1/NR2B subtypes of NMDA receptors, each having different functional and pharmacological properties. In this study, rats were pretreated with Ro 25-6981, a selective antagonist for NR2B-containing NMDA receptors, in order to determine the relative contribution of this NMDA receptor subtype in NMDA-dependent haloperidol-induced c-Fos expression. Furthermore, to determine whether NMDA receptor subtype dependence of haloperidol-induced c-Fos expression is unique to the binding profile of haloperidol or whether it is a property of D2 receptor antagonism, the selective D2/D3 dopamine receptor antagonist, raclopride, was also used. Pretreatment with Ro 25-6981 led to a significant reduction in the number of nuclei showing c-Fos immunoreactivity in both the medial and lateral parts of the striatum. In the medial part of the striatum, this attenuation was almost as marked as that seen following pretreatment with MK-801; however, in the lateral part MK-801 pretreatment led to a significantly greater reduction in the number of c-Fos positive nuclei than did Ro 25-6981 pretreatment. This suggests that NR2B-containing NMDA receptors are involved in mediating most of the NMDA-dependent c-Fos expression in the medial striatum, but only responsible for mediating part of this induction in the lateral striatum. Furthermore, the pattern of attenuation of raclopride-induced c-Fos expression following Ro 25-6981 pretreatment was similar to that of haloperidol-induced c-Fos expression, indicating that the NMDA receptor subtype dependence of haloperidol-induced c-Fos expression is a property of D2 antagonism. The results indicate that NR2B-containing NMDA receptors are mainly involved in mediating haloperidol-induced c-Fos expression in the medial or "limbic" striatum, and suggest that NR2A-containing NMDA receptors may preferentially mediate haloperidol induced c-Fos expression in the lateral or "motor" striatum. This may have implications in the treatment of schizophrenia because co-administration of a selective blocker of NR2A-containing NMDA receptors may be able to reduce the severity of extrapyramidal motor symptoms caused by haloperidol treatment without interfering with its therapeutic effect that is presumably mediated via the medial part of the striatum.

Animals↗
PubMed1998

Expression of Fos protein in the limbic regions of the rat following haloperidol decanoate.

To identify sites of antipsychotic drug action, the effects of acute and chronic haloperidol treatment on Fos protein expression in rat brain regions were examined by immunohistochemical methods. Male Wistar rats were injected with haloperidol decanoate (40 mg/kg, i.m. ) or vehicle. Fourteen days after injection, each rat was given an acute subcutaneous injection of haloperidol (0.25 mg/kg) or vehicle, and was transcardially perfused 2 h after the second injection. A single dose of haloperidol to chronic vehicle-treated rats produced significant increases in Fos-positive neurons in 18 of 21 brain regions examined including the several cortical areas, caudate-putamen, nucleus accumbens, lateral septum, thalamic nuclei, amygdala, hippocampus CA1, mesencephalic dopaminergic nuclei, and periaqueductal grey. The rats treated with acute vehicle after chronic haloperidol showed persistent Fos increases in confined brain regions comprising the lateral and central amygdala, lateral septum, and entorhinal cortex. Additional haloperidol injection to the chronic haloperidol-treated rats induced significant increases in Fos immunoreactivity in more widespread limbic-thalamo-cortical areas, whereas no significant increase was seen in the dorsolateral caudate-putamen. The persisting effects of haloperidol in the limbic and related structures, especially the amygdala, lateral septum, and entorhinal area may be of significance to the efficacy of long-term haloperidol treatment.

Analysis of Variance↗
PubMed2001

Haloperidol-stomach lesions attenuation by pentadecapeptide BPC 157, omeprazole, bromocriptine, but not atropine, lansoprazole, pantoprazole, ranitidine, cimetidine and misoprostol in mice.

The focus was on haloperidol (central dopamine antagonist)-stomach lesion, a longly described suitable counterpart of dopamine blocker cysteamine-duodenal lesion. In this, the contribution of blockade of central/peripheral dopamine receptors and prostaglandins synthesis, along with influence of antiulcer agents was evaluated in mice. Male NMRI Hannnover mice were sacrificed 24 h after haloperidol (25 mg/kg b.w. i.p., given alone or with saline (haloperidol+saline) (i) or in combination (ii,iii)). Supporting central dopamine predominance for haloperidol stomach lesion induction, co-administration of peripheral dopamine receptor antagonist domperidone (5 mg/kg i.p.) (haloperidol+ domperidone) (ii), or prostaglandin synthesis inhibitor indomethacin (10 mg/kg s.c.) (haloperidol+ indomethacin) (iii) did not aggravate this lesion. (i) In haloperidol+saline challenged mice the lesions were inhibited by co-administration (/kg i.p.) of a gastric pentadecapeptide BPC 157, GlyGluProProProGlyLysProAlaAspAspAlaGlyLeuVal, M.W. 1419 (10 microg, 10 ng, 10 pg, but not 1 pg, 100 fg, 10 fg), bromocriptine (10 mg), omeprazole (10 mg, 100 mg, but not 1 mg). Atropine (10, 100, 200 mg), pirenzepine (10, 100, 200 mg), misoprostol (10, 100, 200 microg), pantoprazole (1, 10, 100 mg), lansoprazole (0.1, 1, 10 mg), cimetidine (10, 100, 200 mg) and ranitidine (10, 100, 200 mg) were not effective. (ii) Dopamine peripheral blockade influence: in haloperidol+domperidone mice, previously effective bromocriptine, pentadecapeptide BPC 157 (10 microg) or omeprazole (10 mg) did not attenuate stomach lesions. (iii) Prostaglandins synthesis blockade effect: in haloperidol+indomethacin mice, previously effective agents, bromocriptine or omeprazole were not active, while BPC 157 effect was only lessened.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed2000

Chronic haloperidol-induced alterations in pallidal GABA and striatal D(1)-mediated dopamine turnover as measured by dual probe microdialysis in rats.

Using dual probe microdialysis, assessment of extracellular neurotransmitter levels in the corpus striatum and globus pallidus was performed in ovariectomized and gonadally intact female, Sprague-Dawley rats following chronic (24 weeks) oral haloperidol administration. Vacuous chewing movements, an animal analog of orofacial dyskinesia, were also recorded at several time points during haloperidol administration and throughout the dialysis sampling session. Basal GABA levels were significantly elevated in the globus pallidus of haloperidol-treated rats compared with vehicle animals. Injection of the dopamine D(1) agonist dihydrexidine (3mg/kg, s.c.) decreased striatal dopamine levels in both vehicle and haloperidol-treated rats, with a larger decrease seen in haloperidol-treated rats. Furthermore, dihydrexidine reduced striatal 3,4-dihydroxyphenylacetic acid and homovanillic acid levels only in haloperidol-treated rats. Gonadal status had no effect on any neurochemical measure. Vacuous chewing movements were significantly elevated in haloperidol-treated groups by the sixth week of treatment, with higher counts seen in gonadally intact rats. Vacuous chewing movements were significantly elevated above baseline in all groups following dihydrexidine, with no differential effect of prior haloperidol treatment or gonadal status. These results indicate a tonic increase in pallidal GABA levels and a hypersensitivity of D(1)-mediated striatal dopamine and dopamine metabolite decreases following chronic haloperidol treatment. While not found to be correlated with neurochemical measures, the heightened vacuous chewing movements in gonadally intact vs ovariectomized rats may serve as a model of hormone-mediated differences in neuroleptic-induced oral dyskinesia.

Animals↗
PubMed2006

The effect of nitric oxide on fentanyl and haloperidol-induced catalepsy in mice.

BACKGROUND AND OBJECTIVES: This study was designed to investigate the role of nitric oxide on catalepsy induced by fentanyl and haloperidol. METHODS: Male albino mice were treated either with fentanyl (0.1-0.2 mg kg-1, s.c.) or haloperidol (0.5-2 mg kg-1, i.p.). The non-selective nitric oxide synthase inhibitor, NG-nitro-L-arginine (10 mg kg-1, i.p.), selective neuronal nitric oxide synthase inhibitor, 7-nitroindazole (3 mg kg-1, i.p.), and nitric oxide donors, L-arginine (30-300 mg kg-1, i.p.) and D-arginine (30 mg kg-1, i.p.), were applied 20 min prior to fentanyl or haloperidol injection. A mu-opioid receptor antagonist naloxone (1 mg kg-1, i.p.) was also given in some groups. The cataleptic status of mice was assessed by placing animals in a rearing position in the cage. If the mouse maintained cataleptic posture for more than 20 s, it was scored as cataleptic and duration of catalepsy was expressed in terms of minutes. RESULTS: Both NG-nitro-L-arginine and 7-nitroindazole prolonged fentanyl-induced catalepsy (fentanyl: 3.6+/-0.8 min; fentanyl+NG-nitro-L-arginine: 77.4+/-14.6 min, fentanyl+7-nitroindazole: 56.0+/-10.4 min; n=6; P<0.01). This effect was reversed by L-arginine and naloxone, but not by D-arginine. Nitric oxide synthase inhibitors also prolonged the cataleptic action of haloperidol but to a lesser extent (haloperidol: 72.0+/-6.3 min; haloperidol+NG-nitro-L-arginine: 98.5+/-6.3 min, haloperidol+7-nitroindazole: 89.6+/-2.2 min; n=6; P<0.05). The prolongation of haloperidol-induced catalepsy with nitric oxide synthase inhibitors was not reversed by L-arginine. CONCLUSION: These results suggest a common mechanism between mu-opioid receptors and the nitric oxide system in the development of fentanyl-induced catalepsy in mice different from haloperidol-induced catalepsy.

Animals↗
PubMed2004

Inhibition of ATP-sensitive potassium channels by haloperidol.

Chronic haloperidol treatment has been associated with an increased incidence of glucose intolerance and type-II diabetes mellitus. We studied the effects of haloperidol on native ATP-sensitive potassium (K(ATP)) channels in mouse pancreatic beta cells and on cloned Kir6.2/SUR1 channels expressed in HEK293 cells. The inhibitory effect of haloperidol on the K(ATP) channel was not mediated via the D2 receptor signaling pathway, as both D2 agonists and antagonists blocked the channel. K(ATP) currents were studied using the patch-clamp technique in whole-cell and outside-out patch configurations. Addition of haloperidol to the extracellular solution inhibited the K(ATP) conductance immediately, in a reversible and voltage-independent manner. Haloperidol did not block the channel when applied intracellularly in whole-cell recordings. Haloperidol blocked cloned Kir6.2/SUR1 and Kir6.2DeltaC36 K(ATP) channels expressed in HEK cells. This suggests that the drug interacts with the Kir6.2 subunit of the channel. The IC(50) for inhibition of the K(ATP) current by haloperidol was 1.6 microM in 2 mM extracellular K(+) concentration ([K(+)](o)) and increased to 23.9 microM in 150 mM [K(+)](o). The Hill coefficient was close to unity, suggesting that the binding of a single molecule of haloperidol is sufficient to close the channel. Haloperidol block of K(ATP) channels may contribute to the side effects of this drug when used therapeutically.

Adenosine Triphosphate↗
PubMed2002

A comparison of risperidone and haloperidol for the prevention of relapse in patients with schizophrenia.

BACKGROUND: Prevention of relapse is a major goal of maintenance treatment in patients with psychotic disorders. We performed a long-term comparison of a newer, atypical antipsychotic drug, risperidone, and an older, conventional neuroleptic drug, haloperidol, in terms of the rate of relapse in patients with schizophrenia and schizoaffective disorder. METHODS: In a double-blind, prospective study at 40 sites, we randomly assigned adult outpatients in stable condition with chronic schizophrenia or schizoaffective disorder to receive treatment with flexible doses of either risperidone or haloperidol for a minimum of one year. RESULTS: Of the 397 patients who underwent randomization, data from 2 were excluded because they did not receive study medication; data from all 30 patients from one site were excluded by the sponsor, the Janssen Research Foundation, because of concern about the integrity of the data. The median duration of treatment was 364 days in the risperidone group and 238 days in the haloperidol group (P=0.02). Of the 177 patients assigned to risperidone and the 188 assigned to haloperidol who remained in the analysis, 44.1 percent and 52.7 percent, respectively, discontinued treatment for reasons other than relapse. The Kaplan-Meier estimate of the risk of relapse at the end of the study was 34 percent for the risperidone group and 60 percent for the haloperidol group (P<0.001); the risk ratio for relapse with haloperidol, from the Cox model, was 1.93 (95 percent confidence interval, 1.33 to 2.80; P<0.001). Early discontinuation of treatment for any reason was more frequent among haloperidol-treated patients (risk ratio, 1.52; 95 percent confidence interval, 1.18 to 1.96). Patients in the risperidone group had greater reductions in the mean severity of both psychotic symptoms and extrapyramidal side effects than those in the haloperidol group. CONCLUSIONS: Adult outpatients with clinically stable schizophrenia or schizoaffective disorder have a lower risk of relapse if they are treated with risperidone than if they are treated with haloperidol.

Adult↗