Oral Administration Of Haloperidol Research Articles

Rho kinase inhibitors ameliorate cognitive impairment in a male mouse model of methamphetamine-induced schizophrenia

Schizophrenia (SCZ) is a severe psychiatric disorder characterized by positive symptoms, negative symptoms, and cognitive deficits. Current antipsychotic treatment in SCZ improves positive symptoms but has major side effects and little impact on negative symptoms and cognitive impairment. The pathoetiology of SCZ remains unclear, but is known to involve small GTPase signaling. Rho kinase, an effector of small GTPase Rho, is highly expressed in the brain and plays a major role in neurite elongation and neuronal architecture. This study used a touchscreen-based visual discrimination (VD) task to investigate the effects of Rho kinase inhibitors on cognitive impairment in a methamphetamine (METH)–treated male mouse model of SCZ. Systemic injection of the Rho kinase inhibitor fasudil dose-dependently ameliorated METH-induced VD impairment. Fasudil also significantly suppressed the increase in the number of c-Fos–positive cells in the infralimbic medial prefrontal cortex (infralimbic mPFC) and dorsomedial striatum (DMS) following METH treatment. Bilateral microinjections of Y-27632, another Rho kinase inhibitor, into the infralimbic mPFC or DMS significantly ameliorated METH-induced VD impairment. Two proteins downstream of Rho kinase, myosin phosphatase-targeting subunit 1 (MYPT1; Thr696) and myosin light chain kinase 2 (MLC2; Thr18/Ser19), exhibited increased phosphorylation in the infralimbic mPFC and DMS, respectively, after METH treatment, and fasudil inhibited these increases. Oral administration of haloperidol and fasudil ameliorated METH-induced VD impairment, while clozapine had little effect. Oral administration of haloperidol and clozapine suppressed METH-induced hyperactivity, but fasudil had no effect. These results suggest that METH activates Rho kinase in the infralimbic mPFC and DMS, which leads to cognitive impairment in male mice. Rho kinase inhibitors ameliorate METH-induced cognitive impairment, perhaps via the cortico-striatal circuit.

Bromocriptine loaded chitosan nanoparticles intended for direct nose to brain delivery: Pharmacodynamic, Pharmacokinetic and Scintigraphy study in mice model

The primary aim of this study was to investigate the potential use of chitosan nanoparticles as a delivery system to enhance the brain targeting efficiency of bromocriptine (BRC) following intranasal (i.n.) administration. The BRC loaded chitosan nanoparticles (CS NPs) were prepared by ionic gelation of CS with tripolyphosphate anions. These NPs had a mean size (161.3±4.7nm), zeta potential (+40.3±2.7mV), loading capacity (37.8%±1.8%) and entrapment efficiency (84.2%±3.5%). The oral administration of haloperidol (2mg/kg) to mice produced typical Parkinson (PD) symptoms. Catalepsy and akinesia outcomes in animals receiving BRC either in solution or within CS NPs showed a reversal in catalepsy and akinesia behavior when compared to haloperidol treated mice, this reversal being specially pronounced in mice receiving BRC loaded CS NPs. Biodistribution of BRC formulations in the brain and blood of mice following i.n. and intravenous (i.v.) administration was performed using optimized technetium labeled (99mTc-labeled) BRC formulations. The brain/blood ratio of 0.47±0.04, 0.69±0.031, and 0.05±0.01 for BRC solution (i.n.), BRC loaded CS NPs (i.n.) and (i.v.) respectively, at 0.5h are suggestive of direct nose to brain transport bypassing the blood–brain barrier. Gamma scintigraphy imaging of mice brain following i.v. and i.n. administrations were performed to determine the localization of drug in brain. The drug targeting index and direct transport percentage for BRC loaded CS NPs following i.n. route were 6.3±0.8 and 84.2%±1.9%. These encouraging results confirmed the development of a novel non-invasive nose to brain delivery system of BRC for the treatment of PD.

Chorea in the both lower limbs associated with nonketotic hyperglycemia.

Hemichorea-hemiballism (HC-HB) is a complication of non-ketotic hyperglycemia (NKH); in NKH patients, the frequency of occurrence of HC-HB is greater than that of bilateral chorea. We report the case of a hyperglycemic patient who showed chorea in both the lower limbs. Magnetic resonance imaging (MRI) of the brain revealed high signal intensity on T1-weighted images of the bilateral dorsolateral putamen. The abnormal involuntary movements disappeared after oral administration of haloperidol. Our case report that chorea associated with NKH is correlated with the topography of the basal ganglia.

Brain neurotransmitter receptor-binding characteristics in rats after oral administration of haloperidol, risperidone and olanzapine

The present study was conducted to characterize the binding of neurotransmitter receptors (dopamine D 2, serotonin 5-HT 2, histamine H 1, adrenaline α 1 and muscarine M l receptors) in the rat's brain after the oral administration of haloperidol, risperidone, and olanzapine. Haloperidol at 1 and 3 mg/kg displayed significant activity to bind the D 2 receptor (increase in the Kd value for [ 3H]raclopride binding) in the corpus striatum with little change in the activity toward the 5-HT 2 receptor (binding parameters for [ 3H]ketanserin). In contrast, risperidone (0.1–3 mg/kg) showed roughly 30 times more affinity for the 5-HT 2 receptor than D 2 receptor. Also, olanzapine (1–10 mg/kg) was most active toward the H 1 receptor in the cerebral cortex, corpus striatum, and hippocampus, was less active in binding 5-HT 2 and D 2 receptors, and showed the least affinity for α 1 and M 1 receptors. In conclusion, haloperidol and risperidone administered orally selectively bind D 2 and 5-HT 2 receptors, respectively, in the rat brain, while olanzapine binds H 1, 5-HT 2, and D 2 receptors more than α 1 and M 1 receptors.

Mapping of human cerebral sigma1 receptors using positron emission tomography and [11C]SA4503

The objective of this study was to establish the kinetic analysis for mapping sigma1 receptors (σ1Rs) in the human brain by positron emission tomography (PET) with [11C]SA4503. The σ1Rs are considered to be involved in various neurological and psychiatric diseases. [11C]SA4503 is a recently developed radioligand with high and selective affinity for σ1Rs, and we have first applied it to clinical studies. Nine healthy male subjects each underwent a dynamic 90-min PET scan after injection of [11C]SA4503. In addition to the baseline measurement, three of the nine subjects underwent a second [11C]SA4503-PET after partial blockade of σ1Rs by oral administration of haloperidol, a sigma receptor antagonist. Full kinetic analysis using two times nonlinear estimations was applied for fitting a two-tissue three-compartment model to determine the binding potential (BP) and total distribution volume (tDV) of [11C]SA4503. Graphical analysis with a Logan plot was also applied for estimations of tDV. The regional distribution patterns of BP and tDV in 11 regions were compatible with those of previously reported σ1Rs in vitro. The reduced binding sites of σ1Rs by haloperidol were appropriately evaluated. The tDVs derived from the two methods matched each other well. The Logan plot offered images of the tDV, which reflected σ1R densities, and the tDV in the images decreased after haloperidol loading. Moreover, comparison of BPs calculated with and without metabolite correction for plasma input function indicated that the metabolite correction could be omitted. We concluded that this method enables the quantitative analysis of σ1Rs in the human brain.

Incidence and risk factors in neuroleptic malignant syndrome.

Between October 1981 and September 1989, 564 patients admitted to the Department of Psychiatry of the Hospital of Oita Medical University received antipsychotic treatment. Ten (1.8%) of these patients developed neuroleptic malignant syndrome. This incidence is significantly greater than that reported in a group of other studies (27/17,811, 0.2%). We compared the characteristics of this sample with known risk factors for neuroleptic malignant syndrome. It is possible that Japanese people are at an increased risk for developing neuroleptic malignant syndrome. Psychomotor excitement, refusal of food, a weight loss of greater than 1 kg per week and oral administration of haloperidol at 15 mg/day or above were found to be risk factors for developing the neuroleptic malignant syndrome.

Hypokinetic-rigid extrapyramidal side effects of neuroleptics: the relationship of the silent period in EMG and HVA and 5-HIAA in CSF.

The relationship between cerebrospinal fluid levels of HVA and 5-HIAA and the hypokinetic-rigid symptoms that occurred during oral administration of haloperidol in twenty schizophrenic patients was investigated. Measurement of the silent period in the EMG was used for evaluation of these symptoms. The results support the hypothesis of a positive correlation between the CSF HVA and the hypokinetic-rigid side effect and a negative correlation between the pretherapeutic dopamine turnover and the risk of neuroleptic Parkinsonism.

Effects of prolyl-leucyl-glycinamide and cyclo(leucyl-glycine) on the supersensitivity of dopamine receptors in brain induced by chronic administration of haloperidol to rats

The effects of melanotropin release-inhibiting factor, a tripeptide (Pro-Leu-Gly-NH 2) derived from the hypothalamus, and its enzymatically stable analog, cyclo(Leu-Gly) on the supersensitivity of dopamine receptors in brain induced by chronic administration of haloperidol to male Sprague-Dawley rats was determined. Oral administration of haloperidol (1.5 mg/kg per day) for 21 days induced supersensitivity of dopamine receptors as shown by enhanced locomotor activity in response to apomorphine, and an increase in the number of binding sites for [ 3H]spiroperidol in the striatum. Subcutaneous administration of Pro-Leu-Gly-NH 2 or cyclo(Leu-Gly) in doses of 2 mg/kg per day, given prior to the injection of haloperidol, inhibited both the enhanced response to apormorphine as well as the increase in the number of binding sites for [ 3H]spiroperidol in the striatum. Chronic administration of either of the peptides alone did not modify either the apomorphine-induced response or the binding of [ 3H]spiroperidol in the striatum. These studies suggest that the hypothalamic peptide, Pro-Leu-Gly-NH 2 and its long-acting analog, cyclo (Leu-Gly) can prevent the development of both behavioral and biochemical supersensitivity of dopamine receptors in brain induced by neuroleptic drugs and that these peptides may be useful in preventing the development of neuroleptic-induced tardive dyskinesia.

Schedule-induced water and saccharin polydipsia under haloperidol

Two white rats exhibited water and.4% saccharin polydipsia under a fixed-time 1-min feeding schedule. Oral administration of haloperidol in doses of.25,.50, and.75 mg reduced consumption of both fluids in direct proportion to dose, but saccharin intakes always exceeded those of water. Thus, the suppression of water polydipsia by haloperidol (Keehn, Coulson, & Klieb, 1976) is not merely the result of sedation. We argue that polydipsia occurs because food plus fluid is a greater reinforcer than food alone and that excessive drinking is a side effect of a normal reinforcement process that overpowers homeostatic mechanisms; the effect of haloperidol is to redress this imbalance.