Horizontal Bar Test Research Articles

Adansonia digitata L. fruit shell extract alleviates lead-induced neurotoxicity in mice via modulation of oxidative stress and a possible chelating activity

BackgroundLead is a ubiquitous environmental heavy metal known to induce neurotoxicity. It has been postulated that substance with high antioxidant capacity could alleviate lead-induced neurotoxicity. Adansonia digitata fruit shell extract (ADFS) has been reported to have high phenolic contents and exerts antioxidant activity. This study investigated the effects of Adansonia digitata fruit shell extract on lead-induced neurotoxicity in mice. MethodsMale balb/c mice (n = 7) were administered with Pb-acetate (50 mg/kg) 30 mins before ADFS (250 mg/kg and 500 mg/kg) or succimer (50 mg/kg) per orally for 28 days. Motor activities were evaluated on days 29 and 30 through horizontal bar and open field tests respectively. Further, spectrophotometry, atomic absorption spectrophotometry and haematoxylin and eosin staining were carried-out to determine the expression of oxidative stress biomarkers, level of lead concentration in the brain and histology of the cerebellum respectively. ResultsLead acetate exposure significantly (p < 0.05) induced motor deficits in horizontal bar test and open field test, caused oxidative stress, high concentration of lead in the brain as well as histological aberration in the cerebellum. ADFS significantly (p < 0.05) reversed the motor deficits evident by increased muscle strength and number of lines crossed. Further, ADFS significantly reversed oxidative stress evident by increased levels of SOD, CAT and GSH and decreased level of MDA. There was also significant (p < 0.05) decrease in brain lead concentration as well as reduced cerebellar cells death. ConclusionFindings suggest that ADFS attenuated motor deficits via inhibition of oxidative stress and chelating activity which is comparable to succimer. Hence, ADFS should be explored for possible development of chelating agent against lead and other heavy metals toxicity.

Phenytoin promotes the proliferation of oligodendrocytes and enhances the expression of myelin basic protein in the corpus callosum of mice demyelinated by cuprizone.

Oligodendrocyte loss and myelin sheet destruction are crucial characteristics of demyelinating diseases. Phenytoin promotes the proliferation of endogenous neural precursor cells in the ventricular-subventricular zone in the postnatal brain that help restore the oligodendroglial population. This study aimed to evaluate whether phenytoin promotes myelin recovery of the corpus callosum of demyelinated adult mice. CD1 male mice were exposed to a demyelinating agent (0.2% cuprizone) for 8weeks. We assembled two groups: the phenytoin-treated group and the control-vehicle group. The treated group received oral phenytoin (10mg/kg) for 4weeks. We quantified the number of Olig2 + and NG2 + oligodendrocyte precursor cells (OPCs), Rip + oligodendrocytes, the expression level of myelin basic protein (MBP), and the muscle strength and motor coordination. The oligodendroglial lineage (Olig2 + cells, NG2 + cells, and RIP + cells) significantly increases by the phenytoin administration when compared to the control-vehicle group. The phenytoin-treated group also showed an increased expression of MBP in the corpus callosum and better functional scores in the horizontal bar test. These findings suggest that phenytoin stimulates the proliferation of OPCs, re-establishes the oligodendroglial population, promotes myelin recovery in the corpus callosum, and improves motor coordination and muscle strength.

Haloperidol-induced catalepsy as an animal model for parkinsonism: A systematic review of experimental studies.

Several useful animal models for parkinsonism have been developed so far. Haloperidol-induced catalepsy is often used as a rodent model for the study of motor impairments observed in Parkinson's disease and related disorders and for the screening of potential antiparkinsonian compounds. The objective of this systematic review is to identify publications that used the haloperidol-induced catalepsy model for parkinsonism and to explore the methodological characteristics and the main questions addressed in these studies. A careful systematic search of the literature was carried out by accessing articles in three different databases: Web of Science, PubMed and SCOPUS. The selection and inclusion of studies were performed based on the abstract and, subsequently, on full-text analysis. Data extraction included the objective of the study, study design and outcome of interest. Two hundred and fifty-five articles were included in the review. Publication years ranged from 1981 to 2020. Most studies used the model to explore the effects of potential treatments for parkinsonism. Although the methodological characteristics used are quite varied, most studies used Wistar rats as experimental subjects. The most frequent dose of haloperidol used was 1.0mg/kg, and the horizontal bar test was the most used to assess catalepsy. The data presented here provide a framework for an evidence-based approach to the design of preclinical research on parkinsonism using the haloperidol-induced catalepsy model. This model has been used routinely and successfully and is likely to continue to play a critical role in the ongoing search for the next generation of therapeutic interventions for parkinsonism.

Characterization of motor function in mice developmentally exposed to ethanol using the Catwalk system: Comparison with the triple horizontal bar and rotarod tests

Studies with human subjects indicate that ethanol exposure during fetal development causes long-lasting alterations in motor coordination that are, in part, a consequence of cerebellar damage. Studies with rats exposed to ethanol during the neonatal brain growth spurt have consistently recapitulated these deficits. However, studies with mice have yielded mixed results. We hypothesized that the use of highly sensitive motor function tests, such as the Catwalk test, would reliably detect motor function deficits in mice developmentally exposed to ethanol. Venus-vesicular GABA transporter transgenic mice were ethanol exposed during postnatal days 4–9 using vapor inhalation chambers and then subjected to the Catwalk test during adolescence. Catwalk data were rigorously analyzed using an innovative multistep statistical approach. For comparison, motor coordination and strength were assessed with the triple horizontal bar and rotarod tests. Unexpectedly, we found that out of 186 parameters analyzed in the Catwalk test, only one was affected by ethanol exposure (i.e., reduced coupling between left front paw and the right hind paw). In the triple horizontal bar test, ethanol-exposed mice were able to hold to the bars for less time than controls. Surprisingly, ethanol-exposed mice performed better in the rotarod test than controls. These data indicate that neonatal ethanol exposure of mice causes mixed effects on motor function during adolescence. The Catwalk test suggests that gait is generally preserved in these mice, whereas the triple horizontal bar test revealed deficits on motor strength and the rotarod test an increase in motor coordination.

Antipsychotic Activity Of Ethyl Acetate Extract Of Ficus Benghalensis Linn.

Background: Ficus benghalensis Linn is mentioned to have CNS lively principle and is used for the remedy of various neurological problems. Objective: Ficus benghalensis Linn is mentioned to have CNS lively principle and is used for the remedy of various neurological problems. Consequently, the effect of ethyl acetate extract of Ficus benghalensis Linn changed into investigated for its putative antipsychotic interest, the usage of amphetamine challenged rat version. Ketamine (3 mg/kg intraperitoneally) turned into administered acutely to mice as widespread drug. Material and methods: Successive extraction of ficus was done in different solvents. Phytochemical screening and toxicity studies were performed. Then the extract was screened for its anti-psychotic potential as Locomotor activity (representing positive symptoms)Forced swim test (representing negative symptoms)Catalepsy Scoring (Horizontal bar test)Compulsive behaviour test. Result: The outcomes in spontaneous locomotor activity confirmed that the ethyl acetate extract of the bark of Ficus benghalensis Linn at a dose level of 200 mg/kg, 400 mg/kg, 600 mg/kg, 800 mg/kg, and a 1000 mg/kg confirmed no considerable antipsychotic pastime in amphetamine brought about hyperactivity in mice whilst compared to standard. Conclusion: The extract ethyl acetate of Ficus benghalenis Linn bark has showed decreased effect of locomotor activity and increase in catalepsy scoring. Thus it shows anti-psychotic. : Extract at a dose stage of 200 mg/kg, 400 mg/kg, 600 mg/kg, 800 mg/kg, and 1000 mg/kg showed a reduced in locomotor activity while as compared to the standard.

Inducible nitric oxide synthase inhibitor, 1400W, mitigates DFP-induced long-term neurotoxicity in the rat model

Chemical nerve agents (CNA) are increasingly becoming a threat to both civilians and military personnel. CNA-induced acute effects on the nervous system have been known for some time and the long-term consequences are beginning to emerge. In this study, we used diisopropylfluorophosphate (DFP), a seizurogenic CNA to investigate the long-term impact of its acute exposure on the brain and its mitigation by an inducible nitric oxide synthase (iNOS) inhibitor, 1400W as a neuroprotectant in the rat model. Several experimental studies have demonstrated that DFP-induced seizures and/or status epilepticus (SE) causes permanent brain injury, even after the countermeasure medication (atropine, oxime, and diazepam). In the present study, DFP-induced SE caused a significant increase in iNOS and 3-nitrotyrosine (3-NT) at 24 h, 48 h, 7d, and persisted for a long-term (12 weeks post-exposure), which led to the hypothesis that iNOS is a potential therapeutic target in DFP-induced brain injury. To test the hypothesis, we administered 1400W (20 mg/kg, i.m.) or the vehicle twice daily for the first three days of post-exposure. 1400W significantly reduced DFP-induced iNOS and 3-NT upregulation in the hippocampus and piriform cortex, and the serum nitrite levels at 24 h post-exposure. 1400W also prevented DFP-induced mortality in <24 h. The brain immunohistochemistry (IHC) at 7d post-exposure revealed a significant reduction in gliosis and neurodegeneration (NeuN+ FJB positive cells) in the 1400W-treated group. 1400W, in contrast to the vehicle, caused a significant reduction in the epileptiform spiking and spontaneous recurrent seizures (SRS) during 12 weeks of continuous video-EEG study. IHC of brain sections from the same animals revealed a significant reduction in reactive gliosis (both microgliosis and astrogliosis) and neurodegeneration across various brain regions in the 1400W-treated group when compared to the vehicle-treated group. A multiplex assay from hippocampal lysates at 6 weeks post-exposure showed a significant increase in several key pro-inflammatory cytokines/chemokines such as IL-1α, TNFα, IL-1β, IL-2, IL-6, IL-12, IL-17a, MCP-1, LIX, and Eotaxin, and a growth factor, VEGF in the vehicle-treated animals. 1400W significantly suppressed IL-1α, TNFα, IL-2, IL-12, and MCP-1 levels. It also suppressed DFP-induced serum nitrite levels at 6 weeks post-exposure. In the Morris water maze, the vehicle-treated animals spent significantly less time in the target quadrant in a probe trial at 9d post-exposure compared to their time spent in the same quadrant 11 days previously (i.e., 2 days prior to DFP exposure). Such a difference was not observed in the 1400W and control groups. However, learning and short-term memory were unaffected when tested at 10-16d and 28-34d post-exposure. Accelerated rotarod, horizontal bar test, and the forced swim test revealed no significant changes between groups. Overall, the findings from this study suggest that 1400W may be considered as a potential therapeutic agent as a follow-on therapy for CNA exposure, after controlling the acute symptoms, to prevent mortality and some of the long-term neurotoxicity parameters such as epileptiform spiking, SRS, neurodegeneration, reactive gliosis in some brain regions, and certain key proinflammatory cytokines and chemokine.

IN VIVO STUDY OF THE ACTION MECHANISM OF THE RAPITALAM PHARMACEUTICAL SUBSTANCE

The aimis to study the action mechanisms of the Rapitalam pharmaceutical substance using Parkinsonian syndrome models.Materials and methods.Various effects of a new pharmacological substance, N-chlorophenylmethyl-dihydro-methoxy-methylphenyl-oxopyridazine carboxamide (Rapitalam), were studied in male laboratory mice and rats. During the experiment, the various models of the Parkinsonian syndrome were reproduced: the simulation of the Parkinsonian syndrome by administering 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP) neurotoxin, the simulation of haloperidol-induced catalepsy, the simulation of apomorphine-induced stereotypy and the simulation of oxotremorine-induced tremor followed by tests. The following tests were carried out in order to determine the Rapitalam efficacy with regard to symptoms manifested after the MPTP administration in animals: the open field test, the rotarod performance test, as well as the evaluation of the grip strength and the degree of rigidity using the stride length. When simulating the haloperidol-induced catalepsy, a horizontal bar test was performed. After the administration of apomorphine, the severity of stereotypy was assessed in scores. A simulation of oxotremorine-induced tremor in rats was used to study the cholinergic link. After the administration of oxotremorine, the severity of tremor was assessed against the background of administration of the test compounds.Results.During the analysis of the data obtained in the open field and rotarod tests as well as the stride length and the grip force when simulating the Parkinsonian syndrome by introducing MPTP, no intergroup statistical differences were found. Thus, the tested Rapitalam substance in doses of 2 mg/kg, 6 mg/kg and 20 mg/kg and the Levodopa reference drug at a dose of 60 mg/kg had no effect on the indices of motor activity and motor coordination in mice when administered orally for 10 days. Rapitalam in doses of 1 mg/kg, 3 mg/kg and 10 mg/kg as well as the Levodopa reference drug at a dose of 50 mg/kg, did not affect the severity of haloperidol-induced catalepsy and apomorphine-induced stereotypy in rats. Under the administration of oxotremorine to laboratory animals, a statistically significant decrease in the severity of tremor was observed during the Rapitalam administration in doses of 3 mg/kg and 10 mg/kg.Conclusion.Rapitalam is established to have no effect on motor impairment due to dopaminergic mechanisms. The tested substance is characterized by a pronounced cholinoblocking effect at doses of 3 mg/kg and 10 mg/kg.Conflict of interest: the author declares no conflict of interest.

Naringin Reverses Neurobehavioral and Biochemical Alterations in Intracerebroventricular Collagenase-Induced Intracerebral Hemorrhage in Rats

Intracerebral hemorrhage (ICH) contributes to 10-15% of all strokes and is a high risk factor for morbidity and mortality as compared to other subtypes of stroke, that is, cerebral ischemia and subarachnoid hemorrhage. Oxidative stress (OS)-induced neuroinflammation and neuronal cell death contribute towards the hallmarks of ICH. Spared antioxidant levels, increased inflammatory cytokines and free radicals in ICH lead to neuronal death and exaggerate the hallmarks of ICH. Intracerebroventricular (ICV) collagenase (COL-induced neuronal cell damage and cognitive deficits form a widely recognized experimental model for ICH. Naringin (NGN), a natural antioxidant bioflavonoid, has shown potent neuroprotective effects in different neurodegenerative diseases. However, its potential is least explored in pathological conditions, such as hemorrhagic stroke. This study is aimed at exploring the protective effects of NGN against ICV-COL induced behavioral, neurological and memory deficits in rats. ICV-ICH was induced by single, unilateral intrastriatal injection of COL (1 IU in 2 µL, ICV) over 10 min. From 2nd day onwards, NGN was administered in three different doses (10, 20, and 40 mg/kg; p.o.). Animals were subjected to a battery of behavioral tests to assess behavioral changes, including neurological scoring tests (cylinder test, spontaneous motility, righting reflex, horizontal bar test, forelimb flexion), actophotometer, rotarod, Randall Selitto and von Frey. Poststroke depression and memory deficits were estimated using forced swim test and Morris water maze test, respectively. Poststroke depression, neurological and cognitive deficits were mitigated dose dependently by NGN administration. NGN administration also attenuated the nitro-OS and restored tumor necrosis factor-α and endogenous antioxidant levels. Our research demonstrates that NGN has a protective effect against ICH-induced neurocognitive deficits, along with mitigation of oxido-nitrosative and inflammatory stress.

Resveratrol protects against ICV collagenase-induced neurobehavioral and biochemical deficits

BackgroundIndeed, intracerebral hemorrhage (ICH) account for only 15% of all strokes but it is one of the most devastating subtype of stroke associated with behavioral, cognitive and neurological deficits. The primary cause of neurological deficits in ICH is the hematoma growth, generation of free radicals, inflammatory cytokines and exhausting endogenous anti-oxidant machinery. It has been found that neuroinflammation following ICH leads to exaggeration of hallmarks of ICH. With this background, the study was aimed to evaluate the protective effect of resveratrol (RSV) in intracerebroventricular (ICV) collagenase (COL) induced neurological deficits in rats.MethodsThe present study was designed to explore the protective effects of resveratrol (5, 10, 20 mg/kg) against ICV-COL induced ICH. Animals were subjected to a battery of behavioral tests to access behavioral changes, including neurological scoring tests (cylinder test, spontaneous motility, righting reflex, horizontal bar test, forelimb flexion), actophotometer, rotarod, Randall Sellito and von Frey. Post stroke depression was estimated using forced swim test (FST). Memory deficit was monitored using Morris water maze (MWM).ResultsChronic treatment with RSV (20 mg/kg) for 21 days restored various behavioral changes, including neurological scoring tests (cylinder test, spontaneous motility, righting reflex, horizontal bar test, forelimb flexion), actophotometer, rotarod, Randall Sellito and Von Frey. RSV also restores increase in immobility time forced swim test used to evaluate post stroke depression and impaired memory deficit in Morris water maze. RSV administration also attenuated increased nitro-oxidative stress and TNF-α level. RSV being a potent antioxidant also restores changes in endogenous anti-oxidant levels.ConclusionIn conclusion, our research demonstrates that RSV has a protective effect against ICH by virtue of its anti-inflammatory property and antioxidant and nitrosative stress restoring property.

&lt;i&gt;In situ&lt;/i&gt; epicatechin-loaded hydrogel implants for local drug delivery to spinal column for effective management of post-traumatic spinal injuries

Purpose: To prepare hydrogels loaded with epicatechin, a strong antioxidant, anti-inflammatory, and neuroprotective tea flavonoid, and characterise them in situ as a vehicle for prolonged and safer drug delivery in patients with post-traumatic spinal cord injury.Methods: Five in situ gel formulations were prepared using chitosan and evaluated in terms of their visual appearance, clarity, pH, viscosity, and in vitro drug release. In vivo anti-inflammatory activity was determined and compared with 2 % piroxicam gel as standard. Motor function activity in a rat model of spinal injury was examined comparatively with i.v. methylprednisolone as standard.Results: The N-methyl pyrrolidone solution (containing 1 % w/w epicatechin with 2 to 10 % w/w chitosan) of the in situ gel formulation had a uniform pH in the range of 4.01 ± 0.12 to 4.27 ± 0.02. High and uniform drug loading, ranging from 94.48 ± 1.28 to 98.08 ± 1.24 %, and good in vitro drug release (79.48 ± 2.84 to 96.48 ± 1.02 % after 7 days) were achieved. The in situ gel prepared from 1 % epicatechin and 2 % chitosan (E5) showed the greatest in vivo anti-inflammatory activity (60.58 % inhibition of paw oedema in standard carrageenan-induced hind rat paw oedema model, compared with 48.08 % for the standard). The gels showed significant therapeutic effectiveness against post-traumainduced spinal injury in rats. E5 elicited maximum motor activity (horizontal bar test) in the spinal injuryrat model; the rats that received E5 treatment produced an activity score of 3.62 ± 0.02 at the end of 7 days, compared with 5.0 ± 0.20 following treatment with the standard.Conclusion: In situ epicatechin-loaded gel exhibits significant neuroprotective and anti-inflammatory effects, and therefore can potentially be used for prolonged and safe drug delivery in patients with traumatic spinal cord injury.Keywords: Epicatechin, In situ gel, Chitosan, Spinal injury, Post-traumatic, Motor activity, Antiinflammatory

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 (Cα, α-dialkylated glycyl residues with lactam bridge constraint [ 1–4] and without [ 5–8]) were tested in the same manner (at a dose of 1 μg/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 μg/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.

Unique activation of extracellular striato-pallidal neurotransmitters in rats following acute risperidone

The present study investigated the effects of the putative atypical antipsychotic drug (APD), risperidone, on striatal monoamine and pallidal γ-aminobutyric acid (GABA) function using dual probe in vivo microdialysis. Risperidone (0.03, 0.3, 3 mg/kg) or vehicle was injected (s.c.) into female, Sprague–Dawley rats fitted with dual microdialysis probes in the striatum and the globus pallidus (GP). In the striatum, risperidone increased extracellular levels of dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) at all doses and the serotonin (5-HT) metabolite, 5-hydroxyindoleacetic acid (5-HIAA), at the highest dose. The increase in striatal DA was most pronounced at the lowest dose of risperidone; however, DOPAC showed a dose dependent increase. Risperidone at the medium and high doses significantly reduced extracellular GABA levels in the GP. Simultaneous measurement of limb rigidity during microdialysis showed that risperidone dose-dependently produced significant increases in horizontal bar test catalepsy and fore- and hindlimb paw retraction latencies. The current results suggest novel effects of risperidone on striatal DA release, while the pallidal GABA changes are similar to previous results obtained with the atypical antipsychotic drug, clozapine. Additionally, the behavioral results predict the clinical expression of extrapyramidal motor side effects at high doses. Overall, these results support an atypical profile of risperidone when compared with typical APDs, yet one with unique neurochemical and behavioral properties.

Dopamine D 1- and D 2-dependent catalepsy in the rat requires functional NMDA receptors in the corpus striatum, nucleus accumbens and substantia nigra pars reticulata

This study investigated the anticataleptic activity of MK-801 versus the D 1 antagonist SCH 23390 and the D 2 antagonist raclopride, using the horizontal bar test in the rat. MK-801, 0.2 mg/kg i.p., strongly opposed the cataleptogenic actions of SCH 23390 and raclopride administered systemically (1 and 3 mg/kg i.p., respectively), or directly into the corpus striatum (CS) or nucleus accumbens (NAc; 1 and 10 μg, respectively). Conversely, intraCS and intraNAc pretreatment with MK-801 (10 μg) markedly attenuated the cataleptic response to a systemic injection of SCH 23390 or raclopride. In the latter experiments the anticataleptic effect of MK-801 was pronounced and sustained (>2 h), except with intraCS MK-801 versus raclopride, where it was initially profound but only short-lived (15 min). Stereotaxic injection of MK-801 (1 μg) into the substantia nigra pars reticulata (SNr) prevented catalepsy developing to either dopamine D 1 or D 2 receptor antagonism. These results indicate there must be unimpeded glutamate neurotransmission in the CS and NAc before catalepsy can develop fully to D 1 and D 2 dopamine receptor blockade in these structures. The weaker glutamate–D 2 interaction in the CS than in the NAc may be related to differences in the N-methyl- d-aspartate receptor subpopulations in these nuclei. Finally, the ability of intranigral MK-801 to diminish both D 1- and D 2-dependent catalepsy suggests the SNr acts as a common output pathway for the expression of both forms of catalepsy in the rat.

Single preexposure to fluphenazine produces persisting behavioral sensitization accompanied by tolerance to fluphenazine-induced striatal dopamine overflow in rats

Single, previous exposure to a neuroleptic has been shown to produce long-lasting changes in various measures of behavior and neurochemistry upon subsequent drug exposure. The present study examined the effects of a single preexposure to fluphenazine (0.3 or 1.0 mg/kg) or vehicle on the effects of subsequent fluphenazine administration 15 or 30 days later. Intracranial microdialysis was used to assess changes in striatal extracellular dopamine concentrations. Animals were tested for catalepsy response on a horizontal bar test while concurrently collecting dialysis samples. Previous fluphenazine exposure produced a profound tolerance to the effects of subsequent fluphenazine at day 15 or day 30 on increasing extracellular dopamine levels. In addition, animals that had received fluphenazine on the first trial showed significant sensitization to the cataleptic effects of fluphenazine at both time points. Pretreatment with vehicle did not result in tolerance to dopamine overflow and there was only minimal evidence of cataleptic sensitization to a subsequent fluphenazine challenge. Although the tolerance to dopamine overflow may only indirectly relate to behavioral sensitization, these results support the hypothesis that significant behavioral and neurochemical alterations persist for prolonged time periods following single neuroleptic exposure.

Concentrations of remoxipride and its phenolic metabolites in rat brain and plasma. Relationship to extrapyramidal side effects and atypical antipsychotic profile.

The cataleptic effect of remoxipride was examined in the horizontal bar test after i.v.,i.p. and s.c. administration to male rats. Remoxipride induced immediate catalepsy after high i.v. doses (ED50 = 49 mumol/kg) while peak effects were seen 60-90 min after i.p. administration (ED50 = 38 mumol/kg). Following s.c. administration remoxipride failed to produce a statistically significant catalepsy in the 20-100 mumol/kg dose range (ED50 > 100 mumol/kg). In contrast, haloperidol was found to be more effective in inducing catalepsy after i.v. (ED50 = 0.4 mumol/kg) than after i.p. or s.c. administration (ED50 = 0.9 mumol/kg). The atypical antipsychotic profile of remoxipride was more pronounced when the compound was given i.v. or s.c. as compared with the i.p. route. Plasma and brain (striatum and nucleus accumbens) concentrations of remoxipride and its active phenolic metabolites FLA 797(-) and FLA 908(-) were measured by high performance liquid chromatography. The 40 mumol/kg dose of remoxipride resulted in plasma and brain concentrations of remoxipride which were 300-1000-fold higher (depending on the route of administration) than the most potent of the phenolic metabolites, e.g., FLA 797(-). The plasma and brain concentrations of remoxipride and its phenolic metabolites were related to DA D2 receptor blocking potency and to the temporal course and effectiveness to induce catalepsy. This analysis suggested that the unbound concentrations of the phenolic metabolites were too low to play a major role in the DA blocking action of remoxipride. However, FLA 797(-) may contribute marginally to the cataleptic effects following high (i.p.) doses of remoxipride.

Catalepsy induced by carbachol microinjected into the pontine reticular formation of rats

Rats were implanted stereotaxically with permanent guide tubes aimed at the pontine reticular formation. Carbachol was microinjected in the awake, freely moving rats. Catalepsy was evaluated with the horizontal bar test. Intense and long-lasting, dose-dependent catalepsy was observed following microinjections of 2-8 micrograms of carbachol. Pretreatment with intraperitoneally administered scopolamine significantly reduced the cataleptogenic effect of carbachol. These results show that the pontine reticular formation is part of the neuroanatomical substrate of catalepsy induced by cholinergic drugs.

Effects of five beta-LPH-neuropeptides and DN-1417, a derivative of TRH, on grip test performance in rats: possible neuroleptic action.

Various peptides found in the brain have been considered to have a regulatory role in neural transmission and some of them are suggested to have neuroleptic activity. In the present study, the effects of five endorphins, haloperidol, and DN-1417, a derivative of thyrotropin-releasing hormone (TRH), were examined on two grip tests in rats, which are sensitive methods for screening neuroleptic drugs. Intraperitoneal injections were made with 50μg of α-endorphin, β-endorphin, γ-endorphin and δ-endorphin, 10 μg and 50 μg of [Des -Tyr1] γ-endorphin (DTγE), 10 μg of haloperidol, and 10 μg and 50 μg of DN-1417. The two grip tests, the pencil test and the horizontal bar test, were repeated before, 1 hour and 2 hours after the respective injections. γ-Endorphin, δ-endorphin, both doses of DTγE, haloperidol and both doses of DN-1417 were positive in both grip tests, however, both α-endorphin and β-endorphin were negative in both of the grip tests. These results raise the possibility that small doses of DN -1417 might be effective as neuroleptic agents as well as DTγE.