The current study examined the changes in striatal gene network structure induced by short-term selective breeding from a heterogeneous stock for haloperidol response. Brain (striatum) gene expression data were obtained using the Illumina WG 8.2 array, and the datasets from responding and non-responding selected lines were independently interrogated using a weighted gene coexpression network analysis (WGCNA). We detected several gene modules (groups of coexpressed genes) in each dataset; the membership of the modules was found to be largely concordant, and a consensus network was constructed. Further validation of the network topology showed that using approximately 35 samples is sufficient to reliably infer the transcriptome network. An in-depth analysis showed significant changes in network structure and gene connectivity associated with the selected lines; these changes were validated using a bootstrapping procedure. The most dramatic changes were associated with a gene module richly annotated with neurobehavioral traits. The changes in network connectivity were concentrated in the links between this module and the rest of the network, in addition to changes within the module; this observation is consistent with recent results in protein and metabolic networks. These results suggest that a network-based strategy will help identify the genetic factors associated with haloperidol response.

Repeated pairings of a neutral context and the effects of haloperidol give rise to conditioned catalepsy when the context is subsequently presented in a drug-free test. In order to confirm whether this response is based on Pavlovian processes, we conducted two experiments involving two manipulations that affect conditioning intensity in classical conditioning procedures: time of joint exposure to the conditioned and the unconditioned stimulus, and the length of the inter-stimulus interval (ISI). The results revealed that both an increase in the length of context-drug pairings during conditioning and a reduced ISI between drug administration and context exposure increased conditioned catalepsy. These results are discussed in terms of the temporal peculiarities of those procedures that involve drugs as the unconditioned stimulus along with the role of Pavlovian conditioning in context-dependent catalepsy.

We performed short-term bi-directional selective breeding for haloperidol-induced catalepsy, starting from three mouse populations of increasingly complex genetic structure: an F2 intercross, a heterogeneous stock (HS) formed by crossing four inbred strains (HS4) and a heterogeneous stock (HS-CC) formed from the inbred strain founders of the Collaborative Cross (CC). All three selections were successful, with large differences in haloperidol response emerging within three generations. Using a custom differential network analysis procedure, we found that gene coexpression patterns changed significantly; importantly, a number of these changes were concordant across genetic backgrounds. In contrast, absolute gene-expression changes were modest and not concordant across genetic backgrounds, in spite of the large and similar phenotypic differences. By inferring strain contributions from the parental lines, we are able to identify significant differences in allelic content between the selected lines concurrent with large changes in transcript connectivity. Importantly, this observation implies that genetic polymorphisms can affect transcript and module connectivity without large changes in absolute expression levels. We conclude that, in this case, selective breeding acts at the subnetwork level, with the same modules but not the same transcripts affected across the three selections.

We have shown that buspirone, a partial agonist of 5-hydroxytryptamine 1A (5-HT1A) receptors, improves motor dysfunctions induced by 6-hydroxydopamine (6-OHDA) and haloperidol in rats. The present work extends these findings by investigating the role of 5-HT1A receptors on catalepsy-like immobilization in rats, a model of Parkinson's disease. Catalepsy was induced by unilateral infusion of 6-OH-dopamine (8 μg/2μL/rat) into the central region of the substantia nigra, compact part (SNc) and assayed by bar-test method 5, 60, 120 and 180 min after the drugs administration. The involvement of 5-HT1A receptors in 6-OHDA-induced catalepsy was studied through intraperitoneal (0.25, 0.5 and 1mg/Kg IP) and intrasubstantia nigra, compact part (10 μg/rat, intra-SNc) injection of 8-hydroxy-2-[di-n-propylamino] tetralin (8-OHDPAT) as well as administration of 1-(2-methoxyphenyl)-4-[4-(2-pthalimmido) butyl] piperazine hydrobromide (0.1, 0.5 and 1 mg/Kg, NAN-190, IP). NAN-190 (1 mg/Kg, IP) and 8-OHDPAT (1 mg/Kg, IP and 10 μg/rat, intra-SNc) increased and decreased 6-OHDA-induced catalepsy respectively. In normal (non 6-OHDA-lesioned) rats, NAN-190 (1 mg/Kg, IP) increased the elapsed time in bar-test while 8-OHDPAT did not produce any significant effect. The anticataleptic effect of 8-OHDPAT (1 mg/Kg, IP) was reversed markedly by co-injection with NAN-190 (1 mg/Kg, IP). These findings suggest that 5-HT1A receptors are involved in 6-OHDA-induced catalepsy-like immobilization.

Reserpine-induced orofacial dyskinesia is an animal model of tardive dyskinesia which may be associated with neurodegeneration and free radical damage.

In animal models, the administration of the dopaminergic D2 antagonist haloperidol affects the nigrostriatal pathway, inducing catalepsy, a state of immobility similar to Parkinson's disease (PD) bradykinesia and akinesia. In PD, the motor impairments are due to difficulties in selecting and executing motor actions, associated with dopamine loss in basal ganglia and cortical targets. Motor and affective limbic networks seem to be integrated via a striato-nigro-striatal network, therefore, it is not surprising that the motor impairments in PD can be influenced by the patient's emotional state. Indeed, when exposed to aversive stimuli or life-threatening events, immobile patients are capable of performing sudden movements, a phenomenon known as paradoxical kinesia. Thus, the present study investigated the effects of unconditioned and conditioned aversive stimulation on haloperidol-induced catalepsy in rats. First, male Wistar rats received intraperitoneal administration of saline or haloperidol (1 or 2 mg/kg) and were evaluated in the catalepsy bar test to assess the cataleptic state induced by the different doses of haloperidol over time. Next, we evaluated the effects of two types of unconditioned aversive stimuli-100 lux light (1 and 20 s) or 0.6 mA footshock (1 s)-on the catalepsy. Finally, we evaluated the effects of light conditioned stimuli (Light-CS), previously paired with footshocks, on the cataleptic state. Catalepsy was observed following haloperidol 1 and 2 mg/kg administration. Exposure to footshocks, but not to light, significantly reduced step-down latency during the catalepsy test. Although unconditioned light did not affect catalepsy, paired Light-CS did reduce step-down latency. Here, we have provided evidence of face validity for the study of paradoxical kinesia. In addition to demonstrating that immediate exposure to an aversive stimulus is capable of disrupting the cataleptic state, our findings show that haloperidol-induced catalepsy seems to be differently influenced depending on the modality of aversive stimulation. Our data suggest that the selective recruitment of threat response systems may bypass the dysfunctional motor circuit leading to the activation of alternative routes to drive movement.

Catalepsy bar tests are widely used to measure the failure to correct an imposed posture resulting from muscular rigidity. Procedures for measuring catalepsy vary greatly in the published literature, but one commonly used test measures the time it takes for a rodent to remove one or both of its forelimbs from a bar. The following paper describes an affordable, adjustable, open-source bar test that automatically measures and logs the time it takes for a rat to remove itself from a bar. While commercially available automated bar tests are prohibitively expensive, requiring proprietary software and hardware to operate, the proposed apparatus runs on an Arduino-based microcontroller making it low-cost and customizable. This 3D-printed design costs less than 65 United States dollars to build and is simple to assemble and operate. The beam-break sensor design also eliminates many of the pitfalls of the "complete-the-circuit"-based approach to recording catalepsy. The paper further describes the successful validation of the design using adult male rats injected with different doses of haloperidol to demonstrate a dose-dependent cataleptic effect. This design provides a versatile, low-cost solution to standardizing and automating measurement of catalepsy in rodents.

Typical antipsychotics such as the dopamine D(2) receptor antagonist, haloperidol are known to cause movement disorders or catalepsy in experimental animals. Catalepsy is believed to result from blockade of dopamine D(2) receptors. In this study two drugs that differ in antipsychotic potency but are similar in blocking dopamine D(2) receptors were used to investigate the mechanism for catalepsy and its sensitization. Metoclopramide is a strong postsynaptic dopamine D(2) receptor blocker with no antipsychotic potency. At low doses of 5 or 10 mg/kg given subcutaneously (s.c.), metoclopramide did not produce catalepsy or movement disturbance for seven days after drug treatment. Also metoclopramide at 10 mg/kg given for five days, failed to induce catalepsy. Haloperidol, another potent dopamine D(2) receptor blocker at 0.5 mg/kg (s.c.) rapidly produced catalepsy and suppressed movement 1 h after a single dose of the drug. Chronic as well as acute treatment with metoclopramide caused sensitization of haloperidol-induced catalepsy. Neurochemical analyses revealed significant dopamine D(2) receptor up-regulation in both frontal cortex and striatum of rats chronically treated with metoclopramide. However, no changes in dopamine D(2) receptor numbers were noted in these areas after chronic treatment with low doses of haloperidol. Significant increases in N-methyl-D-aspartate (NMDA) receptor numbers were observed in both frontal cortex and striatum of metoclopramide treated animals, while haloperidol elicited significant decreases in NMDA receptor numbers in both brain areas. These observations plus previous reports have led us to propose a model for catalepsy and its sensitization. According to this model the increase in NMDA receptors by metoclopramide sensitizes the brain to haloperidol-induced catalepsy. Thus, catalepsy appears to be elicited by simultaneous activation of glutamatergic NMDA and dopamine D(1) receptors as well as a blockade of dopamine D(2) receptors.

Deep brain stimulation (DBS) has evolved as a promising alternative treatment for Parkinson's disease (PD), but the underlying mechanisms remain poorly understood. Moreover, conventional DBS protocols targeted at basal ganglia sites can turn out completely ineffective for some PD patients, warranting the search for alternative targets. The inferior colliculus (IC) is a midbrain auditory relay station involved in sensorimotor processes. High-frequency 2500 Hz electrical stimulation of the IC elicits escape behaviour and interferes with haloperidol-induced catalepsy in rats, a state reminiscent of Parkinsonian akinesia, but clinical implication is limited since the protocol is aversive. However, typical DBS stimulation frequencies range between 20-180 Hz. We therefore tested the effects of a low-frequency 30 Hz-DBS protocol on haloperidol-induced catalepsy and aversive behaviour in rats. We show that low-frequency 30 Hz-DBS targeted at the IC strongly ameliorates haloperidol-induced catalepsy without any evidence of stimulation-induced escape behaviour. Furthermore, 30 Hz-DBS of the IC produced no place avoidance in a place conditioning paradigm and induced no anxiety-related behaviour on the elevated plus maze, indicating that the protocol has no aversive or anxiogenic side effects. Our findings provide first evidence that the IC can serve as an alternative, non-conventional DBS target.

It has been proposed that long-acting risperidone could provide a constant antipsychotic efficacy associated with a reduced liability to induce extra-pyramidal symptoms. To ascertain this hypothesis, antagonism of amphetamine-induced hyperlocomotion and catalepsy were analyzed in rats for a period of 1-6 weeks following long-acting risperidone (20-60 mg/kg) injection. Long-acting risperidone reduced amphetamine-induced hyperlocomotion after 2-5 weeks from drug injection, without producing significant extra-pyramidal symptoms. Following the administration of long-acting risperidone a constant ability to antagonize amphetamine-induced hyperlocomotion was observed during the day, but not when the antipsychotic was chronically administered using a short-acting formulation. The pre-clinical results confirmed that long-acting risperidone may represent an advance in antipsychotic therapy.

Catalepsy is a behavioral condition that is associated with severe psychopathologies, including schizophrenia, depression, and Parkinson's disease. In some mouse strains, catalepsy can be induced by pinching the skin at the scruff of the neck. The main locus of hereditary catalepsy in mice has recently been linked to the 105-115 Mb fragment of mouse chromosome 13 by QTL analysis. We performed whole-genome sequencing of catalepsy-resistant and catalepsy-prone mouse strains in order to pinpoint the putative candidate genes related to hereditary catalepsy in mice. We remapped the previously described main locus for hereditary catalepsy in mice to the chromosome region 103.92-106.16 Mb. A homologous human region on chromosome 5 includes genetic and epigenetic variants associated with schizophrenia. Furthermore, we identified a missense variant in catalepsy-prone strains within the Nln gene. Nln encodes neurolysin, which degrades neurotensin, a peptide reported to induce catalepsy in mice. Our data suggest that Nln is the most probable candidate for the role of major gene of hereditary, pinch-induced catalepsy in mice and point to a shared molecular pathway between catalepsy in mice and human neuropsychiatric disorders.

An aqueous root extract from Nardostachys jatamansi was investigated for its antioxidant and anticataleptic effects in the haloperidol-induced catalepsy rat model of the disease by measuring various behavioral and biochemical parameters. Catalepsy was induced by administration of haloperidol (1 mg/kg, ip) in male albino rats. A significant (P < 0.01) reduction in the cataleptic scores were observed in all the drug-treated groups as compared to the haloperidol-treated group; with maximum reduction observed in the Nardostachys jatamansi (250 and 500 mg/kg body weight) administered group. To estimate biochemical parameters: the generation of thiobarbituric acid reactive substances (TBARS); reduced glutathione (GSH) content and glutathione-dependent enzymes; catalase; and superoxide dismutase (SOD), in the brain were assessed. Haloperidol administration increased generation of TBARS and significantly reduced GSH, which were restored to near normal level with the Nardostachys jatamansi treatment. Catalase and SOD levels were also increased to normal levels, having been reduced significantly by haloperidol administration. Our findings of behavioral studies and biochemical estimations show that Nardostachys jatamansi reversed the haloperidol-induced catalepsy in rats. We conclude that the antioxidant potential has contributed to the reduction in the oxidative stress and catalepsy induced by haloperidol administration.

Neuroinflammation and oxidative stress play a key role in pathogenesis of Parkinson's disease (PD). In the present study we investigated the effect of reactive oxygen species (ROS) scavenger WR-1065 on catalepsy and cerebrospinal fluid (CSF) level of interleukin 6(IL-6) and striatum superoxide dismutase (SOD) activity in 6-hydroxydopamine (6-OHDA) induced experimental model of PD.

Neuroinflammation in Parkinson disease (PD) is associated with glial cells activation and production of different inflammatory cytokines. In this study, we investigated the effect of chronic administration of 8-OH-DPAT on 6-OHDA-induced catalepsy and levels of inflammatory cytokines in cerebrospinal fluid (CSF).

Purpose: Modafinil is a vigilance-enhancing drug licensed for narcolepsy. The use of modafinil leads to various neuromodulatory effects with very low abuse potential. A body of evidence suggested that modafinil may have anti-parkinsonian effects. This study was designed to evaluate whether modafinil could improve motor dysfunction in the 6-hydroxydopamine (6-OHDA)-induced rat model of Parkinson's disease. Methods: Male Wistar rats (180-220 g, n= 98) were used in this study. Parkinsonism was induced by injection of 6-hydroxydopamine (10 μg/2μl in 0.2 % ascorbic acid-saline) into the right striatum. Parkinsonian rats received intraperitoneal (ip) injections of modafinil (50, 75, and 100 mg/kg) and catalepsy-like immobility was assessed by the bar test (BT). Furthermore, involvement of dopamine D1 and D2 receptors in modafinil's anti-parkinsonian effects was studied. For this purpose, parkinsonian animals were pretreated with SCH23390 and raclopride (the dopamine D1 and D2 receptor anatgonists, respectively) or SCH23390 + raclopride, and then assessed by the BT. Results: Modafinil (100 mg/kg) showed anti-cataleptic effects in the BT. Notably, the effect of modafinil in the BT was reversed in parkinsonian rats pretreated with raclopride (1.25 mg/kg) and/or SCH23390 + raclopride (0.75 and 1.25 mg/kg, respectively), but not in those pretreated with SCH23390 (0.75 mg/kg). Conclusion: Acute administration of modafinil improves 6-OHDA-induced motor impairment possibly through activation of dopamine D2 receptors.

One important syndrome of psychiatric disorders in humans is catalepsy. Here, we created mice with different predispositions to catalepsy and analysed their pharmacological and behavioural properties.

Deep brain stimulation (DBS) of the colliculus inferior (IC) improves haloperidol-induced catalepsy and induces paradoxal kinesia in rats. Since the IC is part of the brain aversive system, DBS of this structure has long been related to aversive behavior in rats limiting its clinical use. This study aimed to improve intracollicular DBS parameters in order to avoid anxiogenic side effects while preserving motor improvements in rats. Catalepsy was induced by systemic haloperidol (0.5mg/kg) and after 60 min the bar test was performed during which a given rat received continuous (5 min, with or without pre-stimulation) or intermittent (5 x 1 min) DBS (30Hz, 200-600μA, pulse width 100μs). Only continuous DBS with pre-stimulation reduced catalepsy time. The rats were also submitted to the elevated plus maze (EPM) test and received either continuous stimulation with or without pre-stimulation, or sham treatment. Only rats receiving continuous DBS with pre-stimulation increased the time spent and the number of entries into the open arms of the EPM suggesting an anxiolytic effect. The present intracollicular DBS parameters induced motor improvements without any evidence of aversive behavior, pointing to the IC as an alternative DBS target to induce paradoxical kinesia improving motor deficits in parkinsonian patients.

Aging represents the largest risk factor for developing Parkinson's disease (PD); another salient feature of this disorder is a decreased brain levels of somatostatin. Recently, in aged Wistar rats, we simulated the central somatostatinergic deficiency by intracerebroventricular injections of a somatostatin antagonist, cyclosomatostatin (cSST). The treated animals displayed catalepsy, a state that resembles the extrapyramidal signs of Parkinson's disease; young animals were insensitive to cSST. The neuroanatomical substrates responsible for the increased cataleptogenic activity of cSST in aged animals, are currently unknown. To study this issue, we assessed the cSST effect on brain c-Fos-protein expression in aged and young rats; thirty three brain regions were examined. cSST was employed at the dose cataleptogenic for aged animals and non-cataleptogenic for young ones. c-Fos expression patterns in the 'cataleptic' and 'non-cataleptic' animals were very similar, with the only distinction being a decrease in the c-Fos expression in the aged lateral entorhinal cortex (LEntCx). This decrease was not observed when the cSST-induced cataleptic response was inhibited by administration of diphenhydramine and nicotine. Thus, the development of catalepsy in the aged Wistar rats appeared to be associated with a hypoactivation of the LEntCx; possibly, there exists a mechanistic link between the LEntCx hypoactivation and increased susceptibility of aged rats to catalepsy. Apparently, these findings may provide novel insight into the link between mechanisms of parkinsonian motor disorders and aging.

It is known that treadmill exercise has beneficial effects on the nervous system. The brain-derived neurotrophic factor (BDNF) plays a role in such effects. This study aimed at investigating effects of intermittent treadmill exercise-induced behavioral, histology, and immunohistochemistry (H&E, TH) measurement of brain interleukin-10 (IL-10) in a mice male model of Parkinson's disease (PD), which is induced by intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), as well as the role of BDNF gene in exercise effects.

In the suited rat-models, we focused on the stable pentadecapeptide BPC 157, L-NAME, NOS-inhibitor, and L-arginine, NOS-substrate, relation, the effect on schizophrenia-like symptoms. Medication (mg/kg intraperitoneally) was L-NAME (5), L-arginine (100), BPC 157 (0.01), given alone and/or together, at 5 min before the challenge for the acutely disturbed motor activity (dopamine-indirect/direct agonists (amphetamine (3.0), apomorphine (2.5)), NMDA-receptor non-competitive antagonist (MK-801 (0.2)), or catalepsy, (dopamine-receptor antagonist haloperidol (2.0)). Alternatively, BPC 157 10 μg/kg was given immediately after L-NAME 40 mg/kg intraperitoneally. To induce or prevent sensitization, we used chronic methamphetamine administration, alternating 3 days during the first 3 weeks, and challenge after next 4 weeks, and described medication (L-NAME, L-arginine, BPC 157) at 5 min before the methamphetamine at the second and third week. Given alone, BPC 157 or L-arginine counteracted the amphetamine-, apomorphine-, and MK-801-induced effect, haloperidol-induced catalepsy and chronic methamphetamine-induced sensitization. L-NAME did not affect the apomorphine-, and MK-801-induced effects, haloperidol-induced catalepsy and chronic methamphetamine-induced sensitization, but counteracted the acute amphetamine-induced effect. In combinations (L-NAME + L-arginine), as NO-specific counteraction, L-NAME counteracts L-arginine-induced counteractions in the apomorphine-, MK-801-, haloperidol- and methamphetamine-rats, but not in amphetamine-rats. Unlike L-arginine, BPC 157 maintains its counteracting effect in the presence of the NOS-blockade (L-NAME + BPC 157) or NO-system-over-stimulation (L-arginine + BPC 157). Illustrating the BPC 157-L-arginine relationships, BPC 157 restored the antagonization (L-NAME + L-arginine + BPC 157) when it had been abolished by the co-administration of L-NAME with L-arginine (L-NAME + L-arginine). Finally, BPC 157 directly inhibits the L-NAME high dose-induced catalepsy. Further studies would determine precise BPC 157/dopamine/glutamate/NO-system relationships and clinical application.