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The dopamine system plays an important role in regulating many brain functions, including the motor function. The blockade of dopamine receptors results in a serious motor dysfunction, such as catalepsy and Parkinsonism. However, the neuronal mechanism underlying the drug-induced motor dysfunction is not well understood. Here, we examine brain-wide activation patterns in Fos-enhanced green fluorescent protein reporter mice that exhibit cataleptic behavior induced by SCH39166, a dopamine D1-like receptor antagonist, and raclopride, a dopamine D2-like receptor antagonist. Support vector classifications showed that the orbital cortex (ORB) and striatum including the caudoputamen (CP) and nucleus accumbens (ACB), prominently contribute to the discrimination between brains of the vehicle-treated and both SCH39166- and raclopride-treated mice. Interregional correlations indicated that the increased functional connectivity of functional networks, including the ORB, CP, and ACB, is the common mechanism underlying SCH39166- and raclopride-induced cataleptic behavior. Moreover, the distinct mechanisms in the SCH39166- and raclopride-induced cataleptic behaviors are the decreased functional connectivity between three areas above and the cortical amygdala, and between three areas above and the anterior cingulate cortex, respectively. Thus, the alterations of functional connectivity in diverse brain regions, including the ORB, provide new insights on the mechanism underlying drug-induced movement disorders.

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., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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., Competing Interests: The authors have declared that no competing interests exist.

We determined anti-Parkinson's activity of M. chamomilla L. tea in chlorpromazine (CPZ) developed investigational animal model. In this research, effects of M. chamomilla L. tea 2.14ml/ kg P.O were studied on cataleptic behavior and its effect on brain histopathological changes and immunohistochemistry (IHC) in rats. The experimental design was developed by administering CPZ (3mg/kg, I/P) for twenty-one days to produce Parkinson's disease-like symptoms to 4 animal groups. We observed that chlorpromazine significantly produced motor dysfunctions (catalepsy) in a time period of twenty-one days. The M. chamomilla L. significantly (P<0.005) minimized/shorten/taper down catalepsy in rats just like standard group (Levodopa/carbidopa treated group). The maximum reduction was observed from both treated and standard groups on the 21st day. M. chamomilla L. treated rats mid brain sections showed presence of proliferative blood vessels, increase cellularity with reactive glial cells as compared to CPZ group. Furthermore, immunostaining CD68 & CD21 of M. chamomilla L. treated rats mid brain region showed few CD68 cells & no polymorphs neutrophils after CD21 staining. Thus, this research work disclosed the neuroprotective effect of M. chamomilla L. tea against Parkinson's disease-like symptoms or anti-Parkinson's activity induced by CPZ.

Dual target ligands are a promising concept for the treatment of Parkinson's disease (PD). A combination of monoamine oxidase B (MAO B) inhibition with histamine H 3 receptor (H 3 R) antagonism could have positive effects on dopamine regulation. Thus, a series of twenty-seven 4- tert -butylphenoxyalkoxyamines were designed as potential dual-target ligands for PD based on the structure of 1-(3-(4- tert -butylphenoxy)propyl)piperidine ( DL76 ). Probed modifications included the introduction of different cyclic amines and elongation of the alkyl chain. Synthesized compounds were investigated for human H 3 R (hH 3 R) affinity and human MAO B (hMAO B) inhibitory activity. Most compounds showed good hH 3 R affinities with K i values below 400 nM, and some of them showed potent inhibitory activity for hMAO B with IC 50 values below 50 nM. However, the most balanced activity against both biological targets showed DL76 (hH 3 R: K i = 38 nM and hMAO B: IC 50 = 48 nM). Thus, DL76 was chosen for further studies, revealing the nontoxic nature of DL76 in HEK293 and neuroblastoma SH-SY5Ycells. However, no neuroprotective effect was observed for DL76 in hydrogen peroxide-treated neuroblastoma SH-SY5Y cells. Furthermore, in vivo studies showed antiparkinsonian activity of DL76 in haloperidol-induced catalepsy (Cross Leg Position Test) at a dose of 50 mg/kg body weight., Competing Interests: The authors declare no conflict of interest.

Purpose: Parkinson's disease (PD) is a neurodegenerative disorder with progressive motor defects. Therefore, the aim of the present investigation was to examine whether catalepsy, asymmetry, and nociceptive behaviors; the Nissl-body and neuron distribution; brain-derived neurotrophic factor (BDNF); malondialdehyde (MDA); total antioxidant capacity (TAC) levels; and the percentage of dopamine depletion of striatal neurons in the rat model of Parkinson's disease (PD) can be affected by Toxoplasma gondii (TG) infection., Methods: Fifty rats were divided into five groups: control (intact rats), sham (rats which received an intrastriatal injection of artificial cerebrospinal fluid (ACSF)), PD control (induction of PD without TG infection), TG control (rats infected by TG without PD induction), and PD infected (third week after PD induction, infection by TG was done). PD was induced by the unilateral intrastriatal microinjection of 6-hydroxydopamine (6-OHDA) and ELISA quantified dopamine, BDNF, MDA, and TAC in the striatum tissue. Cataleptic, asymmetrical, nociceptive, and histological alterations were determined by bar test, elevated body swing test, formalin test, and Nissl-body and neuron counting in the striatal neurons., Results: The results demonstrated that PD could significantly increase the number of biased swings, descent latency time, and nociceptive behavior and decrease the distribution of Nissl-stained neurons compared to the control and sham groups. TG infection significantly improved biased swing, descent latency time, nociceptive behavior, and the Nissl-body distribution in striatal neurons in comparison to the PD control group. The striatal level of BDNF in the PD-infected and TG control groups significantly increased relative to the PD control group. The striatal MDA was significantly higher in the PD control than other groups, while striatal TAC was significantly lower in the PD control than other groups., Conclusions: The current study indicates that TG infection could improve the cataleptic, asymmetric, nociceptive and behaviors; the level of striatal dopamine release; BDNF levels; TAC; and MDA in PD rats., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2020 Mahnaz Taherianfard et al.)

Phenotypical study was carried out in rats with pendulum movements. The animals exhibited a high level of abortive seizures in response to audiogenic stimuli and longer postictal catalepsy in comparison with those in Wistar population. Seizure severity positively correlated with the duration of poststimulus catalepsy (r=0.90). High aggressiveness towards humans, the absence of BP elevation in stress, lower body weights, and lower weights of the kidneys and spleen in PM rats are considered concomitant traits. Correlations were detected between startle-1 and BP in rats with pendulum movements (r=0.70) and between startle-10 and BP in narcotized Wistar rats (r=-0.0.71). The newly described signs in rats with pendulum movements did not contradict the signs of the focal seizure model with typical automatisms in humans.

Catalepsy - an immobile state in which individuals fail to change imposed postures - can be induced by haloperidol. In rats, the pattern of haloperidol-induced catalepsy is very similar to that observed in Parkinson's disease (PD). As some PD symptoms seem to depend on the patient's emotional state, and as anxiety disorders are common in PD, it is possible that the central mechanisms regulating emotional and cataleptic states interplay. Previously, we showed that haloperidol impaired contextual-induced alarm calls in rats, without affecting footshock-evoked calls. Here, we evaluated the influence of distinct aversive stimulations on the haloperidol-induced catalepsy. First, male Wistar rats were subjected to catalepsy tests to establish a baseline state after haloperidol or saline administration. Next, distinct cohorts were exposed to open-field; elevated plus-maze; open-arm confinement; inescapable footshocks; contextual conditioned fear; or corticosterone administration. Subsequently, catalepsy tests were performed again. Haloperidol-induced catalepsy was verified in all drug-treated animals. Exposure to open-field, elevated plus-maze, open-arm confinement, footshocks, or administration of corticosterone had no significant effect on haloperidol-induced catalepsy. Contextual conditioned fear, which is supposed to promote a more intense fear, increased catalepsy over time. Our findings suggest that only specific defensive circuitries modulate the nigrostriatal system mediating the haloperidol-induced cataleptic state.

Background: The root extract of Albizia zygia (DC.) J.F. Macbr. (Leguminosae) is used to manage mental disorders in African traditional medicine. However, its value, particularly, against negative and cognitive symptoms of schizophrenia have not been evaluated., Aim: The aim of this study was to evaluate the antipsychotic properties of the hydroethanolic root extract of Albizia zygia (AZE) against positive, negative and cognitive symptoms of schizophrenia in animal models., Materials and Methods: The effects of AZE (30-300 mg kg -1 ) were evaluated against apomorphine-induced cage climbing as well as ketamine -induced hyperlocomotion, -enhanced immobility, -impaired social interaction and novel object recognition. The propensity of AZE to induce catalepsy and to attenuate haloperidol-induced catalepsy were also investigated., Results: AZE 30-300 mg kg -1 significantly reduced apomorphine-induced climbing behaviour as well as ketamine-induced hyperlocomotion, immobility and object recognition deficits (at least P < 0.05). Moreover, the extract showed no cataleptic effect but significantly inhibited haloperidol-induced catalepsy at a dose of 30 mg kg -1 (P < 0.05)., Conclusion: The root extract of Albizia zygia exhibited an antipsychotic-like activity in mice with potential to alleviate positive, negative and cognitive symptoms of schizophrenia., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Total sleep deprivation (SD) has been found to mitigate motor dysfunctions in Parkinson's disease. Apparently, the similar sensitivity of an animal model for parkinsonism would support the model's validity. Recently, we described catalepsy induced in Wistar rats by somatostatin antagonist, cyclosomatostatin (cSST); this model simulates such a disease-associated abnormality as a fall in brain somatostatin levels. To evaluate the similarity between the cSST model and Parkinson's disease, we assessed here the responsiveness of cSST-induced catalepsy to 1-h and 3-h SD. In parallel, the influence of SD on catalepsy induced by a dopamine receptor antagonist, haloperidol, was examined. It was found that the short-term SD failed to influence cataleptic responses of both types (sleep deprived rats and undisturbed ones displayed a similar duration of immobility, p > 0.05). By contrast, 3-h SD suppressed (p < 0.01) cSST-induced catalepsy, however, enhanced (p < 0.01) cataleptic response to haloperidol. Thus, the anti-cataleptic effect of SD appears to be cSST-specific. These findings support the validity of the cSST-induced catalepsy in Wistar rats as a model for parkinsonian motor dysfunctions., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The effects of antipsychotic drugs (APDs) on the adolescent brain are poorly understood despite a dramatic increase in prescription of these drugs in adolescents over the past twenty years. Neuronal systems continue to be remodeled during adolescence. Therefore, when given in adolescence, antipsychotic drugs (APDs) have the potential to affect this remodeling. In this study we investigated the effects of chronic 22-day risperidone treatment (1.3mg/kg/day) in both adolescent and adult rats. We examined short- and long-term changes in behaviour (catalepsy, locomotion and conditioned avoidance response (CAR)), and dopaminergic and serotonergic neurochemistry in the striatum and the nucleus accumbens. Here, we report that, both during chronic treatment and after a lengthy drug-free interval, risperidone induced a sensitised cataleptic response regardless of the age of exposure. Selectively in adolescents, risperidone-induced catalepsy was inversely correlated with striatal dopamine turnover immediately after chronic treatment. After a drug-free interval, a significant proportion of rats with prior adolescent risperidone treatment also failed to acquire CAR to a defined criterion. Our data provide evidence that the same chronic risperidone treatment regimen can induce contrasting short- and long-term neural outcomes in the adolescent and adult brains., (Crown Copyright © 2017. Published by Elsevier Ltd. All rights reserved.)

Narcolepsy is a sleep disorder caused by the loss of orexin (hypocretin)-producing neurons and marked by excessive daytime sleepiness and a sudden weakening of muscle tone, or cataplexy, often triggered by strong emotions. In a mouse model for narcolepsy, we previously demonstrated that serotonin neurons of the dorsal raphe nucleus (DRN) mediate the suppression of cataplexy-like episodes (CLEs) by orexin neurons. Using an optogenetic tool, in this paper we show that the acute activation of DRN serotonin neuron terminals in the amygdala, but not in nuclei involved in regulating rapid eye-movement sleep and atonia, suppressed CLEs. Not only did stimulating serotonin nerve terminals reduce amygdala activity, but the chemogenetic inhibition of the amygdala using designer receptors exclusively activated by designer drugs also drastically decreased CLEs, whereas chemogenetic activation increased them. Moreover, the optogenetic inhibition of serotonin nerve terminals in the amygdala blocked the anticataplectic effects of orexin signaling in DRN serotonin neurons. Taken together, the results suggest that DRN serotonin neurons, as a downstream target of orexin neurons, inhibit cataplexy by reducing the activity of amygdala as a center for emotional processing., Competing Interests: The authors declare no conflict of interest.

Central nervous system plays a vital role in regulation of most of biological functions which are abnormally affected in various disorders including cerebral ischemia, Alzheimer's and Parkinson's (AD and PD) worldwide. Cerebral stroke is an extremely fatal and one of the least comprehensible neurological disorders due to limited availability of prospective clinical approaches and therapeutics. Since, some endogenous peptides like thyrotropin-releasing hormone have shown substantial neuroprotective potential, hence present study evaluates the newer thyrotropin-releasing hormone (TRH) analogue L-pGlu-(1-benzyl)-l-His-l-Pro-NH 2 for its neuroprotective effects against oxygen glucose deprivation (OGD), glutamate and H 2 O 2 induced injury in pheochromocytoma cell lines (PC-12 cells) and in-vivo ischemic injury in mice. Additionally, the treatment was further analyzed with respect to models of AD and PD in mice. Cerebral ischemia was induced by clamping both bilateral common carotid arteries for ten minutes. Treatment was administered to the mice five minute after restoration of blood supply to brain. Consequential changes in neurobehavioural, biochemical and histological parameters were assessed after a week. L-pGlu-(1-benzyl)-l-His-l-Pro-NH 2 showed significant reduction in glutamate, H 2 O 2 and OGD -induced cell death in concentration and time dependent manner. Moreover, L-pGlu-(1-benzyl)-l-His-l-Pro-NH 2 resulted in a substantial reduction in CA1 (Cornus Ammonis 1) hippocampal neuronal cell death, inflammatory cytokines, TNF-α, IL-6 and oxidative stress in hippocampus. In addition, L-pGlu-(1-benzyl)-l-His-l-Pro-NH 2 was found to be protective in two acute models of AD and PD as well these findings demonstrate the neuroprotective potential of L-pGlu-(1-benzyl)-l-His-l-Pro-NH 2 in cerebral ischemia and other diseases, which may be mediated through reduction of excitotoxicity, oxidative stress and inflammation., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

A series of novel benzisothiazolylpiperazine derivatives combining potent dopamine D2 and D3, and serotonin 5-HT1A and 5-HT2A receptor properties were synthesized and evaluated for their potential antipsychotic properties. The most-promising derivative was 9j. The unique pharmacological features of 9j were a high affinity for D2, D3, 5-HT1A, and 5-HT2A receptors, together with a 20-fold selectivity for the D3 versus D2 subtype, and a low affinity for muscarinic M1 (reducing the risk of anticholinergic side effects), and for hERG channels (reducing incidence of QT interval prolongation). In animal behavioral models, 9j inhibited the locomotor-stimulating effects of phencyclidine, blocked conditioned avoidance response, and improved the cognitive deficit in the novel object recognition tests in rats. 9j exhibited a low potential for catalepsy, consistent with results with risperidone. In addition, favorable brain penetration of 9j in rats was detected. These studies have demonstrated that 9j is a potential atypical antipsychotic candidate., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Potential roles of natural products have been identified for preventing or treating various diseases. Our aim was to investigate the effectiveness of camel milk in an animal model of Parkinson's disease and compare it with standard treatment (levodopa + carbidopa combination). 40 Wistar albino rats weighing 200-250 gram were divided into four groups of 10 animals each. Group I was kept on water and served as normal control, group II served as negative control, treated with chlorpromazine (5mg/kg i.p.), group III was given camel milk (33ml/kg p.o) and group IV the standard combination of levodopa + carbidopa (100+10mg/kg) respectively, 30 minutes after chlorpromazine treatment. All animals were subjected to the drugs treatment for 30 days. Catalepsy was assessed by Bar test on day 21 and day 30 at 30, 60, 90 and 120 minutes interval. On 30th day animals were sacrificed and whole brains were examined for histopathological changes. The results revealed highly significant (p<0.001) anti-cataleptic effect of camel milk on day 21 and 30 in comparison to chlorpromazine. When compared with standard therapy, the results showed that anti-Parkinson's activity of camel milk was significant (p<0.01) on day 21. However, the difference in activity was non-significant on day 30. Histopathology of the brain showed that administration of camel milk reveals intact architecture with mild degenerative changes than chlorpromazine and levodopa + carbidopa treated animals. In conclusion, camel milk possesses anti-Parkinson's activity. However, its long term efficacy and safety needs to be evaluated clinically.

Autophagy is necessary for neuronal homeostasis and its dysfunction has been implicated in Parkinson's disease (PD) as it can exacerbate endoplasmic reticulum (ER) stress and ER stress-induced apoptosis. Quercetin is a flavonoid known for its neuroprotective and antioxidant effects. The present study investigated the protective, autophagy-modulating effects of quercetin in the rotenone rat model of PD. Rotenone was intraperitoneally injected at dose of 2 ml/kg/day for 4 weeks. Simultaneous intraperitoneal injection of quercetin was given at a dose of 50 mg/kg/day also for 4 weeks. Neurobehavioral changes were studied. Oxidative/antioxidant status, C/EBP homologous protein (CHOP), Beclin-1, and dopamine levels were assessed. DNA fragmentation and histopathological changes were evaluated. This research work revealed that quercetin significantly attenuated rotenone-induced behavioral impairment, augmented autophagy, ameliorated ER stress- induced apoptosis with attenuated oxidative stress. From the current study, quercetin can act as an autophagy enhancer in PD rat model and modulates the microenvironment that leads to neuronal death., (© 2016 Wiley Periodicals, Inc.)

The present study was undertaken to evaluate the possible protective effect of thymoquinone on chlorpromazine induced catalepsy, locomotor activity and cerebral oxidative stress in rats. The rats were divided into four groups, each group containing eight animals. The animals were evaluated after repeated administration of chlorpromazine (CPZ) 30 min before the administration of thymoquinone (TQ) for 21 days. Catalepsy was assessed using block method whereas the locomotor activity was assessed using acceleratory rotarod and actophotometer. Markers of oxidative stress parameters (LPO, GSH, GPx, GR, GST and CAT) were evaluated in the brain of rats. The cataleptic scores were significantly increased in CPZ treated rats when compared with normal control rats. Oral administration of TQ (5 and 10 mg/kg) significantly decreased cataleptic scores when compared with chlorpromazine (CPZ) treated rats. The muscle coordination and spontaneous locomotor activity was significantly decreased in CPZ treated rats when compared with normal control rats. Treatment with TQ significantly improved the muscle coordination and spontaneous locomotor activity when compared with CPZ treated rats. TQ treated rats significantly reduced the elevated levels of lipid peroxidation (LPO), increased levels of antioxidant enzymes i.e., reduced glutathione (GSH), glutathione peroxidase (GPx), glutathione reductase (GR), glutathione-S-transferase (GST) and catalase (CAT) when compared with CPZ treated rats. The results clearly suggest that supplementation with TQ can be used to preclude CPZ induced extrapyramidal side effects and may find a role in reducing the oxidative stress.

Recent evidence points to a neuroprotective action of bee venom on nigral dopamine neurons in animal models of Parkinson's disease (PD). Here we examined whether bee venom also displays a symptomatic action by acting on the pathological functioning of the basal ganglia in rat PD models. Bee venom effects were assessed by combining motor behavior analyses and in vivo electrophysiological recordings in the substantia nigra pars reticulata (SNr, basal ganglia output structure) in pharmacological (neuroleptic treatment) and lesional (unilateral intranigral 6-hydroxydopamine injection) PD models. In the hemi-parkinsonian 6-hydroxydopamine lesion model, subchronic bee venom treatment significantly alleviates contralateral forelimb akinesia and apomorphine-induced rotations. Moreover, a single injection of bee venom reverses haloperidol-induced catalepsy, a pharmacological model reminiscent of parkinsonian akinetic deficit. This effect is mimicked by apamin, a blocker of small conductance Ca2+-activated K+ (SK) channels, and blocked by CyPPA, a positive modulator of these channels, suggesting the involvement of SK channels in the bee venom antiparkinsonian action. In vivo electrophysiological recordings in the substantia nigra pars reticulata (basal ganglia output structure) showed no significant effect of BV on the mean neuronal discharge frequency or pathological bursting activity. In contrast, analyses of the neuronal responses evoked by motor cortex stimulation show that bee venom reverses the 6-OHDA- and neuroleptic-induced biases in the influence exerted by the direct inhibitory and indirect excitatory striatonigral circuits. These data provide the first evidence for a beneficial action of bee venom on the pathological functioning of the cortico-basal ganglia circuits underlying motor PD symptoms with potential relevance to the symptomatic treatment of this disease.

Non-motor symptoms of Parkinson's disease are under-studied and therefore not well treated. Here, we investigated the role of combined depletions of dopamine, norepinephrine and/or serotonin in the manifestation of motor and non-motor deficits in the rat. Then, we studied the impact of these depletions on the efficacy of deep brain stimulation of the subthalamic nucleus (STN-DBS). We performed selective depletions of dopamine, norepinephrine and serotonin, and the behavioral effects of different combined depletions were investigated using the open field, the elevated plus maze and the forced swim test. Bilateral dopamine depletion alone induced locomotor deficits associated with anxiety and mild "depressive-like" behaviors. Although additional depletions of norepinephrine and/or serotonin did not potentiate locomotor and anxiety disorders, combined depletions of the three monoamines dramatically exacerbated "depressive-like" behavior. STN-DBS markedly reversed locomotor deficits and anxiety behavior in animals with bilateral dopamine depletion alone. However, these improvements were reduced or lost by the additional depletion of norepinephrine and/or serotonin, indicating that the depletion of these monoamines may interfere with the antiparkinsonian efficacy of STN-DBS. Furthermore, our results showed that acute STN-DBS improved "depressive-like" disorder in animals with bilateral depletion of dopamine and also in animals with combined depletions of the three monoamines, which induced severe immobility in the forced swim test. Our data highlight the key role of monoamine depletions in the pathophysiology of anxiety and depressive-like disorders and provide the first evidence of their negative consequences on the efficacy of STN-DBS upon the motor and anxiety disorders in the context of Parkinson's disease., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Catalepsy--passive defense freezing reaction in response to the threatening stimuli. In hypertrophic form, it is a symptom of brain dysfunction. In mice, the major gene that determines predisposition to catalepsy localized in the distal fragment 111.35-116.16 m. p. n. of chromosome 13. This chromosome fragment using backcrossing was transferred from the cataleptic CBA mouse stain to the genome of catalepsy resistant mouse strain C57BL/6. It was obtained two recombinant lines C57BL6.CBA-Dl3Mit76C and C57BL6.CBA-D13Mit76B, carrying the fragment of CBA and C57BL/6, respectively. It has been shown that in C57BL6.CBA-D13Mit76C mice the number of cataleptic higher compared with the control line C57BL6.CBA-Dl3Mit76B. In tests "startle reflex reaction" and "social interaction" differences in behavior were not found. At the same time reduction of exploratory behavior in the "open field" test of C57BL6.CBA-D13Mit76C mice compared with C57BL6.CBA-D13Mit76B mice was shown. Immobility time of C57BL6.CBA-D13Mit76C mice in the "forced swimming" test was also significantly lower compared to control mice C57BL6.CBA-D13Mit76B.

The inferior colliculus (IC) plays an important role in the normal processing of the acoustic message and is also involved in the filtering of acoustic stimuli of aversive nature. The neural substrate of the IC can also influence haloperidol-induced catalepsy. Considering that (i) paradoxical kinesia, observed in some parkinsonian patients, seems to be dependent of their emotional state and (ii) deep brain stimulation (DBS) represents an alternative therapeutic route for the relief of parkinsonian symptoms, the present study investigated the consequence of DBS at the IC on the catalepsy induced by haloperidol in rats. Additionally, we investigated if DBS of the IC can elicit motor responses in anesthetized rats and whether DBS elicits distinct neural firing patterns of activity at the dorsal cortex (DCIC) or central nucleus (CNIC) of the IC. A significant reduction of the catalepsy response was seen in rats previously given haloperidol and receiving DBS at the IC. In addition, electrical stimulation to the ventral part of the CNIC induced immediate motor responses in anesthetized rats. The neuronal spontaneous activity was higher at the ventral part of the CNIC than the dorsal part. DBS to the ventral part but not to the dorsal part of the CNIC increased the spike rate at neurons a few hundred microns away from the stimulation site. It is possible that the IC plays a role in the sensorimotor gating activated by emotional stimuli, and that DBS at the IC can be a promising new animal model to study paradoxical kinesia in rats., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Behavioral effects of classic antidepressants, fluoxetine and imipramine, and new psychotropic benzopentathiepin TC-2153 (20 mg/kg, per os) were studied on mice differing in the predisposition to catalepsy-noncataleptic AKR strain and cataleptic strains CBA and AKR.CBA-D13Mit76 (D13). Mice of D13 strain was created by transferring the CBA-allele of major locus of catalepsy to AKR genome. In the forced swim test (FST) fluoxetine showed antidepressant effect on mice of all three strains, imipramine was effective only in D13 mice, while TC-2153 produced antidepressant effect on AKR and D13 mice. Unlike to imipramine and fluoxetine, TC-2153 did not produce negative side effects in the open field and elevated plus-maze tests. Thus, TC-2153 produces antidepressant effects similar to imipramine and fluoxetine, without any visible negative side effect on locomotory activity and anxiety. The D13 mice in the FST showed high sensitivity to the studied drugs in comparison to the parent strains and can be used as new genetic model for investigation of the mechanism of antidepressant effects.

Catalepsy usually is caused by imbalance of dopamine (DA) and serotonin (5-HT) systems of brain. The aim of our work was to verify if this imbalance plays an important role in the mechanism of hereditary catalepsy in mice. Maintenance of DA, 5-HT and their main metabolites--5-hydroxyindoleacetic acid, 3,4-dihydroxyphenylacetic acid, homovanilic acid was determined in cortex, hypothalamus, hippocampus, striatum, substantia nigra and nuclei raphes in catalepsy-resistant AKR/J mice strain and catalepsy-prone CBA/LacJ mice strain and recombinant mice AKR/J.CBA-D13Mit76 (D13) strain. The latest strain was selected by transferring of a fragment of the chromosome 13 from CBA/LacJ carrying the main gene of hereditary catalepsy to AKR/J genome. There were no interstrain differences in concentration of biogenic amines and their metabolites in all brain regions. As a result of our work the hypothesis about the important role of 5-HT and/or DA systems of brain in the mechanism of hereditary catalepsy in mice was denied.

We recently identified ASP5736, (N-(diaminomethylene)-1-(3,5-difluoropyridin-4-yl)-4-fluoroisoquinoline-7-carboxamide (2E)-but-2-enedioate), a novel antagonist of 5-HT5A receptor, and here describe the in vitro and in vivo characterization of this compound. ASP5736 exhibited a high affinity for the human 5-HT5A receptor (Ki = 3.6 ± 0.66 nM) and antagonized 5-carboxamidotryptamine (5-CT)-induced Ca(2+) influx in human cells stably expressing the 5-HT5A receptor with approximately 200-fold selectivity over other receptors, including other 5-HT receptor subtypes, enzymes, and channels except human 5-HT2c receptor (Ki = 286.8 nM) and 5-HT7 receptor (Ki = 122.9 nM). Further, ASP5736 dose-dependently antagonized the 5-CT-induced decrease in cAMP levels in HEK293 cells stably expressing the 5-HT5A receptor. We then evaluated the effects of ASP5736 on cognitive impairments in several animal models of schizophrenia. Working memory deficit in MK-801-treated mice and visual learning deficit in neonatally phencyclidine (PCP)-treated mice were both ameliorated by ASP5736. In addition, ASP5736 also attenuated MK-801- and methamphetamine (MAP)-induced hyperactivity in mice without causing sedation, catalepsy, or plasma prolactin increase. The addition of olanzapine did not affect ASP5736-induced cognitive enhancement, and neither the sedative nor cataleptogenic effects of olanzapine were worsened by ASP5736. These results collectively suggest that ASP5736 is a novel and potent 5-HT5A receptor antagonist that not only ameliorates positive-like symptoms but also cognitive impairments in animal models of schizophrenia, without adverse effects. Present studies also indicate that ASP5736 holds potential to satisfy currently unmet medical needs for the treatment of schizophrenia by either mono-therapy or co-administered with commercially available antipsychotics., (Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.)

The inferior colliculus (IC) is an important midbrain relay station for the integration of descending and ascending auditory information. In addition, it has also been implicated in the processing of acoustic information of aversive nature, as well as in sensory-motor gating. There is evidence that glutamate-mediated mechanisms at the IC level influence haloperidol-induced catalepsy. The present study investigated the influence of glutamate-mediated mechanisms in the IC on catalepsy induced by intrastriatal microinjection of haloperidol (10 μg/0.5 μl). Male Wistar rats received bilateral intracollicular microinjections of the glutamate receptor agonist NMDA (10 or 20 nmol/0.5 μl), the NMDA receptor antagonists MK-801 (15 or 30 nmol/0.5 μl) or physiological saline (0.5 μl), followed by bilateral microinjections of haloperidol (10 μg/0.5 μl) or vehicle (0.5 μl) into the dorso-rostral or ventro-rostral striatum. The catalepsy test was performed positioning both forepaws of the rats on an elevated horizontal wooden bar and recording the time during which the animal remained in this position. The results showed that the administration of physiological saline in the IC followed by the microinjection of haloperidol in the dorso-rostral region of the striatum was not able to induce catalepsy. However, when the bilateral administration of NMDA into the IC was followed by microinjection of haloperidol into the dorso-rostral striatum, catalepsy was observed. The microinjection of haloperidol into the ventro-rostral striatum induced catalepsy, counteracted by previous administration of MK-801 into the IC. These findings suggest that glutamate-mediated mechanisms in the IC can influence the intrastriatal haloperidol-induced catalepsy and that the IC plays an important role as a sensorimotor interface., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Objective: To examine the effects of dehydroepiandrosterone (DHEA) on animal models of schizophrenia., Methods: Seventy Swiss albino female mice (25-35 g) were divided into 4 groups: amphetamine-free (control), amphetamine, 50, and 100 mg/kg DHEA. The DHEA was administered intraperitoneally (ip) for 5 days. Amphetamine (3 mg/kg ip) induced hyper locomotion, apomorphine (1.5 mg/kg subcutaneously [sc]) induced climbing, and haloperidol (1.5 mg/kg sc) induced catalepsy tests were used as animal models of schizophrenia. The study was conducted at the Animal Experiment Laboratories, Department of Pharmacology, Medical School, Eskisehir Osmangazi University, Eskisehir, Turkey between March and May 2012. Statistical analysis was carried out using Kruskal-Wallis test for hyper locomotion, and one-way ANOVA for climbing and catalepsy tests., Results: In the amphetamine-induced locomotion test, there were significant increases in all movements compared with the amphetamine-free group. Both DHEA 50 mg/kg (p<0.05), and 100 mg/kg (p<0.01) significantly decreased all movements compared with the amphetamine-induced locomotion group. There was a significant difference between groups in the haloperidol-induced catalepsy test (p<0.05). There was no significant difference between groups in terms of total climbing time in the apomorphine-induced climbing test (p>0.05)., Conclusion: We observed that DHEA reduced locomotor activity and increased catalepsy at both doses, while it had no effect on climbing behavior. We suggest that DHEA displays typical neuroleptic-like effects, and may be used in the treatment of schizophrenia.

Repeated haloperidol treatment administered to nonhuman primates (NHPs) over several months or even years leads to the gradual appearance of drug-induced dystonic reactions in the orofacial region (mouth opening, tongue protrusion or retraction, bar biting) and in the whole body (writhing of the limbs and trunk, bar grasping). The propensity of antipsychotics to induce dystonia in NHPs is not correlated with their propensity to induce catalepsy in rodents, suggesting that the two types of effects are dissociated and may represent distinct aspects of the extrapyramidal symptoms induced by antipsychotics. In view of the clear homology to clinically observed phenomena, antipsychotic-induced dystonias in antipsychotic-primed NHPs would appear to possess a high degree of translational validity. These NHP phenomena could therefore serve as a useful model for predicting the occurrence of similar abnormal movements with novel substances developed for the treatment of schizophrenia or other psychotic disorders. Moreover, the NHP dystonia model could possibly serve as a biomarker for substances that will eventually cause tardive dyskinesia in patients.

Zolpidem is a non-benzodiazepine hypnotic drug acting preferentially at α1-containing GABAA receptors expressed in various parts of the brain, including the basal ganglia. The aim of the present study was to provide preliminary characteristics of zolpidem-induced catalepsy in Wistar rats. Zolpidem (2.5-10.0mg/kg), but not diazepam and midazolam, produced dose-dependent cataleptic responses in the bar test, which were similar to those produced by a reference antipsychotic drug, haloperidol. Zolpidem-induced catalepsy was abolished by a benzodiazepine site antagonist, flumazenil (5.0mg/kg), D2/3 receptor agonist, quinpirole (1.0mg/kg), and a non-competitive NMDA receptor antagonist, MK-801 (0.1mg/kg), but not by a non-selective opioid receptor antagonist, naltrexone (3.0mg/kg). The present results indicate that systemic injections of zolpidem may produce short-lasting, neuroleptic-like catalepsy in the rat., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

ASC mice, which were selected for high predisposition to catalepsy, are convenient genetic model for research of central mechanisms related to disorder of motor regulation. The aim of the work was to study the effect of glial cell line-derived neurotrophic factor (GDNF) on catalepsy, locomotor activity, stereotyping behavior in the marble burying test and on the dopamine level in striatum of ASC mice. It was shown that GDNF increased the locomotor activity in the open field, reduced catalepsy expression and stimulated the stereotyping obsessive-compulsive behavior. These changes in behavior were accompanied by increasing dopamine level in striatum.

Catalepsy is a passive defensive strategy in response to threatening stimuli. In exaggerated forms it is associated with brain dysfunctions. The study was aimed to examine (1) possible association of the hereditary catalepsy with neuroanatomical characteristics and (2) sensitivity of the catalepsy expression, HPA and brain serotonin (5-HT) systems to restraint stress (for one hour) in mice of catalepsy-prone (CBA/Lac, ASC (Antidepressant Sensitive Catalepsy), congenic AKR.CBA-D13M76) and catalepsy-resistant (AKR/J) strains. Magnetic resonance imaging showed that the catalepsy-prone mice were characterized by the smaller size of the pituitary gland and the larger size of the thalamus. In ASC mice, diencephalon region (including hypothalamus) and striatum were significantly reduced in size. Restraint stress provoked catalepsy in AKR mice and enhanced it in the catalepsy-prone mice. Stress-induced corticosterone elevation was diminished, while 5-HT metabolism (5-HIAA level or 5-HIAA/5-HT ratio) in the midbrain was significantly augmented by stress in the catalepsy-prone mice. The multivariate factor analysis revealed interactions between the basal levels and the stress-induced alterations of 5-HT metabolism in the hippocampus and midbrain suggesting the interaction between multiple alterations in 5-HT neurotransmission in several brain structures in the regulation of hereditary catalepsy. The study indicated an association between the hereditary catalepsy, neuroanatomical characteristics, and neurochemical responses to emotional stress. The catalepsy-prone genotypes seem to be more susceptible to stress that suggests them as the adequate models to study the genetic predisposition to stress-based neuropathology. The data support the association of hereditary catalepsy with the inherited brain dysfunction of a neurodegenerative nature., (Copyright © 2013 Elsevier B.V. All rights reserved.)

The gut-derived orexigenic peptide hormone ghrelin enhances neuronal firing in the substantia nigra pars compacta, where dopaminergic neurons modulate the function of the nigrostriatal system for motor coordination. Here we describe a novel mechanism by which ghrelin enhances firing of nigral dopaminergic neurons by inhibiting voltage-gated potassium Kv7/KCNQ/M-channels through its receptor GHS-R1a and activation of the PLC-PKC pathway. Brain slice recordings of substantia nigra pars compacta neurons reveal that ghrelin inhibits native Kv7/KCNQ/M-currents. This effect is abolished by selective inhibitors of GHS-R1a, PLC and PKC. Transgenic suppression of native Kv7/KCNQ/M-channels in mice or channel blockade with XE991 abolishes ghrelin-induced hyperexcitability. In vivo, intracerebroventricular ghrelin administration causes increased dopamine release and turnover in the striatum. Microinjection of ghrelin or XE991 into substantia nigra pars compacta results in contralateral dystonic posturing, and attenuation of catalepsy elicited by systemic administration of the D2 receptor antagonist haloperidol. Our findings indicate that the ghrelin/KCNQ signalling is likely a common pathway utilized by the nervous system.

Decreases in brain dopamine (DA) lead to catalepsy, quantified by the time a rat remains with its forepaws resting on a suspended horizontal bar. Low doses of the DA D2 receptor-preferring antagonist haloperidol repeatedly injected in a particular environment lead to gradual day-to-day increases in catalepsy (catalepsy sensitization) and subsequent testing following an injection of saline reveal conditioned catalepsy. We tested the hypothesis that D1-like and D2 receptors play different roles in catalepsy sensitization and in acquisition and expression of conditioned catalepsy. Rats were repeatedly treated with the DA D1-like receptor antagonist SCH 23990 (0.05, 0.1 and 0.25 mg/kg i.p.), the D2 receptor-preferring antagonist haloperidol (0.1, 0.25 and 0.5 mg/kg i.p.) or a combination of the two drugs and tested for catalepsy each day in the same environment. Following 10 drug treatment days, rats were injected with saline and tested for conditioned catalepsy in the previously drug-paired environment. Haloperidol did not elicit cataleptic responses in the initial session; however, rats developed sensitization with repeated testing. Significant catalepsy sensitization was not observed in rats repeatedly tested with SCH 23390. When rats were injected and tested with saline following haloperidol sensitization they exhibited conditioned catalepsy in the test environment; conditioned catalepsy was not seen following SCH 23390. Rats treated with 0.05 mg/kg SCH 23390+0.25 mg/kg haloperidol showed catalepsy sensitization but failed to show conditioned catalepsy. Conversely, SCH 23390 (0.05 mg/kg) given on the test day after sensitization to haloperidol (0.25 mg/kg) failed to block conditioned catalepsy. Repeated antagonism of D2 receptors leads to catalepsy sensitization with repeated testing in a specific environment. Conditioned catalepsy requires intact D1-like receptor function during sensitization sessions but not during test sessions. In conclusion, repeated antagonism of D2, but not D1-like receptors leads to catalepsy sensitization with repeated testing in a specific environment. Conditioned catalepsy requires functional D1-like receptors during sensitization sessions but not during test sessions.

The comparative immunohistochemical researches of dofamine containing neurons and fibers are carried uot in telencephalic and diencephalic departments of the brain in different vertebratts (adults rats, rats aged 14 and 30 days and frogs). For analysis of quantitative changes dynamics in thyrozinhydroxylase, D1 and D2 immunoreactive material in sleep-wakefulness cycle the model of sleepdeprivation is used. There are found the facts of morphofunctional correlations in the reactions of dophaminergic system during ontogeny and phylogeny. Besides, the pharmacological effects of dofamine agonist and antagonists on the sleep-wakefulness cycle in young rats and in frogs are shown. So, dopamine and its agonist apomorphine increase in sleep-wakefulness cycle duration of sleep-like state ofcataplexy (homolog of the sleep) in frogs, in 30-day-old rats it increase the share of wakefulness and catalepsy. D1 receptors antagonist (SCH 23390) adminisrated to frogs, caused increase of wakefulness and catatonic type states duration, where as D2 receptors antagonist (apomorphine) increased cataleptic condition. Administration of dopamine antagonist (haloperidol) to 30-day-old rats previously causes the increase of cataleptic state, after which the slow wave sleep state is enhanced. The questions of phylo-, ontogenetic formation of dopaminergic system regulating role in sleep-wakefulness cycle, when transition mainly from neurosecretory diencephalic influences of dophamine to the mainly neurotransmittory functins of telencephalic regions occured, is discussed.

Experiments in vitro on hippocampal slices of mouse have shown that solutions prepared from polymorphic modifications α- and γ-glycine have different effect on the aberrant activity of neurons. In the presence of α-glycine the excitability of these neurons decreased more slowly, prolonging its modulating effect on NMDA type glutamate receptors. This effect agrees with higher biological activity of α-polymorphic modifications (as compared with that of the α-form) that previously observed with respect to behavior of mice from the line with genetic diathesis to catalepsy, which were used as a biological model for investigation of some pathological behavior forms.

Rationale: The α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor positive allosteric modulators (AMPA-PAMs), Org 24448 and Org 26576, and the glycine transporter-1 (GlyT-1) inhibitor Org 25935 are developed for treatment of schizophrenia., Objectives: Here we examined experimentally the ability of co-administration of these AMPA-PAMs or the GlyT-1 inhibitor to augment the antipsychotic activity and effect on cortical N-methyl-D: -aspartate (NMDA) receptor-mediated transmission of risperidone, olanzapine, or haloperidol., Methods: We examined antipsychotic efficacy using the conditioned avoidance response (CAR) test, extrapyramidal side effect liability using a catalepsy test, and cortical NMDA receptor-mediated glutamatergic transmission using intracellular electrophysiological recording technique in vitro., Results: Both AMPA-PAMs enhanced the suppression of CAR induced by risperidone or olanzapine, and Org 24448 also enhanced the effect of haloperidol. In contrast, the GlyT-1 inhibitor did not cause any behaviorally significant effect in the CAR test. However, the GlyT-1 inhibitor, but not the AMPA-PAMs, produced a large facilitation of NMDA-induced currents. All three drugs potentiated the effect of risperidone but not haloperidol on these currents. The GlyT-1 inhibitor also facilitated the effect of olanzapine. All drugs potentiated the effect of risperidone on electrically stimulated excitatory postsynaptic potentials (EPSP) in cortical pyramidal cells, whereas only the GlyT inhibitor facilitated the effect of olanzapine., Conclusions: Our results suggest that the AMPA-PAMs, when compared to the GlyT-1 inhibitor, show differential effects in terms of augmentation of antipsychotic efficacy, particularly when combined with risperidone or olanzapine. Both AMPA-PAMs and the GlyT-1 inhibitor may also improve negative symptoms and cognitive impairments in schizophrenia, in particular when combined with risperidone.

Stressing reduces the intensity of haloperidol-induced catalepsy in intact female rats and increases it in ovariectomized animals. Ovarioectomy reduces the severity of haloperidol catalepsy. Circadian rhythm acrophase of the cataleptogenic haloperidol activity in female rats after ovariectomy and stress exhibits significant displacement.

Intranasal administration of dopamine (0.3; 3 and 30 microg/kg) on anxious behaviour of mice was studied using elevated plus-maze and open fields tests and the pinch-induced catalepsy on parallel bars test. Dopamine was introduced as nose drops or inhalation of nanoparticles of the compound solution in C57B1/6J and CBA/Lac mice with differences of dopaminergic function features. In our experiment, dopamine had anxiolytic and elevated motor activity effects in C57B1/6J, but not in the CBA/Lac mice. Nose drops were more effective than inhalation; perhaps, it was a more stressful manipulation. Apparently dopamine increased the number of CBA/Lac mice who demonstrated catalepsy and the reflex duration. Indeed, the neurotransmitter is active in different psycho-emotional phenomena.

A decrease in the total count of follicles in the diestrus and proestrus and higher incidence of permanent estruses were found in 3-month-old females of the catatonic GC rat strain in comparison with Wistar females (control). At the age of 6-12 months, GC females had lower incidence of long estrus and diestrus. The estrous cycle of GC females was shorter than of Wistar rats. With aging (at the age of 18 months), the counts of growing and maturing follicles significantly decreased. Higher counts of growing single-layer and bilayer follicles were found in 18-month-old GC females. Differences in the length of estrus and diestrus and in the incidence of abnormal phases in the two strains also disappeared at this age. Selection by high catatonic reactivity was associated with a decrease in body weight.

A delicate balance exists between the central dopaminergic and cholinergic neurotransmitter systems with respect to motor function. An imbalance can result in motor dysfunction as observed in Parkinson's disease patients and in patients treated with antipsychotic compounds. Cholinergic receptor antagonists can alleviate extrapyramidal symptoms in Parkinson's disease and motor side effects induced by antipsychotics. The effects of anticholinergics are mediated by muscarinic receptors of which five subtypes (M(1)-M(5)) exist. Muscarinic M(4) receptors are found at high concentrations in motor parts of the striatum, suggesting a role for muscarinic M(4) receptors in the motor side effects of antipsychotics, and in the alleviation of these side effects by anticholinergics. Here we investigated the potential role of the muscarinic M(4) receptor in catalepsy induced by antipsychotics (haloperidol and risperidone) as well as the anti-cataleptic effects of the non-selective anticholinergic drug scopolamine in fully backcrossed muscarinic M(4) receptor knockout mice. The drug-induced catalepsy was strongly attenuated, but not abolished, in M(4) knockout mice as compared to wild-type controls. Scopolamine further attenuated the cataleptic response in M(4) knockout mice, suggesting that non-M(4) muscarinic receptors also participate in the anti-cataleptic effects. In conclusion, these data indicate an important role for M(4) receptors in antipsychotic-induced motor side effects and suggest that M(4) receptors could be a target for future pharmacological treatment of antipsychotic-induced as well as idiopathic parkinsonism., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Fish oil (FO) supplementation could cause an increase in the concentration of plasmatic free fatty acids and, consequently, could compete with pro-inflammatory arachidonic acid (ARA) derived from brain biomembranes metabolism in the cerebrospinal fluid. Essential fatty acids (EFA) (n-3) have been reported by their antioxidant and neuroprotective properties, and therefore the influence of the FO supplementation on the reserpine-induced motor disorders was studied. Wistar rats were orally treated with FO solution for 5 days, and co-treated with reserpine (R; 1 mg/kg/mL) or its vehicle for 3 days (every other day). Reserpine-induced orofacial dyskinesia and catalepsy (P < 0.05) were prevented by FO (P < 0.05). Biochemical evaluations showed that reserpine treatment increased the lipid peroxidation in the cortex and striatum (P < 0.05), while the FO supplementation prevented this oxidative effect in both brain regions (P < 0.05). Our results showed the protective role of FO in the brain lipid membranes, reinforcing the beneficial effect of n-3 fatty acids in the prevention of degenerative and motor disorders.

Epidermal growth factor (EGF) is one of the ErbB receptor ligands implicated in schizophrenia neuropathology as well as in dopaminergic development. Based on the immune inflammatory hypothesis for schizophrenia, neonatal rats are exposed to this cytokine and later develop neurobehavioral abnormality such as prepulse inhibition (PPI) deficit. Here we found that the EGF-treated rats exhibited persistent increases in tyrosine hydroxylase levels and dopamine content in the globus pallidus. Furthermore, pallidal dopamine release was elevated in EGF-treated rats, but normalized by subchronic treatment with risperidone concomitant with amelioration of their PPI deficits. To evaluate pathophysiologic roles of the dopamine abnormality, we administered reserpine bilaterally to the globus pallidus to reduce the local dopamine pool. Reserpine infusion ameliorated PPI deficits of EGF-treated rats without apparent aversive effects on locomotor activity in these rats. We also administered dopamine D1-like and D2-like receptor antagonists (SCH23390 and raclopride) and a D2-like receptor agonist (quinpirole) to the globus pallidus and measured PPI and bar-hang latencies. Raclopride (0.5 and 2.0 µg/site) significantly elevated PPI levels of EGF-treated rats, but SCH23390 (0.5 and 2.0 µg/site) had no effect. The higher dose of raclopride induced catalepsy-like changes in control animals but not in EGF-treated rats. Conversely, local quinpirole administration to EGF-untreated control rats induced PPI deficits and anti-cataleptic behaviors, confirming the pathophysiologic role of the pallidal hyperdopaminergic state. These findings suggest that the pallidal dopaminergic innervation is vulnerable to circulating EGF at perinatal and/or neonatal stages and has strong impact on the D2-like receptor-dependent behavioral deficits relevant to schizophrenia.

Extrapyramidal syndromes (EPS) impose a heavy burden on patients receiving antipsychotic therapy. Anticholinergics are the drugs of choice for preventing EPS, but they also produce many adverse reactions. Using the EPS model of haloperidol-induced catalepsy we evaluated the potential therapeutic value of a mixture of low doses of the non-selective adenosine antagonist theophylline (0.93 and 1.86 mg/kg), and the muscarinic antagonists benztropine (0.134 and 0.268 mg/kg) and ethopropazine (0.116 and 0.232 mg/kg). In rats pretreated with vehicle (distilled water), the cumulative catalepsy time over 5 h was 4199±228 s, and the mean latency was 67.5±7.8 min. Applied separately, neither of the drugs at the doses used caused significant changes of catalepsy intensity vs. control rats. However, the combination of the larger doses of theophylline and benztropine caused a significant reduction of catalepsy intensity (-41±10%) compared with the effects of the vehicle, vs. the lower dose of benztropine, and vs. both doses of theophylline alone. The mixture of the larger doses of theophylline and benztropine also delayed catalepsy onset (156±21 min) as compared with the lower doses of these same drugs applied alone. In the case of theophylline plus ethopropazine, only the association of the larger doses showed a non-significant tendency to inhibit catalepsy (-21±8%) and to prolong its latency (108±13 min). Further, neither catalepsy intensity nor its latency was affected by a combination of the selective A(1)R antagonist DPCPX (1 mg/kg), with the larger doses of both anticholinergics. In contrast, the anticholinergics showed synergism with a subthreshold dose of the selective A(2A)R antagonist ZM 241395 (0.5 mg/kg), causing a significant reduction of catalepsy intensity (ethopropazine, -27±5%; benztropine, -35±9%) and prolonging its latency (ethopropazine, 65±9 min; benztropine, 78±11 min), compared with the effect of their respective vehicle (DMSO plus mineral oil: catalepsy time, 5100±196 s; latency, 17.5±2.5 min). These findings suggest that neuroleptic-induced EPS could be effectively controlled by a combination of lower doses of theophylline and anticholinergics, with the advantage of maximizing their efficacy and minimizing their adverse reactions., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Objective: The globus pallidus plays a critical role in movement regulation. Previous studies have indicated that the globus pallidus receives neurotensinergic innervation from the striatum, and systemic administration of a neurotensin analog could produce antiparkinsonian effects. The present study aimed to investigate the effects of pallidal neurotensin on haloperidol-induced parkinsonian symptoms., Methods: Behavioral experiments and electrophysiological recordings were performed in the present study., Results: Bilateral infusions of neurotensin into the globus pallidus reversed haloperidol-induced parkinsonian catalepsy in rats. Electrophysiological recordings showed that microinjection of neurotensin induced excitation of pallidal neurons in the presence of systemic haloperidol administration. The neurotensin type-1 receptor antagonist SR48692 blocked both the behavioral and the electrophysiological effects induced by neurotensin., Conclusion: Activation of pallidal neurotensin receptors may be involved in neurotensin-induced antiparkinsonian effects.

Congenic mouse strain AKR.CBA-D13Mit76 carries the 59-70 cM fragment of chromosome 13 transferred from genome of cataleptic CBA/Lac strain to genome of AKR/J none-cataleptic strain. This fragment contains the major gene of predisposition to pinch-induced catalepsy. We investigated contribution of the fragment to regulation of sensitivity of catalepsy, sexual motivation and social investigation to classical tricyclic antidepressant imipramine. The sexual motivation was higher in AKR.CBA-D13Mit76 than in AKR mice. Chronic imipramine treatment (25 mg/kg) reduced it in AKR.CBA-D13Mit76 mice and had no effect on weakly expressed sexual motivation of AKR males. No significant effects of genotype or chronic imipramine treatment on characteristics of social interest were observed. Imipramine failed to alter catalepsy expression in AKR.CBA-DI3Mit76 mice. Possible molecular genetic mechanisms underlying difference in behavioral responses to antidepressant administration are discussed.

The direct and indirect pathways of the basal ganglia have been proposed to oppositely regulate locomotion and differentially contribute to pathological behaviors. Analysis of the distinct contributions of each pathway to behavior has been a challenge, however, due to the difficulty of selectively investigating the neurons comprising the two pathways using conventional techniques. Here we present two mouse models in which the function of striatonigral or striatopallidal neurons is selectively disrupted due to cell type-specific deletion of the striatal signaling protein dopamine- and cAMP-regulated phosphoprotein Mr 32kDa (DARPP-32). Using these mice, we found that the loss of DARPP-32 in striatonigral neurons decreased basal and cocaine-induced locomotion and abolished dyskinetic behaviors in response to the Parkinson's disease drug L-DOPA. Conversely, the loss of DARPP-32 in striatopallidal neurons produced a robust increase in locomotor activity and a strongly reduced cataleptic response to the antipsychotic drug haloperidol. These findings provide insight into the selective contributions of the direct and indirect pathways to striatal motor behaviors.

ASC (Antidepressant-Sensitive Catalepsy) mice, bred for a high predisposition to catalepsy, are characterized by depression-like behavior and decreased immune responses. Chronic administration of fluoxetine, which is a selective serotonin reuptake inhibitor antidepressant widely used in clinical practice, to mice of this strain weakened catalepsy and normalized the number of rosette-forming cells in the spleen. In mice of the parental cataleptic strain CBA/Lac, fluoxetine had no effect on the level of catalepsy or the immune response. Analysis of the effects of fluoxetine on the functional activity of 5-HT(1A) and 5-HT(2A) receptors, and the expression of 5-HT(1A) receptor genes in the frontal cortex and midbrain and 5-HT(2A) receptors in the frontal cortex, as well as the tryptophan hydroxylase-2 and the serotonin transporter genes in the midbrain showed that the antidepressant had no effect on these parameters in ASC mice, but decreased the functional activity of 5-HT(2A) receptors in CBA/Lac mice. The possibility that the actions of fluoxetine on catalepsy and the immune response in mice with depression-like states are mediated via other serotoninergic mechanisms is discussed.

Adenosine and endocannabinoids are very ubiquitous non-classical neurotransmitters that exert a modulatory role on the transmission of other more 'classical' neurotransmitters. In this review we will focus on their common role as modulators of dopamine and glutamate neurotransmission in the striatum, the main input structure of the basal ganglia. We will pay particular attention to the role of adenosine A(2A) receptors and cannabinoid CB(1) receptors. Experimental results suggest that presynaptic CB(1) receptors interacting with A(2A) receptors in cortico-striatal glutamatergic terminals that make synaptic contact with dynorphinergic medium-sized spiny neurons (MSNs) are involved in the motor-depressant and addictive effects of cannabinoids. On the other hand, postsynaptic CB(1) receptors interacting with A(2A) and D(2) receptors in the dendritic spines of enkephalinergic MSNs and postsynaptic CB(1) receptors in the dendritic spines of dynorphinergic MSN are probably involved in the cataleptogenic effects of cannabinoids. These receptor interactions most probably depend on the existence of a variety of heteromers of A(2A), CB(1) and D(2) receptors in different elements of striatal spine modules. Drugs selective for the different striatal A(2A) and CB(1) receptor heteromers could be used for the treatment of neuropsychiatric disorders and drug addiction and they could provide effective drugs with fewer side effects than currently used drugs.

Catalepsy is a natural passive defense strategy in animals and a syndrome of some mental di sorders. The main gene encoding catalepsy was located in mice on the distal fragment 55-75 cM of chromosome 13. Two congenic lines AKR.CBA-D13Mit76 and AKR.CBA-D 13Mit78 carrying the 55- to 71-, and 71- to 75-cM fragments of chromosome 13 transferred from the cataleptic strain CBA to the non-cataleptic strain AKR genome were created. It was shown that half of mice of congenic AKR.CBA-D 13 Mit76 line containing fragment 55-71 cM displayed pronounced catalepsy similar to the donor CBA strain. Also we demonstrated decreased of exploratory behavior in the open field test and an increased of intermale aggression of AKR.CBA-D 13Mit76 mice compared with the parent strain AKR. No differences were found in the forced swim test between AKR.CBA-D 13Mit76 and AKR mice. Behavior of congenic mice AKR.CBA-D 13Mit78 did not differ from the parent strain AKR in all used tests.

Proportion of animals which developed pinch-induced catalepsy and the duration of this state were analyzed in rats of several genotypes which differed in audiogenic epilepsy proneness and compared with "audiogenic" catalepsy after a sound-induced seizure fit. The following genotypes were studied: Wistar, KM (Krushinsky-Molodkina) strain and substrains "4" and "0" (selected from KM and Wistar hybrid population for high "4" and low "0" audiogenic epilepsy proneness). Adult KM and substrain "4" rats developed the most intense pinch induced catalepsy, whereas Wistar and 2-month-old KM showed practically no catalepsy. After a single sound exposure pinch-induced catalepsy developed in all animals which demonstrated an audiogenic seizure fit--in KM, substrain "4", part of Wistar rats and several animals of substrain "0", latency of the fit onset in all rats being shorter than initially. After sound exposure pinch-induced catalepsy was revealed even in those substrain "0" rats, which demonstrated no audiogenic fits. It is suggested that despite the phenomenological similarity between cataleptic states of different origin (pinch-induced, "audiogenic") their neurophysiologic substrates overlap only partially. The findings are considered as presenting genetic model for further analysis of catalepsy.

Metabotropic glutamate (mGlu) receptors modulate synaptic transmission in the central nervous system and represent promising therapeutic targets for symptomatic treatment of Parkinson's disease (PD). Among the eight mGlu receptor subtypes, mGlu7 receptor is prominently expressed in the basal ganglia, but its role in restoring motor function in animal models of PD is not known. The effects of N,N'-dibenzhydrylethane-1,2-diamine dihydrochloride (AMN082), the first selective allosteric activator of mGlu7 receptors, were thus tested in different rodent models of PD. Here, we show that oral (5 mg/kg) or intrastriatal administration (0.1 and 0.5 nmol) of AMN082 reverses haloperidol-induced catalepsy in rats. AMN082 (2.5 and 5 mg/kg) reduces apomorphine-induced rotations in unilateral 6-hydroxydopamine (6-OHDA)-lesioned rats. In a more complex task commonly used to evaluate major akinetic symptoms of PD patients, 5 mg/kg AMN082 reverses the increased reaction time to respond to a cue of bilateral 6-OHDA-lesioned rats. In addition, AMN082 reduces the duration of haloperidol-induced catalepsy in a mGlu7 receptor-dependent manner in wild-type but not mGlu7 receptor knockout mice. Higher doses of AMN082 (10 and 20 mg/kg p.o.) have no effect on the same models of PD. Overall these findings suggest that mGlu7 receptor activation can reverse motor dysfunction associated with reduced dopamine activity. Selective ligands of mGlu7 receptor subtypes may thus be considered as promising compounds for the development of antiparkinsonian therapeutic strategies.