Cannabis sativa terpenes are cannabimimetic and selectively enhance cannabinoid activity.

Limited evidence has suggested that terpenes found in Cannabis sativa are analgesic, and could produce an "entourage effect" whereby they modulate cannabinoids to result in improved outcomes. However this hypothesis is controversial, with limited evidence. We thus investigated Cannabis sativa terpenes alone and with the cannabinoid agonist WIN55,212 using in vitro and in vivo approaches. We found that the terpenes α-humulene, geraniol, linalool, and ß-pinene produced cannabinoid tetrad behaviors in mice, suggesting cannabimimetic activity. Some behaviors could be blocked by cannabinoid or adenosine receptor antagonists, suggesting a mixed mechanism of action. These behavioral effects were selectively additive with WIN55,212, suggesting terpenes can boost cannabinoid activity. In vitro experiments showed that all terpenes activated the CB1R, while some activated other targets. Our findings suggest that these Cannabis terpenes are multifunctional cannabimimetic ligands that provide conceptual support for the entourage effect hypothesis and could be used to enhance the therapeutic properties of cannabinoids.

Taurine and coenzyme Q10 synergistically prevent and reverse chlorpromazine-induced psycho-neuroendocrine changes and cataleptic behavior in rats.

Over the years, mounting evidences have suggested a strong association between chronic chlorpromazine therapy, a popular first-generation antipsychotic drug, and psycho-neuroendocrine changes. In this study, we aim to examine whether treatment with taurine and coenzyme Q10 (COQ-10), compounds with steroidogenic-gonadotropin hormone-enhancing properties, can attenuate the negative impacts of chlorpromazine on steroidogenic, gonadotropin, thyroid and HPA-axis hormones, dopamine levels, catalepsy behavior and neuronal cells of the hypothalamus and pituitary gland in the preventive and reversal treatments in male Wister rats. In the drug treatment alone or preventive protocol, rats received oral administration of saline (10 mL/kg), taurine (150 mg/kg/day), COQ-10 (10 mg/kg/day), or both (taurine + COQ-10/day) alone for 56 consecutive days, or in combination with oral chlorpromazine (30 mg/kg/day) treatment from days 29 to 56. In the reversal protocol, the animals received chlorpromazine or saline for 56 days prior to taurine, COQ-10, or the combination from days 29 to 56. Thereafter, serum prolactin, steroidogenic (testosterone, estrogen, progesterone), gonadotropin (luteinizing hormone, LH, follicle-stimulating hormone, FSH), thyroid (thyrotropin-stimulating hormone, tetraiodothyronine, triiodothyronine) hormones, corticosterone, brain dopamine levels and cataleptic behavior were investigated. The histopathological features of the hypothalamus and pituitary gland were also evaluated. Taurine, COQ-10, or their combination prevented and reversed chlorpromazine-induced hyperprolactinemia, decrease in FSH, LH, testosterone, progesterone and dopamine concentrations, as well as the increase in estrogen levels. Taurine and COQ-10 reduced the changes in thyroid hormones, corticosterone release, histological distortions of the hypothalamus and the pituitary gland of chlorpromazine-treated rats. Taurine and COQ-10 attenuated chlorpromazine-induced catalepsy. The study showed that taurine and COQ-10 prevented and reversed chlorpromazine-induced changes in reproductive, thyroid hormones, dopamine level, corticosterone release, neurodegenerations, and cataleptic behavior in rats.

Effect of M. chamomilla L. tea on chlorpromazine induced catalepsy: A neuroprotective study.

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.

Discovery, Structure-Activity Relationship, and Biological Characterization of a Novel Series of 6-((1 H-Pyrazolo[4,3- b]pyridin-3-yl)amino)-benzo[ d]isothiazole-3-carboxamides as Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 4 (mGlu4).

This work describes the discovery and characterization of novel 6-(1 H-pyrazolo[4,3- b]pyridin-3-yl)amino-benzo[ d]isothiazole-3-carboxamides as mGlu4 PAMs. This scaffold provides improved metabolic clearance and CYP1A2 profiles compared to previously discovered mGlu4 PAMs. From this work, 27o (VU6001376) was identified as a potent (EC50 = 50.1 nM, 50.5% GluMax) and selective mGlu4 PAM with an excellent rat DMPK profile ( in vivo rat CLp = 3.1 mL/min/kg, t1/2 = 445 min, CYP1A2 IC50 > 30 µM). Compound 27o was also active in reversing haloperidol induced catalepsy in a rodent preclinical model of Parkinson's disease.

Celecoxib, a cyclooxygenase-2 inhibitor, offers chemoprevention against reproductive and neurobehavioural abnormalities induced by atrazine in male Wistar rats.

The cyclooxygenase-2/prostanoid pathway (COX-2) serves as a potential therapeutic target in various pathological conditions. Thus, the modulatory effect of celecoxib (CXB), a COX-2 inhibitor, in atrazine-induced toxicity was investigated. Five groups (n = 6 rats per group) of adult male Wistar rats received corn oil (2 ml/kg), atrazine (ATZ, 300 mg/kg) and CXB (5.7 mg/kg) respectively and their combinations via the oral route. Results obtained showed reduced (p < 0.05) sperm motility (25.8%) and counts (27.6%), testosterone (29.9%), luteinizing (33%) and follicle stimulating hormones (78.7%) plus elevated total cholesterol (112.3%), triglyceride (115.7%), malondialdehyde levels respectively in ATZ-treated rats. Similarly, ATZ administration causes reduced locomotion (33.6%), spontaneous motor activity (46.6%) and catalepsy effects (157.3%) respectively. However, CXB divided doses moderately reverse reproductive abnormalities, modulate neurobehavioural deficits and slightly preserved COX-2 elevation following ATZ intoxication. Furthermore, histopathology of testis shows improvement in treated rats. Overall, our data suggest chemopreventive actions via pharmacological inhibition of COX-2 activity during ATZ toxicity.

Synthesis and biological investigation of tetrahydropyridopyrimidinone derivatives as potential multireceptor atypical antipsychotics.

In the present study, a series of tetrahydropyridopyrimidinone derivatives, possessing potent dopamine D2, serotonin 5-HT1A and 5-HT2A receptors properties, was synthesized and evaluated as potential antipsychotics. Among them, 3-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (10d) held the best pharmacological profile. It not only exhibited potent and balanced activities for D2, 5-HT1A, and 5-HT2A receptors, but was also endowed with low activities for α1A, 5-HT2C, H1 receptors and hERG channels, suggesting a low propensity for inducing orthostatic hypotension, weight gain and QT prolongation. In animal models, compound 10d reduced phencyclidine-induced hyperactivity with a high threshold for catalepsy induction. On the basis of its robust in vitro potency and in vivo efficacy in preclinical models of schizophrenia, coupled with a good pharmacokinetic profile, 10d was selected as a candidate for further development.

GPR55: A therapeutic target for Parkinson's disease?

The GPR55 receptor is expressed abundantly in the brain, especially in the striatum, suggesting it might fulfill a role in motor function. Indeed, motor behavior is impaired in mice lacking GPR55, which also display dampened inflammatory responses. Abnormal-cannabidiol (Abn-CBD), a synthetic cannabidiol (CBD) isomer, is a GPR55 agonist that may serve as a therapeutic agent in the treatment of inflammatory diseases. In this study, we explored whether modulating GPR55 could also represent a therapeutic approach for the treatment of Parkinson's disease (PD). The distribution of GPR55 mRNA was first analyzed by in situ hybridization, localizing GPR55 transcripts to neurons in brain nuclei related to movement control, striatum, globus pallidus, subthalamic nucleus, substantia nigra and cortex. Striatal expression of GPR55 was downregulated in parkinsonian conditions. When Abn-CBD and CBD (5 mg/kg) were chronically administered to mice treated over 5 weeks with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and probenecid (MPTPp), Abn-CBD but not CBD prevented MPTPp induced motor impairment. Although Abn-CBD protected dopaminergic cell bodies, it failed to prevent degeneration of the terminals or preserve dopamine levels in the striatum. Both compounds induced morphological changes in microglia that were compatible with an anti-inflammatory phenotype that did not correlate with a neuroprotective activity. The symptomatic relief of Abn-CBD was further studied in the haloperidol-induced catalepsy mouse model. Abn-CBD had an anti-cataleptic effect that was reversed by CBD and PSB1216, a newly synthesized GPR55 antagonist, and indeed, two other GPR55 agonists also displayed anti-cataleptic effects (CID1792197 and CID2440433). These results demonstrate for the first time that activation of GPR55 might be beneficial in combating PD.

Serotonin neurons in the dorsal raphe mediate the anticataplectic action of orexin neurons by reducing amygdala activity.

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.

Exposure to an enriched environment facilitates motor recovery and prevents short-term memory impairment and reduction of striatal BDNF in a progressive pharmacological model of parkinsonism in mice.

Previous studies showed that the repeated administration with a low dose of reserpine (RES) induces a gradual appearance of motor signs and cognitive deficits compatible with parkinsonism in rodents. Environmental stimulation has neuroprotective effects in animal models of neurodegenerative damage, including acutely induced parkinsonism. We investigated the effects of exposure to an enriched environment (EE) on motor, cognitive and neuronal (levels of tyrosine hydroxylase, TH and brain derived neurotrophic factor, BDNF) deficits induced by a progressive model of Parkinson's disease (PD) in mice. Male mice were repeatedly treated with vehicle or 0.1mg/kg of RES (s.c) and kept under two housing conditions: standard environment (SE) and EE. In animals kept in SE, the treatment with RES induced deficits in motor function (catalepsy test, open field and oral movements), in novel object recognition (NOR) and plus-maze discriminative avoidance tasks. The environmental stimulation facilitated the recovery of motor deficits assessed by the catalepsy test after the end of treatment. Additionally, exposure to EE prevented the memory deficit in the NOR task. Treatment with RES induced a reduction in the number of TH positive cells in SNpc and VTA, which recovered 30days after the end of treatment. Finally, RES reduced the levels of BDNF in the striatum and the exposure to the EE prevented this effect. These results suggest that plastic brain changes induced by EE promote beneficial effects on the progression of neuronal impairment related to PD.

Alteration of the brain morphology and the response to the acute stress in the recombinant mouse lines with different predisposition to catalepsy.

Catalepsy is an inability to correct an externally imposed awkward posture; it is associated with schizophrenia and depression in human. We created new recombinant B6.CBA-D13Mit76C and B6.CBA-D13Mit76B mouse lines on the C57Bl/6 genome, carrying the 102.73-110.56Mbp fragment of chromosome 13 derived from the catalepsy-prone CBA strain and catalepsy-resistant C57BL/6 strain, respectively. We compared the behavior and brain morphology (11.7T BioSpec 117/16 USR tomograph, Germany) in these lines. The effects of acute emotional stress on corticosterone's level in the blood and mRNA expression of Bdnf and Arc genes in the brain were investigated. The B6.CBA-D13Mit76B mice were non-cataleptic, while about 17% of B6.CBA-D13Mit76C mice demonstrated catalepsy-like immobility. No difference between these lines was revealed in the open field and social interaction tests. In the Morris water maze test, both lines effectively found the platform on the fourth day; however B6.CBA-D13Mit76B mice achieved significantly better results than cataleptic-prone animals. B6.CBA-D13Mit76C mice were characterized by decreased volume of the total brain and reduced sizes of striatum, cerebellum and pituitary gland. The both lines showed the similar basal and stress-induced levels of corticosterone, while the brain expression of Bdnf and Arc genes was more vulnerable to stress in the catalepsy-prone B6.CBA-D13Mit76C line.

Effect of L-pGlu-(1-benzyl)-l-His-l-Pro-NH2 against in-vitro and in-vivo models of cerebral ischemia and associated neurological disorders.

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-NH2 for its neuroprotective effects against oxygen glucose deprivation (OGD), glutamate and H2O2 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-NH2 showed significant reduction in glutamate, H2O2 and OGD -induced cell death in concentration and time dependent manner. Moreover, L-pGlu-(1-benzyl)-l-His-l-Pro-NH2 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-NH2 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-NH2 in cerebral ischemia and other diseases, which may be mediated through reduction of excitotoxicity, oxidative stress and inflammation.

Beneficial anti-Parkinson effects of camel milk in Chlorpromazineinduced animal model: Behavioural and histopathological study.

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.

[STUDY CATALEPSY AND OTHER FORMS OF BEHAVIOR WITH RECOMBINANT MICE].

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.

Changes in the expression of genes encoding for mGlu4 and mGlu5 receptors and other regulators of the indirect pathway in acute mouse models of drug-induced parkinsonism.

Neuroadaptive changes involving the indirect pathway of the basal ganglia motor circuit occur in the early phases of parkinsonism. The precise identification of these changes may shed new light into the pathophysiology of parkinsonism and better define the time window of pharmacological intervention. We examined some of these changes in mice challenged with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), or with the dopamine receptor blocker, haloperidol. These two models clearly diverge from Parkinson's disease (PD); however, they allow an accurate time-dependent analysis of neuroadaptive changes occurring in the striatum. Acute haloperidol injection caused a significant increase in the transcripts of mGlu4 receptors, CB1 receptors and preproenkephalin-A at 2 and 24 h, and a reduction in the transcripts of mGlu5 and A2A receptors at 2 h. At least changes in the expression of mGlu4 receptors might be interpreted as compensatory because haloperidol-induced catalepsy was enhanced in mGlu4(-/-) mice. Mice injected with 30 mg/kg of MPTP also showed an increase in the transcripts of mGlu4 receptors, CB1 receptors, and preproenkephalin-A at 3 d, and a reduction of the transcript of A2A receptors at 1 d in the striatum. Genetic deletion of mGlu4 receptors altered the functional response to MPTP, assessed by counting c-Fos(+) neurons in the external globus pallidus and ventromedial thalamic nucleus. These findings offer the first evidence that changes in the expression of mGlu4 and mGlu5 receptors occur in acute models of parkinsonisms, and lay the groundwork for the study of these changes in models that better recapitulate the temporal profile of nigrostriatal dysfunction associated with PD.

Colloidal soft nanocarrier for transdermal delivery of dopamine agonist: ex vivo and in vivo evaluation.

Ropinirole, an antiparkinsoism dopamine agonist, is used to treat Restless Legs Syndrome. However, orally it undergoes degradation in gastrointestinal tract and extensive first pass metabolism, resulting in its poor and variable bioavailability of the commercially available oral tablets. In the present investigation, soft nanocarriers, viz., microemulsion of ropinirole with the globule size of 160.2 ± 3.87 nm and zeta potential of -4.24 mV was explored for transdermal application. Transdermal drug delivery offers benefits such as sustained therapeutic plasma levels of drugs, avoidance of first pass effect, and improved patient compliance. In comparison to the hydrogel, the developed microemulsion enhanced the drug permeation across the rat skin and porcine ear skin by 3.5 and 2 folds, respectively. Further, the developed microemulsion antagonized the catalepsy in the haloperidol-induced catalepsy rat model by 10 folds as compared to the marketed tablets. Additionally, in rotenone induced Parkinsonism rat model, the microemulsion showed improvement in the motor function by 76% whereas the oral tablet showed only 5% restoration of the normal function. Besides this, the developed formulation successfully restored the catalase and superoxide dismutase levels which were significantly reduced by rotenone administration. Overall, the in vivo studies suggested the potential of the developed transdermal microemulsion of Ropinirole as a viable alternative to marketed formulations.

[Il6st gene mRNA and gp130 protein distribution in the brain structures in mice differing in exagerrated freezing reaction (catalepsy)].

Glycoprotein gp130 is involved in the intracellular transduction of signals from receptors ofinterleukin-6--related cytokines. The linkage between Il6st gene encoding gp130 and predisposition to excessive freezing (catalepsy) in mice was shown. The aim of present study was to investigate the Il6st mRNA concentration, the level and the rate of glycosilation of gp130 in five brain structures in catalepsy-resistant AKR/J mice strain and in catalepsy-prone CBA/LacJ, AKR.CBA-D13Mit76 with the CBA-derived Il6st gene variant in the AKR/J genome, and ASC created by selection of back-crosses between CBA and AKR strains on catalepsy. Highest concentrations of the nonglycosilated and the glycosilated gp130 protein levels were detected in the midbrain. High levels of Il6st mRNA were discovered in the midbrain, the striatum and the hypothalamus in all mouse strains. The level of Il6st mRNA in the striatum of AKR.CBA-D13Mit76 mice was significantly higher compared with AKR/J. An association between hereditary catalepsy and Il6st expression in the striatum in mice was suggested.

Blood-brain barrier unlocked.

The brain is protected by a physiological blood-brain barrier (BBB) against toxins and some metabolites circulating in the blood. At the same time, the BBB limits penetration into the brain of many neuroactive drugs. Efficient ways to increase BBB permeability for delivery of drugs of different chemical nature into the brain are unknown. This work deals with delivery into the brain of 10(-2) M dopamine, a substance that does not penetrate the BBB under normal circumstances. It was studied in two independent experiments: (i) penetration of (3)H-labeled dopamine from its mixture with 10(-5) M H2O2 into hypothalamus and striatum structures of intact rat brain, and (ii) effect of unlabeled dopamine from a mixture with H(2)O(2) on the rat motor activity in a haloperidol catalepsy model. It was shown that (i) at the third minute after nasal application of the dopamine + H(2)O(2) mixture, the dopamine level increases 45-fold in the hypothalamus and almost 30-fold in the striatum and (ii) motility of animals in the catalepsy haloperidol model is recovered 90 sec after intranasal introduction of dopamine. No such effects were observed after replacement of H(2)O(2) by 0.9% NaCl solution. Thus, it was shown on the example of dopamine that its introduction into the nasal cavity simultaneously with H(2)O(2) provides for rapid delivery of the drug into the brain. These results expand our knowledge concerning the biological role of exoROS in modulating BBB permeability and may contribute to the development of a new therapeutic strategy for neurological diseases.

L-NOARG-induced catalepsy can be influenced by glutamatergic neurotransmission mediated by NMDA receptors in the inferior colliculus.

The inferior colliculus (IC), a midbrain structure that processes acoustic information of aversive nature, is distinguished from other auditory nuclei in the brainstem by its connections with structures of the motor system. Recent evidence relating the IC to motor behavior shows that glutamate-mediated mechanisms in the neural circuits at the IC level modulate haloperidol-induced catalepsy. It has been shown that N(G)-nitro-L-arginine (L-NOARG), inhibitor of enzyme nitric oxide synthase (NOS), can induce catalepsy after intraperitoneal (ip), intracerebroventricular or intrastriatal administration. The present study examined whether the catalepsy induced by L-NOARG (ip) can be influenced by collicular glutamatergic mechanisms and if a NO-dependent neural substrate into the IC plays a role in this immobility state. L-NOARG-induced catalepsy was challenged with prior intracollicular microinjections of glutamate NMDA receptor antagonists, AP7 (20 or 40 nmol/0.5 µl), or of the NMDA receptor agonist N-methyl-D-aspartate (NMDA, 30 nmol/0.5 µl). Catalepsy was evaluated by positioning both forepaws of the rats on an elevated horizontal wooden bar and recording the time for which the animal maintained this position. The results showed that intracollicular microinjection of AP7 previous to systemic injections of L-NOARG (90 mg/kg) significantly attenuated the catalepsy. Conversely, intracollicular microinjection of NMDA increased the time of catalepsy when administered 10 min before systemic L-NOARG (10 or 45 mg/kg). The microinjection of L-NOARG (50 or 100 nmol) directly into the IC was not able to induce catalepsy. These findings suggest that glutamate-mediated mechanisms in the neural circuits of the IC modulate L-NOARG-induced catalepsy and participate in the regulation of motor activity.

Antipsychotic-induced catalepsy is attenuated in mice lacking the M4 muscarinic acetylcholine receptor.

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.

Glutamatergic neurotransmission mediated by NMDA receptors in the inferior colliculus can modulate haloperidol-induced catalepsy.

The inferior colliculus (IC) is primarily involved in the processing of auditory information, but it is distinguished from other auditory nuclei in the brainstem by its connections with structures of the motor system. Functional evidence relating the IC to motor behavior derives from experiments showing that activation of the IC by electrical stimulation or excitatory amino acid microinjection causes freezing, escape-like behavior, and immobility. However, the nature of this immobility is still unclear. The present study examined the influence of excitatory amino acid-mediated mechanisms in the IC on the catalepsy induced by the dopamine receptor blocker haloperidol administered systemically (1 or 0.5 mg/kg) in rats. Haloperidol-induced catalepsy was challenged with prior intracollicular microinjections of glutamate NMDA receptor antagonists, MK-801 (15 or 30 mmol/0.5 microl) and AP7 (10 or 20 nmol/0.5 microl), or of the NMDA receptor agonist N-methyl-d-aspartate (NMDA, 20 or 30 nmol/0.5 microl). The results showed that intracollicular microinjection of MK-801 and AP7 previous to systemic injections of haloperidol significantly attenuated the catalepsy, as indicated by a reduced latency to step down from a horizontal bar. Accordingly, intracollicular microinjection of NMDA increased the latency to step down the bar. These findings suggest that glutamate-mediated mechanisms in the neural circuits at the IC level influence haloperidol-induced catalepsy and participate in the regulation of motor activity.