Tremulous jaw movements (TJMs) have become a commonly used rat model of Parkinsonian tremor. TJMs can be induced by a number of neurochemical conditions that parallel those seen in human Parkinsonism, including DA depletion, DA antagonism, and cholinomimetic administration, and can be reduced by various antiparkinsonian agents. TJMs typically occur in bursts with the peak frequency in the range of 3-7.5Hz, which is similar to the Parkinsonian tremor frequency range. While the vast majority of this work has been done using rats, current efforts have focused on extending the TJM model to mice. The aim of the present studies was to establish a mouse model of Parkinsonian resting tremor using the anticholinesterase galantamine, and to investigate the effects of adenosine A2A antagonism on galantamine-induced TJMs. Galantamine significantly induced TJMs in a dose-dependent manner (0.5, 1.0, 1.5, 2.0, 2.5mg/kg IP). The TJMs tended to occur in bursts in the 3-7.5Hz frequency range, with a peak frequency of approximately 6Hz. Systemic administration of the adenosine A2A antagonist MSX-3 (2.5, 5.0, 10.0mg/kg) significantly attenuated galantamine-induced TJMs. Co-administration of MSX-3 also altered the local frequency of galantamine-induced TJMs, decreasing the peak frequency from approximately 6Hz to 5Hz, though the vast majority of TJMs remained in the frequency range characteristic of Parkinsonian resting tremor. These results indicate that adenosine A2A antagonism is capable of reducing anticholinesterase-induced TJMs in mice. Extending the TJM model to mice gives researchers an additional avenue for investigating drug-induced Parkinsonism and tremorogenesis, and could be a useful addition to the study of motor abnormalities observed in mouse genetic models of Parkinsonism.
Oilseed rape (Brassica napus L.) was formed ~7500 years ago by hybridization between B. rapa and B. oleracea, followed by chromosome doubling, a process known as allopolyploidy. Together with more ancient polyploidizations, this conferred an aggregate 72x genome multiplication since the origin of angiosperms and high gene content. We examined the B. napus genome and the consequences of its recent duplication. The constituent An and Cn subgenomes are engaged in subtle structural, functional, and epigenetic cross-talk, with abundant homeologous exchanges. Incipient gene loss and expression divergence have begun. Selection in B. napus oilseed types has accelerated the loss of glucosinolate genes, while preserving expansion of oil biosynthesis genes. These processes provide insights into allopolyploid evolution and its relationship with crop domestication and improvement.
Olean-12-en-3beta-24 diol (A), auranamide (B), aurantiamide acetate (C), 2alpha,3beta-dihydroxy-olean-12-en-28-oic acid (D) and quindoline (E) were isolated from the dichloromethane (CH2Cl2) extract of the stems of Justicia secunda (Acanthaceae). Liquid chromatography with ultraviolet and mass spectrometric detection was used to acquire more knowledge of the chemical composition of this extract and to monitor variations in profiles of both the isolated and the other non-identified compounds in Justicia refractifolia and Justicia graciliflora. The compound classes, phenolic and olefinic amides, feruloyltyramine amides, 2,5-diaryl-3,4-dimethyltetrahydrofuranoid lignans, peptide alkaloids, phenylalanine derivatives, conjugated ynones, indolquinoline alkaloids, triterpenes and pigments, were tentatively identified based on the LC-DAD-APCI-MS analysis. The most frequently encountered compound among the species was auranamide while the distribution of quindoline was limited to J. secunda. Moreover, the acetylcholinesterase inhibitory activity of the isolated compounds was determined.
Title: Nucleus accumbens neurotransmission and effort-related choice behavior in food motivation: effects of drugs acting on dopamine, adenosine, and muscarinic acetylcholine receptors Nunes EJ, Randall PA, Podurgiel S, Correa M, Salamone JD Ref: Neurosci Biobehav Rev, 37:2015, 2013 : PubMed
Mesolimbic dopamine (DA) is a critical component of the brain circuitry regulating behavioral activation and effort-related processes. Although nucleus accumbens (NAc) DA depletions or antagonism leave aspects of appetite and primary food motivation intact, rats with impaired DA transmission reallocate their instrumental behavior away from food-reinforced tasks with high response requirements, and instead select less effortful food-seeking behaviors. Previous work showed that adenosine A2A antagonists can reverse the effects of DA D2 antagonists on effort-related choice, and that stimulation of adenosine A2A receptors produces behavioral effects that are similar to those induced by DA antagonism. The present review summarizes the literature on the role of NAc DA and adenosine in effort-related processes, and also presents original data on the effects of local stimulation of muscarinic acetylcholine receptors in NAc core. Local injections of the muscarinic agonist pilocarpine directly into NAc core produces shifts in effort-related choice behavior similar to those induced by DA antagonism or A2A receptor stimulation, decreasing lever pressing but increasing chow intake in rats responding on a concurrent fixed ratio/chow feeding choice task. In contrast, injections into a neostriatal control site dorsal to the NAc were ineffective. The actions of pilocarpine on this task were attenuated by co-administration of the muscarinic antagonist scopolamine. Thus, drugs that act on DA, adenosine A2A, and muscarinic receptors regulate effort-related choice behavior, which may have implications for the treatment of psychiatric symptoms such as psychomotor slowing, fatigue or anergia that can be observed in depression and other disorders.
Tremulous jaw movements are rapid vertical deflections of the lower jaw that resemble chewing but are not directed at any particular stimulus. In rats, tremulous jaw movements can be induced by a number of conditions that parallel those seen in human parkinsonism, including dopamine depletion, dopamine antagonism, and cholinomimetic drugs. Moreover, tremulous jaw movements in rats can be attenuated using antiparkinsonian agents such as L-DOPA, dopamine agonists, muscarinic antagonists, and adenosine A(2)A antagonists. In the present studies, a mouse model of tremulous jaw movements was established to investigate the effects of adenosine A(2)A antagonism, and a conditional neuronal knockout of adenosine A(2)A receptors, on cholinomimetic-induced tremulous jaw movements. The muscarinic agonist pilocarpine significantly induced tremulous jaw movements in a dose-dependent manner (0.25-1.0mg/kg IP). These movements occurred largely in the 3-7.5 Hz local frequency range. Administration of the adenosine A(2)A antagonist MSX-3 (2.5-10.0 mg/kg IP) significantly attenuated pilocarpine-induced tremulous jaw movements. Furthermore, adenosine A(2)A receptor knockout mice showed a significant reduction in pilocarpine-induced tremulous jaw movements compared to littermate controls. These results demonstrate the feasibility of using the tremulous jaw movement model in mice, and indicate that adenosine A(2)A receptor antagonism and deletion are capable of reducing cholinomimetic-induced tremulous jaw movements in mice. Future studies should investigate the effects of additional genetic manipulations using the mouse tremulous jaw movement model.
Bananas (Musa spp.), including dessert and cooking types, are giant perennial monocotyledonous herbs of the order Zingiberales, a sister group to the well-studied Poales, which include cereals. Bananas are vital for food security in many tropical and subtropical countries and the most popular fruit in industrialized countries. The Musa domestication process started some 7,000 years ago in Southeast Asia. It involved hybridizations between diverse species and subspecies, fostered by human migrations, and selection of diploid and triploid seedless, parthenocarpic hybrids thereafter widely dispersed by vegetative propagation. Half of the current production relies on somaclones derived from a single triploid genotype (Cavendish). Pests and diseases have gradually become adapted, representing an imminent danger for global banana production. Here we describe the draft sequence of the 523-megabase genome of a Musa acuminata doubled-haploid genotype, providing a crucial stepping-stone for genetic improvement of banana. We detected three rounds of whole-genome duplications in the Musa lineage, independently of those previously described in the Poales lineage and the one we detected in the Arecales lineage. This first monocotyledon high-continuity whole-genome sequence reported outside Poales represents an essential bridge for comparative genome analysis in plants. As such, it clarifies commelinid-monocotyledon phylogenetic relationships, reveals Poaceae-specific features and has led to the discovery of conserved non-coding sequences predating monocotyledon-eudicotyledon divergence.
Title: Effects of the adenosine A 2A antagonist KW 6002 (istradefylline) on pimozide-induced oral tremor and striatal c-Fos expression: comparisons with the muscarinic antagonist tropicamide Betz AJ, Vontell R, Valenta J, Worden L, Sink KS, Font L, Correa M, Sager TN, Salamone JD Ref: Neuroscience, 163:97, 2009 : PubMed
Typical antipsychotic drugs, including haloperidol and pimozide, have been shown to produce parkinsonian motor effects such as akinesia and tremor. Furthermore, there is an antagonistic interaction between adenosine A(2A) and dopamine D(2) receptors in the basal ganglia, which is important for motor functions related to the production of parkinsonian symptoms. Several experiments were conducted to assess the effects of the selective adenosine A(2A) antagonist KW 6002 on both the motor and cellular effects of subchronic administration of pimozide. The motor test employed was tremulous jaw movements, which is used as a model of parkinsonian tremor. In addition, c-Fos expression in the ventrolateral neostriatum, which is the striatal area most associated with tremulous jaw movements, was used as a marker of striatal cell activity in animals that were tested in the behavioral experiments. Repeated administration of 1.0 mg/kg pimozide induced tremulous jaw movements and increased ventrolateral striatal c-Fos expression, while administration of 20.0 mg/kg of the atypical antipsychotic quetiapine did not. The tremulous jaw movements induced by pimozide were significantly reduced by co-administration of either the adenosine A(2A) antagonist KW 6002 or the muscarinic antagonist tropicamide. Pimozide-induced increases in ventrolateral striatal c-Fos expression were reduced by a behaviorally effective dose of KW 6002, but c-Fos expression in pimozide-treated rats was actually increased by tropicamide. These results indicate that two different drug manipulations that act to reduce tremulous jaw movements can have different effects on DA antagonist-induced c-Fos expression, suggesting that adenosine A(2A) antagonism and muscarinic receptor antagonism exert their motor effects by acting on different striatal circuits.
The ethidium bromide (EB) demyelinating model was associated with vitamin E (Vit E) and ebselen (Ebs) treatment to evaluate acetylcholinesterase (AChE) activity in the striatum (ST), hippocampus (HP), cerebral cortex (CC) and erythrocytes. Rats were divided into seven groups: I-Control (saline), II-(canola); III-(Ebs), IV-(Vit E); V-(EB); VI-(EB+Ebs) and VII-(EB+Vit E). At 3 days after the EB injection, AChE activity in the CC and HC was significantly reduced in groups III, IV, V, VI and VII (p<0.05) and in the ST it was reduced in groups III and V (p<0.05) when compared to the control group. At 21 days after the EB injection, AChE activity in the CC was significantly reduced in groups III, IV and V, while in groups VI and VII a significant increase was observed when compared to the control group. In the HC and ST, AChE activity was significantly reduced in groups V, VI and VII when compared to the control group (p<0.05). In the erythrocytes, at 3 days after the EB injection, AChE activity was significantly reduced in groups III, IV, V, VI and VII and at 21 days there was a significant reduction only in groups VI and VII (p<0.05) when compared to the control group. In conclusion, this study demonstrated that Ebs and Vit E interfere with the cholinergic neurotransmission by altering AChE activity in the different brain regions and in the erythrocytes. Furthermore, treatment with Vit E and Ebs protected against the demyelination lesion caused by EB. In this context, we can suggest that ebselen and Vit E should be considered potential therapeutics and scientific tools to be investigated in brain disorders associated with demyelinating events.
The objective of the present study was to investigate the effect of the administration of resveratrol (RV) on memory and on acetylcholinesterase (AChE) activity in the cerebral cortex, hippocampus, striatum, hypothalamus, cerebellum and blood in streptozotocin-induced diabetic rats. The animals were divided into six groups (n=6-13): Control/saline; Control/RV 10 mg/kg; Control/RV 20 mg/kg; Diabetic/saline; Diabetic/RV 10 mg/kg; Diabetic/RV 20 mg/kg. One day after 30 days of treatment with resveratrol the animals were submitted to behavioral tests and then submitted to euthanasia and the brain structures and blood were collected. The results showed a decrease in step-down latency in diabetic/saline group. Resveratrol (10 and 20 mg/kg) prevented the impairment of memory induced by diabetes. In the open field test, no significant differences were observed between the groups. In relation to AChE activity, a significant increase in diabetic/saline group (P<0.05) was observed in all brain structures compared to control/saline group. However, AChE activity decreased significantly in control/RV10 and control/RV20 (P<0.05) groups in cerebral cortex, hippocampus and striatum, while no significant differences were observed in diabetic/RV10 and diabetic/RV20 groups in all brain structures compared to control/saline group. Blood AChE activity increased significantly in diabetic/saline group (P<0.05) decreased in control/RV10, control/RV20 and diabetic/RV20 groups (P<0.05) compared to control/saline group. In conclusion, the present findings showed that treatment with resveratrol prevents the increase in AChE activity and consequently memory impairment in diabetic rats, demonstrating that this compound can modulate cholinergic neurotransmission and consequently improve cognition.
The aim of the present study was to investigate the effects of resveratrol (RV), an important neuroprotective compound on NTPDase, 5'-nucleotidase and acetylcholinesterase (AChE) activities in cerebral cortex synaptosomes of streptozotocin (STZ)-induced diabetic rats. The animals were divided into six groups (n=8): control/saline; control/RV 10mg/kg; control/RV 20mg/kg; diabetic/saline; diabetic/RV 10mg/kg; diabetic/RV 20mg/kg. After 30 days of treatment with resveratrol the animals were sacrificed and the cerebral cortex was removed for synaptosomes preparation and enzymatic assays. The results demonstrated that NTPDase and 5'-nucleotidase activities were significantly increased in the diabetic/saline group (p<0.05) compared to control/saline group. Treatment with resveratrol significantly increased NTPDase, 5'-nucleotidase activities in the diabetic/RV10 and diabetic/RV20 groups (p<0.05) compared to diabetic/saline group. When resveratrol was administered per se there was also an increase in the activities of these enzymes in the control/RV10 and control/RV20 groups (p<0.05) compared to control/saline group. AChE activity was significantly increased in the diabetic/saline group (p<0.05) compared to control/saline group. The treatment with resveratrol prevented this increase in the diabetic/RV10 and diabetic/RV20 groups. In conclusion, this study demonstrated that the resveratrol interfere with the purinergic and cholinergic neurotransmission by altering NTPDase, 5'-nucleotidase and AChE activities in cerebral cortex synaptosomes of diabetic rats. In this context, we can suggest that resveratrol should be considered potential therapeutics and scientific tools to be investigated in brain disorders associated with the diabetes.
Carbofuran and malathion, well known pesticides, and paraquat, a world widely used herbicide, were tested on acetylcholinesterase (AChE) from Bungarus sindanus venom and butyrylcholinesterase (BChE) from human serum. The calculated IC(50 )values for inhibition of venom enzyme by malathion, carbofuran and paraquat were 2.5, 0.14, and 0.16 microM, respectively. The values for inhibition of serum butyrylcholinesterase (BChE) were 3.5, 0.09 and 0.18 microM, respectively. Analysis of kinetic data indicated that the inhibition caused by malathion, carbofuran and paraquat was mixed for venom AChE. For BChE from human serum, the inhibition caused by malathion and paraquat was mixed and for carbofuran it was uncompetitive. The present results suggest a commercial paraquat preparation (a popular herbicide) inhibits cholinesterases with similar or higher potency than classical pesticide inhibitors. Furthermore, this inhibition was observed both in human serum and snake venom, a newly studied source of AChE.
Kinetic parameters of the effect of tacrine as a cholinesterase inhibitor have been studied in two different sources: snake venom (Bungarus sindanus) acetylcholinesterase (AChE) and human serum butyrylcholinesterase (BChE). Tacrine inhibited both venom acetylcholinesterase (AChE) as well as human serum butyrylcholinesterase (BChE) in a concentration-dependent manner. Kinetic studies indicated that the nature of inhibition was mixed for both enzymes, i.e. Km values increase and Vmax decrease with the increase of the tacrine concentration. The calculated IC50 for snake venom and for human serum were 31 and 25.6 nM, respectively. Ki was observed to be 13 nM for venom acetylcholinesterase (AChE) and 12 nM for serum butyrylcholinesterase (BChE). KI (constant of AChE-ASCh-tacrine complex into AChE-ASCh complex and tacrine) was estimated to be 20 nM for venom and 10 nM for serum butyrylcholinesterase (BChE), while the gammaKm (dissociation constant of AChE-ASCh-tacrine complex into AChE-tacrine complex and ASCh) were 0.086 and 0.147 mM for snake venom AChE and serum BChE, respectively. The present results suggest that this therapeutic agent used for the treatment of Alzheimer's disease can also be considered an inhibitor of snake venom and human serum butyrylcholinesterase. Values of Ki and KI show that tacrine had more affinity with these enzymes as compared with other cholinesterases from the literature.
The ethidium bromide (EB) demyelinating model was associated with interferon beta (IFN-beta) to evaluate acetylcholinesterase (AChE) activity in the striatum (ST), hippocampus (HP), cerebral cortex (CC), cerebellum (CB), hypothalamus (HY), pons (PN) and synaptosomes from the CC. Rats were divided into four groups: I control (saline), II (IFN-beta), III (EB) and IV (EB and IFN-beta). After 7, 15 and 30 days rats (n = 6) were sacrificed, and the brain structures were removed for enzymatic assay. AChE activity was found to vary in all the brain structures in accordance with the day studied (7-15-30 days) (P < 0.05). In the group III, there was an inhibition of the AChE activity in the ST, CB, HY, HP and also in synaptosomes of the CC (P < 0.05). It was observed that IFN-beta per se was capable to significantly inhibit (P < 0.05) AChE activity in the ST, HP, HY and synaptosomes of the CC. Our results suggest that one of the mechanisms of action of IFN-beta is through the inhibition of AChE activity, and EB could be considered an inhibitor of AChE activity by interfering with cholinergic neurotransmission in the different brain regions.
The organophosphorus insecticides, including malathion, are used indiscriminately in large amounts, causing environmental pollution and risk to human health. Classically, this toxicity is attributed mainly to the accumulation of acetylcholine (ACh), due to inhibition of acetylcholinesterase (AChE), and consequently overstimulation of the nicotinic and muscarinic receptors. The present study investigated the effects of acute and chronic malathion administration in immobility time in the forced swimming test (FST), open-field test and AChE activity in neural tissue of rats. Malathion was administered intraperitoneally once a day for one day (acute) or for 28 days (chronic) (in both protocols malathion was administered at 25, 50, 100 and 150 mg/kg). No significant effect was seen in immobility time in the FST after acute malathion treatment. The chronic malathion treatment induced an increase in the time of immobility in the FST. Both treatments do not interfere in locomotor activity evaluated in a novel environment. The inhibition of AChE activity was significant in the hippocampus (25, 50, 100 and 150 mg/kg), cortex (100 and 150 mg/kg) and striatum (150 mg/kg) after chronic treatment, but not significantly after acute treatment. These data suggest a possible interaction between increased immobility time in the FST and activation of cholinergic receptors by accumulated ACh subsequent to AChE inhibition.
Title: Dopamine agonists suppress cholinomimetic-induced tremulous jaw movements in an animal model of Parkinsonism: tremorolytic effects of pergolide, ropinirole and CY 208-243 Salamone JD, Carlson BB, Rios C, Lentini E, Correa M, Wisniecki A, Betz A Ref: Behavioural Brain Research, 156:173, 2005 : PubMed
Considerable evidence indicates that cholinomimetic-induced tremulous jaw movements in rats share many characteristics with human Parkinsonian tremor, and several antiparkinsonian drugs suppress cholinomimetic-induced tremulous jaw movements. The present study investigated three different types of dopamine agonists, which have known antiparkinsonian characteristics, for their ability to suppress the tremulous jaw movements induced by tacrine (5.0 mg/kg). The non-selective dopamine agonist pergolide, a widely used antiparkinsonian drug, was highly potent at suppressing tacrine-induced jaw movements (e.g. 0.125-1.0 mg/kg). The selective D2 agonist ropinirole, which also is used clinically as an antiparkinsonian drug, suppressed jaw movements in the dose range of 2.5-20.0 mg/kg. The D1 agonist CY 208-243, which has been reported to suppress tremor, also reduced jaw movement activity (4.0 mg/kg). Across several studies, the rank order of potency for suppressing cholinomimetic-induced jaw movements in rats is related to the potency for producing antiparkinsonian effects in humans. Together with previous studies, the present results suggest that cholinomimetic-induced jaw movements in rats can be used to characterize dopaminergic antiparkinsonian agents and to investigate the basal ganglia circuits involved in the generation of tremulous movements.
Title: The GABA uptake inhibitor beta-alanine reduces pilocarpine-induced tremor and increases extracellular GABA in substantia nigra pars reticulata as measured by microdialysis Ishiwari K, Mingote S, Correa M, Trevitt JT, Carlson BB, Salamone JD Ref: Journal of Neuroscience Methods, 140:39, 2004 : PubMed
Substantia nigra pars reticulata (SNr) is a major output nucleus of the basal ganglia that receives GABAergic projections from neostriatum and globus pallidus. Previous research has shown that local pharmacological manipulations of GABA in SNr can influence tremulous jaw movements in rats. Tremulous jaw movements are defined as rapid vertical deflections of the lower jaw that resemble chewing but are not directed at a particular stimulus, and evidence indicates that these movements share many characteristics with parkinsonian tremor in humans. In order to investigate the role of GABA in motor functions related to tremor, the present study tested the GABA uptake blocker beta-alanine for its ability to reduce pilocarpine-induced tremulous jaw movements. In a parallel experiment, the effect of an active dose of beta-alanine on dialysate levels of GABA in SNr was assessed using microdialysis methods. GABA levels in dialysis samples were measured using high performance liquid chromatography with electrochemical detection. beta-Alanine (250-500 mg/kg) significantly reduced tremulous jaw movements induced by pilocarpine (4.0 mg/kg). Moreover, systemic administration of beta-alanine at a dose that reduced tremulous jaw movements (500 mg/kg) resulted in a substantial increase in extracellular levels of GABA in SNr compared to the pre-injection baseline. Thus, the present results are consistent with the hypothesis that GABAergic tone in SNr plays a role in the regulation of tremulous jaw movements. This research may lead to a better understanding of how parkinsonian symptoms are modulated by SNr GABA mechanisms.
Title: Motor effects of GABA(A) antagonism in globus pallidus: studies of locomotion and tremulous jaw movements in rats Wisniecki A, Correa M, Arizzi MN, Ishiwari K, Salamone JD Ref: Psychopharmacology (Berl), 170:140, 2003 : PubMed
RATIONALE: Although most rodent studies related to parkinsonian symptoms have focused on locomotion, tremulous jaw movements also have been used as a rodent model of tremor for investigating the circuitry of the basal ganglia. OBJECTIVE: There are multiple pathways involved in the generation of parkinsonian symptoms. The globus pallidus is a basal ganglia relay nucleus, and the present study was conducted to investigate the effect of pallidal GABA antagonism on locomotion and tremulous jaw movements. METHODS: Suppression of locomotion and induction of tremulous jaw movements were produced by repeated (i.e., 14 day) systemic administration of the dopamine D2 antagonist haloperidol, and by acute systemic injection of the muscarinic agonist pilocarpine. The GABA(A) antagonist bicuculline was injected into the globus pallidus, and its effects on locomotion in haloperidol- and pilocarpine-treated rats were assessed in the first group of experiments. In the second group of experiments, the effects of intrapallidal infusions of bicuculline on haloperidol- and pilocarpine-induced jaw movements were observed. RESULTS: Pallidal GABA antagonism stimulated locomotion when no other treatment was present, and also when animals were coadministered haloperidol or pilocarpine. Bicuculline suppressed haloperidol-induced jaw movements in a dose-related manner, and had no effect on pilocarpine-induced jaw movements. CONCLUSIONS: These results support the notion that there are distinct pathways conveying basal ganglia outflow and demonstrate that the striatopallidal pathway is involved in the generation of the haloperidol-induced tremulous jaw movements. These findings are consistent with some features of current models of basal ganglia function and may lead to an understanding of the specific mechanisms that generate parkinsonian symptoms.
Several studies have shown that a number of pharmacological and neurochemical conditions in rats can induce jaw movements that are described as "vacuous" or "tremulous". For several years, there has been some debate about the clinical significance of various drug-induced oral motor syndromes. Nevertheless, considerable evidence now indicates that the non-directed, chewing-like movements induced by cholinomimetics have many of the characteristics of parkinsonian tremor. These movements are characterized largely by vertical deflections of the jaw, which occur in the same 3-7 Hz peak frequency that is typical of parkinsonian tremor. Cholinomimetic-induced tremulous jaw movements are suppressed by a number of different antiparkinsonian drugs, including scopolamine, benztropine, L-DOPA, apomorphine, bromocriptine, ropinirole, pergolide, amantadine, diphenhydramine and clozapine. A combination of anatomical and pharmacological research in rats has implicated M4 receptors in the ventrolateral neostriatum in the generation of tremulous jaw movements. Mice also show cholinomimetic-induced jaw movements, and M4 receptor knockout mice demonstrate subtantially reduced levels of jaw movement activity, as well as increased locomotion. Taken together, these data are consistent with the hypothesis that a centrally-acting M4 antagonist may be useful as a treatment for parkinsonian symptoms, including tremor.
