Extrapyramidal Motor Disorders Research Articles

Formulation, Optimisation and Evaluation of Levodopa and Entacapone Loaded Transdermal Patches for the Treatment of Parkinson’s Disease

Parkinson’s disease is an extrapyramidal motor disorder leading to progressive degeneration of neurons in substantia niagra, pars compacta and the dopaminergic tract. The most promising drugs used to treat Parkinson’s disease, i.e., levodopa and entacapoe have very low oral bioavailability because of first-pass metabolism, therefore to increase the bioavailability of levodopa and entacapone, these were incorporated in transdermal patches. Different formulations of the levodopa and entacapone drugs were prepared with different polymeric ratios, by using the solvent casting method and the formulations were evaluated for in-vitro and in-vivo tests, which focus on drug release and drug excipient compatibilities. Various models were applied to ascertain the kinetics of drug release by using in-vitro release data. Nine formulations were prepared and evaluated out of which F6 was found to be the best formulation, which contained HPMC and ethyl cellulose in the ratio of 2:3. It showed drug release of 99.11% in about 12 hours.

Frontotemporal lobar degeneration.

Frontotemporal lobardegeneration (FTLD)is one of the most common causes of early-onset dementia and presents with early social-emotional-behavioural and/or language changes that can be accompanied by a pyramidal or extrapyramidal motor disorder. About 20-25% of individuals with FTLD are estimated to carry a mutation associated with a specific FTLD pathology. The discovery of these mutations has led to important advances in potentially disease-modifying treatments that aim to slow progression or delay disease onset and has improved understanding of brain functioning. In both mutation carriers and those with sporadic disease, the most common underlying diagnoses are linked to neuronal and glial inclusions containing tau(FTLD-tau) or TDP-43 (FTLD-TDP), although 5-10% of patients may have inclusions containing proteins from the FUS-Ewing sarcoma-TAF15 family (FTLD-FET). Biomarkers definitively identifying specific pathological entities in sporadic disease have been elusive, which has impeded development of disease-modifying treatments. Nevertheless, disease-monitoring biofluid and imaging biomarkers are becoming increasingly sophisticated and are likely to serve as useful measures of treatment response during trials of disease-modifying treatments. Symptomatic trials using novel approaches such as transcranial direct current stimulation are also beginning to show promise.

Reversal of haloperidol-induced orofacial dyskinesia and neuroinflammation by isoflavones.

Schizophrenia is a mental illness and its pharmacological treatment consists in the administration of antipsychotics like haloperidol. However, haloperidol often causes extrapyramidal motor disorders such as tardive dyskinesia (TD). So far, there is no effective treatment against TD and alternatives for it have been sought. Isoflafones have been studied as neuroprotector and inhibitor of monoamine oxidase enzyme. Thus, the objective is to evaluate the possible protective effect of isoflavones against the induction of involuntary movements induced by haloperidol in an animal model. Male Wistar rats were treated with haloperidol (1mg/kg/day) and/or isoflavones (80mg/kg) for 28 days. Rats were submitted to behavioral evaluation to quantify vacuous chewing movements (VCM) and locomotor activity. In addition, the levels of pro-inflammatory cytokines were measured in the striatum. Haloperidol treatment reduced the locomotor activity and increased the number of VCM in rats. Co-treatment with isoflavones was able to reverse hypolocomotion and reduce the number of VCM. Besides, haloperidol caused significant increase in the proinflammatory cytokines (interleukin-1β:IL-1β, tumor necrosis factor-α: TNF-α and IL-6 and the co-treatment with isoflavones was able to reduce the levels of IL-1β and TNF-α, but not IL-6. It is believed that the beneficial effect found with this alternative treatment is related to its anti-inflammatory potential and to the action on estrogen receptors (based on scientific literature findings). Finally, further studies are needed to elucidate the mechanisms of isoflavones in reducing motor disorders induced by antipsychotics.

Pantothenate kinase-associated neurodegeneration (Hallerworden–Spatze disease): clinical aspects, diagnosis, treatment (literature review and own data)

Aim. To analyze current data of scientific literature on the etiology, pathogenesis, approaches to the diagnosis and treatment of rare orphan disease – pantothenate kinase-associated neurodegeneration and to describe the clinical case of this disease. Pantothenate kinase-associated neurodegeneration (PKAN) is a rare inherited autosomal recessive disorder caused by mutations in the PANK2 gene, which is located at the chromosomal locus: 20p13-p12.3. The article presents a literature review and a case report of the diagnosis and treatment of 8-year-old girl with pantothenate kinase-associated neurodegeneration who suffered from progressive motor impairment. Among the dominant clinical manifestations is a growing extrapyramidal motor disorder, the so-called “dystonic storm”, which can range from severe sensorimotor motor deficits in infants and young children to mild parkinsonism in adults. MRI signs in the form of specific changes in the T2-weighted mode, which detects typical areas of hyperintensive signal in globus pallidus, surrounded by a border of hypointensive signal (“tiger’s eye”) are particular important. Neuroimaging data most likely make possible to suspect a correct diagnosis, reducing the time and cost of additional examinations. There is no pathogenetic treatment of this disease now. The main directions of currently available symptomatic drug therapy are described. Clinical trials of detoxifying drugs that reduce iron levels in the body (chelation) and surgical treatments are currently underway. Conclusions. The presented clinical observation once again confirms the complexity of the diagnostic search for orphan diseases of the nervous system. A key place in the diagnosis of pantothenate kinase-associated neurodegeneration belongs to the neuroimaging methods and molecular genetic testing data.

Evaluation of Antipsychotic Activity of Ethanolic Extract of Dhatryadi Ghrita on Wistar Rats

Objective: Herbal formulations based on plants are effective against psychosis. The effects of Dhatryadi Ghrita on Wistar rats against psychosis were investigated. Background: An increased preference nowadays is obvious towards the use of herbal drugs in the treatment of chronic ailments. Treatment of psychiatric diseases has become easier, but the extrapyramidal motor disorders are the major adverse effect exists with most of the antipsychotic drugs. Methods: For the assessment of neuroleptic activity of the ethanolic extract of Dhatryadi Ghrita, prepared with different antipsychotic animal models, three doses of the extract (100, 200 and 300 mg/kg) were used for the study with different animal models. Result: A significant reduction of amphetamine-induced stereotype and conditioned avoidance response was observed in the extract-treated animals compared to control. Minor signs of catalepsy were visible in the extract-treated group as compared to the control group. Conclusion: The study revealed that the extract may be possessing the property to alleviate the positive symptoms of Psychosis.

Mechanisms underlying the pathogenesis and treatment of neurological disorders: Extrapyramidal motor disorders

Mechanisms underlying the pathogenesis and treatment of neurological disorders: Extrapyramidal motor disorders

International Union of Basic and Clinical Pharmacology. CI. Structures and Small Molecule Modulators of Mammalian Adenylyl Cyclases.

Adenylyl cyclases (ACs) generate the second messenger cAMP from ATP. Mammalian cells express nine transmembrane AC (mAC) isoforms (AC1-9) and a soluble AC (sAC, also referred to as AC10). This review will largely focus on mACs. mACs are activated by the G-protein Gαs and regulated by multiple mechanisms. mACs are differentially expressed in tissues and regulate numerous and diverse cell functions. mACs localize in distinct membrane compartments and form signaling complexes. sAC is activated by bicarbonate with physiologic roles first described in testis. Crystal structures of the catalytic core of a hybrid mAC and sAC are available. These structures provide detailed insights into the catalytic mechanism and constitute the basis for the development of isoform-selective activators and inhibitors. Although potent competitive and noncompetitive mAC inhibitors are available, it is challenging to obtain compounds with high isoform selectivity due to the conservation of the catalytic core. Accordingly, caution must be exerted with the interpretation of intact-cell studies. The development of isoform-selective activators, the plant diterpene forskolin being the starting compound, has been equally challenging. There is no known endogenous ligand for the forskolin binding site. Recently, development of selective sAC inhibitors was reported. An emerging field is the association of AC gene polymorphisms with human diseases. For example, mutations in the AC5 gene (ADCY5) cause hyperkinetic extrapyramidal motor disorders. Overall, in contrast to the guanylyl cyclase field, our understanding of the (patho)physiology of AC isoforms and the development of clinically useful drugs targeting ACs is still in its infancy.

Comments on Lucire and Crotty, 2011.

Dear editor In a recent article, Yolande Lucire and Christopher Crotty presented their findings in an ongoing naturalistic study concerning a possible relationship between variant alleles in three CYP450 genes and a variety of behavioral problems.1 Unfortunately, the tested population of 129 persons was very heterogeneous and poorly characterized from a phenomenological perspective. In the results section of their article, the authors use the term “akathisia” to describe the adversity, but without defining this phenomenon. They also use this term in the title of their paper. Since they state that the majority of the persons who experienced adverse clinical events had akathisia, which is not expected considering their clinical characteristics, it is possible that the term has been used to describe other types of problems rather than this well-defined extrapyramidal motor disorder.2,3 In our opinion, this is unfortunate as it may lead to false interpretation of the mechanistic background of these putative side effects. As a matter of fact, such a false interpretation of the relationship between aggression and akathisia has probably led to misunderstandings during a number of court trials in the Netherlands. On one occasion, an accused person was sentenced to 24 years in prison because of an erroneous interpretation of the message of Lucire and Crotty’s paper.4 Because the motor symptoms of akathisia were not confirmed by a small number of layman observers prior to his committing the felony, the judges rejected akathisia as a possible explanation for this aggressive behavior. It is important, therefore, not to use the term “akathisia” as being synonymous with drug-induced aggression. There are many other possible mechanisms which could cause selective serotonin reuptake inhibitors to lead to this type of adversity5 and, in addition, it should be noted that adverse clinical events are only very rarely monocausally related to the intake of a drug.

PET - diagnostics of cognitive impairment in patients with parkinson’s disease

Traditionally, Parkinson’s disease is associated with a deficit of dopaminergic system, manifested in the extrapyramidal motor disorders. In addition, the disease is characterized by a wide variety of not movement disorders. For example, the spectrum of autonomic, mental, cognitive and sensory symptoms is presented. Cognitive impairment, including mild cognitive impairment and dementia in Parkinson’s disease are among the most common disorders are not motor. The purpose of this study was aimed to investigate the relationship of early cognitive impairment and rate of glucose metabolism in different parts of the brain in patients with Parkinson’s disease. Positron emission tomography (PET) with fluorodeoxyglucose synthesis in patients suffering from Parkinson’s disease was performed. Study group consisted of patients (31 persons, age 41-77 years). Patients have passed inpatient and/or outpatient treatment at the clinic of the Institute of Human Brain of the Russian Academy of Sciences. The control group (15 persons) consisted of patients of similar age group without cognitive impairment. To estimate the rate of glucose metabolism was used an original technique of the Institute of Human Brain. Immediately prior to the intravenous administration of radiopharmaceutical [18F]-deoxyglucose was synthesized. Psychological testing consisted of a clinical interview, observation, survey, test, as described in a brief assessment of mental status (MMSE) and the battery frontal dysfunction (BFD). The study found that when the initial cognitive impairment observed pattern of changes in the rate of metabolism of glucose, characteristic of patients with severe cognitive impairment in Parkinson’s disease. This fact leads to the assumption of a high validity of the test battery frontal dysfunction for early diagnosis of cognitive impairment in Parkinson’s disease.

Interaction between anti-Alzheimer and antipsychotic drugs in modulating extrapyramidal motor disorders in mice

Antipsychotics are often used in conjunction with anti-Alzheimer drugs to treat the behavioral and psychological symptoms of dementia (BPSD). Here, we examined the effects of cholinesterase inhibitors (ChEIs), donepezil and galantamine, on antipsychotic-induced extrapyramidal side effects (EPS) in mice. The effects of serotonergic agents on the EPS drug interaction were also evaluated. Donepezil (0.3–3 mg/kg) did not induce EPS signs by itself; however, it significantly potentiated bradykinesia induction with a low dose of haloperidol (0.5 mg/kg) in dose-dependent and synergistic manners. Galantamine (0.3–3 mg/kg) elicited mild bradykinesia at a high dose and dose-dependently augmented haloperidol-induced bradykinesia. The EPS potentiation by galantamine was blocked by trihexyphenidyl (a muscarinic antagonist), but not by mecamylamine (a nicotinic antagonist). In addition, the bradykinesia potentiation by galantamine was significantly reduced by (±)-8-hydroxy-2-(di-n-propylamino)-tetralin (a 5-HT1A agonist), ritanserin (a 5-HT2 antagonist), and SB-258585 (a 5-HT6 antagonist). The present results give us a caution for the antipsychotics and ChEIs interaction in inducing EPS in the treatment of BPSD. In addition, second generation antipsychotics, which can stimulate 5-HT1A receptors or antagonize 5-HT2 and 5-HT6 receptors, seem to be favorable as an adjunctive therapy for BPSD.

Ethanolic extracts of Alstonia Scholaris and Bacopa Monniera possess neuroleptic activity due to anti-dopaminergic effect.

Background:An increased inclination has been observed for the use of herbal drugs in chronic and incurable diseases. Treatment of psychiatric diseases like schizophrenia is largely palliative and more importantly, a prominent adverse effect prevails with the majority of anti-psychotic drugs, which are the extrapyramidal motor disorders. Existing anti-psychotic drug therapy is not so promising, and their adverse effect is a matter of concern for continuing the therapy for long duration.Objective:This experimental study was done to evaluate the neuroleptic activity of the ethanolic extracts of two plants Alstonia Scholaris and Bacopa Monnieri with different anti-psychotic animal models with a view that these plant extracts shall have no or at least reduced adverse effect so that it can be used for long duration.Materials and Methods:Two doses of both the extracts (100 and 200 mg/kg) and also standard drug haloperidol (0.2 mg/kg) were administered to their respective groups once daily with 5 different animal models. After that, the concentration of the dopamine neurotransmitter was estimated in two different regions of the brain viz. frontal cortex and striatum.Results:The result of the study indicated a significant reduction of amphetamine-induced stereotype and conditioned avoidance response for both the extracts compared with the control group, but both did not have any significant effect in phencyclidine-induced locomotor activity and social interaction activity. However, both the extracts showed minor signs of catalepsy compared to the control group. The study also revealed that the neuroleptic effect was due to the reduction of the dopamine concentration in the frontal cortex region of the rat brain. The results largely pointed out the fact that both the extract may be having the property to alleviate the positive symptoms of schizophrenia by reducing the dopamine levels of dopaminergic neurons of the brain.Conclusion:The estimation of dopamine in the two major regions of brain indicated the alteration of dopamine levels was the reason for the anti-psychotic activity as demonstrated by the different animal models.

Depotantipsychotika

Recent investigations have demonstrated a significant reduction of relapse and hospitalization rates associated with the use of long-acting injectable antipsychotics (LAIs) in the treatment of schizophrenia. There are only marginal differences in the effectiveness of different specific LAIs. Furthermore, LAIs are comparable to the oral equivalents with respect to effectiveness and side effects. The occurrence of extrapyramidal motor disorders (EPD) is less frequent in second generation (SG) LAIs than in first generation (FG) LAIs. Moreover, specific characteristics of some substances should be considered: In SG-LAIs immediate onset of action is only applicable for olanzapine and paliperidone and FG-LAIs should always be given as a test dose first to assure a general tolerance. All LAIs have a high variability of plasma levels which complicates the dose titration. Last but not least, current research concerning long-term consequences of continuous treatment with antipsychotics and the potentially poorer response to antipsychotics should be considered.

Improving the Treatment of Schizophrenia: Role of 5-HT Receptors in Modulating Cognitive and Extrapyramidal Motor Functions

Patients with schizophrenia exhibit various clinical symptoms including positive and negative symptoms, neurocognitive impairments and mood disturbances. Although a series of second generation antipsychotics (SGAs) (e.g., risperidone, olanzapine and quetiapine) have been developed in the past two decades, clinical reports do not necessarily show advantages over first generation antipsychotics (FGAs) in the treatment of schizophrenia, especially in their efficacy against cognitive impairment and ability to cause extrapyramidal side effects (EPS). Recently, several lines of studies have revealed therapeutic roles of 5-HT receptors in modulating cognitive impairments and extrapyramidal motor disorders. Specifically, inhibition of 5-HT1A, 5-HT3 and 5-HT6 receptors or activation of 5-HT4 receptors alleviates cognitive impairments (e.g., deficits in learning and memory). In addition, stimulation of 5-HT1A receptors or inhibition of 5-HT3 and 5-HT6 receptors as well as 5-HT2A/2C receptors can ameliorate extrapyramidal motor disorders. Thus, controlling the activity of 5-HT1A, 5-HT3 or 5-HT6 receptors seems to provide benefits by both alleviating cognitive impairments and reducing antipsychotic-induced EPS. This article reviews the functional roles and mechanisms of 5-HT receptors in the treatment of schizophrenia, focusing on the serotonergic modulation of cognitive and extrapyramidal motor functions, and illustrates future therapeutic strategies.

Pathophysiological Roles of Serotonergic System in Regulating Extrapyramidal Motor Functions

The serotonergic nervous system plays crucial roles in regulating psycho-emotional, cognitive, sensori-motor and autonomic functions. It is now known that multiple serotonin (5-hydroxytryptamine; 5-HT) receptors regulate extrapyramidal motor functions, which are implicated in pathogenesis and/or treatment of various neurological disorders (e.g., Parkinson's disease and drug-induced extrapyramidal motor deficits). Specifically, antagonism of 5-HT2A/2C receptors alleviates antipsychotic-induced extrapyramidal side effects (EPS) by relieving the 5-HT2A/2C receptor-mediated inhibition of nigral dopaminergic neuron activity and striatal dopamine release. Indeed, many of the second generation antipsychotics (e.g., risperidone, perospirone and olanzapine) commonly possess potent 5-HT2A/2C blocking actions which contribute to their atypical antipsychotic property. In addition, activation of 5-HT1A receptors also improves antipsychotic-induced EPS and motor disabilities in animal models of Parkinson's disease. Microinjection studies revealed that stimulation of postsynaptic 5-HT1A receptors in the striatum or motor cortex plays an important role in the antiparkinsonian actions. Furthermore, recent studies demonstrated that antagonism of 5-HT3 and 5-HT6 receptors alleviates extrapyramidal motor disorders while 5-HT4, 5-HT5, and 5-HT7 receptors are mostly inactive. These results encourage drug discovery research into new 5-HT receptor ligands that could improve current therapies for extrapyramidal motor disorders.

Dopamine receptors and Parkinson's disease.

Parkinson's disease (PD) is a progressive extrapyramidal motor disorder. Pathologically, this disease is characterized by the selective dopaminergic (DAergic) neuronal degeneration in the substantia nigra. Correcting the DA deficiency in PD with levodopa (L-dopa) significantly attenuates the motor symptoms; however, its effectiveness often declines, and L-dopa-related adverse effects emerge after long-term treatment. Nowadays, DA receptor agonists are useful medication even regarded as first choice to delay the starting of L-dopa therapy. In advanced stage of PD, they are also used as adjunct therapy together with L-dopa. DA receptor agonists act by stimulation of presynaptic and postsynaptic DA receptors. Despite the usefulness, they could be causative drugs for valvulopathy and nonmotor complication such as DA dysregulation syndrome (DDS). In this paper, physiological characteristics of DA receptor familyare discussed. We also discuss the validity, benefits, and specific adverse effects of pharmaceutical DA receptor agonist.

Serotonergic modulation of extrapyramidal motor disorders in mice and rats: Role of striatal 5-HT3 and 5-HT6 receptors

Previous studies showed that 5-HT1A and 5-HT2 receptors play an important role in controlling the extrapyramidal motor disorders. However, the functions of other 5-HT receptor subtypes remain elusive. To elucidate the role of 5-HT receptors, specifically of 5-HT3∼5-HT7 subtypes, in modifying antipsychotic- induced extrapyramidal side effects (EPS), we studied the effects of the 5-HT stimulant 5-hydroxytryptophan (5-HTP) and various 5-HT receptor antagonists on haloperidol (HAL)-induced bradykinesia and catalepsy in mice and rats. Pretreatment of mice with 5-HTP (25–100mg/kg, i.p.) dose-dependently enhanced HAL (0.3mg/kg, i.p.)-induced bradykinesia and catalepsy. The potentiation of HAL-induced EPS by 5-HTP (50mg/kg, i.p.) was significantly inhibited by ritanserin (5-HT2 antagonist, 0.3-3mg/kg, i.p.), ondansetron (5-HT3 antagonist, 0.1–1mg/kg, i.p.), or SB-258585 (5-HT6 antagonist, 1–10mg/kg, i.p.) in a dose-dependent manner. However, neither WAY-100135 (5-HT1A antagonist, 1–10mg/kg, i.p.), GR-125487 (5-HT4 antagonist, 1–10mg/kg, i.p.), SB-699551 (5-HT5A antagonist, 1–10mg/kg, i.p.) nor SB-269970 (5-HT7 antagonist, 1–10mg/kg, i.p.) reduced the 5-HTP and HAL-induced bradykinesia or catalepsy. In addition, both ondansetron (0.1–1mg/kg, i.p.) and SB-258585 (3 and 10mg/kg, i.p.) also alleviated bradykinesia and catalepsy induced by HAL (0.5mg/kg, i.p.) alone in mice. Furthermore, bilateral microinjection of ondansetron (5μg (13.7nmol) per side) or SB-258585 (5μg (8.92nmol) per side) into the dorsolateral striatum (dlST) attenuated haloperidol-induced catalepsy in rats. These results suggest that serotonergic stimulation augments extrapyramidal motor disorders by activating the striatal 5-HT3 and 5-HT6 receptors and the antagonism of these receptors effectively alleviates antipsychotic-induced EPS.

Effects of ω-3 Essential Fatty Acids (ω-3 EFAs) on Motor Disorders and Memory Dysfunction Typical Neuroleptic-induced: Behavioral and Biochemical Parameter

The effects of fish oil supplementation on motor disorders, memory dysfunction, and lipid peroxidation (LP) induced by typical neuroleptics were studied. Wistar rats received a suspension prepared with fish oil containing omega-3 fatty acids, water, and Tween 80 (1%) in the place of drinking water (FO group) or vehicle (C group) for 8 weeks. After 4 weeks of treatment, half of the animals of both groups were treated with haloperidol (H and FO + H groups; experiment 1), fluphenazine (F and FO + F groups; experiment 2), or vehicle (C group), administered once a week (12 mg/kg/im) for 4 weeks, maintaining the treatment with FO. Extrapyramidal motor disorders by haloperidol and fluphenazine were observed by an increase in vacuous chewing movements and catalepsy (P < 0.05). These effects were reduced by FO treatment (P < 0.05). Both neuroleptics displayed impairment in memory retention observed by latency time to find the original location of platform in water-maze task, after 4 days of training performed in the last treatment week. This effect was reduced by FO (P < 0.05) to both haloperidol and fluphenazine treatments. Haloperidol increased the LP in plasma and hippocampus, and these effects were decreased by FO treatment (P < 0.05). Fluphenazine increased the LP in plasma and substantia nigra, which were completely decreased by FO treatment (P < 0.05). The FO decreased the motor disorders, memory dysfunction, and oxidative damage typical neuroleptic-induced. Our results indicate that FO exhibits a neuroprotector role useful on diseases related to oxidative damages, and may be considered in the prevention of motor and memory side effects induced by the antipsychotic treatment.

Therapeutic potential of α 2 adrenoceptor antagonism for antipsychotic-induced extrapyramidal motor disorders

We examined the effects of JP-1302 (a selective α 2C antagonist), BRL-44408 (a selective α 2A antagonist) and yohimbine (a non-selective α 2 antagonist) on haloperidol-induced bradykinesia and catalepsy in mice to elucidate the role of α 2 adrenoceptor subtypes in modifying extrapyramidal motor disorders. JP-1302 (0.1–1 mg/kg, s.c.) dose-dependently ameliorated haloperidol-induced bradykinesia in the pole-test and reversed the catalepsy time increased by haloperidol. Antibradykinetic and anticataleptic actions of JP-1302 were statistically significant at 0.3 and 1 mg/kg, and these doses did not alter the ambulatory distance, rearing or center–perimeter residence time in the open-field test. BRL-44408 (1–10 mg/kg, s.c.) and yohimbine (0.3–3 mg/kg, i.p.) also ameliorated haloperidol-induced bradykinesia and catalepsy. However, both agents significantly decreased ambulatory distance and rearing in the open-field test, possibly reflecting their anxiogenic actions associated with α 2A antagonism. The present study shows for the first time that blockade of α 2C receptors can alleviate antipsychotic-induced extrapyramidal motor disorders without affecting gross behaviors.

Anticataleptic 8-OH-DPAT preferentially counteracts with haloperidol-induced Fos expression in the dorsolateral striatum and the core region of the nucleus accumbens

We studied the effects of the 5-HT 1A/7 agonist 8-OH-DPAT on haloperidol-induced catalepsy and forebrain Fos expression in mice to clarify its mechanism in modulating extrapyramidal motor disorders. 8-OH-DPAT (0.1–1 mg/kg, i.p.) markedly attenuated haloperidol-induced catalepsy in a dose-dependent manner with a potency greater than that of the antiparkinsonian agent trihexyphenidyl. The anticataleptic action of 8-OH-DPAT was completely antagonized by WAY-100135 (a selective 5-HT 1A antagonist), but not by SB-269970 (a selective 5-HT 7 antagonist). Depletion of cerebral 5-HT by p-chlorophenylalanine (300 mg/kg, i.p. for 3 days) did not attenuate, but rather potentiated the action of 8-OH-DPAT. Furthermore, the anticataleptic dose of 8-OH-DPAT showed a regionally specific reduction of haloperidol-induced Fos expression in the dorsolateral striatum (dlST) and the core region of the nucleus accumbens (AcC), without affecting that in the medial prefrontal cortex, the shell region of the nucleus accumbens or the lateral septal nucleus. These results suggest that 8-OH-DPAT alleviates antipsychotic-associated extrapyramidal motor disorders by stimulating the postsynaptic 5-HT 1A receptors, which specifically counteracts the D 2 receptor blocking actions of antipsychotics in the dlST and AcC.

Evaluation of the antibradykinetic actions of 5-HT 1A agonists using the mouse pole test

To clarify the role and mechanism of the 5-HT 1A receptor in modulating extrapyramidal motor disorders, we studied the actions of 5-HT 1A agonists in the mouse pole test, a valid model of parkinsonian bradykinesia. Haloperidol markedly delayed pole-descending behavior of mice in the pole test, and this effect was alleviated by the antiparkinsonian agent trihexyphenidyl (a muscarinic antagonist). The selective 5-HT 1A agonists, 8-hydroxydipropylaminotetraline (8-OH-DPAT) and tandospirone, significantly attenuated haloperidol-induced bradykinesia in a dose-dependent manner. The alleviation of haloperidol-induced bradykinesia by 8-OH-DPAT was completely antagonized by WAY-100135 (a selective 5-HT 1A antagonist), but was unaffected by cerebral 5-HT depletion with p-chlorophenylalanine (PCPA) treatment (300 mg/kg, i.p. for 3 days). These results suggest that 5-HT 1A agonists improve extrapyramidal motor disorders associated with antipsychotic treatments by stimulating the postsynaptic 5-HT 1A receptor.