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At least 685 records · Page 38Linked to original sources
PubMed2001

Antagonism at 5-HT(2A) receptors potentiates the effect of haloperidol in a conditioned avoidance response task in rats.

High affinity for serotonin-2A (5-HT(2A)) over dopamine (DA) D(2) receptors is a leading hypothesis for clozapine's favorable therapeutic profile. Recent preclinical studies also indicate that a sufficient antipsychotic effect might be obtained by a combined high 5-HT(2A)/low D(2) receptor blockade. Thus, addition of a 5-HT(2A) receptor antagonist to an ineffective dose of a D(2) receptor antagonist produces a robust antipsychotic-like effect in the conditioned avoidance response (CAR) test. Electrophysiological and biochemical studies also show that 5-HT(2A) receptor antagonists can confer an atypical (clozapine-like) profile on a D(2) receptor antagonist. Improved therapeutic efficacy by adjunctive 5-HT(2A) receptor antagonist treatment to a traditional D(2) receptor blocking regimen has been suggested. However, the ability of 5-HT(2A) receptor blockade to protect against, or ameliorate, parkinsonian symptoms still remains unclear. Using the CAR and the catalepsy (CAT) tests as indices for antipsychotic activity and extrapyramidal side effect (EPS) liability, respectively, the effects of the selective 5-HT(2A) receptor antagonist MDL 100,907 in combination with the DA D(2) receptor antagonists haloperidol or raclopride were studied in rats. Haloperidol (0.025 or 0.1 mg/kg sc, -30 min) produced a dose-dependent suppression of CAR. Pretreatment with MDL 100,907 (0.5, 1.0, or 1.5 mg/kg sc; -60 min) enhanced and prolonged the haloperidol-induced suppression of CAR without escape failures. MDL 100,907 (1 mg/kg sc, -60 min) had no effect on CAT when coadministered with ineffective doses of raclopride. Raclopride (1 mg/kg sc, -30 min) alone produced a submaximal cataleptic response that was significantly enhanced by pretreatment with MDL 100,907. The present results confirm and extend previous results by showing that 5-HT(2A) receptor blockade can enhance the antipsychotic-like effects of a very low dose of a commonly used traditional antipsychotic. 5-HT(2A) receptor blockade does not, however, prevent EPS (CAT). The therapeutic advantage of this combination might, therefore, operate within a fairly narrow window.

Animals↗
PubMed1999

The involvement of the mediodorsal nucleus of the thalamus and the midbrain extrapyramidal area in locomotion elicited from the ventral pallidum.

Motor activity is regulated by projections from the nucleus accumbens to the ventral pallidum, but it is unclear which efferents regulate behavioral output from the ventral pallidum. Motor activity was elicited pharmacologically by microinjecting either the mu opioid receptor agonist, Tyr-D-Ala-Gly-NmePhe-Gly-OH (DAMGO) or the glutamate receptor agonist, alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) into the ventral pallidum. The involvement of efferent projections was determined by microinjecting the local anesthetic procaine into the mediodorsal nucleus of the thalamus (MD) or the midbrain extrapyramidal area (MEA) prior to administering DAMGO or AMPA into the ventral pallidum. The motor activity induced by DAMGO was blocked by procaine microinjected into either the MD or the MEA. In contrast, procaine microinjected into the MD did not block motor activity elicited by AMPA while procaine into the MEA abolished the behavioral activation. These data indicate that the involvement of efferent projections from the ventral pallidum to either the MD or MEA in motor activation depends upon the type of receptor stimulated in the ventral pallidum.

Analgesics, Opioid↗
PubMed1999

Dopamine D-1 regulation of caudate neurotensin mRNA in the presence or absence of the nigrostriatal dopamine pathway.

Changes in extrapyramidal dopamine (DA) function significantly alter the activity of striatal neurotensin (NT) systems. Specifically, stimulation of DA D-1 or D-2 receptors increases or decreases striatal NT tissue levels, respectively. In contrast, removal of D-2 receptor basal activity with either an antagonist or lesion of the nigrostriatal DA projection increases striatal NT content. To understand better the significance of these changes in the levels of NT peptide, we determined the effects of treatment with the selective D-1 agonist, SKF 82958, alone or in combination with a lesion of the nigrostriatal DA pathway, on the levels of NT mRNA in various regions of the caudate nucleus. Removal of at least 90% of this DA pathway significantly increased NT mRNA in most, but not all, regions throughout the caudate nucleus. In contrast, four, but not one, administrations of SKF 82958 (2 mg kg-1 dose-1) increased NT mRNA levels in principally middle, but not rostral, caudate regions. Lesioning the nigrostriatal DA pathway enhanced the effects of SKF 82958 so that a lower, single dose (1 mg/kg) of this D-1 agonist also increased NT mRNA levels predominantly in the middle caudate sections. These findings demonstrate that DA D-1 receptors profoundly regulate the striatal expression of NT mRNA in a regionally selective fashion, which appears to be unique from that principally influenced by DA D-2 regulation.

Animals↗
PubMed1982

Anatomical and biochemical basis of the extrapyramidal disorders.

1. Degeneration of various components of the extrapyramidal system has been correlated with specific clinical syndromes. 2. In Parkinson's disease, loss of ascending nigrostriatal fibers is associated with reduction of presynaptic dopamine binding and increase of postsynaptic dopamine binding. The latter is reversed by treatment with dopamine agonists. 3. In Huntington's disease, multiple types of striatal neurons are lost, with their corresponding enzymes and receptors. 4. In tardive dyskinesias, there are no specific neuropathological findings, but increased amounts of striatal dopamine receptors. 5. Knowledge of the chemical nature of the pallidal outflow to the thalamus may be the next most important step in the pharmacological control of extrapyramidal function.

Basal Ganglia Diseases↗
PubMed1997

Blood levels of reduced haloperidol versus clinical efficacy and extrapyramidal side effects of haloperidol.

1. The studies of relationships between blood levels of reduced haloperidol HL (RH) and clinical efficacy in haloperidol (HL)-treated patients have yielded variable results. On the other hand, the contribution of RH upon HL's extrapyramidal side effects (EPS) had been suggested in animal models as well as in preliminary clinical studies with limited subjects. 2. This study explored the relationships between blood drug levels and clinical effects and EPS of HL in 48 Chinese acutely exacerbated schizophrenic inpatients. After a single-blind placebo period of one week, the patients were treated with a fixed dose 10 mg of HL for two weeks. Steady-state levels of HL and RH in plasma (n = 48) and in red blood cells (RBC) (n = 37) were measured by high performance liquid chromatography. 3. The mean RH/HL ratio in RBC in the Chinese (0.55) is lower than that in non-Chinese patients as reported in the literature (> 2), so is the RH/HL ratios in plasma. 4. No significant relationship emerged between percent improvement in BPRS total score and any of drug indices (HL, RH, sum of two compounds (HL+RH), and RH/HL ratio) in plasma and in RBC. Furthermore, the responders did not differ significantly from the nonresponders in each drug index. 5. Plasma RH levels were significantly higher in 30 patients experiencing EPS compared with the other 18 patients (mean 2.14 +/- 1.71 (S.D.) ng/ml vs. 1.38 +/- 0.37 ng/ml, p < 0.05). No significant differences in other drug indices were noted between subjects with or without EPS.

Adolescent↗
PubMed1981

The origin of forebrain afferents to the habenula in rat, cat and monkey.

Injections of horseradish peroxidase (HRP) involving the entire habenular complex in rat, cat and squirrel monkey (Saimiri sciureus) label (1) numerous cells in anterior lateral hypothalamic area, (2) a moderate number of cells in lateral preoptic area, substantia innominata, nucleus of diagonal band and postcommissural septum, and (3) a few cells in medial hypothalamus, ipsilaterally, in all three species. Some labeled cells also occur in corresponding regions contralaterally. The contribution of these limbic structures to the innervation of habenula is thus strikingly similar in the three groups. In contrast, significant species variations are found in respect to pallidal afferents. Whereas the entopeduncular nucleus in rat stands out as the main source of forebrain habenular afferents, the same structure in cat appears to contribute less substantially than adjoining lateral hypothalamus to the innervation of habenula. In monkey habenular afferents also arise principally from lateral hypothalamic neurons. At pallidal levels, labeled cells are nevertheless abundant in the rostral pole of primate internal pallidum. More caudally, they are found in significant number along internal and accessory medullary laminae where they intermingle with acetylcholinesterase-containing neurons which do not themselves project significantly upon habenula. This heterogeneous distribution of labeled pallidal cells indicates that the pallidohabenular projections in primate may arise, at least in part, from specific neuronal subpopulations within internal pallidum.

Afferent Pathways↗
PubMed1990

REM sleep abnormalities in severe athetoid cerebral palsy.

Various abnormalities of sleep have been reported in extrapyramidal diseases in adults. We have investigated the disturbances of REM sleep (SREM) in severe athetoid cerebral palsy (ACP) originating perinatally. Ten ACP patients, 5 males and 5 females ranging from 15 to 30 years old, were studied by means of all-night polygraphic examination. Three cases showed a marked decrease in rapid eye movements in SREM. Moreover, the tone of submental muscle in SREM was also disturbed in three. Regarding body movements during sleep, gross movements and twitch movements of the submental muscle were analyzed. In most of the patients, an abnormal distribution of body movements according to sleep stages was observed, the rate being significantly reduced in SREM. REMs, atonia and body movements are considered to be related to the brainstem function in animals. The results of the present study suggest that perinatal extrapyramidal diseases could also coincide with brainstem dysfunctions.

Adolescent↗
PubMed1996

Pediatric clozapine intoxication.

Clozapine is a tricyclic dibenzodiazepine derivative used as an antipsychotic in adults. Clozapine's safety in children has not been established. This report describes three unintentional clozapine ingestions in pediatric patients. These are the first reported cases of clozapine intoxication in children. All three patients demonstrated dramatic alterations in mental status and tone, and two demonstrated extrapyramidal effects. Serum clozapine levels obtained in two patients were within the average range of steady state plasma concentrations for adults. These cases show the dramatic presentations of pediatric ingestion of clozapine and the differences between adult and pediatric intoxications.

Antidepressive Agents, Tricyclic↗
PubMed2003

Familial pediatric rapidly progressive extrapyramidal syndrome: is it Hallervorden-Spatz disease?

The clinical features of two children of a family with rapidly progressive extrapyramidal-pyramidal-dementia complex have been described. Inheritance seems most likely to be autosomal recessive. Magnetic resonance imaging results of brain were negative. Even so, the authors argued in favor of a diagnosis of Hallervorden-Spatz disease because the cases fulfilled the clinical criteria for diagnosis of this disease. Apart from the negative magnetic resonance findings, the other unusual feature was the early development of levodopa-induced dyskinesia. Few conditions need to be considered in the differential diagnosis of a childhood-onset rapidly progressive extrapyramidal syndrome. Such conditions include Wilson's disease, Hallervorden-Spatz disease (HSD), juvenile form of Huntington's disease, juvenile neuronal ceroid lipofuscinosis, early-onset Machado-Joseph disease neuroacanthocytosis, storage disorders, and variant form of dopa-response dystonias (DRD). Rarer conditions are Leigh's disease, Lafora body disease, and dentato-rubro-pallido-luysian atrophy. HSD is a rare disorder characterized by progressive extrapyramidal dysfunction and dementia. Onset is most commonly in late childhood or early adolescence. The disease can be familial or sporadic. When familial, it is inherited recessively and has been linked to chromosome 20. Recently, a mutation in the pantothenate kinase (PANK2) gene on band 20pl3 has been described in patients with typical HSD. HSD produces typical magnetic resonance imaging (MRI) changes in brain, aiding in antemortem diagnosis. The typical finding is of bilaterally symmetrical hyperintense signal changes in the external segment of globus pallidus, with surrounding hypointensity on T(2)-weighted image. These imaging features are fairly diagnostic and have been termed the "eye-of-the tiger sign". The hyperintensity represents pathologic changes, including gliosis, demyelination, neuronal loss, and axonal swelling, and the surrounding hypointensity is caused by loss of signal secondary to iron deposition. Described herein are the clinical aspects of a family with autosomal recessive inheritance with rapidly progressive extrapyramidal-pyramidal-dementia complex but with negative brain MRI results. The diagnosis should be considered a variant form of HSD.

Basal Ganglia Diseases↗
PubMed1983

Adverse effects of anticholinergic medication on positive schizophrenic symptoms.

In a series of 36 patients with acute schizophrenia flupenthixol dosage was blindly adjusted to give a fixed level of sedation. Patients were than randomly allocated to procyclidine or placebo. The patients receiving procyclidine experienced more positive schizophrenic symptoms and less severe extrapyramidal features by comparison with placebo patients. Blood levels of prolactin and flupenthixol estimated by radioimmunoassay were not significantly changed by the addition of procyclidine. Flupenthixol dosage and levels and prolactin levels were significantly related. There was no significant association between clinical and laboratory measures, with the exception that a curvilinear (inverted U) relationship was demonstrated between flupenthixol levels and antipsychotic and extrapyramidal effects. This relationship may be due to the fact that, in a study of this design, patients resistant to the effects of neuroleptic medication are likely to be given the highest doses. The findings support earlier claims that anticholinergic medication has adverse effects on schizophrenic symptoms.

Adult↗
PubMed1980

Organization of GABA-containing neurons in some extrapyramidal nuclei.

Nuclei of the extrapyramidal system contain among the highest levels of GABA and its synthesizing enzyme glutamic acid decarboxylase (GAD) in the central nervous system. In recent years the anatomical organization of GABAergic neurons in the extrapyramidal experimental system has been the subject of considerable experimental enquiry. In this note, current knowledge concerning the origin and projections of GABAergic neurons in certain extrapyramidal nuclei is briefly reviewed.

Animals↗
PubMed2000

Early suppression of striatal cyclic GMP may predetermine the induction and severity of chronic haloperidol-induced vacous chewing movements.

Haloperidol persists in brain tissue long after discontinuation while haloperidol-induced tardive dyskinesia often worsens after withdrawal of the drug. The mechanism of haloperidol-associated tardive dyskinesia is unknown, although neurotoxic pathways are suspected. Nitric oxide (NO) synthase (NOS) inhibitors exacerbate haloperidol-induced catalepsy, while haloperidol itself is a potent neuronal NOS inhibitor in vitro. Since NO and cGMP are involved in striatal neural plasticity, this study investigates a possible relation between cGMP and extrapyramidal symptoms as early predictors of haloperidol-associated tardive dyskinesia. Sprague-Dawley rats were administered either water or oral haloperidol (0.25 mg/kg/d p.o.) for 17 weeks, followed by 3 weeks withdrawal. Saline (i.p.) or the nNOS/guanylate cyclase inhibitor, methylene blue (5 mg/kg/d i.p.), were co-administered with haloperidol for the first three weeks of treatment. Vacous chewing movements (VCM's) were continuously monitored, followed by the determination of striatal cGMP and peripheral serum nitrogen oxide (NOx) levels. Chronic haloperidol engendered significant VCM's, with acute withdrawal associated with significantly reduced striatal cGMP levels as well as reduced serum NOx. Furthermore, suppressed cGMP levels were maintained and VCM's were significantly worse after early administration of methylene blue to the chronic haloperidol group. However, serum NOx was unchanged from control. We conclude that the central effects of chronic haloperidol on striatal NO-cGMP function persist for up to 3 weeks post-withdrawal. Moreover, suppression of striatal cGMP constitutes an early neuronal insult that determines the presence and intensity of haloperidol-associated motor dysfunction.

Animals↗