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At least 757 records · Page 42Linked to original sources
PubMed1992

Metabotropic glutamate receptor activation produces extrapyramidal motor system activation that is mediated by striatal dopamine.

Little is known about the in vivo function of the GTP-binding protein-coupled "metabotropic" excitatory amino acid (EAA) receptor. In vitro studies on agonist-induced brain phosphoinositide hydrolysis have shown that (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid is a highly selective and efficacious metabotropic EAA agonist. We have recently reported that in vivo unilateral intrastriatal injection of (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid induces transient extrapyramidal motor activation that manifests itself as contralateral turning. In this study, we fully characterized the onset of turning behavior following intrastriatal (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid injection and the possible involvement of striatal dopamine neurons in the mediation of this effect. Rats were anesthetized with the short-acting agent halothane to allow for rapid surgical recovery and thus early behavioral measurements. Intrastriatal (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1 mumol/2 microliters) produced an incremental increase in contralateral turning starting at 1 h and plateauing 3-6 h after injection (peak effect, 39.1 +/- 6.7 rotations per 5 min). Dopamine depletion with alpha-methyl-DL-p-tyrosine (250 mg/kg i.p., 80% depletion) resulted in greater than 85% inhibition of (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid-induced contralateral turning. The dopamine antagonist haloperidol (0.3 mg/kg i.p.) produced 48% inhibition of the (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid response. In time course studies, turning behavior correlated with increases in levels of the dopamine metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid. These results suggest a functional interaction between the metabotropic EAA receptor and the dopaminergic system in the striatum.

Animals↗
PubMed1973

Some initial animal and human pharmacological studies with benapryzine (BRL 1288).

1. The pA2 anti-acetylcholine activity in vitro for benapryzine was 6.55 compared with 9.02 for benzhexol.2. In vivo, the anti-acetylcholine activity of benapryzine relative to benzhexol was 0.038 as assessed by the mydriatic response of mice after subcutaneous administration. The relative activity assessed by the inhibition of pilocarpine-induced salivation was 0.13 after oral administration and 0.056 following subcutaneous administration of the drugs.3. Benapryzine had the same order of activity as benzhexol in inhibiting oxotremorine-induced tremors in mice.4. Benapryzine had anticonvulsant properties but no analgesic activity, whilst in high doses it antagonized the extrapyramidal symptoms induced by perphenazine in rats.5. In patients benapryzine was effective in reducing the symptoms of Parkinson's disease without overt anti-cholinergic effects or central hallucinogenic actions.6. Benapryzine abolished the excess tremor and reduced the rigidity and akinesia induced by physostigmine in Parkinsonian subjects.

Acetylcholine↗
PubMed1979

Developments in understanding the physiology and pharmacology of parkinsonism.

While the era of major advances in understanding and treating parkinsonism seems to be over, steady progress is being made in elucidating physiological and pharmacological aspects of extrapyramidal function. The dramatic impact of levodopa therapy has been followed by the recognition of serious limitations to its long-term use, which provides a continuing stimulus for efforts to analyze the physiological and pharmacological properties of the basal ganglia and substantia nigra. There are reasonable grounds for the hope that this research will lead to significant developments in therapy.

Animals↗
PubMed1989

Relationship between primitive reflexes, extra-pyramidal signs, reflective apraxia and severity of cognitive impairment in dementia of the Alzheimer type.

Controversy exists in the literature about the significance of primitive reflexes (PR) and extrapyramidal signs (EP) as diffuse cortical dysfunction signs and their relationship to age and cognitive impairment. A sample of 91 patients with a dementia of the Alzheimer type were examined with a standardized technique to assess the relationship between the finding of PR, EP and severity of cognitive impairment measured by Mini-Mental Status Examination. The value of a short cognitive test, the reflective apraxia (i.e. imitation of meaningless gestures), were also assessed. A significantly lower MMS score was correlated with the number of present PR and with presence of snout, sucking and grasping reflexes. No correlation was found between presence or absence of PR and age, depression, or drug therapy. EP score was correlated with the number of present PR and MMS, but not with age. Reflective apraxia score was significantly correlated with the degree of cognitive impairment and was found with lower cognitive impairment than PR.

Aged↗
PubMed1995

F wave in acute cerebellar damage.

Studies of occurrence of the F wave can be considered as a method of assessment of excitability of the spinal cord motoneurones. So far it has been analyzed in relation to the damage to the pyramidal and extrapyramidal systems. In the present paper, various parameters of the F response (maximal and mean amplitude-absolute and in relation to the M response, frequency of occurrence of all and identical F waves, minimal latency and chronodyspersion) were given analysis in 15 patients with hypotonia after acute cerebellar damage, and in 35 healthy subjects. In the patients, the F response was found to be decreased in amplitude (mean-absolute and ratio to M) and in frequency. Therefore, a conclusion can be drawn that it confirms the decrease of segmental motoneurone excitability after cerebellar damage.

Adult↗
PubMed1978

High doses of fluphenazine enanthate in schizophrenia. A controlled study.

The results from this controlled study of 12 schizophrenics refractory to ordinary doses of neuroleptics indicate that treatment with fluphenazine enanthate in higher doses than normal (10--20 times higher) might give reduction in psychopathology beyond what can be obtained with normal doses. In four patients the symptom reduction on high doses was pronounced. Moreover, we found that the high fluphenazine plasma levels demonstrated did not increase extrapyramidal and general side effects. The results presented also speak in favour of certain "non-responding" patients needing a higher plasma level of a neuroleptic drug than the average patient.

Adult↗
PubMed1979

Neuroleptic-potentiating effect of alpha-methyl-p-tyrosine compared with haloperidol and placebo in a double-blind cross-over trial.

The hypothesis that schizophrenia results from overactive dopaminergic influences suggests that reducing dopamine synthesis may increase the clinical effects of dopamine receptor blocking neuroleptic drugs. The neuroleptic potentiating role of alpha-methyl-paratyrosine (AMPT), a tyrosine hydroxylase inhibitor, was compared with haloperidol and placebo in a double-blind cross-over trial. Both AMPT and haloperidol increased the anti-schizophrenic effect of neuroleptic treatment in reduced dose compared with placebo (P less than 0.05), though two patients relapsed during the AMPT period. Both drugs slightly increased extrapyramidal symptoms, but the effect was greater with haloperidol. The limited antipsychotic effect and the potential for aggravating neurological symptoms suggest that the combination of AMPT and neuroleptics does not offer a superior advantage to treating schizophrenia. AMPT, however, may still be used as a research tool in elucidating pathogenetic mechanisms.

Adult↗
PubMed1990

Neuropharmacological and behavioural properties of remoxipride in the rat.

Remoxipride blocks dopamine agonist-induced effects in the rat, mediated by dopamine D2 receptors with an in-vivo potency less than that of haloperidol but greater than that of chlorpromazine, thioridazine, and sulpiride. Unlike haloperidol and sulpiride, remoxipride has weaker antagonistic effects towards presynaptic dopamine activity compared to its effects on postsynaptically mediated activity. Remoxipride causes a preferential inhibition of dopamine agonist-induced locomotion as compared to stereotyped behaviour, suggesting that it may exert a preferential blockade of mesolimbic dopamine neurotransmission. The low tendency of remoxipride to cause catalepsy in the rat is indicative of a weak effect on striatal dopamine neurotransmission and predicts a low liability to induce extrapyramidal side effects in man. Remoxipride causes a smaller elevation of prolactin than sulpiride at doses producing central dopamine receptor blockade. The results suggest that remoxipride, unlike haloperidol, can discriminate between different types of dopamine mediated functions probably by having a preferential action on subpopulations of functionally coupled dopamine D2 receptors.

Animals↗
PubMed1994

D2-dopamine receptor occupancy differs between patients with and without extrapyramidal side effects.

To investigate whether the occurrence of extrapyramidal side effects was related to D2 dopamine receptor occupancy, iodobenzamide single positron emission computed tomography was carried out in 27 schizophrenic patients and 10 controls. Eighteen patients were treated with haloperidol; 9 patients were treated with clozapine. Our data suggest a relationship between D2 receptor occupancy and extrapyramidal side effects as well as the existence of a neuroleptic threshold of a striatal:frontal cortex ratio of 1.2, below which drug-induced exptrapyramidal side effects can be expected.

Adult↗
PubMed1989

Attenuation of water intake and operant responding by dopamine D2 antagonists: raclopride provides important cues for understanding the functional mechanism of action.

The selective dopamine (DA) D2 receptor antagonist raclopride was found to attenuate operant lever-pressing with water as reward in a dose dependent manner and more potently than the corresponding consummatory act, i.e. the unconditioned water intake. This is the same way as previously reported for other DA D2 antagonists. In screening experiments raclopride has been selected on the basis of great separation between antagonism of DA-agonist induced hyperactivity, stereotypies and production of catalepsy. We found that attenuation of lever-pressing and water intake by raclopride were not more separated in dose than after, for example, haloperidol. We further found that attenuation of lever-pressing and water intake occurred in doses relatively lower than those producing catalepsy, thus excluding catalepsy as a cause for the attenuation. Decreased water intake in thirsty animals caused by a low dose of apomorphine (APO) was counteracted by raclopride. This has previously been found with DA D2, but not with D1, antagonists, which further supports that this apomorphine-effect is mediated via D2 receptors. However, raclopride only showed this antagonism in a narrow dose-range, like haloperidol. The selective profile previously found for sulpiride, proposed to be related to low incidence of extrapyramidal side-effects in the clinic, was thus not replicated.

Animals↗