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Biomedical subjects

E Costa

Publications and source records attributed to E Costa.

At least 541 records · Page 30Linked to original sources
PubMed1977

Mechanisms by which diazepam, muscimol, and other drugs change the content of cGMP in cerebellar cortex.

THE CEREBELLUM CONSISTS OF TWO PARTS: the cerebellar nuclei whose connections to the various parts of the central nervous system coordinate muscle movements, and the cerebellar cortex which exerts an inhibitory influence on the cerebellar nuclei through the release of gamma-aminobutyric acid (gammaAbu) from Purkinje cells. The activity of Purkinje cells is regulated by two excitatory inputs to the cerebellar cortex-the climbing and mossy fibers-and by a neuronal network within the cortex which inhibits the activity of Purkinje cells through the release of gammaAbu from interneurons. The net activity of Purkinje cells is related to their content of guanosine 3':5'-cyclic monophosphate (cGMP) which increases or decreases according to changes in the activity of climbing and mossy fibers as well as to changes in the activation of gammaAbu receptors. When these receptors are activated, the cGMP of Purkinje cells decreases; when they are inhibited, the cGMP increases.The cGMP content of the cerebellar cortex is altered by drugs that change either the excitatory input of climbing or mossy fibers or the inhibitory input mediated by the activation of gammaAbu receptors. Mechanisms by which various drugs alter the cerebellar content of cGMP were investigated. By using various experimental designs, it was shown that diazepam and muscimol lowered the cGMP content by activating gammaAbu receptors. In contrast, morphine and haloperidol lowered the cerebellar cortex cGMP by decreasing the excitation of mossy fibers whereas harmaline increased the cGMP by increasing the excitation of the climbing fibers.

Alkaloids↗
PubMed1977

Pharmacologically induced changes in the 3':5'-cyclic guanosine monophosphate content of rat cerebellar cortex: difference between apomorphine, haloperidol and harmaline.

Harmaline increases cerebellar 3':5'-cyclic guanosine monophosphate (cGMP) content in a dose-related manner; this increase is prevented by a pretreatment with 3-acetylpyridine (3-AP) (0.66 mmol/kg) which destroys climbing fibers and inhibits harmaline-induced tremor. The cerebellar cGMP content increases after isoniazid; this response remains unchanged in rats pretreated with 3-AP. Since isoniazid decreases cerebellar gamma-aminobuturic acid (GABA) levels, the increase in cGMP content might reflect a reduction in the availability of GABA at the level of postsynaptic receptors. Apomorphine (a dopamine receptor agonist) and haloperidol (a dopamine receptor blocker) increase or decrease the cGMP content of cerebellar cortex, respectively. Neither drug changes the guanylate cyclase activity of cerebellar homogenates; moreover their action on cerebellar cGMP content persists after 3-AP. Chloropromazine, like haloperidol, decreases the cerebellar cGMP content. The increase in cerebellar cGMP content elicited by apomorphine can be differentiated from that elicited by harmaline or isoniazid; presumably apomorphine indirectly activates mossy fibers. The decrease in cerebellar cGMP content elicited by haloperidol can be differentiated from that elicited by diazepam; perhaps haloperidol reduces the mossy fiber input to the cerebellum. We suggest that the cGMP content of cerebellar cortex fluctuates in response to changes in the afferent stimulatory input to the cerebellum; it increases when the activity of either climbing or mossy fibers is increased; it decreases when either of these two stimulatory inputs is reduced.

Alkaloids↗
PubMed1977

The turnover rate of gamma-aminobutyric acid in the nuclei of telencephalon: implications in the pharmacology of antipsychotics and of a minor tranquilizer.

The turnover rate of GABA is measured in substantia nigra, globus pallidus, N. accumbens, and striatum of rats injected with muscimol, a potent GABA agonist, and diazepam. The similarity of action of the two drugs on GABA turnover further supports the theory that diazepam acts as a GABA-mimetic drug. Haloperidol and clozapine affect GABA turnover differently in different nuclei. Haloperidol decreases GABA turnover in caudate but does not affect that in substantia nigra, whereas clozapine increases GABA turnover in both areas. However, both drugs accelerate GABA turnover in globus pallidus and N. accumbens. It is suggested that an increase of GABA turnover and perhaps of GABA release in striatum and substantia nigra may account for the lack of tardive dyskinesia and extrapyramidal side effects of clozapine.

Aminobutyrates↗
PubMed1977

Application of principles of steady-state kinetics to the estimation of gamma-aminobutyric acid turnover rate in nuclei of rat brain.

13C-labeled glucose (50 mumol/kg/min) was infused into the rat tail vein for 10 minutes. The animals were killed by a microwave beam focused to the skull at various times after the infusion. In brain nuclei the concentrations of glutamate and gamma-aminobutyric acid (GABA) and their enrichment in 13C were measured by mass fragmentography. The results showed that in the five brain areas studied, substantia nigra contained the highest GABA concentration, followed by globus pallidus, N. accumbens, deep cerebellar nuclei, N. caudatus and cerebellar cortex. The concentrations of glutamate and GABA were comparable in some nuclei (substantia nigra and globus pallidus), but not in others. The glutamate content was 3 to 6 times greater than GABA content in cerebellum (cortex and nuclei) N. accumbens and N. caudatus. The turnover rates of GABA in substantia nigra, globus pallidus, N. caudatus and N. accumbens were calculated by applying principles of steady-state kinetics to the changes with time in the 13C enrichment of glutamic acid and GABA. In substantia nigra, N. accumbens and N. caudatus, the percentage of 13C incorporation into glutamic acid and GABA reached its maximum 10 to 15 minutes after the infusion. In N. caudatus and N. accumbens, the percentage of 13C incorporation into GABA was higher than that in substantia nigra and globus pallidus. The turnover rates of GABA were very similar in N. caudatus, N. accumbens, substantia nigra and globus pallidus (385-562 nmol/mg of protein per hr), but the turnover times were much faster in N. caudatus and N. accumbens. It must be kept in mind that in N. caudatus and N. accumbens the glutamate pool was several-fold greater than that of GABA. Since the data obtained indicate that the compartmentation is more complicated than in the model assumed for turnover estimations, this method should be used only for comparative purposes in drug studies. The validity of this method to obtain absolute measurements of GABA turnover remains to be documented.

Aminobutyrates↗