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G Bartholini

Publications and source records attributed to G Bartholini.

At least 37 records · Page 2Linked to original sources
PubMed1983

Pharmacological and therapeutic actions of GABA receptor agonists.

GABA receptor agonists, e.g. progabide, modify the activity of several brain neuronal systems which are implicated in the pathogenesis of some neuropsychiatric disorders. Thus, alterations in noradrenergic and serotoninergic transmissions induced by progabide may be a mechanism involved in the antidepressant action of this drug in the clinic. The antagonism of the neuroleptic-induced increase in dopamine receptor sensitivity and the decrease in dopamine synthesis and release may be responsible for the effectiveness of the GABA receptor agonists in the treatment of neuroleptic- and L-DOPA-induced dyskinesia. This action of GABA receptor agonists also suggests their therapeutic potential in mania. Finally, decrease in cellular excitability induced by GABA receptor agonists, e.g. progabide, accounts for their efficacy in epilepsy.

Bipolar Disorder↗
PubMed1982

[3H]Haloperidol labels brain dopamine receptors after its injection into the internal carotid artery of the rat.

Pulse injection of [3H]haloperidol (0.2 microCi; 0.003 microgram) into the internal carotid artery of the rat specifically labelled dopamine receptors in striatum and olfactory tubercle, as indicated by the kinetics of, and the effects of neuroleptic drugs on, the ligand disposition. The described method may prove useful for labelling brain receptors with ligands which readily cross the blood-brain barrier but which do not selectively mark their receptors if injected systemically.

Animals↗
PubMed1982

Cortical modulation of striatal function.

The effect of bilateral section of the corticostriatal projections or of selective bilateral ablation of the frontal cortex on behavioral and biochemical parameters related to striatal function were investigated in the rat. Either lesion almost completely prevented the cataleptogenic action of haloperidol: this effect was observed as soon as 3 days and lasted for at least 3 months after surgery, paralleling a reduction in striatal glutamate uptake. Also, such lesions enhanced the apomorphine-induced stereotyped behavior (as measured 21 days after surgery). In the striatum, dopamine, dihydroxyphenylacetic acid, acetylcholine and substance P levels as well as choline acetyltransferase and glutamic acid decarboxylase activities were unaffected 10 or 21 days after either type of lesion. In the substantia nigra, substance P levels were unchanged 10 days following suction of the frontal cortex, but glutamic acid decarboxylase was reduced at 21 days postsurgery. Cortical lesions only partially prevented the reduction in striatal acetylcholine concentrations and did not affect the increase in striatal dihydroxyphenylacetic acid caused by haloperidol. Finally, lesions of the corticostriatal pathways failed to affect the apomorphine-induced increase in striatal acetylcholine levels, reduction of the potassium (20 mM) evoked [3H]acetylcholine release in striatal slices preloaded with [3H]choline and decrease of striatal dihydroxyphenylacetic acid concentrations. These findings indicate that the frontal cortex influences extrapyramidal function by a mechanism which--in behavioral terms--is antagonistic to dopamine-mediated events. As indicated by the biochemical data, this mechanism does not involve changes in striatal dopaminergic and cholinergic neuron activity. This mechanism may utilize: (1) corticostriatal glutamatergic neurons as suggested by the reduction in striatal glutamate uptake following lesions; and (2) GABAergic pathways as suggested by the reduction of nigral glutamic acid decarboxylase activity as well as by the finding that GABA receptor agonists reinstate haloperidol-induced catalepsy.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1982

gamma-Aminobutyric acid (GABA) receptor stimulation. II. Specificity of progabide (SL 76002) and SL 75102 for the GABA receptor.

Progabide and its immediate metabolite SL 75102 displace [3H]gamma-aminobutyric acid (GABA), [3H]muscimol and [3H]isoguvacine from their binding sites to membranes prepared from rat brain or human cerebellum and increase (SL 75102) [3H]flunitrazepam binding to rat cerebral cortex membranes. In contrast, these compounds have very weak or no effects on alpha or beta noradrenergic, histamine, muscarinic cholinergic or glycine receptors or on the [3H]imipramine or [3H]kainate binding sites. Neither progabide nor SL 75102 inhibit GABA synthesis, metabolism or uptake. Also, the uptake of norepinephrine, serotonin and dopamine into synaptosomes of cerebral regions is not affected by progabide. [3H]GABA release from substantia nigra slices is decreased by SL 75102 and progabide, in agreement with the hypothesis of a GABAergic autoreceptor controlling GABA release from its nerve terminals. These data suggest a specific agonist action of progabide and SL 75102 on GABA receptors.

Animals↗
PubMed1982

gamma-Aminobutyric acid (GABA) receptor stimulation. I. Neuropharmacological profiles of progabide (SL 76002) and SL 75102, with emphasis on their anticonvulsant spectra.

Progabide (4-([(4-chlorophenyl) (5-fluoro-2-hydroxyphenyl)-methylene]amino) butanamide) is a gamma-aminobutyric acid (GABA) receptor agonist which readily enters the brain. In the body, progabide is metabolized to three active metabolites: SL 75102, gabamide and GABA. Progabide and SL 75102 readily enter the brain and GABA and gabamide are also formed within this organ. Both progabide and SL 75102 exhibit a broad spectrum of anticonvulsant activities against seizures which involve GABA-mediated events (bicuculline, picrotoxinin and pentylenetetrazol) or which are apparently independent of GABAergic mechanisms (penicillin, strychnine, electroshock and audiogenic seizures). These data support the hypothesis that direct GABA receptor stimulation is an effective means of controlling convulsions of various origins. Progabide and SL 75102 have relatively minor secondary effects in comparison to commonly used antiepileptics. Myorelaxation occurs, but only at doses higher than the ED50 values in convulsant tests. Furthermore, these compounds are not sedative. Finally, these GABA agonists have a complex action in the extrapyramidal system. Anticonvulsant doses are antagonistic to dopamine receptor-mediated behaviors, whereas much lower doses seem to facilitate the effects of dopaminergic transmission.

Animals↗
PubMed1980

Increase in striatal acetylcholine levels by GABAergic agents: dependence on corticostriatal neurons.

Surgical lesion of the corticostriatal projections almost totally reduced the ability of GABA agonist agents but not apomorphine to increase rat striatal ACh concentrations. This suggests that in intact rats, the GABAergic inhibition of striatal cholinergic neurons depends, at least in part, upon the corticostriatal (possibly glutamatergic) tract whereas the action of the dopaminergic pathway on cholinergic cells is independent of corticostriatal neurons.

Acetylcholine↗
PubMed1980

The potential of GABA-mimetics in the therapy of extrapyramidal disorders.

GABA mimetics inhibit extrapyramidal DA and ACh neurons and affect an unknown system beyond both DA and ACh receptors, which is involved in extrapyramidal motor outputs. Based on these data, the rationale is discussed for the clinical use of GABA mimetics in Huntington's chorea, parkinsonian tremor, L-DOPA or neuroleptic-induced dyskinesias.

Antipsychotic Agents↗
PubMed1980

New anticonvulsants: Schiff bases of gamma-aminobutyric acid and gamma-aminobutyramide.

Schiff bases of gamma-aminobutyric acid (gammaAbu) and gamma-aminobutyramide (gammaAbuNH2) were prepared and tested for anticonvulsant and gammaAbu mimetic activity. 4-[[(4-Chlorophenyl)(5-fluoro-2-hydroxyphenyl)methylene]amino]butanoic acid monosodium salt (4) and 4-[[(4-chlorophenyl)(5-fluoro-2-hydroxyphenyl)methylene]amino]butanamide (5) blocked bicuculline-induced lethality and convulsions and displaced [3H]gammaAbu from its membrane binding sites. In the rat dorsal root sensory ganglion, compound 4 exhibited gammaAbu agonist properties. Compounds 4 and 5 are thus anticonvulsants and directly acting gammaAbu mimetics.

Animals↗
PubMed1980

Effect of the new gamma-aminobutyric acid agonist SL 76 002 on striatal acetylcholine: relation to neuroleptic-induced extrapyramidal alterations.

A single injection of the new GABA receptor agonist SL 76 002 reduces the activity of striatal cholinergic neurons. Behaviorally, SL 76 002 (in large dose) potentiates haloperidol-induced catalepsy and antagonizes apomorphine-induced stereotypies. Repeated coadministration of haloperidol and SL 76 002 for 10 days does not affect the tolerance of the cholinergic system which is observed after haloperidol alone. In contrast, coadministration of the two drugs results in a marked prevention of the tolerance to the cataleptogenic action of haloperidol and of the increased sensitivity to apomorphine. It is suggested that (a) GABA mimetic medication inhibits striatal cholinergic transmission by a direct action on ACh cells; (b) behavioral effects resulting from alteration of dopaminergic transmission are--in contrast to the current view--not exclusively mediated by changes of cholinergic activity; (c) GABA affects striatal function via at least two mechanisms: by a direct input on, and independently from, both dopaminergic and cholinergic neurons; and (d) SL 76 002 possibly exerts a beneficial action in L-DOPA-induced abnormal movements in parkinsonian patients and neuroleptic-induced tardive dyskinesias.

Acetylcholine↗
PubMed1979

[Potential therapeutic activity of GABA-mimetic drugs in neuropsychiatry].

Several pieces of evidence support the view that GABA neurons inhibit the DA system both in extrapyramidal and limbic regions. This inhibition is exerted on cell bodies and terminals of DA neurons and is involved in the regulation of their activity. A recently synthesized GABAmimetic compound SL 76.002 has considerably helped in elucidating the role of GABA in this regulation as well as the therapeutic implication of changes of GABAergic transmission in human brain. Thus, impairment of dopaminergic transmission by SL 76.002 has been shown to be effective in iatrogenic extrapyramidal syndromes such as L-DOPA-induced involuntary movements in parkinsonian patients and neuroleptic-induced tardive dyskinesias: the first attributed to an exaggerated formation and liberation of DA, the second to supersensitivity of target cells of DA neurons. Furthermore, GABAergic medication has been confirmed to be useful in Huntington's chorea in which some symptoms originate from degeneration of striatal GABAergic neurons. Finally, GABAergic inhibition on cellular excitability has been proved to ameliorate epilepsy. However, SL 76.002, contrary to the expectation, was not effective in schizophrenia suggesting that GABA does not play a major role in the pathogenesis of this disorder.

4-Aminobutyrate Transaminase↗