DL-2-[3,4-3H]amino-4-phosphonobutyrate binding sites in the rat hippocampus: distribution and possible physiological role.

Binding sites for the novel, glutamate-like radioligand DL-2-[3,4-3H]amino-4-phosphonobutyrate (DL-[3H]APB) on rat hippocampal synaptic membranes were identified and characterised. The existence of a single, saturable population of binding sites was demonstrated. These appeared to be indistinguishable, in terms of their pharmacological profile and ionic dependence, from those described previously in the striatum and whole brain. The distribution of these sites was also examined using a number of discrete neuronal lesions. A majority of sites (approx. 55%) were located on dentate gyrus granule cells. Smaller populations appeared to be situated on perforant path terminals and on pyramidal cells. However, L-APB was found to be ineffective as an inhibitor of basal and potassium evoked D-[3H]aspartate release from hippocampal slices. A presynaptic location can therefore presumably be ruled out. The likely postsynaptic location of DL-[3H]APB-binding sites in the hippocampus suggests that this site may be involved in synaptic neurotransmission. This possibility is discussed with regard to electrophysiological data concerning the synaptic pharmacology of neuronal connections within the hippocampus.

Enteric gamma-aminobutyric acid-containing neurons and the relevance to motility of the cat colon.

gamma-Aminobutyric acid (GABA)-containing neurons were identified and the functional relevance in the motility of the colon was studied. Autoradiography of the cat colon treated with [3H]GABA demonstrated scattered neurons in the myenteric plexus selectively labeled with [3H]GABA. Electrical transmural stimulation of the isolated cat colon led to an increase in the Ca2+-dependent, tetrodotoxin-sensitive release of endogenous GABA. gamma-Aminobutyric acid increased the amplitude of rhythmic contractions of the circular muscle of the colon and also the release of acetylcholine, which was Ca2+-dependent and tetrodotoxin-sensitive. Scopolamine inhibited the GABA-evoked rhythmic contractions, without effect on the evoked release of acetylcholine. Bicuculline and furosemide reduced the amplitude of spontaneous rhythmic contractions and the tone, which was reversed by GABA. These results suggest that GABA-containing neurons are involved in the control of motility of the cat colon, due to the stimulation of cholinergic neurons.

Gabaminergic and serotonergic modulation of the antidyskinetic effects of tiapride and oxiperomide in the model using 2-(N,N-dipropyl)animo-5,6-dihydroxytetralin.

The activities of oxiperomide and tiapride were compared with those of control "neuroleptic" agents in the dyskinesia model using 2-(N,N-dipropyl)amino-5,6-dihydroxytetralin to induce peri-oral movements, in order to determine whether the differential activities (oxiperomide and tiapride being comparatively more effective as antagonists) may involve striatal gabaminergic and serotonergic mechanisms. The peri-oral movements induced by the 2-aminotetralin compound (0.05 mg/kg s.c.) were antagonised by intrastriatal GABA (2.5--10 microgram bilateral) and serotonin (25--100 microgram bilateral). Sodium valproate (i.p.) had little effect but 1.25 mg/kg s.c. quipazine abolished the peri-oral dyskinesia. Subthreshold doses (i.p.) of oxiperomide and tiapride synergised with subthreshold intrastriatal doses of both GABA and serotonin, and with s.c. quipazine, to antagonise the peri-oral movements induced by the 2-aminotetralin compound. Subthreshold doses of haloperidol, sultopride, metoclopramide and pimozide failed to consistently antagonise peri-oral movements when similarly combined with GABA, serotonin or quipazine. It is suggested that, in addition to their known action on cerebral dopamine mechanisms, oxiperomide and tiapride may modify abnormal peri-oral movements by modulation of striatal gabaminergic and serotonergic mechanisms.

Benzodiazepines: potentiation of a GABA inhibitory response in the dorsal raphe nucleus.

Based on evidence that the dorsal raphe nucleus (DR) has specific and independent receptors for 5HT, GABA and glycine (Gallager and Aghajanian, 1976; Wang and Aghajanian, 1977), alterations in the firing rate of DR neurons following the administration of benzodiazepines (BZ) were evaluated to determine whether they were the result of a direct interaction with 5HT receptors or due to interactions of these drugs with GABA and/or glycine. The effects of BZs after both direct and systemic application were tested in rats using microiotophoretic and single-cell recording techniques. Although the BZs did not alter the spontaneous firing rate of the DR, both the systemic and iontophoretic administration of these drugs were found to potentiate the inhibitory response produced by GABA. The data suggest that this potentiation is mediated postsynaptically. Since the effects of BZs on the spontaneous activity of the DR are only apparent following pretreatments with AOAA, it is speculated that these drugs may only have pronounced effects when GABAergic input is prominent.

Specific antagonism of GABA-mediated postsynaptic inhibition in cultured mammalian spinal cord neurons: a common mode of convulsant action.

Mammalian spinal neurons grown in tissue culture were used to study the effects of the four convulsants-penicillin, pentylenetetrazol, picrotoxin, and bicuculline-on these neurons' responses to amino acids. Bath application of all four convulsants produced paroxysmal depolarizing events in the neurons; iontophoresis of the four convulsants selectively depressed responses produced by iontophoresis of the putative inhibitory transmitter GABA, and effected this depression without altering either inhibitory responses to beta-alanine or glycine, or excitation mediated by glutamate. These results support the hypothesis that the convulsant activity of these agents comes in part from selective antagonism of GABA-mediated postsynaptic inhibition.

Involvement of gamma-amino butyric acid (GABA) in the anticonvulsant action of methaqualone.

The effects of methaqualone on isonicotinic acid hydrazide, 6-mercapto propionic acid, picrotoxin, and strychnine-induced convulsion were studied in mice and the results compared with diazepam. Methaqualone, like diazepam, was found to be a selective antagonist of isoniazid-induced convulsion and a much less effective inhibitor of strychnine convulsion. Methaqualone elicits muscle-relaxant, sedative, and anticonvulsant effects at different dose levels. At low, nonsedative doses the drug produces anticonvulsant effects, and at higher doses, muscle-relaxant and sedative effects. It appears that the mechanism(s) of action of methaqualone in on GABA deficiency or receptor blockade, rather than on glycine receptors.

GABA-mediated control of transient signals in the inner retina.

The effects of chemicals on visual activity was investigated by recording the proximal negative response (PNR) in the perfused eyecup of frogs. Various amino acids reversibly decrease or abolish the PNR over an equivalent concentration range but differ in this depressive action in the presence of convulsant alkaloids. Depression produced by GABA was antagonized by picrotoxin or bicuculline; while glycine-produced depression was selectively antagonized by strychnine. In addition to selective antagonism of amino acids, the convulsants produced differential enhancement of sustained and transient phases of the PNR. In this respect, the effects of picrotoxin and bicuculline are similar to those of semicarbazide and chloride-free solutions which may also inactivate GABA pathways. The effects of these chemicals on the time course and input-output relation of the PNR suggest that processes involving GABA may regulate the transformation from sustained to transient signals which occurs in the inner retina.

The effect of endogenous and exogenous GABA on the level and turnover of noradrenaline and dopamine in the rat brain.

The effect of endogenous and exogenous GABA on the level and turnover of noradrenaline and dopamine in the rat brain. Acta Physiol. Pol., 1978, 29 (2): 117--121. GABA administered to the lateral ventricle of the rat brain (i.v.c.) in doses of 200 and 600 microgram decreased the level of noradrenaline and had no effect on dopamine level. A similar effect was obtained after raising the level of endogenous GABA in the brain by means of intraperitoneal hydroxylamine (Hx) in doses of 50 and 75 mg/kg. It was also observed that GABA given i.v.c. in a dose of 600 mg/kg reduces the turnover of dopamine in the brain.

GABA involvement in memory consolidation: evidence from posttrial amino-oxyacetic acid.

In order to assess the possible effects of central GABA activation on the consolidation of shock avoidance, the GABA-T inhibitor amino-oxyacetic acid (AOAA) was administered posttrial to adult male rats. Learning was assessed over nine widely spaced sessions of 20 trials each. AOAA-treated animals showed learning within sessions and a lack of consolidation across sessions. Controls, on the other hand, showed learning both within and across sessions. This evidence agrees with previous reports suggesting GABA involvement in memory processes.

Is GABA involved in analgesia?

The effect of morphine and naloxone on gamma-aminobutyric acid (GABA) concentration in discrete areas of the rat brain has been studied. Neither morphine nor naloxone had a significant effect on regional steady-state concentrations of GABA. The results have been discussed with respect to the role of GABA in pain and analgesia.

[GABA system as a factor facilitating the development of compensation of disordered cerebral hemodynamics]. / Sistema GAMK kak faktor, sposobstvuiushchii vozniknoveniiu kompensatsii narushennoi mozgovoi gemodinamiki.

Shifts in the system of GABA transformation in ischemia and specific inhibition of GABA-transaminase under conditions of quantitative measurement of the blood circulation by means of hydrogen clearance permitted to establish a definite association between the increased GABA level in the brain and the tissues of the wall of its arteries, and the development of compensation of disturbed cerebral circulation. Consequently, one of the principal manifestations of an increased amount of endogenous GABA in deficiency of the brain blood supply was GABA capacity to improve the cerebral circulation.

Possible involvement of GABA mechanisms in central cardiovascular and respiratory control. Studies on the interaction between diazepam, picrotoxin and clonidine.

Various doses (0.1-1 mg/kg) of diazepam were given to chloralose anesthetized rats, with both systemic (i.p.) and central injections being tested. Arterial pressure, heart rate, respiration depth and frequency were recorded. Diazepam caused a dose-dependent decrease in the arterial pressure after systemic administration and also decreased it after central administration. However, only intraventricular but not intracisternal injections of diazepam were effective. The hypotensive effect of systemic diazepam was competitively counteracted by pretreatment with picrotoxin, a putative gamma-aminobutyric acid receptor blocking agent. The hypotensive effect of the centrally acting alpha-adrenoreceptor agonist clonidine was not influenced by picrotoxin pretreatment. The effect of diazepam on heart rate was inconsistent. Diazepam caused a reduction of respiratory frequency, which was not counteracted by picrotoxin pretreatment. It is concluded that central gabergic mechanisms are to some extent involved in the hypotensive effect of diazepam, probably at a supramedullary level. The hypotensive effect of a threshold dose of diazepam was blocked by a small dose of clonidine. Likewise, diazepam pretreatment could counteract the hypotension, bradycardia and respiratory frequency reduction caused by a threshold dose of clonidine. These results suggest that gabergic and/or other benzodiazepine-sensitive receptors may interact with alpha-adrenoreceptors in the control of central cardiovascular and respiratory mechanisms.