Antagonism between bicuculline and GABA in the cat brain

1 The structural requirements for activation of the glycine receptor were studied in isolated ventromedial hypothalamic neurones of rats by use of a 'concentration-clamp' technique under singleelectrode voltage-clamp conditions. 2 a-Amino acids (L-a-alanine, and D-a-alanine, and L-serine), and glycine-methylester, glycineethylester and f-amino acids (fl-alanine and taurine) produced a transient inward Cl -current, which was similar to that induced by glycine.3 The responses to individual a-and #-amino acids were selectively antagonized by strychnine, but were not affected by bicuculline, picrotoxin or the taurine antagonist, TAG (6-aminomethyl-3-methyl-4H,1,2,4-benzothiadiazine-1,1-dioxide hydrochloride), suggesting that a-and fl-amino acids activate the same glycine receptor. 4 fl-Amino acids were slightly more potent than the a-amino acids in causing cross-desensitization of the glycine response. 5 From the results of the structure-activity analysis of the optical isomers of a-alanine, serine and cysteine, a tentative structure of the glycine receptor is proposed.

Section: Discussionmentioning

confidence: 99%

What confers specificity on glycine for its receptor site?

Tokutomi

Kaneda

Akaike

1989

“…In the cortex, however, where GABA is about 4 times more potent than glycine (Krnjevic & Phillis, 1963;Curtis et al, 1968a;Kelly & Krnjevic, 1969;Johnson, Roberts & Straughan, 1970), Kelly & Kmjevic (1969) found that only GABA mimicked the effect of the inhibitory transmitter on the cell membrane. GABA was also considered a more effective depressant than glycine on the spike-discharge of Deiters' neurones (Bruggencate & Engberg, 1969Obata, Takeda & Shinozaki, 1970), Purkinje cells of the cerebellum (Kawamura & Provini, 1970;Curtis et al, 1971b) and the mitral cells of the olfactory bulb (Nicoll, 1971), three situations where the inhibitory transmitter may well be GABA. Since GABA and glycine are equipotent depressants of cuneate relay cells the transmitter released by the final interneurones of the separate inhibitory pathways which impinge on cuneo-thalamic relay cells.…”

Section: Discussionmentioning

confidence: 99%

On the pharmacology of the γ‐aminobutyric acid receptors on the cuneo‐thalamic relay cells of the cat

Kelly

Renaud

1973

Summary1. y-Aminobutyric acid (GABA) and glycine applied by iontophoresis were equipotent depressants of cuneo-thalamic relay neurones isolated from the middle third of the cuneate nucleus of cats either decerebrated or anaesthetized with sodium pentobarbitone. 2. Glycine 13+2 nA and GABA 20+2 nA were equipotent depressors of hair cells (n=22) and, bicuculline applied by iontophoresis caused a parallel shift to the right of the GABA but not the glycine log-current response curves. The GABA equipotent dose-ratio was 20 + 0-2 for bicuculline currents of approximately 144 nA lasting about 11 min in cells excited either transynaptically by peripheral stimulation or postsynaptically by glutamate. 3. Although a maximal bicuculline current seldom caused a significant shift of the glycine-log current response curve, many of our records show the onset of the glycine response to be slowed by doses in excess of 84 nA.4. Bicuculline also antagonized depressions by fl-guanidinopropionic acid, and 8-aminovaleric acid which mimicked the action of GABA. 5. When tested on the same neurone, bicuculline and picrotoxin applied by iontophoresis were equipotent and their effects appear to be additive. 6. The GABA sensitivity was not modified by repetitive (5 or 6) doses of i.v. bicuculline (0-2 mg/kg). 7. The antagonism of GABA by bicuculline and picrotoxin appears to be of sufficient specificity to enable the separate roles of GABA and glycine as putative inhibitory transmitters of cuneo-thalamic relav cells to be determined.

“…Glycine and glycine-like amino acids can be used as control agonists on cat cortical neurones with moderate success (Curtis et al, 1970;Curtis, Duggan, Felix, Johnston & McLennan, 1971), although recent reports on rat cortical neurones would suggest that it is not always easy to separate antagonism of GABA and glycine (Biscoe, Duggan & Lodge, 1972). In an attempt to use glycine.…”

Section: Control Agonistsmentioning

confidence: 99%

A comparative study of some convulsant substances as γ‐aminobutyric acid antagonists in the feline cerebral cortex

Hill

Simmonds

Straughan

1973

Summary1. By the use of microiontophoretic techniques, quantitative estimates were obtained of the depressant effects of y-aminobutyric acid (GABA) on single feline cortical neurones. 2. Picrotoxin, bicuculline, strychnine, ( +)-tubocurarine, penicillin and leptazol were also applied microiontophoretically to single neurones. Sequential GABA applications were made before, during and after the microiontophoresis of these substances and any effects on the time course of the GABA depression were measured as an estimate of antagonism or potentiation of GABA. 3. (+ )-Tubocurarine was found to be a potent GABA antagonist. Picrotoxin and bicuculline were rather less potent and strychnine and penicillin only weakly active as GABA antagonists. Leptazol appeared to be inactive against GABA depressions. 4. In addition, bicuculline and strychnine were found to be capable of potentiating the depressant action of GABA. This property was not shared by the other substances studied. 5. All the substances studied produced changes in neuronal firing rate that did not correlate with GABA antagonism. 6. In conclusion, several potent convulsants have been shown to be capable or GABA antagonism. It is not yet clear that this effect, rather than a direct effect on neuronal excitability, is the prime mechanism behind their convulsant properties.