Pharmacology of cortical inhibition

We have studied the effects of various pharmacological agents on the cortical inhibitory process described in the previous two papers (Krnjević, Randić the drugs were mostly administered directly by iontophoresis from micropipettes and by systemic injection (I.V.).2. Strychnine given by iontophoresis or by the application of a strong solution to the cortical surface potentiated excitatory effects, but very large iontophoretic doses also depressed neuronal firing. Subconvulsive and even convulsive systemic doses had little or no effect at the cortical level. There was no evidence, with any method of application, that strychnine directly interferes with the inhibitory process.3. Tetanus toxin, obtained from two different sources and injected into the cortex 12-48 hr previously, also failed to block cortical inhibition selectively. As with strychnine, there was some evidence of increased responses to excitatory inputs.4. Other convulsant drugs which failed to block cortical inhibition included picrotoxin, pentamethylene tetrazole, thiosemicarbazide, longchain omega-amino acids and morphine.5. The inhibition was not obviously affected by cholinomimetic agents or by antagonists of ACh.6. alpha- and beta-antagonists of adrenergic transmission were also ineffective.7. Cortical inhibition was fully developed in the presence of several general anaesthetics, including ether, Dial, pentobarbitone, Mg and chloralose. A temporary reduction in inhibition which is sometimes observed after systemic doses of pentobarbitone, is probably secondary to a fall in blood pressure.8. Several central excitants such as amphetamine, caffeine and lobeline also failed to show any specific antagonistic action on cortical inhibition.9. In view of the possibility that GABA is the chemical agent mediating cortical inhibition, an attempt was made to find a selective antagonist of its depressant action on cortical neurones. None of the agents listed above, nor any other of the substances tested, were able to block this action.10. It was concluded that cortical inhibition differs from spinal inhibition in its pharmacological properties; and that our observations are consistent with the possibility that GABA is the cortical inhibitory transmitter.