The effect of GABA and related drugs on 3'5' cAMP and 3'5' cGMP was investigated in slices of guinea-pig cerebral cortex, kept at rest or electrically stimulated. GABA 1 X 10(-4) - 1 X 10(-3) M raised the cAMP basal levels, bud reduced its increase due to electrical stimulation. These effects were antagonized by picrotoxin 1.6 X 10(-5) M. On the contrary, endogenous GABA did not influence cAMP and cGMP content. In fact, neither ethanolamine-O-sulphate 2 X 10(-3) M nor picrotoxin 1.6 X 10(-5) M affected the normal nucleotide values at all. Higher picrotoxin concentrations (3.2 - 8 X 10(-5) M), however, increased both cyclic nucleotides. Phentolamine counteracted the actions of both GABA 1 X 10(-4) M and picrotoxin 8 X 10(-5) M: therefore, the observed increase in cyclic nucleotides were due to norepinephrine release. Tetrodotoxin antagonized GABA but not picrotoxin metabolic effects. Thus it is suggested that the exogenous amino acid released norepinephrine through a sodium-dependent process, while picrotoxin released the monoamine directly from its storage sites. Clearly, attention must be paid when putative transmitters or their antagonists are added at high concentrations to isolated tissue to study the effect of endogenous compounds.