Possible resolution of a paradox concerning the use of p-chlorophenylalanine and 5-hydroxytryptophan: evidence for a mode of action involving adrenaline in manipulating the surge of luteinizing hormone in rats.

Various functions involving the central nervous system can be manipulated by the sequential administration of p-chlorophenylalanine and 5-hydroxytryptophan, compounds which respectively inhibit and restore the synthesis of 5-hydroxytryptamine in the brain. An involvement of 5-hydroxytryptamine in the control of a particular function has been considered established when the effect of p-chlorophenylalanine on that function can be overcome by treatment with 5-hydroxytryptophan. This assumption is not, however, invariably substantiated when the functional consequences of other methods of depleting 5-hydroxytryptamine are considered; studies on the control of the daily surge of luteinizing hormone in oestrogen-treated ovariectomized rats present such a paradox. The surge can be prevented by p-chlorophenylalanine and restored by 5-hydroxytryptophan. Nevertheless, neurotoxin-induced lesions of the 5-hydroxytryptamine projections from the raphe nuclei are compatible with a normal occurrence of the surge. We have therefore examined the effects of p-chlorophenylalanine and 5-hydroxytryptophan on hypothalamic monoamines in oestrogen-treated ovariectomized rats and find that the drugs respectively suppress and elevate the concentration of adrenaline in addition to that of 5-hydroxytryptamine. Phenylethanolamine N-methyltransferase, the enzyme responsible for converting noradrenaline to adrenaline, is shown to be inhibited in vivo by p-chlorophenylalanine and in vitro by its metabolite, p-chlorophenylethylamine. The reciprocal effects of p-chlorophenylalanine and 5-hydroxytryptophan on the concentration of adrenaline are of particular interest since drugs which inhibit adrenaline synthesis can block the luteinizing hormone surge. It is proposed that when the 5-hydroxytryptophan-reversible effects of treatment with p-chlorophenylalanine are not reproduced by other procedures which deplete 5-hydroxytryptamine, the significant action of these compounds may involve adrenaline.