Abstract

Depletion of norepinephrine and dopamine in brain by α-methyltryrosine had no effect on the anticonvulsant potency of methazolamide in rats and only a slight antagonist action in mice. Depletion of 5-hydroxytryptamine by p-chlorophenylalanine reduced anticonvulsant potency to some degree and increased seizure susceptibility. Marked reduction in anticonvulsant potency, unrelated to changes in seizure susceptibility, was associated with simultaneous depletion of the three amines, as seen after treatment with reserpine, reserpine in combination with α-methyltyrosine or p-chlorophenylalanine or joint treatment with the latter two agents. Based on consistency between 1) depletion and reduced anticonvulsant effect, 2) endogenous repletion and regain of anticonvulsant effect and 3) exogenous repletion and restoration of anticonvulsant effect, norepinephrine appears to be the involved catecholamine. 5-Hydroxytryptamine is also implicated because of 1) the synergistic antagonist effect of joint treatment with α-methyltyrosine and p-chlorophenylalanine, 2) inhibition of its synthesis in reserpine-treated rats prevented complete regain of anticonvulsant effect and 3) exogenous repletion restored anticonvulsant potency. Anticonvulsant potency can be maintained almost undiminished with adequate function of either an adrenergic (norepinephrine) on a serotonergic system. Norepinephrine appears to be the more important amine because of 1) better consistency between its depletion and changes in potency, 2) inhibition of its synthesis more effectively reduced anticonvulsant potency and 3) upon exogenous repletion of the two amines in brain, restoration of anticonvulsant potency required a lower concentration of norepinephrine.