4. In conscious rabbits, intravenous infusion of histidine in the dose range 62 to 1,500 mg/kg, raised significantly (P<0-01) the concentration of histamine in all regions of the brain examined, the pattern of distribution remaining unchanged. The largest increases occurred in the mid brain (90 to 320%) and in the hypothalamus (50 to 250%); in these areas the higher doses produced higher concentrations. Elsewhere in the brain the concentration rose in response to the lowest dose of histidine, but was not increased when higher doses were given. Concentrations in the anterior lobe of the hypophysis were unaltered. 5. The infusion of histidine, unlike that of amino acid precursors, of the monoamines, produced no obvious disturbance in the animals. 6. The rise in brain histamine after dosage with histidine persisted for several hours, depending on the dose; with 500 mg/kg, the rise was virtually unchanged after 16 hours. 7. Histamine (5 mg/kg by intravenous infusion) raised the concentration of histamine in the hypophysis but not in the brain.8. After the infusion of DOPA, a-methyldopa or 5-hydroxytryptophan, the histamine concentration rose in the mid-brain but not in other parts of the brain.9. These amino acids, when infused singly with histidine, did not interfere with the histidine-induced rise of brain histamine.

1 The behavioural effects induced by histidine were studied in two species. In rabbits, sedation was assessed by the presence of blepharospasm, loss of righting reflex, and loss of response to painful stimuli. In mice, sedation and arousal were assessed by changes in the locomotor activity, exploratory activity, and minimal electroshock seizure threshold. 2 The administration of histidine to normal rabbits or mice, in doses of 800 mg/kg and 1000 mg/kg respectively, had no apparent effect on behaviour. Moreover, it did not affect the behavioural excitation induced by L-DOPA (100 mg/kg i.v. in rabbits and 750 mg/kg i.p. in mice) in these animals. 3 The administration of histidine with or after L-DOPA in reserpine-treated rabbits (2.5 mg/kg i.v.) or mice (5 mg/kg, i.p.) produced sedation. This sedative effect was dose-dependent. 4 The sedative effects induced by histidine after DOPA-induced arousal in reserpine-treated rabbits and mice were prevented by prior injection of the histamine H1-receptor blockers, chlorpheniramine (2.5 mg/kg) or diphenhydramine (5 mg/kg). 5 Imipramine (7 to 10 mg/kg, i.v.)induced arousal in reserpine-treated rabbits was also reversed by histidine infusion. 6 The infusion of 5-hydroxytryptophan (100 mg/kg, i.v.) with L-DOPA, or of arginine (450 mg/kg, i.v.) with or after L-DOPA, or of histamine (100 gg/kg), i.v.) after L-DOPA, did not affect the DOPA-induced arousal in reserpine-treated rabbits. 7 These findings indicate that histamine, formed centrally from exogenous histidine, and released in increased amounts at the synapses in reserpine-treated animals, possesses a central sedative effect. This effect may be sufficient to antagonize the behavioural excitation induced by high levels of catecholamines in the brain of these animals when aroused by L-DOPA administration. 8 It is concluded that in addition to the other monoamines, histamine may also be implicated in the regulation of brain excitability.

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