Pharmacological effects of carcinine on histaminergic neurons in the brain

Carcinine (β-alanyl histamine) is an imidazole dipeptide. The present study was designed to characterize the pharmacological effects of carcinine on histaminergic activity in the brain and on certain neurobehavior. Carcinine was highly selective for the histamine H ₃ receptor over H ₁ or H ₂ receptor (K _i (μM) = 0.2939 ± 0.2188 vs 3621.2 ± 583.9 or 365.3 ± 232.8 μM, respectively). Carcinine at a dose of 20mgkg ^-1 slightly increased histidine decarboxylase (HDC) activity in the cortex (from 0.186 ± 0.069 to 0.227 ± 0.009 pmol mg protein ^-1min ^-1). In addition, carcinine (10, 20, and 50 mgkg ^-1) significantly decreased histamine levels in mice brain. Like thioperamide, a histamine H ₃ receptor antagonist, carcinine (20, 50 μM) significantly increased 5-HT release from mice cortex slices, but had no apparent effect on dopamine release. Carcinine (20 mgkg ^-1) significantly inhibited pentylenetetrazole-induced kindling. This inhibition was completedly reversed by (R)-α-methylhistamine, a representative H ₃ receptor agonist, and α-fluromethylhistidine. a selective HDC inhibitor. Carcinine (20 mgkg ^-1) ameliorated the learning deficit induced by scopolamine. This amelioration was reversed by (R)-α- methylhistamine as evaluated by the passive avoidance test in mice. Like thioperamide, carcinine dose-dependently increased mice locomotor activity in the open-field test. The results of this study provide first and direct evidence that carcinine, as a novel histamine H ₃ receptor antagonist, plays an important role in histaminergic neurons activation and might be useful in the treatment of certain diseases, such as epilepsy, and locomotor or cognitive deficit.