RESUMO
The histidine-containing dipeptide, carnosine (beta-alanyl-L-histidine), is present in high concentrations in mammalian brain of mammals. There are many theories about its biological functions, such as anti-inflammatory agent, free radical scavenger, and protein glycosylation inhibitor, however, the role of carnosine in morphine addiction is less understood. Therefore, the objectives of this study were to determine the effects of carnosine on the development of morphine-induced conditioned place preference (CPP) and investigate its possible mechanism of action in Sprague-Dawley rats. Intraperitioneal (i.p.) injection of carnosine (200, 500, 1000 mg/kg) significantly inhibited the development of morphine-induced CPP in a dose-dependent manner. Although carnosine had no appreciable effect on the levels of histamine in the ventral tegmental area (VTA), nucleus accumbens (NAc) and prefrontal cortex (PFC), it significantly decreased glutamate level in the VTA, dopamine levels in the NAc and PFC, and DOPAC level in the NAc of morphine-treated rats. These results indicate that carnosine inhibits morphine-induced CPP in rats, and its action may be due to modulation of dopaminergic and glutaminergic activity. The study suggests that carnosine has potential as a new anti-addictive drug.
Assuntos
Analgésicos Opioides/antagonistas & inibidores , Analgésicos Opioides/farmacologia , Carnosina/farmacologia , Condicionamento Operante/efeitos dos fármacos , Morfina/antagonistas & inibidores , Morfina/farmacologia , Animais , Química Encefálica/efeitos dos fármacos , Dopamina/metabolismo , Relação Dose-Resposta a Droga , Histamina/metabolismo , Masculino , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Ratos , Ratos Sprague-Dawley , Área Tegmentar Ventral/efeitos dos fármacos , Área Tegmentar Ventral/metabolismoRESUMO
Since the histidine-containing dipeptide carnosine (beta-alanyl-L-histidine) is believed to have many physiological functions in the brain, we investigated the neuroprotective effects of carnosine and its mechanisms of action in an in vitro model of neurotoxicity induced by N-methyl-d-aspartate (NMDA) in differentiated PC12 cells. Pretreatment with carnosine increased the viability and decreased the number of apoptotic and necrotic cells measured by MTT and Hoechst 33342 and propidium iodide (PI) double staining assays. Carnosine also can inhibit the glutamate release and increase HDC activity and the intracellular and extracellular contents of carnosine, histidine and histamine detected by high-performance liquid chromatography (HPLC). The protection by carnosine was reversed by alpha- fluoromethylhistidine, a selective and irreversible inhibitor of histidine decarboxylase (HDC). Pyrilamine and thioperamide, selective central histamine H(1) and H(3) antagonists also significantly reversed the protection of carnosine. Further, the inhibition of glutamate release by carnosine was reversed by thioperamide. Therefore, the protective mechanism of carnosine may not only involve the carnosine-histidine-histamine pathway, but also H(1)/H(3) receptors and the effective inhibition of glutamate release. This study indicates that carnosine may be an endogenous protective factor and calls for its further study as a new antiexcitotoxic agent.