su-6656 and Substance-Withdrawal-Syndrome

Src kinase is reported to regulate neuronal nicotinic acetylcholine receptor activity, which is among the principal receptor systems acted upon by nicotine. Src kinase is documented to mediate the pathogenesis of substance dependence. Therefore, the present study has been designed to investigate the effect of SU-6656, selective src kinase inhibitor, on the development of nicotine dependence in a mouse model of mecamylamine-induced nicotine withdrawal syndrome.. Our experimental protocol consisted of administration of nicotine (2.5 mg/kg, subcutaneously), 4 times daily for 7 days. In order to precipitate nicotine withdrawal, mice were given 1 injection of mecamylamine (3 mg/kg, intraperitoneally), 1 hr after the last nicotine injection on the test day (Day 8). Behavioral observations were made for a period of 30 min immediately after mecamylamine treatment. Withdrawal syndrome was quantitated in terms of a composite withdrawal severity score (WSS), and withdrawal syndrome-related anxiety was assessed by elevated plus maze test results.. SU-6656 markedly and dose dependently (p < .01) attenuated mecamylamine-induced experimental nicotine withdrawal syndrome in mice measured in terms of WSS and anxiety score.. Thus, it is suggested that src kinase is involved in the development of nicotine dependence-induced precipitation of its withdrawal syndrome and thus may serve as a viable pharmacological target to tackle the problem of nicotine addiction.

Topics: Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Indoles; Injections, Intraperitoneal; Injections, Subcutaneous; Male; Mecamylamine; Mice; Narcotic Antagonists; Nicotine; src-Family Kinases; Substance Withdrawal Syndrome; Sulfonamides; Tobacco Use Disorder

This study was designed to investigate the effect of 2,3-dihydro-N, N-dimethyl-2-oxo-3-[(4,5,6,7-tetrahydro-1H-indol-2-yl)methylene]-1H-indole-5-sulfonamide (SU-6656), a selective inhibitor of src family kinase, on the development of naloxone-induced opioid withdrawal syndrome in mice. Subacute morphine administration followed by a single injection of naloxone (8 mg/kg, intraperitoneally) was used to precipitate the opioid withdrawal syndrome in mice. Behavioral observations were made immediately after naloxone treatment. The withdrawal syndrome was quantitatively assessed in terms of withdrawal severity score and frequency of jumping, rearing, forepaw licking, and circling. Daily single administration of SU-6656 was continued during the morphine treatment procedure. Injection of naloxone precipitated severe withdrawal in morphine-dependent mice. However, once-daily administration of SU-6656 (1.5, 3, and 6 mg/kg, intraperitoneally) markedly and dose-dependently attenuated the naloxone-induced morphine withdrawal syndrome. Therefore, it seems that an src family-kinase-linked mechanism is involved in the development of physiological opioid dependence; thus, src family kinase may serve as a potential target to address the pathological condition of physiological dependence and abstinence associated with continuous opioid usage.

Topics: Animals; Dose-Response Relationship, Drug; Drug Delivery Systems; Female; Indoles; Male; Mice; Morphine Dependence; Naloxone; Narcotic Antagonists; Severity of Illness Index; src-Family Kinases; Substance Withdrawal Syndrome; Sulfonamides