sm-346 and Substance-Withdrawal-Syndrome

Effect of trimetazidine (20 and 30 mg/kg) on elevated plus maze behavior of rodents was assessed in the genetic and pharmacological anxiety models. Single intraperitoneal injection of trimetazidine in a dose of 20 mg/kg prevented anxiety development in highly emotional male BALB/c mice and increased the time spent in open arms of the maze. In outbred male rats receiving 10% ethanol solution for 20 weeks, trimetazidine administered intraperitoneally in a dose of 20 mg/kg for 28 days abolished ethanol withdrawal-induced anxiogenesis developed against the background of 4-week alcohol deprivation: it increased the time spent in open arms, the number of entries into open arms, and total locomotor activity in the maze. Anxiolytic properties of trimetazidine were not inferior to those of the non-benzodiazepine anxiolytic Afobazole (fabomotizole) in acute and chronic administration.

Topics: Alcoholism; Animals; Animals, Outbred Strains; Anti-Anxiety Agents; Anxiety; Benzimidazoles; Drug Evaluation, Preclinical; Ethanol; Male; Mice, Inbred BALB C; Morpholines; Rats; Substance Withdrawal Syndrome; Trimetazidine

Long-term administration of benzodiazepines is known to be associated with drug dependence. The aim of the present work was to investigate the effects of non-benzodiazepine anxiolytic afobazole in the treatment of benzodiazepine withdrawal syndrome. Male outbred rats were treated with either diazepam (4.0 mg/kg, i.p.) or vehicle for 30 days and then abruptly withdrawn for 48 h. Animals were tested in the elevated plus maze test. In addition, neurochemical shifts were evaluated in the selected brain structures (striatum, hippocampus, hypothalamus, and frontal cortex) during diazepam withdrawal. Withdrawn animals made fewer entries and spent less time on the open arms than did vehicle-treated rats and demonstrated a decrease in the dopamine level in striatum as compared with vehicle and diazepam-treated ones. Afobazole (5.0 mg/kg, i.p.) effectively (i) ameliorated withdrawal-induced anxiety, returning behavioral pattern in the elevated plus maze test up to levels comparable to that in vehicle-treated animals, and (ii) increased withdrawal-reduced dopamine level (+23.8%, p < 0.05) in striatum. It is suggested that afobazole, due to its multitarget receptor action, can be useful in the diazepam withdrawal-induced anxiety blockade through modulation of dopaminergic system activity.

Topics: Animals; Anti-Anxiety Agents; Anxiety Disorders; Behavior, Animal; Benzimidazoles; Brain; Brain Chemistry; Diazepam; Male; Maze Learning; Morpholines; Rats; Substance Withdrawal Syndrome

Effect of afobazole upon morphine dependency has been studied in rats upon the administration of incremental doses of morphine (10-20 mg/kg, i.p.) for 5 days. The state of dependency was evaluated by monitoring sixteen specific behavioral indices of "spontaneous" (24 h after the last morphine injection) or naloxone-induced withdrawal syndrome. The effect of afobazole (a single dose of 5 mg/kg injected before the test or subchronically for 5 days) was estimated through its influence upon the total index of withdrawal syndrome, which was calculated using the set of behavioural signs. It is established that afobazole upon either single or subchronic injections significantly decreased the expression of spontaneous morphine withdrawal syndrome. The effect was also statistically significant but less pronounced in the case of naloxone-induced withdrawal syndrome. The obtained data suggest that afobazole can be considered as potential effective drug for the correction of various clinical symptoms of morphine withdrawal syndrome.

Topics: Animals; Animals, Outbred Strains; Anti-Anxiety Agents; Behavior, Animal; Benzimidazoles; Body Weight; Drug Administration Schedule; Drug Dosage Calculations; Male; Maze Learning; Morphine; Morpholines; Motor Activity; Naloxone; Narcotic Antagonists; Narcotics; Rats; Substance Withdrawal Syndrome