Drugs that increase GABAA-mediated inhibition (e.g., benzodiazepines, barbiturates) are commonly prescribed for their anxiolytic, sedative, hypnotic, muscle relaxant, and anticonvulsant properties. Prolonged administration of ben-zodiazepines and barbiturates can result in tolerance and physical dependence. The spectrum of behavioral signs and symptoms that occur following withdrawal from barbiturates and benzodiazepines—including hyperexcitability, tremors, and seizures—is similar to that occurring following alcohol withdrawal (Busto et al., 1986; Hillbom et al., 2003). In addition, genetic characteristics that influence susceptibility to alcohol withdrawal also affect susceptibility to barbiturate and benzodiazepine withdrawal (Metten and Crabbe, 1994, 1999). Furthermore, there is cross-tolerance among benzodiazepines, ethanol, and barbiturates, and ben-
TABLE 4 Comparison of the Potencies of Anticonvulsant Substances for Protection Against Alcohol Withdrawal Seizures and in Conventional Seizure Models
Alcohol withdrawal Conventional seizure models
Substance AGS (rat) HIC (mice) AGS (mice) PTZ (mice) MES (mice)
Carbamazepine 150" NE' 11.2c >50c 7.8c
Chlormethiazole ~100á 36e 137.6
Dizocilpine (MK-801) 0.33* 0.1' 0.047" 1.17" 0.95'
Gabapentin ~50 (mice)" 91.1c 47.5c 78.2c
Valproic acid 300' 55-300-'220c 263"
ED50, median effective dose; HIC, handling-induced convulsions; PTZ, pentylenetetrazol seizure test; MES, maximal electroshock seizure test; NE, not effective. Conventional AGS testing is performed in strains of mice that are genetically susceptible to AGS, mainly DBA/2 but also Frings.
"Chu, 1979; 'Grant et al., 1992; "White et al., 2002; "Green et al., 1990; "Ogren, 1986; /Pilip et al., 1998; «Little et al., 1986; 'Crabbe, 1992; Chapman et al., 1984; JSwinyard and Castellion, 1996; 'Morrissett et al., 1990; 'Grant et al., 1982; "Chapman et al., 1989; "Rogawski et al., 1991; "Watson et al., 1997; ?Chu et al., 1981; «Gessner, 1974; 'Goldstein, 1979.
Relevance of Alcohol Withdrawal Seizures in Rodents to the Human Condition
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