The aims of this proposal are to evaluate RO-15,4513 as 1) an antagonist of the acute intoxicating effects of ethanol, 2) an antagonist of reinforcing effects of ethanol, and 3) to evaluate irs capacity to precipitate an abstinence syndrome in ethanol- dependent monkeys. RO-15,4513 has been shown to antagonize the sedation and ataxia produced by ethanol in rats (Bonetti et al., 1985; Polc et al., 1985), and more recently to produce a RO- 15,1788-reversible antagonism of the intoxication and punishment- attenuating effects of ethanol (Suzdak et al., submitted, 1986). The effects appear to be specific to ethanol in that RO-15,4513 does not antagonize similar effects of barbiturates. Pilot studies will undertake an evaluation of the effects of RO-15,4513 on the reinforcing and intoxicating effects of ethanol in rhesus monkeys. Monkeys with indwelling intravenous catheters will be able to respond on a lever and deliver i.v. ethanol (0.1 gm/kg/inj) during two 3-hour sessions each day. Rates of responding maintained by ethanol will be compared to those maintained by saline, until a clear differential develops between these rates. The effects of 2 mg/kg RO-15,4513 given intramuscularly prior to a session of ethanol availability will be evaluated; different doses of RO- 15,4513 and different doses of ethanol will be attempted as necessary and as time permits. The effects of RO-15,4513 on the reinforcing effects of methohexital, a short-acting barbiturate, and midazolam, a short-acting benzodiazepine, will also be evaluated for comparison. The intoxicating effects of ethanol will be evaluated by cumulative administration of intravenous ethanol, every 15 min until various states of effect are observed, e.g., ataxia, eyelid droop, coma. The effects of RO-15,4513 on ethanol's dose-related capacity to produce these effects will be evaluated. Dependence to ethanol will be produced by administration of high doses of ethanol i.v. every eight hours for one week. Observations will be made of RO- 15,4513-induced withdrawal signs in these dependent monkeys.
| Winger, G (1988) Effects of ethanol withdrawal on ethanol-reinforced responding in rhesus monkeys. Drug Alcohol Depend 22:235-40 |
