for alcohol's anxiolytic actions has focused on the involvement of the GABA-benzodiazepine receptor complex (see chapter 4). Interest in this receptor complex is partially the result of the discovery that the experimental drug RO 15-4513 can counteract some of alcohol's intoxicating effects (Lister 1987; Suzdak et al. 1988) by its actions at the GABA-benzodiazepine receptor complex. RO 15-4513 reduces the effectiveness of alcohol as an anxiolytic (Koob et al. 1986; Lister 1988). Thus, alcohol may act on the same system as the benzodiazepines, which are commonly prescribed anxiolytic drugs (e.g., Librium). RO 15-4513 and the chemically similar drugs FG 7142 and RO 19-4603 can reduce alcohol intake (Balakleevsky et al. 1990; June et al. 1991; Samson et al. 1989), but other effects of these drugs make them unsuitable as pharmacological agents for treating alcohol abuse and alcoholism.

The aversive properties of alcohol are relevant to alcohol abuse for two reasons: First, they may place an upper limit on the amount of alcohol that can be consumed, and second, tolerance to the aversive effects of alcohol may account for increases in alcohol intake over time.

The 5-HT system has also been implicated in the control of anxiety (Chopin and Briley 1987). Some of the same serotonin-related drugs that reduce alcohol self-administration (e.g., buspirone) also reduce anxiety (Dunn et al. 1989) or alter the anxiolytic effects of alcohol (Durcan et al. 1988). The selectively bred P and NP rats, which differ in GABA and serotonergic functioning (McBride et al. 1990), also differ in sensitivity to the anxiolytic effects of alcohol; NP rats show reduced anxiety at lower doses of alcohol than the P rats (Baldwin et al. 1991).

The effects of alcohol on anxiety in rats have also been studied by using stressors that are more likely to occur in a rat's natural environment, for example, the presence of a predator (Blanchard et al. 1990). Reductions in anxiety may be correlated with increased aggressiveness. Pretreatment with low doses of alcohol was found to increase the attack behavior of male and female rats toward male intruders (Blanchard, Flannelly et al. 1987; Blanchard,

Hori, and Blanchard 1987). Psychomotor stimulants such as amphetamine also increase attack behavior. In contrast, high doses of alcohol reduce aggression (Miczek et al. 1989). Taken together, these findings suggest that the low-dose stimulatory effects of alcohol (discussed previously with reference to the biphasic actions of alcohol) may, in some situations, be associated with increased aggression. It is interesting that, in a naturalistic social colony group, subordinate male rats voluntarily drink more alcohol solution than dominant males, thus suggesting that the social stress of subordination may be a factor in alcohol consumption (Blanchard, Hori et al. 1987).

Aversive Effects of Alcohol

At least some of the postingestional effects of alcohol are aversive or dysphoric, especially when high doses are administered. The aversive properties of alcohol are relevant to alcohol abuse for two reasons: First, they may place an upper limit on the amount of alcohol that can be consumed, and second, tolerance to the aversive effects of alcohol may account for increases in alcohol intake over time (Cappell and LeBlanc 1981). These ideas are supported by the observation that when alcohol-naive animals are tested, selectively bred P rats are less sensitive to the aversive effects of alcohol than NP rats (Froehlich et al. 1988). Furthermore, the aversive effects of alcohol are attenuated in P rats with a history of oral alcohol self-administration, thereby suggesting that tolerance had developed to the aversive effects of alcohol during chronic drinking (Stewart et al. 1991). This tolerance, as well as an innate reduced sensitivity to the aversive effects of alcohol, could contribute to the high alcohol intake shown by P rats.

The aversive effects of alcohol have been most often studied in rats by using the conditioned taste aversion procedure (figure 4). In this procedure, the consumption of a drug-free fluid with a novel taste is associated with a drug treatment and aversion to the drug's effects are inferred from the animal's subsequent avoidance of that flavor. A related procedure involves associating the effects of a drug with environmental cues rather than with a flavor (e.g., Cunningham 1979). Several physiological features may be involved in the aversive effects of alcohol. For example, alcohol interferes with body temperature regulation (Cunningham et al. 1988); in addition, alterations in the GABA-benzodiazepine receptor complex may be involved in mediating alcohol's

consistent with the idea that alcohol abusers may also abuse other sedative drugs. A second kind of interaction occurs when two or more drugs are taken together. For example, the combination of alcohol and pentobarbital appears to be synergistic, that is, the combination is more reinforcing than either drug alone (Meisch and Lemaire 1990); a similar effect is observed for the combination of alcohol and morphine (Marglin et al. 1988). Cocaine and alcohol are frequently used together by humans. The administration of these drugs together results in an interactive facilitation of BSR in rats (Lewis 1985) that may be mediated by ethylcocaine (cocaethylene), an active metabolite of cocaine and alcohol (Dean et al. 1991; Jatlow et al. 1991; see Chapter 7, Biochemical Effects of Alcohol Metabolism). This byproduct of the joint use of alcohol and cocaine may function as a reinforcer, thus increasing the motivation to use both drugs again. Because many abused drugs share common mechanisms of action, the future discovery of other similar interactions seems likely.

Summary

Substantial progress is being made in elucidating many of the neural systems responsible for alcohol reinforcement. These advances in turn are beginning to lead to the development of pharmacological agents that offer the potential to reduce alcohol drinking in animal models. As a direct result of this research, medications aimed at reducing excessive alcohol drinking are beginning to be tested in humans. Ample evidence suggests that alcohol reinforcement is a physiological or biological process. The work with selectively bred animal lines also suggests that the degree of alcohol reinforcement is heritable.

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