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facilitation of BSR is not always evident in rats that have received alcohol injections (Kornetsky et al. 1988; Schaefer and Michael 1987). Although the size of the alcohol dose and the location of the stimulation electrode are key experimental factors in BSR studies (Lewis and Phelps 1987), recent studies have pointed to two additional factors that may be instrumental in determining whether alcohol facilitates BSR performance.

The first factor is the route of alcohol administration. Unlike involuntary alcohol administration (i.e., by injection), voluntary consumption immediately before BSR testing clearly facilitates BSR in rats. With voluntary consumption, animals demonstrate an increase in the response rate for the stimulation (Bain and Kornetsky 1989) and a reduction in the current threshold (Moolten and Kornetsky 1990). These data suggest that voluntary drinking of alcohol is superior to involuntary administration for studying BSR in laboratory animals.

Studies using morphine have also demonstrated the significance of voluntary versus involuntary drug administration. In these studies, the neuronal and biochemical changes produced by morphine varied depending on whether the drug was self-administered by the animals or administered to the animals by the experimenters (Smith et al. 1982).

The second factor is the time interval between alcohol administration and testing. Lewis and June (1990) found that the threshold-lowering effects of alcohol occur shortly after alcohol administration. These investigators observed that alcohol enhanced BSR performance during the first 20 minutes after alcohol injection. This timeframe corresponds to the rising phase of the blood alcohol concentration (BAC) time curve, a rise that illustrates the stage during which the alcohol is absorbed into the circulating blood. When BAC was decreasing, no enhancement of BSR was found (Lewis and June 1990). These results suggest that the euphoric effects of alcohol occur soon after drinking. In addition, these findings suggest that the facilitation of BSR performance by alcohol in rats may be a model of drug-induced euphoria.

Human studies that concomitantly measure subjective mood and BAC have provided further evidence for the role of alcohol's rewarding properties in alcohol reinforcement. Self-reports of intense pleasure or euphoria after consuming alcohol correlate with the rising phase of the

BAC time curve (Lukas and Mendelson 1988; Lukas et al. 1986).

The Biphasic Action of
Alcohol: Effects on Motor
Activity

High doses of alcohol produce motor impair-
ment, sedation, and sleep. However, shortly
after low doses of alcohol are administered and
during the rising phase of the BAC time curve,
stimulatory effects that are similar to but weaker
than those produced by stimulant drugs (i.e.,
amphetamine) are observed. Because alcohol
can produce first stimulation and then depres-
sion, its actions are said to be biphasic (Po-
horecky 1977). These effects are quantified
experimentally by placing an animal in an en-
closed area and measuring spontaneous motor
activity (SMA) when the animal is under the in-
fluence of alcohol. Low doses of alcohol in-
crease SMA; high doses of alcohol reduce it
(Friedman et al. 1980; Frye and Breese 1981).
As with BSR, stimulation of locomotor behavior
occurs when BAC concentrations are increasing
(Lewis and June 1990). Study findings suggest
that alcohol and such stimulant drugs as am-
phetamine and cocaine induce locomotor stimu-
lation by a similar mechanism: enhancing the
neurotransmitter dopamine (Liedman and Strom-
bom 1982; Liljequist and Carlsson 1978) in the
ventral tegmental area (VTA) of the brain (Gessa
et al. 1985). The VTA is part of the brain rein-
forcement system, and dopamine is an important
neurotransmitter in this system (Wise 1980).

Human studies that concomitantly measure subjective mood and BAC have provided further evidence for the role of alcohol's rewarding properties in alcohol reinforcement.

Researchers have proposed that the increased SMA induced by alcohol is a manifestation of the drug's reinforcing effects (Waller et al. 1986; Wise and Bozarth 1987). This hypothesis is supported by the observation that alcohol-induced changes in BSR threshold (Lewis and June 1990) and response rate for electrical self-stimulation (Schaefer et al. 1988) are correlated with changes in SMA.

Genetic Studies of the
Stimulatory Effects of
Alcohol

Recent research suggests that the propensity for
a strong motor stimulatory response to low
doses of alcohol can be an inherited trait (Phil-
lips et al. 1991). This hypothesis arises from se-
lective breeding studies in which animals from a
genetically heterogeneous population with a cer-
tain desired characteristic are mated and their off-
spring are screened for that characteristic. The
offspring bearing the desired characteristic are
then bred. If the characteristic is a heritable trait,
lines of animals that "breed true" for the charac-
teristic are produced in successive generations.

Several rodent lines have been developed that show sensitivity or insensitivity to several of alcohol's actions (Phillips et al. 1989). Among these lines are the alcohol-preferring (P) and alcohol-nonpreferring (NP) rats, selected on the basis of the preference for alcohol (Li et al. 1981), and the FAST and SLOW mice, selected on the basis of their locomotor-stimulation responses to alcohol (Crabbe et al. 1987; Phillips et al. 1989, 1991) (see Chapter 3, Genetic and Other Risk Factors for Alcoholism). Differences in alcohol-induced activation have also been noted in strains and lines of mice that were selectively bred for other characteristics, such as sensitivity to the soporific or hypnotic response to high doses of alcohol (Dudek et al. 1991; Phillips and Dudek 1991; Randall et al. 1975). Such studies are valuable because they address questions of genetic mechanism (i.e., How many genes determine the characteristic?), physiological mechanism (e.g., Which neurotransmitters are involved?), and correlation among traits (e.g., Is alcohol less intoxicating at high doses for mice that show the strongest locomotor stimulation at low doses?). The answers to these questions will greatly enhance knowledge about the basis of alcohol reinforcement.

Models of Alcohol
Self-Administration

The most direct way to investigate the biological
mechanisms that promote alcohol reinforcement
is to study alcohol intake. Such studies in hu-
mans have important limitations. For example,
it is difficult to sequester human subject popula-
tions that are uniform in such germane variables

as genetic background, socioeconomic level, and previous alcohol- and drug-taking history. In addition, ethical constraints preclude administering alcohol to alcohol-naive or alcohol-dependent persons. Thus animal models have offered significant advantages for studying the effects of alcohol.

Primates have been used in studies examining patterns of alcohol intake and individual variation during the acquisition of alcohol self-administration behavior in previously alcohol-naive animals (see Carroll et al. 1990 for a review). The effects of social variables (Crowley et al. 1990; Higley et al. 1991), hormones (Komet et al. 1991), and coupling alcohol with other abused drugs (Meisch and Lemaire 1990) on alcohol selfadministration in nonhuman primates have also been investigated recently.

For a variety of reasons, however, rodents (rats and mice) have been used most frequently in studies of alcohol self-administration. The first reason is that large, genetically uniform subject populations can be obtained for study. Second, because several generations of rodents can be studied in a reasonably short time, these animals are well suited for genetic selective-breeding programs. Third, it is possible to control for various factors such as housing, diet, and previous drug experience when using rodents in studies. Finally, because humans and rodents evolved from common mammalian ancestors, the rodent brain contains few functional components or classes of neurochemicals that are not also found in the human brain.

There is some question whether rodents consume alcohol for the same reason humans do, that is, to achieve the drug's effects on the central nervous system. In addition to being a psychoactive drug, alcohol is a food and provides energy (calories) in much the same way sugar does (Wallgren and Barry 1970). Animals whose food intake is reduced and body weights are kept low show large increases in alcohol intake (Carroll and Meisch 1984; Westerfield and Lawrow 1953). However, it is not clear that increased alcohol intake in hungry rats is due solely to the animals' attempting to obtain calories from alcohol; this question arises because weight reduction increases the reinforcing value of most, if not all, abused drugs regardless of whether the drugs contain calories (Carroll and Meisch 1984).

Alcohol also has the foodlike property of flavor. Rats perceive solutions of alcohol and water as tasting bittersweet (Kiefer and Lawrence

1988). When drops of alcohol solution are placed in the mouths of previously alcohol-naive rats, a combination of ingestive facial responses (e.g., tongue protrusions) and expulsive responses (e.g., gaping and head shaking) are evoked, which can be quantified as a measure of how much they like or dislike the flavor (Kiefer and Dopp 1989). Rats with a history of alcohol self-administration exhibit more ingestive responses during taste tests than they did when they were alcohol naive (Bice and Kiefer 1990). This observation indicates that developing a preference for the flavor of alcohol results from experiencing the pharmacological effects of the drug.

To ensure that the self-administration of alcohol by experimental animals is motivated by the drug's pharmacological effects and not by its taste, nonoral routes of administration are sometimes employed. Experimental animals are surgically implanted with intravenous or intragastric catheters and must make a lever-pressing response to self-infuse the drug. These methods have been used more widely with monkeys (Deneau et al. 1969) than with rats (Smith and Davis 1974). However, intravenously administered alcohol appears to be a weaker reinforcer than intravenously administered cocaine or morphine (Winger et al. 1983).

Selective Breeding for
Alcohol Preference and
Nonpreference

Selective breeding of rats with a propensity for
high or low alcohol intake has produced lines of
rats that consistently self-administer very high or
very low amounts of alcohol. These include the
AA (ALKO Alcohol) and ANA (ALKO Nonalco-
hol) lines developed in Finland (Eriksson 1968),
as well as the SP (Sardinian alcohol-preferring)
and SNP (Sardinian alcohol-nonpreferring) lines
developed in Italy (Fadda et al. 1989, 1990). In
the United States, selective breeding has resulted
in the P and NP lines (Li et al. 1979) and, more
recently, the HAD (high-alcohol-drinking) and
LAD (low-alcohol-drinking) lines of rats (Li et al.
1988). Researchers continue to study the effect
of different experimental conditions on the abil-
ity of alcohol to function as a reinforcer for these
animals (Files et al. 1992; Lankford et al. 1991;
Murphy et al. 1989; see figure 2). These selec-
tively bred animals also are being used to ex-
amine other effects of alcohol, such as the
development of tolerance (Gatto et al. 1987;

Le and Kiianmaa 1988; Murphy et al. 1990; Sinclair et al. 1989) and alcohol-induced changes in brain wave arousal (Morzorati et al. 1988).

Recently, investigators have reported that P rats will self-administer alcohol directly into the VTA region of the brain (Gatto et al. 1990; McBride et al. 1991). This finding suggests that P rats consume alcohol for its effects in the brain. These studies also provide further evidence that the VTA is one region involved in the mediation of alcohol reinforcement.

In addition to providing experimental confirmation of the importance of genetic factors in determining the risk for alcohol abuse (see

Cloninger 1987 and Pickens et al. 1991 for reviews), such selection studies also afford an opportunity to determine whether there is a genetic basis for the association between high alcohol consumption and certain anatomical and biochemical traits (see chapter 3). Thus, the P and NP lines have been compared to determine whether there are any differences in neurophysiological or biochemical functioning that may be related to their propensities to consume or to avoid alcohol. Briefly, certain brain regions of P and NP rats show differences in content of dopamine (Murphy et al. 1987), serotonin (Murphy et al. 1987; Wong et al. 1990; Zhou et al.

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1990), y-aminobutyric acid (GABA) (Hwang et al. 1990), and endogenous opiate (Froehlich et al. 1987) neurotransmitter or neuropeptide systems. Similar differences have also been observed in HAD and LAD lines (Gongwer et al. 1989; Hwang et al. 1990). The following sections describe how these systems are involved in the reinforcing and anxiety-reducing effects of alcohol (see also chapter 4).

Neurochemical Mechanisms of Alcohol Reinforcement

Dopamine

The neurotransmitter dopamine is a key component in the addictive profile of cocaine, a highly abused drug (Kilty et al. 1991; Shimada et al. 1991). Specifically, assessment by microdialysis shows that cocaine produces an increase in extracellular fluid levels of dopamine in the nucleus accumbens, part of the brain reinforcement system (Carboni et al. 1989). Alcohol also stimulates the release of dopamine in the nucleus accumbens, but to a lesser degree than cocaine (Di Chiara and Imperato 1988); in addition, alcohol increases dopamine metabolism in other brain areas thought to be involved in the brain reinforcement system (Fadda et al. 1989). The systemic administration of dopamine agonists (drugs that mimic the action of dopamine) and antagonists (drugs that block the action of dopamine) alters alcohol self-administration by rats (McBride et al. 1990; Pfeffer and Samson 1985, 1988; Weiss et al. 1990). The direct administration of a dopamine antagonist into the nucleus accumbens increases alcohol intake (Levy et al. 1991); chemical destruction of dopamine neurons (i.e., nerve cells) in this area also increases alcohol drinking (Quarfordt et al. 1991). These data suggest that under these conditions the animals may be consuming more alcohol in an attempt to compensate for the lack of dopaminergic stimulation in the nucleus accumbens. Many of these studies indicate that alcohol may exert its reinforcing effects in the neuronal membranes at a site called the D2 receptor, a subtype of the dopamine receptor (McBride et al. 1990).

Serotonin

Serotonin (5-hydroxytryptamine, 5-HT) is another neurotransmitter that is associated with the reinforcing effects of alcohol. The administration of alcohol to rats increases levels of serotonergic metabolites, suggesting increased activity in several areas of the brain, including the nucleus accumbens, frontal cortex, and anterior striatum (Khatib et al. 1988; Murphy, McBride et al. 1988; Yoshimoto et al. 1991). Various brain regions of P rats contain lower concentrations of serotonin (Murphy et al. 1987). The systemic administration of drugs that increase serotonergic activity or act as serotonin agonists reduces alcohol intake (Haraguchi et al. 1990; McBride et al. 1990; Murphy, Waller et al. 1988; Svensson et al. 1989; see Gill and Amit 1989 and McBride et al. 1989 for reviews). Serotonin antagonists also reduce alcohol drinking (Fadda et al. 1991; Weiss et al. 1990), a finding that warrants further investigation because of the expected differences between agonist and antagonist drugs. Recent studies suggest that the 5-HT3 and 5-HT1A receptor subtypes may be involved in these responses (McBride et al. 1990).

The Endogenous Opiates

This class of neuropeptides, including the endorphins and enkephalins, acts on the same receptors that are activated by opiate drugs. These drugs, which include morphine and heroin, produce euphoric effects. After ingesting alcohol, humans experience a release of endogenous opioid peptides (Gianoulakis et al. 1990) that may produce euphoric effects. The euphoria in turn may motivate further consumption of alcohol. In rats, alcohol drinking increases after morphine administration (Reid and Hunter 1984; Wild et al. 1988) and after treatment with a drug that prolongs the action of the enkephalins (Froehlich et al. 1991). Opiate receptor antagonists appear to reduce the reinforcing effects of alcohol (Altshuler et al. 1980; Froehlich et al. 1990; Marfaing-Jallet and Le Magnen 1983; Reid and Hunter 1984; Samson and Doyle 1985; and Weiss et al. 1990). However, researchers have not yet determined which opiate receptor subtype (i.e., delta or kappa) is more important in the regulation of alcohol drinking (Froehlich et al. 1991; Sandi et al. 1988, 1990).

Physiological systems other than dopamine, 5-HT, and endogenous opiates also have been strongly implicated in the regulation of alcohol intake, including the noradrenergic system

(Amit et al. 1991; Daoust et al. 1990), the reninangiotensin system (Grupp et al. 1989, 1991), and the prostaglandin system (George 1989). It remains to be determined whether and how all these various systems may interact to affect alcohol's ability to function as a reinforcer.

The Discriminative Stimulus Effects of Alcohol

Animals can be trained to make a certain response after being administered alcohol and a different response in the absence of alcohol. However, when an alcohol-exposed animal is given a new drug and perceives that new drug to be like alcohol (i.e., it cannot discriminate the new drug from alcohol), then the animal responds in the manner it was taught for alcohol. By using this technique, it has been established that certain types of drugs such as barbiturates (Jarbe and McMillan 1983), benzodiazepines (De Vry and Slangen 1986), and inhalant anesthetics and solvents (Rees et al. 1987) have stimulus properties similar to those of alcohol, while other drugs such as cocaine and pentylenetetrazole do not (Emmett-Oglesby 1990). To determine the mechanisms by which the discriminative effects of alcohol are produced, drugs that affect specific receptor systems have been tested. Such studies suggest that the N-methyl-D-aspartate (NMDA) receptor (Grant et al. 1991) and serotonin receptors (Signs and Schechter 1988)— particularly the 5-HT3 receptor subtype (Grant and Barrett 1991)-are involved (see chapter 4). However, dopamine receptors do not seem to mediate the discriminative effects of alcohol (Signs and Schechter 1988), and the evidence for the involvement of the GABA-benzodiazepine receptor complex is mixed (Hiltunen and Jarbe 1988; Middaugh et al. 1991). The discrimination procedure has also been used to study the stimulus properties of the alcohol-withdrawal state (Gauvin et al. 1989) and to compare lines of rats selectively bred for various responses to alcohol (Krimmer 1991; Krimmer and Schechter 1991). Together with self-administration studies, these investigations are providing valuable information about different receptor subtypes that are important in the physiological basis of alcohol's reinforcing effects.

Alcohol's Effects on
Anxiety and Aggression

Although one possible motivation for the con-
sumption of alcohol is to achieve euphoric or re-
warding effects, other factors may contribute to
excessive alcohol drinking. For example, it has
been proposed that alcohol can act as an anx-
iolytic drug, that is, one that can relieve anxiety.
Thus, alcohol may be consumed by anxious per-
sons in an attempt to self-medicate this state
(Cappell and Herman 1972; Pohorecky 1981,
1990). Cloninger (1987) has proposed that one
subtype of alcoholism (type I alcoholism) may
relate to ingestion of alcohol to relieve anxiety,
while a second subtype (type II alcoholism) may
involve self-administration of alcohol to experi-
ence pleasurable or euphoric effects of the drug
(see chapter 3).

Animal models have been used to help identify the pharmacological mechanisms responsible for the anxiolytic properties of alcohol. Researchers have also sought to determine the environmental conditions under which this anxiolytic effect is likely to occur (Dalterio et al. 1988; Durcan and Lister 1988; Koob et al. 1986). Figure 3, the plus maze, illustrates one of the behavioral tests used for this purpose. Recent research aimed at determining the mechanism

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