Alcohol-induced disinhibition in humans can be modeled in animals by evaluating the anti-stress or anti-anxiety (anxiolytic) effects of alcohol. The anti-anxiety and tension-reducing-like properties of alcohol have been demonstrated in various behavioral situations in animals. An early observation in 1946 illustrated the effects of alcohol on “neurotic”-like behavior induced in cats in a conflict situation. The cats were trained to run down an alley and open a box to obtain food when signaled by a bell-light conditioned stimulus. The “conflict” arose when a blast of air accompanied the food delivery at irregular intervals. The animals subsequently developed bizarre, neurotic-like behaviors, such as inhibition of feeding, startle reflexes, phobic responses, and aversive behavior in response to stimuli associated with the food/air blast conditioned stimuli. Alcohol significantly reduced this neurotic-like behavior. The cats showed a restoration of simpler responses and an attenuation of phobias, motor disturbances, and other abnormal behaviors. Nonetheless, alcohol also disrupted the timing, spatial orientation, sequence, and efficiency of normal goal-oriented responses. This early study elaborated many of the features of alcohol’s effect on conflict behavior, notably the ability of alcohol to block or reduce the suppression of behavior induced by punishment and decrease unpunished behavior, often at the same time or at the same doses.
Similarly to benzodiazepines and barbiturates, alcohol dose-dependently increases punished responding in the Geller–Seifter conflict test, in which the animals learn to press a lever for food or some other reward. After they are trained, each reward delivery is accompanied by an aversive stimulus, such as a mild footshock or puff of air (see Animal Models). Alcohol increases the number and/or intensity of aversive stimuli that the animal will endure. Alcohol exerts anxiolytic-like effects in several animal models of anxiety, including the lick suppression test, social interaction test, elevated plus maze, and behavioral contrast test (see Animal Models).
In animals, alcohol has similar reinforcing effects to that in humans. Early paradigms that assessed the reinforcing effects of alcohol typically used an oral preference paradigm, in which animals were allowed to drink alcohol or water. A later approach was the development of a training procedure that involved access to a sweetened solution and subsequent fading in of alcohol to temper alcohol’s naturally aversive taste. When the sweetness was finally faded out of the solution, the rats readily self-administered alcohol, resulting in blood alcohol levels of 0.04–0.08 g% (see Animal Models). In both procedures, rodents appear to readily learn to associate the ingestion of alcohol with psychotropic effects and to negate the aversive taste effects.
The use of animal models of the acute reinforcing effects of alcohol and selective receptor antagonists for specific neurochemical systems has shown that alcohol at intoxicating doses has wide but selective actions on neurotransmitter systems in the brain reward systems. Neuropharmacological studies have implicated multiple neurochemical systems in the acute reinforcing effects of alcohol, including GABA, opioid peptides, dopamine, serotonin, and glutamate (Figure 6.10). Systemic injections of GABAA receptor antagonists reversed the motor-impairing effects of alcohol, anxiolytic-like effects of alcohol, and alcohol drinking. The opioid antagonist naltrexone decreased alcohol self-administration in various animal models, suggesting a role for endogenous opioid peptide systems in the reinforcing effects of alcohol. Such studies led to the clinical use of naltrexone for reducing alcohol consumption and preventing relapse (Figure 6.11).
Figure 6.10 Sagittal section through a representative rodent brain that illustrates the pathways and receptor systems implicated in the acute reinforcing actions of alcohol. Alcohol activates γ-aminobutyric acid-A (GABAA) receptors in the ventral tegmental area, nucleus accumbens, and amygdala via either direct actions at the GABAA receptor or through the indirect release of GABA. Alcohol is hypothesized to facilitate the release of opioid peptides in the ventral tegmental area, nucleus accumbens, and central nucleus of the amygdala. Alcohol facilitates the release of dopamine (red) in the nucleus accumbens via an action either in the ventral tegmental area or nucleus accumbens. Endogenous cannabinoids and adenosine may interact with postsynaptic elements in the nucleus accumbens, involving dopamine and/or opioid peptide systems. The blue arrows represent the interactions within the extended amygdala system hypothesized to play a key role in alcohol reinforcement. AC, anterior commissure; AMG, amygdala; ARC, arcuate nucleus; BNST, bed nucleus of the stria terminalis; Cer, cerebellum; C-P, caudate-putamen; DMT, dorsomedial thalamus; FC, frontal cortex; Hippo, hippocampus; IF, inferior colliculus; LC, locus coeruleus; LH, lateral hypothalamus; N Acc., nucleus accumbens; OT, olfactory tract; PAG, periaqueductal gray; RPn, reticular pontine nucleus; SC, superior colliculus; SNr, substantia nigra pars reticulata; VP, ventral pallidum; VTA, ventral tegmental area. [Taken with permission from Koob GF, Le Moal M. Neurobiology of Addiction. Academic Press, London, 2006.]
The mesocorticolimbic dopamine system also participates in the reinforcing properties of alcohol. Systemic injections of dopamine receptor antagonists decrease responding for alcohol. Alcohol self-administration increases extracellular levels of dopamine in the nucleus accumbens in nondependent rats (Figure 6.12). Such increases not only occur during the actual self-administration session but also precede the self-administration session, possibly reflecting the incentive motivational properties of environmental cues associated with alcohol. Mesocorticolimbic dopamine, however, does not appear to be critical for the acute reinforcing effects of alcohol. Lesions of the mesocorticolimbic dopamine system in rats failed to block operant alcohol self-administration. The modulation of various other aspects of monoamine transmission can also decrease alcohol intake, including increases in the synaptic availability of serotonin with precursor loading, the blockade of serotonin reuptake, and the antagonism of serotonin 5-HT3 and 5-HT2 receptors (for further reading, see Koob, 2003).
Figure 6.11 Effects of saline (0.9% NaCl, 1.0 ml, i.m.) or naltrexone (1.0, 3.0, or 5.0 mg/kg, i.m.) on intravenous alcohol self-administration over a 4 h session in rhesus monkeys. Each bar represents the mean alcohol intake for all animals and all days of pretreatment with a given naltrexone dose or saline. All doses of naltrexone were associated with alcohol intake below saline levels (*p < 0.05, compared with saline; **p < 0.01, compared with saline). The differences between the effects of 1.0 and 3.0 mg/kg naltrexone were not significant, but the effects of 5.0 mg/kg differed significantly from the 1.0 and 3.0 mg/kg doses (+p < 0.05). These data show that naltrexone injected intramuscularly in rhesus monkeys dose-dependently decreased intravenous alcohol self-administration. Such early studies ultimately led to the use of naltrexone as a medication to treat alcoholism (see Medications for the Treatment). [Taken with permission from Altshuler HL, Phillips PE, Feinhandler DA. Alteration of ethanol self-administration by naltrexone. Life Sciences, 1980, (26), 679–688.]
The neuroanatomical substrates for the reinforcing actions of alcohol involve the same ventral striatal neurocircuitry and extended amygdala circuitry as elaborated for psychostimulants and opioids. Very low doses of the dopamine receptor antagonist fluphenazine injected directly into the nucleus accumbens block alcohol self-administration at low doses (Figure 6.13). A potent GABAA receptor antagonist, SR 95531, when microinjected into the nucleus accumbens, bed nucleus of the stria terminalis, and central nucleus of the amygdala, reduced alcohol intake, with the most sensitive site being the central nucleus of the amygdala (Figure 6.14). Injections of an opioid receptor antagonist into the nucleus accumbens, ventral tegmental area, and central nucleus of the amygdala also reduced alcohol consumption, suggesting a role for opioid peptides in both the ventral striatum and extended amygdala in the acute reinforcing actions of alcohol (Figure 6.15).