Animal models of alcoholism: neurobiology of high alcohol-drinking behavior in rodents.
This review discusses efforts to develop rodent models for the study of neurobiological mechanisms underlying chronic alcohol drinking, alcoholism, and abnormal alcohol-seeking behavior. Selective breeding has produced stable lines of rats that reliably exhibit high and (for comparison purposes) low voluntary alcohol consumption. In addition, animal models of chronic ethanol self-administration have been developed in rodents, who do not have a genetic predisposition for high alcohol-seeking behavior, to explore environmental influences in ethanol drinking and the effects of physical dependence on alcohol self-administration. The selectively bred high-preference animals reliably self-administer ethanol by free-choice drinking and operantly respond for oral ethanol in amounts that produce pharmacologically meaningful blood alcohol concentrations (50 to 200 mg% and higher). In addition, the alcohol-preferring rats will self-administer ethanol by intragastric infusion. With chronic free-choice drinking, the high alcohol-preferring rats develop tolerance to the high-dose effects of ethanol and show signs of physical dependence after the withdrawal of alcohol. Compared with nonpreferring animals, the alcohol-preferring rats are less sensitive to the sedative-hypnotic effects of ethanol and develop tolerance more quickly to high-dose ethanol. Nonselected common stock rats can be trained to chronically self-administer ethanol following its initial presentation in a palatable sucrose or saccharin solution, and the gradual replacement of the sucrose or saccharin with ethanol (the sucrose/saccharin-fade technique). Moreover, rats that are trained in this manner and then made dependent by ethanol-vapor inhalation or liquid diet increase their ethanol self-administration during the withdrawal period. Both the selectively bred rats and common-stock rats demonstrate "relapse" and an alcohol deprivation effect following 2 or more weeks of abstinence. Systemic administration of agents that (1) increase synaptic levels of serotonin (5-HT) or dopamine (DA); (2) activate 5-HT1A, 5-HT2, D2, D3, or GABA(A) receptors; or (3) block opioid and 5-HT3 receptors decrease ethanol intake in most animal models. Neurochemical, neuroanatomical, and neuropharmacological studies indicate innate differences exist between the high alcohol-consuming and low alcohol-consuming rodents in various CNS limbic structures. In addition, reduced mesolimbic DA and 5-HT function have been observed during alcohol withdrawal in common stock rats. Depending on the animal model under study, abnormalities in the mesolimbic dopamine pathway, and/or the serotonin, opioid, and GABA systems that regulate this pathway may underlie vulnerability to the abnormal alcohol-seeking behavior in the genetic animal models.
McBride
W J
WJ
Department of Psychiatry, Indiana University School of Medicine, Indianapolis 46202-4887, USA.
Li
T K
TK
D000293:Adolescent; D000294:Adolescent Behavior; D000427:Alcohol Deterrents / Q000627:therapeutic use; D000428:Alcohol Drinking / Q000235:genetics / Q000503:physiopathology*; D000437:Alcoholism / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D051381:Rats / Q000235:genetics; D011954:Receptors, Dopamine / Q000235:genetics; D018079:Receptors, GABA / Q000235:genetics; D011957:Receptors, Opioid / Q000235:genetics; D011985:Receptors, Serotonin / Q000235:genetics
D000427:Alcohol Deterrents; D011954:Receptors, Dopamine; D018079:Receptors, GABA; D011957:Receptors, Opioid; D011985:Receptors, Serotonin