Can experimental paradigms and animal models be used to discover clinically effective medications for alcoholism?

Abstract

Evaluating medications in animal laboratory paradigms can reveal whether the compound is effective in an established alcoholism model, at clinically relevant doses and exposure conditions, when administered orally (or transdermally) and without serious limiting side effects. Positive outcomes constitute a possible discovery for relevance to alcoholism and, under favorable marketing conditions, encourage further development. Medication testing using animal models of alcoholism might also guide clinical testing by discriminating clinically effective from clinically ineffective compounds. This ability rests on whether there are tests or, more reasonably, batteries of tests having this discriminative ability. The present paper examines this possibility. Effects of naltrexone and acamprosate in animal paradigms which model behavioral aspects of alcoholism are reviewed and compared with the effects of compounds which have limited effects in alcoholics. It is not clear at present whether any single paradigm or combination of paradigms differentiates clinically effective from clinically limited compounds. Steps are suggested to improve the use of preclinical laboratory tests to predict which compounds are likely to be effective medications for reducing drinking and sustaining abstinence in human alcoholics.

FunctionalCRHvariation increases stress-induced alcohol consumption in primates

“…Studies in both non-primate and primate species have shown that an up-regulated CRF system can produce anxiety-and/or depression-like phenotypes (15)(16)(17)(18), and rodent studies show that it leads to escalated alcohol drinking (19)(20)(21)(22)(23). Based on these findings, CRF1 antagonists have been proposed for the treatment of stress-related disorders, including alcohol dependence (24,25). Genetic variation that drives further recruitment of the CRF system in response to stress or alcohol exposure would be expected to increase sensitivity to the negative reinforcing effects of alcohol (relief drinking).…”

Targeting brain angiotensin and corticotrophin-releasing hormone systems interaction for the treatment of mood and alcohol use disorders

“…Interestingly, AT 1 receptor blockade could be helpful both in models of reward and relief craving because AT 1 receptors, besides the RAS-CRH system interaction proposed here, may also affect dopamine release [16]. Compiled from [21,23,35]. Targeting CRH and RAS in the dependence-induced drinking model.…”

“…Targeting CRH and RAS in the dependence-induced drinking model. Forced intermittent ethanol exposure can be used to induce excessive dependence-related ethanol consumption, which appears to have improved predictive validity for medication development than assessment of basal ethanol consumption [21]. In our model, dependence is induced by daily cycles of ethanol vapor intoxication and withdrawal.…”

“…However, voluntary consumption in laboratory rodents rarely leads to blood alcohol concentrations required for induction of dependence, and thus the predictive validity of consumption at this level for human alcoholism is unclear [21]. To model the neurochemical changes of alcoholism and to induce persistent behavioral changes in laboratory animals, we used repeated cycles of ethanol intoxication and withdrawal over prolonged periods of time, thereby paralleling the clinical course of alcoholism and achieving pharmacological validity for target identification and medication development [22].…”

The Alcohol Dependence Syndrome, 30 years Later—a Response to the Commentaries

“…There is a rich literature on validation of the ADS in animal models [8], and we hope that, in the future, methods will be developed to measure alcohol exposures and responses in humans as well as we now do in animals. While we believe that statistical methodology has advanced tremendously over the last two decades [1,9] we agree, in the main, that our problems are with measurement and not concept.…”