From controlled drug intake to loss of control: the irreversible development of drug addiction in the rat.

The development of drug taking from controlled intake to drug addiction was studied by means of an animal model. Outbred rats had continuous free access to water and drinking fluids containing different concentrations of a drug for 7-9 months. After an abstinence period of 4-9 months, the drug was offered again (retest). Previous ethological classification of each rat and changes of housing conditions were used to study the modifiability of drug taking. With ethanol and the mu-agonistic opiate etonitazene, two stages followed each other. Controlled drug intake was adjusted to situational and individual variables. Social isolation of the rats raised the intake of ethanol and opiate. Dominant rats took less drugs than subordinate ones, but, in contrast to the latter, increased drug consumption after social disturbances. The adjustment of drug taking to social variables, was accompanied by changes in the dopaminergic and GABAA-ergic neurotransmission and by altered responses to acute drug administrations. Further, place preference, associated with reinforcing stimuli was modulated by subchronic sensitization/desensitization of dopaminergic transmission. Controlled drug intake lasted for 6-8 months, after which a spontaneous increase of drug consumption was found which latently continued during abstinence periods of 1 month. In the retest after abstinence, drug intake of these rats was strongly increased compared with both their previous consumption and that of drug-naive controls. Since drug taking could no longer be modulated by gustatory, environmental or individual factors (loss of control), it was considered as addictive. Addiction appeared to be specific to the kind of the drug. It persisted for the rest of the rat's life. After long periods of abstinence, ethanol-addicted rats revealed a completely altered pattern of response to self-administered alcohol compared with controlled drinkers. Their dopaminergic D1-transmission was irreversibly altered. Drug addiction only developed when the rat had free choice between water and drug-containing solutions. Long-term forced administration of ethanol or opiate, only led to physical dependence bot not to addiction. Some applications of the animal model are discussed, concerning the assessment of risk factors, the intake of drug combinations, residual neurochemical changes and concepts of treatment.