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 addictio n was studied by means of an animal model. Outbred rats had continous free access to water and drinking fluids containing different concentr ations of a drug for 7-9 months. After an abstinence period of 4-9 mon ths, the drug was offered again (retest). Previous ethological classif ication of each rat and changes of housing conditions were used to stu dy the modifiability of drug taking. With ethanol and the mu-agonistic opiate etonitazene, two stages followed each other. Controlled drug i ntake was adjusted to situational and individual variables. Social iso lation of the rats raised the intake of ethanol and opiate. Dominant r ats took less drugs than subordinate ones, but, in contrast to the lat ter, increased drug consumption after social disturbances. The adjustm ent of drug taking to social variables, was accompanied by changes in the dopaminergic and GABA(A)-ergic neurotransmission and by altered re sponses to acute drug administrations. Further, place preference, asso ciated with reinforcing stimuli was modulated by subchronic sensitizat ion/desensitization of dopaminergic transmission. Controlled drug inta ke lasted for 6-8 months, after which a spontaneous increase of drug c onsumption was found which latently continued during abstinence period s of 1 month. In the retest after abstinence, drug intake of these rat s 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 spe cific 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 D-1-transmissio n was irreversibly altered. Drug addiction only developed when the rat had free choice between water and drug-containing solutions. Long-ter m forced administration of ethanol or opiate, only led to physical dep endence but not to addiction. Some applications of the animal model ar e discussed, concerning the assessment of risk factors, the intake of drug combinations, residual neurochemical changes and concepts of trea tment.