Morphine-induced Behavioral Sensitization in Alcohol-preferring and Alcohol-avoiding Rat Lines

Repeated use of drugs of abuse induces permanent changes in the brain that together with environmental factors can promote the development of addiction. Addiction to alcohol or drugs is a chronic disease that is characterized by a compulsion to seek and take the drug, loss of control in limiting intake, continued use despite obvious harm, and recurrent relapses. Behavioral animal models of addiction are invaluable tools for evaluating the neuroadaptations underlying these behaviors. Behavioral sensitization is a form of neuronal plasticity where repeated administration of drugs induces a progressive and enduring enhancement in their behavioral and neurochemical effects. The aim of this study was to investigate differences in susceptibility to morphine-induced behavioral and neurochemical sensitization in alcohol-preferring AA and alcohol-avoiding ANA rat lines, and to clarify its role on voluntary intake of ethanol. In vivo microdialysis was used to examine dopaminergic, glutamatergic and GABAergic neurotransmission in the brain. Interactions between behavioral sensitization and voluntary ethanol intake were assessed in AA rats during and after the rats were sensitized to morphine. The results showed that AA rats are more susceptible to morphine-induced behavioral sensitization than ANA rats. Neurochemical studies indicated a dissociation between the locomotor stimulant effects of morphine and extracellular levels of dopamine in the nucleus accumbens. In addition, sensitization to morphine affected glutamatergic transmission in the ventral tegmental area differently in AA and ANA rats. In contrast, extracellular levels of GABA differed neither between the lines nor between morphinesensitized rats and controls. Glutamatergic transmission is therefore potentially involved in the higher susceptibility to morphine-induced sensitization in AA rats relative to ANAs, but the role of GABA remains unclear. Morphine-induced behavioral sensitization or other long-term adaptations in the brain induced by repeated morphine administration were not critically involved in the regulation of voluntary ethanol drinking. Opioid receptor activation with morphine injection, however, was shown to dramatically increase ethanol drinking in morphine-sensitized AA rats. Thus, the neuronal mechanisms underlying behavioral sensitization to morphine probably are distinct from those mediating ethanol reinforcement. In contrast, when given an additional morphine injection, reinforcing effects of ethanol were enhanced in AA rats sensitized to morphine.