Lasting alterations of dopamine uptake sites in animal brain after repeated administration of cocaine.

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In animals, a long-term behavioral sensitization (LTBS) to cocaine or releasing amines (reverse tolerance phenomenon) has been confirmed after subchronic administration of these central stimulants. A challenge injection of these stimulants to sensitized animals induces a significantly greater increase in dopamine (DA) release in the striatum and nucleus accumbens, which relates to induction and manifestation of the LTBS and the brain vulnerability to psychotic relapse. Since cocaine acts at a dopamine transporter (DAT), DAT may play an essential role for the cocaine-induced LTBS.The cocaine analogue RTI 55 is one of the most potent ligand for DAT.To determine if subchronic administration of cocaine produces long-lasting alterations in DAT,we examined the regional accumulation of [^<125>I] RTI 55 in the cocaine sensitized rat brain by ex vivo autoradiography and in vitro binding of [^<125>I] RTI 55 to DAT in the striatum of cocaine sensitized rats. Male Sprague Dawley rats received a daily injection of cocaine (20 mg/kg, i.p.) for 21 days. Seven days after the last injection, rats in the steady state received i.p.injection of [^<125>I] RTI 55 for the autoradiographical analysis or were decapitated for the radio-labeled receptor assay. In the cocaine sensitized animals, the accumulation of radioactivity decreased significantly more in the brain regions including frontal cortex, striatum and nucleus accumbens. But [^<125>I] RTI 55 binding to the striatal DAT did not change in neither low or high affinity sites. These results suggest that it is difficult to explain the cocaineinduced LTBS by a change in striatal DAT.