Behavioral sensitization and tolerance to cocaine and the occupation of dopamine receptors by dopamine

Data from the authors’ laboratory on the neural substrates of Pavlovian conditioning and behavioral sensitization to psychomotor stimulants are reviewed. The findings of a recent experiment on the role of occupation of dopamine receptors by dopamine and its association to behavioral sensitization are reported. Daily intermittent injections of cocaine produced behavioral sensitization to the locomotor response in rats, whereas continuous cocaine infusions produced behavioral tolerance. Behavioral sensitization to cocaine was blocked by coadministration of nimodipine, anL-type calcium channel blocker. The increases in locomotion produced by cocaine was associated with an increase in the occupation of striatal dopamine D₁ and D₂ receptors, measured as the density of receptors protected from denaturation byN-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ). This association was not observed when rats were given a challenge injection of cocaine 10 d after withdrawal from similar treatment regimens. Rats given a cocaine challenge after withdrawal from either intermittent or continuous cocaine treatment regimens exhibited increased occupations of striatal D₁ and D₂ receptors. This increase was similar in magnitude to that observed in rats without a history of cocaine treatments after a challenge injection of cocaine. This suggests tnat the differences in occupancy of striatal dopamine receptors by dopamine observed in the prewithdrawal condition are likely the result of differences in brain levels of cocaine achieved by the two treatment regimens. Occupancy of striatals dopamine D₁ and D₂ receptors does not appear to be related to the development of sensitization to the motor-stimulating effects of cocaine.