Time course of the development of behavioral sensitization and dopamine receptor up-regulation during binge cocaine administration.

Cocaine is a widely abused psychomotor stimulant that potentiates dopaminergic neurotransmission by inhibiting the re-uptake of dopamine. This study investigated whether cocaine administered in a paradigm that mimics the human pattern of cocaine abuse produces behavioral sensitization and if there are concomitant changes in dopamine receptor levels. The time course of alterations in cocaine-induced locomotor activity and dopamine receptor densities was determined. Male Fischer rats were injected with saline or cocaine (15 mg/kg) three times daily at 1-hr intervals at the beginning of the light cycle to approximate the manner in which cocaine is often abused by humans both in terms of temporal pattern and in relation to circadian rhythm. Cocaine administered in this binge-like regimen produced an increase in locomotor activity during each hour postinjection. The increase in activity was significantly greater on the 13th day of drug administration than on the first day indicating sensitization to the locomotor-activating effects of cocaine. D1 and D2 dopamine receptors were measured after 2, 7 and 14 days of saline or cocaine injections using quantitative in vitro receptor autoradiography. Up-regulation of D1 receptors occurred in the olfactory tubercle, nucleus accumbens, ventral pallidum and substantia nigra after 14 days of cocaine treatment. Transient increases in D2 receptor number were found in the olfactory tubercle, rostral nucleus accumbens and rostral caudate putamen after 7 days of cocaine injections which returned to baseline levels after 14 days of cocaine treatment. The temporal pattern of receptor up-regulation suggests that D1 receptors are involved in the development of behavioral sensitization to cocaine.