Progression of changes in dopamine transporter binding site density as a result of cocaine self-administration in rhesus monkeys

The present study examined the time course of alterations in levels of dopa mine transporter (DAT) binding sites that accompany cocaine self-administra tion using quantitative in vitro receptor autoradiography with [H-3]WIN 35, 428. The density of dopamine transporter binding sites in the striatum of r hesus monkeys with 5 d, 3.3 months, or 1.5 years of cocaine self-administra tion experience was compared with DAT levels in cocaine-naive control monke ys. Animals in the long-term (1.5 years) exposure group self-administered c ocaine at 0.03 mg/kg per injection, whereas the initial (5 d) and chronic ( 3.3 months) treatment groups were each divided into lower dose (0.03 mg/kg per injection) and higher dose (0.3 mg/kg per injection) groups. Initial co caine exposure led to moderate decreases in [3H]WIN 35,428 binding sites, w ith significant changes in the dorsolateral caudate (-25%) and central puta men (-19%) at the lower dose. Longer exposure, in contrast, resulted in ele vated levels of striatal binding sites. The increases were most pronounced in the ventral striatum at the level of the nucleus accumbens shell. At the lower dose of the chronic phase, for example, significant increases of 21- 42% were measured at the caudal level of the ventral caudate, ventral putam en, olfactory tubercle, and accumbens core and shell. Systematic variation of cocaine dose and drug exposure time demonstrated the importance of these factors in determining the intensity of increased DAT levels. With self-ad ministration of higher doses especially, increases were more intense and in cluded dorsal portions of the striatum so that every region at the caudal l evel exhibited a significant increase in DAT binding sites (20-54%). The si milarity of these findings to previous studies in human cocaine addicts str ongly suggest that the increased density of dopamine transporters observed in studies of human drug abusers are the result of the neurobiological effe cts of cocaine, ruling out confounds such as polydrug abuse, preexisting di fferences in DAT levels, or comorbid psychiatric conditions.