Effect of cocaine self-administration on dopamine D2 receptors in rhesus monkeys

Abstract

The present study used autoradiography to examine the effects of chronic self-administration of cocaine on the density of dopamine D2 receptors in nonhuman primates. Three rhesus monkeys intravenously self-administered an average of 1.35 mg/kg cocaine per day for 18-22 months until they were euthanized immediately after a self-administration session. Binding site density of the D2 ligand [3H]raclopride (2 nM) was assessed in these monkeys as well as three untreated controls, using quantitative in vitro receptor autoradiography. As compared to untreated controls, D2 binding site density was significantly lower in the animals that self-administered cocaine in all regions of the striatum rostral to the anterior commissure. These regions include the anterior and central regions of the caudate nucleus, putamen, olfactory tubercle, and both the shell and core of the nucleus accumbens. Within the substantia nigra and ventral tegmental area, by contrast, no differences were found in the density of D2 binding sites. These findings suggest a pervasive effect of cocaine on the regulation of D2 receptors in the striatum. The lack of change within the ventral midbrain, however, suggests a differential regulation of D2 receptors in the striatum and ventral midbrain. This study confirms and extends our knowledge of the neurobiological changes in the mesolimbic dopamine system that result from chronic exposure to cocaine.

Effects of Cocaine Self-administration on Striatal Dopamine Systems in Rhesus Monkeys Initial and Chronic Exposure

“…The decreases in D 2 receptor density described in the present study are similar to the reductions we previously reported (Moore et al 1998b;Nader et al 2002) in monkeys that had self-administered cocaine for over 18 months. Both sets of findings are also consistent with data from PET imaging studies demonstrating that long-term cocaine exposure can produce decreases in D 2 receptor binding potential in humans (Volkow et al 1990(Volkow et al , 1993.…”

The effects of cocaine: A shifting target over the course of addiction

“…Prolonged selfadministration results in an upregulation in these monkeys of dopamine transporter binding sites (Letchworth et al, 2001) and preprodynorphin mRNA (Fagergren et al, 2003), as well as downregulation of D 2 receptors (Moore et al, 1998;Nader et al, 2002). The pattern of these adaptations followed an identical progression from ventral to dorsal striatum, as well as an expansion to more rostral and caudal portions of the striatum with increasing durations of cocaine self-administration history.…”

Cocaine Dependence and D2 Receptor Availability in the Functional Subdivisions of the Striatum: Relationship with Cocaine-Seeking Behavior

“…Studies in nonhuman primates are less numerous, but more consistent. D 2 receptor density is unaffected by short-term administration of cocaine (Farfel et al, 1992;Nader et al, 2002), but is decreased following prolonged exposure (Moore et al, 1998;Nader et al, 2002). Thus, the hypothesis that the decrease in D 2 receptor availability observed in CCD subjects is a consequence of prolonged exposure to cocaine is supported by nonhuman primate data and cannot be ruled out.…”