Effect of cocaine self‐administration on striatal dopamine D1 receptors in rhesus monkeys

Abstract

An array of evidence indicates that long-term exposure to cocaine alters several components of the brain dopamine system. Because the release of dopamine in the nucleus accumbens (NAc) has been implicated in mediating the reinforcing effects of cocaine, changes in dopamine function can have profound effects on drug-seeking and drug-taking behavior. The present study examined the effects of the chronic self-administration of cocaine on the D1 family of dopamine receptors in the rhesus monkey. The brains of three rhesus monkeys that had intravenously self-administered an average of 1.35 mg/kg cocaine per day for 18-22 months were compared to the brains of three cocaine-naive controls. The in vitro quantitative autoradiographic technique was used to quantify binding densities of the D1 ligand [3H]SCH-23390 on cryostat-cut sections of fresh frozen tissue. In animals that self-administered cocaine, the density of D1 binding was significantly lower in the regions of the striatum at the level where the nucleus accumbens is most fully developed. The shell of the NAc showed the largest difference with significantly lower D1 binding also detected in adjacent regions of the caudate nucleus and the putamen. No differences were found in the rostral pole of the NAc or the dorsal striatum at that level. These findings suggest that chronic self-administration of cocaine can modulate the density of dopamine D1 receptors in specific portions of the primate striatum. Such changes might underlie some of the behavioral consequences, like drug dependence and craving, of long-term cocaine use.

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

“…However, the significant increases in D 1 receptor densities in some parts of the PCS following chronic cocaine exposure reported here are not consistent with our earlier report (Moore et al 1998a), in which decreases in D 1 receptor density were observed. In our previous study, however, monkeys self-administered cocaine for 18 months, compared with 3.3 months in the present study.…”

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

“…In summary, the present study confirms and extends previous findings which indicate that long-term cocaine use produces pervasive neurobiological changes in the nigrostriatal and mesolimbic dopamine systems. There is now evidence from the monkey that D 1 receptors are downregulated (Farfel et al, 1992;Moore et al, 1998), and that D 2 receptors in the monkey and human are downregulated as well Volkow et al, 1990Volkow et al, , 1993present study). Because parts of these systems, including dopamine D 2 receptors, have been strongly implicated in the reinforcing effects of cocaine, functional alterations induced by continued cocaine use could represent at least part of the neural substrate responsible for drug craving and the maintenance of compulsive drug use.…”

“…This widespread effect, evident at the anterior as well as more posterior analysis regions, is in contrast to more localized cocaine effects we have previously de-scribed on D 1 -like receptors and the dopamine transporter. In those previous studies, cocaine-induced effects on D 1 receptors were found to be restricted to the posterior analysis regions, corresponding to the rostrocaudal level where the NAc and OT are most fully developed (Moore et al, 1998), whereas effects on the dopamine transporter were also more prominent in these posterior regions, but were further restricted to the ventral striatum (Letchworth et al, unpublished observations).…”

Cocaine self‐administration is increased after frontal traumatic brain injury and associated with neuroinflammation

“…In the current study, we were able to assess the contributions of multiple dopamine-related proteins in the striatum, as well as a host of inflammatory signaling molecules within frontal regions, to explore potential mechanisms influencing drug-taking after TBI. Brain injury caused a reduction in D1 receptor density in the dorsal striatum, which is reminiscent of observations after chronic cocaine use, although in those cases the accumbens was typically affected as well (Moore et al, 1998;Ramôa et al, 2014). However, it should be noted that these measurements were taken after self-administration, and changes in D1 and DAT in the accumbens, as well as D2 receptor levels in the striatum, could be directly attributed to the effects of cocaine (Fig.…”