Doses of GBR12909 that suppress cocaine self-administration in non-human primates substantially occupy dopamine transporters as measured by [11C] WIN35,428 PET scans

Abstract

GBR12909 (GBR) is a high-affinity, selective, and long-acting inhibitor of dopamine (DA) uptake that produces a persistent and noncompetitive blockade of DA transporters and substantially reduces cocaine-induced increases in extracellular DA in the nucleus accumbens of rats. Prior studies showed that intravenous infusion of GBR to Rhesus monkeys selectively reduced (1 mg/kg) and eliminated (3 mg/kg) cocaine self-administration. This study tested the hypothesis that doses of GBR that reduce cocaine self-administration in nonhuman primates produce significant occupation of DA transporters. DA transporters were quantitated in two baboons using [11C]WIN35,428 and positron emission tomography (PET). Each baboon underwent paired control/blocked PET scans (performed on three separate study days, 3-4 weeks apart). On the first scan the baboon received saline (3 ml/kg) 90 minutes before the injection of the radiotracer. GBR (1 mg/kg i.v.) was infused 90 minutes before the second [11C]WIN 35,428 study. The same experimental design was repeated with GBR doses of 3 and 10 mg/kg, respectively. Doses of 1 (n = 2), 3 mg/kg (n = 2), and 10 mg/kg (n = 2) reduced binding potential by 26, 53, and 72%, respectively. GBR was well tolerated in all baboons. These results demonstrate that doses of GBR that suppress cocaine self-administration in nonhuman primates also produce high occupancy of the DA transporter. These data strongly suggest that occupancy for the DA transporter by GBR explains its ability to attenuate cocaine-induced increases in extracellular DA and to suppress cocaine self-administration. Moreover, these data suggest that experimental human studies of orally administered GBR to test the DA hypothesis of cocaine addiction should use doses that produce at least 70% occupancy of the DA transporter.

Dopamine transport inhibitors based on GBR12909 and benztropine as potential medications to treat cocaine addiction

“…A PET study in baboons using [ 11 C]WIN35,428 has shown that a dose of GBR12909 that completely suppresses cocaine self-administration (10 mg/kg) occupies about 70% of the DAT sites in the brain (Fig. 5) [52]. Similar results have been reported using the phenyltropane derivative, RTI-113 [53,54].…”

Oxygenated Analogues of 1-[2-(Diphenylmethoxy)ethyl]- and 1-[2-[Bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazines (GBR 12935 and GBR 12909) as Potential Extended-Action Cocaine-Abuse Therapeutic Agents

“…This has been shown to occur in both the medial frontal cortex and nucleus accumbens, but not in the striatum of rats, which lacks noradrenergic innervation . The inability of cocaine to elevate extracellular DA in the striatum of DAT knockout mice is consistent with the lack of NE transporters in this brain region …”

Effects of Dopamine Transporter Inhibitors on Cocaine Self-Administration in Rhesus Monkeys: Relationship to Transporter Occupancy Determined by Positron Emission Tomography Neuroimaging

“…Similar levels of DAT occupancy have been reported for RTI-113 at doses that suppressed cocaine self-administration . Likewise, doses of GBR 12909 that decreased cocaine self-administration in rhesus monkeys (Glowa et al, 1995) resulted in DAT occupancies greater than 50% in baboons (Villemagne et al, 1999). Interestingly, DAT occupancy for the ED 50 dose of RTI-112 was below the threshold of detection in the present study.…”