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

Self Cite

The dopamine transporter (DAT) is a critical recognition site for cocaine and contributes to its significant abuse liability. Accordingly, the development of compounds that target the DAT represents a logical approach in the pharmacological treatment of cocaine abuse. The present study characterized the effects of DAT inhibitors as pretreatments in rhesus monkeys trained to self-administer cocaine under a second-order schedule of i.v. drug delivery. The drugs also were substituted for cocaine to characterize their effectiveness in maintaining drug selfadministration. Positron emission tomography neuroimaging with [ All drugs produced dose-related reductions in cocaine self-administration. Doses of GBR 12909 and RTI-177 that reduced responding by 50% (ED 50 ) resulted in DAT occupancies of 67 Ϯ 5 and 73 Ϯ 5%, respectively. In contrast, DAT occupancy was below the limit of detection for the ED 50 dose of RTI-112. Both GBR 12909 and RTI-177 reliably maintained drug selfadministration, and DAT occupancies at doses that maintained peak rates of responding were 57 Ϯ 1 and 92 Ϯ 7%, respectively. In contrast, RTI-112 failed to maintain robust drug selfadministration in any subject. The results indicate that selective DAT inhibitors may require high DAT occupancy to reduce cocaine self-administration and maintain drug self-administration. Moreover, the behavioral profile of DAT inhibitors may be influenced by actions at other monoamine transporters.Despite extensive efforts directed toward the development of medications to treat cocaine abuse, no effective pharmacotherapy is currently in clinical use. The therapeutic approach of substitute agonist or replacement medication has been successful in the context of methadone maintenance for heroin dependence and nicotine replacement for tobacco use. These positive outcomes, combined with recent advances in the understanding of the neuropharmacology of cocaine, support efforts to develop a similar type of medication for cocaine abuse. Of the various types of medications being pursued, dopamine transporter (DAT) inhibitors represent a promising approach in drug development (Mello and Negus, 1996;Carroll et al., 1999;Howell and Wilcox, 2001). The DAT is an important recognition site for cocaine and likely mediates its reinforcing effects that contribute to significant abuse liability (Ritz et al., 1987;Kuhar et al., 1991;Woolverton and

Section: Discussionmentioning

confidence: 96%

Section: -Yl)] Hcl (Rti-177); and A Nonselective Inhibitor Of Dopamimentioning

confidence: 99%

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

Lindsey¹,

Wilcox²,

Votaw³

et al. 2004

Self Cite

“…In rhesus monkeys, doses of cocaine that maintained peak responding in drug self-administration studies resulted in DAT occupancy greater than 65% Lindsey et al, 2004). Doses of GBR12909 that decreased cocaine self-administration in rhesus monkeys resulted in DAT occupancy greater than 50% in baboons (Villemagne et al, 1999) and rhesus monkeys (Lindsey et al, 2004). Likewise, doses of cocaine analogs with selectivity for DAT decreased cocaine self-administration in rhesus monkeys at DAT occupancies greater than 70% Lindsey et al, 2004).…”

mentioning

confidence: 99%

Effects of Combined Dopamine and Serotonin Transporter Inhibitors on Cocaine Self-Administration in Rhesus Monkeys

Howell¹,

Carroll²,

Votaw³

et al. 2006

Dopamine transporter (DAT) inhibitors may represent a promising class of drugs in the development of cocaine pharmacotherapies. In the present study, the effects of pretreatments with the selective DAT inhibitor 3␤-(4-chlorophenyl)tropane-2␤-[3-(4Ј-methylphenyl)isoxazol-5-yl] hydrochloride (RTI-336) (0.3-1.7 mg/kg) were characterized in rhesus monkeys trained to self-administer cocaine (0.1 and 0.3 mg/kg/injection) under a multiple second-order schedule of i.v. drug or food delivery. In addition, RTI-336 (0.01-1.0 mg/kg/injection) was substituted for cocaine to characterize its reinforcing effects. Last, the dose of RTI-336 that reduced cocaine-maintained behavior by 50% (ED 50 ) was coadministered with the selective serotonin transporter (SERT) inhibitors fluoxetine (3.0 mg/kg) and citalopram (3.0 mg/kg) to characterize their combined effects on cocaine self-administration. PET neuroimaging with the selective DAT ligand [18 F]8-(2-[ 18 F]fluoroethyl)-2␤-carbomethoxy-3␤-(4-chlorophenyl)nortropane quantified DAT occupancy at behaviorally relevant doses of RTI-336. Pretreatments of RTI-336 produced dose-related reductions in cocaine self-administration, and the ED 50 dose resulted in approximately 90% DAT occupancy. RTI-336 was reliably self-administered, but responding maintained by RTI-336 was lower than responding maintained by cocaine. Doses of RTI-336 that maintained peak rates of responding resulted in approximately 62% DAT occupancy. Coadministration of the ED 50 dose of RTI-336 in combination with either SERT inhibitor completely suppressed cocaine self-administration without affecting DAT occupancy. Hence, at comparable levels of DAT occupancy, coadministration of SERT inhibitors with RTI-336 produced more robust reductions in cocaine self-administration compared with RTI-336 alone. Collectively, the results indicate that combined inhibition of DAT and SERT warrants consideration as a viable approach in the development of cocaine medications.The neurochemical mechanisms that mediate the behavioral effects of cocaine are complex and probably involve multiple neurotransmitter systems. In vitro studies have demonstrated that cocaine blocks the uptake of the monoamines dopamine, serotonin, and norepinephrine (Heikkila and Manzino, 1984;Reith et al., 1986). However, the behavioral effects of cocaine have been linked more closely to inhibition of dopamine uptake (Ritz et al., 1987;Woolverton and Kleven, 1988). Evidence to support this conclusion is derived from a variety of behavioral studies characterizing the acute effects of dopamine transporter (DAT) inhibitors administered alone or in combination with cocaine. Preclinical studies have demonstrated a relationship between the potency of cocaine analogs at binding to the DAT in vitro and their potency in producing locomotor-stimulant effects in rodents (Cline et al., 1992;Kuhar, 1993). Likewise, a high correlation was found between the potency of cocaine analogs to displace [ 3 H]cocaine in the caudate and the potency of these compounds to produce coc...

“…In positron emission tomography (PET) imaging, ligands of interest are radiolabeled with unstable atomic isotopes (see Phelps and ABBREVIATIONS: PET, positron emission tomography; fMRI, functional magnetic resonance imaging; MDMA, 3,4-methylenedioxymethamphetamine; DAT, dopamine transporter; SERT, serotonin transporter; FCP, fluoroclebopride; FDG, fluorodeoxyglucose; FECNT, 8-(2-fluoroethyl)-2-carbomethoxy-3-(4-chlorophenyl) nortropane; CFT, 2␤-carbomethoxy-3␤-(4-fluorophenyl)tropane; ZIENT, 2␤-carbomethoxy-3␤-[4Ј-((Z)-2-iodoethenyl) phenyl]nortropane; DASB, 3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile; McN5652,2,3,5,6,phenyl]pyrrolo-[2,1-a]-isoquinolone); DTBZ, (ϩ)-␣-dihydrotetrabenazine; SCH23390, 7-chloro-3-methyl-1-phenyl-1,2,4,5-tetrahydro-3-benzazepin-8-ol; raclopride, (S) Dewey et al, 1992;Villemagne et al, 1999;Volkow et al, 1999;van Berkel et al, 2006;Seneca et al, 2006 ͓ 18 F͔Fallypride Dopamine D2 receptors Antagonist Occupancy; availability Mukherjee et al, 1997;Slifstein et al, 2004 ͓ 11 C͔MNPA Dopamine D2 receptors Agonist Occupancy; availability Seneca et al, 2006;Tokunaga et al, 2009 Mazziotta, 1985; Senda et al, 2002;Fowler et al, 2007). Detector arrays and computer algorithms map the source and concentration of the radiotracer.…”

Section: Introductionmentioning

confidence: 99%

Nonhuman Primate Positron Emission Tomography Neuroimaging in Drug Abuse Research

Howell¹,

Murnane²

2011

Positron emission tomography (PET) neuroimaging in nonhuman primates has led to significant advances in our current understanding of the neurobiology and treatment of stimulant addiction in humans. PET neuroimaging has defined the in vivo biodistribution and pharmacokinetics of abused drugs and related these findings to the time course of behavioral effects associated with their addictive properties. With novel radiotracers and enhanced resolution, PET neuroimaging techniques have also characterized in vivo drug interactions with specific protein targets in the brain, including neurotransmitter receptors and transporters. In vivo determinations of cerebral blood flow and metabolism have localized brain circuits implicated in the effects of abused drugs and drug-associated stimuli. Moreover, determinations of the predisposing factors to chronic drug use and long-term neurobiological consequences of chronic drug use, such as potential neurotoxicity, have led to novel insights regarding the pathology and treatment of drug addiction. However, similar approaches clearly need to be extended to drug classes other than stimulants. Although dopaminergic systems have been extensively studied, other neurotransmitter systems known to play a critical role in the pharmacological effects of abused drugs have been largely ignored in nonhuman primate PET neuroimaging. Finally, the study of brain activation with PET neuroimaging has been replaced in humans mostly by functional magnetic resonance imaging (fMRI). There has been some success in implementing pharmacological fMRI in awake nonhuman primates. Nevertheless, the unique versatility of PET imaging will continue to complement the systems-level strengths of fMRI, especially in the context of nonhuman primate drug abuse research.