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

Abstract

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...

Medication Development for the Treatment of Cocaine Addiction – Progress at Preclinical and Clinical Levels

“…This differs from GBR-12909, which selectively inhibits cocaine self-administration but not food-taking behavior. RTI-336, like many other DAT inhibitors, reliably maintained self-administration behavior in all non-human primates tested (Howell et al, 2007) and produced locomotor stimulating effects in mice and rats, suggesting abuse potential by itself. However, compared to cocaine, RTI-336 maintained lower rates of responding and lower progressive-ratio (PR) break-points in the self-administration paradigm.…”

“…The ED 50 dose of RTI-336 for reducing cocaine self-administration resulted in approximately 90% DAT occupancy, suggesting that high levels of DAT occupancy by RTI-336 are required to reduce cocaine self-administration. However, co-administration of the ED 50 dose of RTI-336 with the SERT inhibitors fluoxetine or citalopram produced more robust reductions in cocaine self-administration in non-human primates than RTI-336 alone (Howell et al, 2007), suggesting that blockade of both DAT and SERT may be more effective in attenuating cocaine's reinforcing effects than selective blockade of DAT alone (Rothman et al, 2007). In addition, at the doses that effectively suppressed cocaine self-administration, RTI-336 also inhibited food-taking behavior (Howell et al, 2007).…”

“…It has >1000-and >400-fold selectivity for DAT over serotonin transporter (SERT) and norepinepherine transporter (NET), respectively . Pretreatment with RTI-336 produced a dose-dependent reduction in cocaine self-administration in both rats and nonhuman primates (Haile et al, 2005;Howell et al, 2007). The ED 50 dose of RTI-336 for reducing cocaine self-administration resulted in approximately 90% DAT occupancy, suggesting that high levels of DAT occupancy by RTI-336 are required to reduce cocaine self-administration.…”

“…Based upon the above finding that a combination of DAT and SERT inhibitors appears to be more potent and effective than DAT inhibitor alone in attenuation of cocaine selfadministration (Howell et al, 2007), we studied slow-onset long-acting monamine transporter (MAT) inhibitors that have higher affinity for both DAT and SERT over to NET. In addition, our interest in non-selective MAT inhibitors as potential anti-cocaine medications originally stems from the fact that cocaine is also a non-selective MAT inhibitor.…”

Design and Synthesis of 2- and 3-Substituted-3-phenylpropyl Analogs of 1-[2-[Bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine and 1-[2-(Diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine: Role of Amino, Fluoro, Hydroxyl, Methoxyl, Methyl, Methylene, and Oxo Substituents on Affinity for the Dopamine and Serotonin Transporters

“…12,18 In behavioral intervention and knock-out mice experiments, the serotonergic system has been found to influence the reinforcing effects of cocaine. 14,[25][26][27] In contrast to the extensive structure-activity relationship (SAR) studies for DAT-selective ligands, fewer SAR studies have been focused on the discovery and development of ligands with a variety of transporter selectivity for both DAT and SERT. 14,[28][29][30][31] Novel ligands that differ in their transporter affinity and SERT:DAT ratio may help reveal the pharmacological mechanisms relevant to stimulant abuse, and also lead to an high efficacy medication for cocaine abuse, with few adverse reactions.…”