Faster onset and dopamine transporter selectivity predict stimulant and reinforcing effects of cocaine analogs in squirrel monkeys

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Abstract

Although the behavioral-stimulant and reinforcing effects of cocaine and related psychomotor stimulants have been attributed to their actions at the dopamine transporter (DAT), the reinforcing effectiveness of these compounds varies. The properties that confer these differences are important considerations when developing agonist pharmacotherapies for the treatment of stimulant abuse. The present studies focused on the time course of action and pharmacological specificity of six 3-phenyltropane analogs of cocaine (RTI-112, RTI-126, RTI-150, RTI-171, RTI-177, and RTI-336) by observing their behavioral-stimulant, neurochemical, and reinforcing effects in squirrel monkeys. The faster-onset analogs (RTI-126, RTI-150, and RTI-336), and one of the slower-onset DAT selective analogs (RTI-177 and RTI-171) produced behavioral-stimulant effects, while the slower-onset nonselective analog RTI-112 did not. The time to the peak behavioral-stimulant effect and the peak caudate dopamine levels was strongly correlated, but the area under the curve of the time course of behavioral-stimulant effect and dopamine levels was not correlated. These results suggest that the rate of onset plays a more important role than duration of action in the stimulant effect of these analogs. In addition, the slower-onset nonselective analog (RTI-112) clearly did not exhibit any reinforcing effects while the faster-onset nonselective (RTI-126) and all the DAT-selective analogs showed robust reinforcing effects (RTI-150, and RTI-177) or showed trends towards reinforcing effects (RTI-336 and RTI-171). Hence, there was a general trend for compounds that had a faster onset and/or DAT selectivity to produce significant behavioral-stimulant and reinforcing effects.

Introduction

Cocaine is a nonselective inhibitor of monoamine transporters, including dopamine, serotonin, and norepinephrine, and also binds to sodium channels (Kennedy and Hanbauer, 1983, Madras et al., 1989, Reith et al., 1986, Schoemaker et al., 1985). However, the behavioral effects of cocaine have been attributed primarily to its actions at the dopamine transporter (DAT) (Ritz et al., 1987). DAT inhibitors from distinct chemical structural classes produce behavioral-stimulant (Cline et al., 1992, Gatley et al., 1999, Kuhar, 1993) and reinforcing (Bergman et al., 1989, Ritz et al., 1987, Wilcox et al., 2000) effects that correlate with their potency and occupancy at DAT. However, in order to produce equivalent increases in locomotor activity in rodents, selective DAT inhibitors must exhibit greater occupancy of DAT than does the nonselective monoamine transporter inhibitor cocaine (Rothman et al., 1992, Vaugeois et al., 1993). Neuroimaging studies in humans have found a significant correlation between DAT occupancy and the subjective high following administration of cocaine (Volkow et al., 1997) or methylphenidate (Volkow et al., 1999). However, DAT inhibitors differ in their effectiveness as positive reinforcers. For example, the selective DAT inhibitor GBR12909 maintains self-administration in animals (Bergman et al., 1989, Howell and Byrd, 1991), but it seems to be a less robust reinforcer than cocaine in maintaining behavior under a progressive-ratio schedule (Stafford et al., 2001). In addition, several local anesthetics are effective DAT inhibitors, but are weaker reinforcers than cocaine in maintaining behavior under progressive-ratio or second-order schedules (Wilcox et al., 2005, Wilcox et al., 2000). These studies suggest that DAT inhibition alone does not fully account for the reinforcing properties of cocaine and that neurotransmitters other than dopamine may influence the reinforcing effects of cocaine and related stimulants. For example, increasing serotonin activity attenuates cocaine-induced increases in dopamine, cocaine-induced behavioral-stimulant effects, and cocaine self-administration in nonhuman primates (Czoty et al., 2002, Howell and Byrd, 1995, Lindsey et al., 2004). Determining the pharmacological properties that influence the reinforcing effectiveness of behavioral stimulants can provide insights for medications development for treating stimulant abuse.

The use of agonist pharmacotherapies in the treatment of substance abuse has been successful, as shown with methadone maintenance for heroin dependence and nicotine replacement for tobacco use. These agonists provide positive subjective effects and improve compliance (Gorelick, 1998). These results support efforts to develop similar pharmacotherapeutic strategies to treat cocaine dependence (Grabowski et al., 2004, Howell and Wilcox, 2001, Mello and Negus, 1996). Several preclinical studies with DAT inhibitors provide evidence that substitute agonists may be used to reduce cocaine use (Lindsey et al., 2004, Mello and Negus, 1996, Rothman and Glowa, 1995). However, a possible limitation to the use of selective DAT inhibitors as medications for cocaine abuse is their potential for abuse. Both the phenyltropane analog, RTI-113 (Howell et al., 2000), and the phenylpiperazine derivative, GBR12909 (Bergman et al., 1989, Howell and Byrd, 1991), reliably maintain i.v. self-administration in nonhuman primates. A viable approach to limit the reinforcing effectiveness of DAT inhibitors is to manipulate their time course of action. The rate of onset plays an important role in the reinforcing effectiveness of a variety of drugs in animals and in humans. In rodents, drugs that occupied DAT more rapidly produced more robust behavioral effects (Desai et al., 2005, Pogun et al., 1991, Stathis et al., 1995). The more rapidly cocaine (Volkow et al., 2000) or methylphenidate (Volkow et al., 2002) enter the brain, the greater the reported “high” in humans. Orally-administered methylphenidate did not elicit as great of a high as did intravenously administered methylphenidate or cocaine, presumably due to the slow rate of uptake of the orally-administered drug in brain (Volkow et al., 2002). Accordingly, a slow onset of action may reduce the abuse liability of the medications (Gorelick, 1998, Sellers et al., 1989). In addition, a long duration of action is necessary to provide reasonable dosing schedules (Carroll et al., 1999). However, duration of action has not been found to be a critical factor in the reinforcing effects of opioid drugs in rodents (Panlilio and Schindler, 2000) or nonhuman primates (Ko et al., 2002).

The purpose of the present study was to characterize the time course of the effects of six 3-phenyltropane analogs of cocaine on behavior and dopamine neurochemistry in squirrel monkeys. The cocaine analogs examined in the present study are more potent than cocaine at binding to the dopamine transporter (Carroll et al., 2006, Kuhar et al., 1999), and produce robust increases in locomotor activity when administered systemically to mice (Carroll et al., 2004, Kimmel et al., 2001). In these locomotor studies, the nonselective monoamine transporter inhibitor RTI-126 and the DAT-selective inhibitors RTI-150 and RTI-336 both had a faster rate of onset (30 min) and a short duration of action (4 h). In contrast, the nonselective monoamine transporter inhibitor RTI-112 had a slower rate of onset (30–60 min) and a longer duration of action (10 h). The DAT-selective inhibitors RTI-171 and RTI-177 also had slower rates of onset (30–120 min), but RTI-171 had a short duration of action (2.5 h) while RTI-177 had a very long duration of action (20 h). The behavioral-stimulant and neurochemical effects of the cocaine analogs were compared directly to their effectiveness to maintain i.v. drug self-administration. The hypothesis was that compounds with a faster rate of onset would exhibit increased behavioral-stimulant and reinforcing effects.

Section snippets

Subjects

Twenty-two adult male squirrel monkeys (Samiri sciureus) weighing 700–1200 g served as subjects. Animals lived in individual home cages and had daily access to food (Harlan Teklad monkey chow; Harlan Teklad, Madision, WI; fresh fruit and vegetables) and unlimited access to water. All monkeys had prior exposure to cocaine and other drugs with selective dopaminergic or serotonergic activity in various behavioral studies. Animal use procedures were in strict accordance with the National Institutes

Results

For each compound, a dose–response curve of the average response rate during the 13-component fixed-interval behavioral session was determined (Fig. 1). With the exception of RTI-112, all of the compounds produced an inverted U-shaped dose–response curve that is typical of psychomotor stimulants. Doses of RTI-112 greater than 0.03 mg/kg produced adverse effects in the animals, including stereotypic behaviors and seizures, so higher doses were not tested. One-way repeated measures ANOVAs

Discussion

The present study in nonhuman primates compared the behavioral-stimulant, in vivo neurochemical, and reinforcing effects of several phenyltropane analogs of cocaine with varying time course of action and selectivity of binding to monoamine transporters. The time to the peak of drug-induced increases in extracellular dopamine indicated that RTI-126, RTI-150, and RTI-336 each had a faster rate of onset while RTI-112, RTI-177, and RTI-171 each had slower rates of onset. In this study, the rate of

Acknowledgements

This research was supported by U.S. Public Health Service grants DA00517 (LLH), DA12514 (LLH), DA15092 (HLK), DA13326 (FIC), and RR00165 (Division of Research Resources, National Institutes of Health). The authors would like to thank Paula D. Martin, Aeneas C. Murnane, and Janet M. Ojeda for their expert technical assistance.

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