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

Lindsey, Kimberly P.; Wilcox, Kristin M.; Votaw, John R.; Goodman, Mark M.; Plisson, Christophe; Carroll, F. Ivy; Rice, Kenner C.; Howell, Leonard L.

doi:10.1124/jpet.103.060293

Cited by 58 publications

(99 citation statements)

References 34 publications

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“…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.…”

Section: Introductionmentioning

confidence: 59%

“…In the present studies, the nonselective monoamine transporter inhibitor RTI-112 did not have behavioral-stimulant effects, although the doses used in this study clearly increased dopamine levels in the caudate to approximately 200% of baseline. Published studies show that high doses of RTI-112 are associated with high DAT occupancy in rhesus monkeys (Lindsey et al, 2004), so the lack of behavioral-stimulant effects cannot be attributed to a lack of an effect at DAT. That RTI-112 did not maintain self-administration behavior when substituted for cocaine in the present study also corresponds well with earlier studies in rhesus monkeys showing that RTI-112 did not function as a reinforcer, ostensibly due to its serotonergic effects (Lindsey et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

“…Published studies show that high doses of RTI-112 are associated with high DAT occupancy in rhesus monkeys (Lindsey et al, 2004), so the lack of behavioral-stimulant effects cannot be attributed to a lack of an effect at DAT. That RTI-112 did not maintain self-administration behavior when substituted for cocaine in the present study also corresponds well with earlier studies in rhesus monkeys showing that RTI-112 did not function as a reinforcer, ostensibly due to its serotonergic effects (Lindsey et al, 2004). Consistent with the latter interpretation, previous studies showed that increasing serotonergic activity reduced cocaine self-administration in rats (Richardson and Roberts, 1991) and in monkeys (Czoty et al, 2002;Kleven and Woolverton, 1993) as well as cocaine-induced increases in extracellular dopamine in nonhuman primates (Czoty et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

“…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 selfadministration 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.…”

Section: Introductionmentioning

confidence: 99%

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

Kimmel

O’Connor

Carroll

et al. 2007

Pharmacology Biochemistry and Behavior

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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 sloweronset 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.

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Section: Introductionmentioning

confidence: 59%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Kimmel

O’Connor

Carroll

et al. 2007

Pharmacology Biochemistry and Behavior

Self Cite

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show abstract

“…Similarly, a high correlation was found between the potency of cocaine analogs to displace cocaine in the caudate nucleus and the potency of these compounds to produce cocaine-like behavioral effects in squirrel monkeys Madras et al, 1989;Spealman et al, 1989). Cocaine and selective DAT inhibitors typically exert similar effects on schedule-controlled behavior and are reliably self-administered in squirrel monkeys Howell and Byrd, 1991;Howell et al, 2000) and rhesus monkeys Lindsey et al, 2004;Nader et al, 1997;Wilcox et al, 2005). The relevance of the DAT in the abuse liability of cocaine is supported further by neuroimaging studies.…”

Section: Introductionmentioning

confidence: 98%

Relationship between rate of drug uptake in brain and behavioral pharmacology of monoamine transporter inhibitors in rhesus monkeys

Kimmel¹,

Negus²,

Wilcox³

et al. 2008

Pharmacology Biochemistry and Behavior

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Although inhibition of dopamine transporters (DAT) and the subsequent increase in dopamine clearly play a role in the effects of psychomotor stimulants, the reinforcing effectiveness of DAT inhibitors varies. Previous studies suggest that pharmacokinetic and pharmacodynamic properties of these drugs account for this variability. The present studies compared the time-course and behavioral effects of five phenyltropane analogs of cocaine with high affinity for DAT and varying time courses of action in rhesus monkeys. The rate of drug uptake in putamen was measured using positron emission tomography neuroimaging. The rank order of the time to peak drug uptake was cocaine < RTI-336 < RTI-150 < RTI-113 < RTI-177. Cocaine and all five analogs fully substituted for the cocaine cue in animals trained to discriminate cocaine from saline. All of the drugs were selfadministered under a progressive-ratio schedule of drug self-administration and reinstated previously extinguished self-administration maintained under a second-order schedule. The time to peak drug uptake corresponded closely with the time to peak discriminative-stimulus effects, and there was a trend for the time of peak drug uptake to correspond negatively with the peak number of drug infusions. Collectively, these results indicate that the rate of drug entry in brain can play an important role in the behavioral pharmacology of psychomotor stimulants.

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Psychostimulants

Howell

Kimmel

2007

Handbook of Contemporary Neuropharmacology

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Psychstimulants are a broadly defined class of drugs that stimulate the central and peripheral nervous systems as their primary pharmacological effect. The abuse liability of psychostimulants is well established and represents a significant public health concern. An extensive literature documents the critical importance of monoamines (dopamine, serotonin, and norepinephrine) in the behavioral pharmacology and addictive properties of psychostimulants. In particular, dopamine plays a primary role in the reinforcing effects of psychostimulants in animals and humans. However, there is a growing body of evidence that highlights complex interactions among additional neurotransmitter, neuroendocrine, and neuropeptide systems. Cortical glutamatergic systems provide important regulation of dopamine function, and inhibitory amino acid ?‐aminobutyric acid (GABA) systems can modulate basal dopamine and glutamate release. Psychostimulants also activate the hypothalamic‐pituitary axis and thereby engage neuroendocrine systems linked to stress reactivity. Finally, endogenous neuropeptide systems, including opioids and neurotensin, appear to play an important role in the neuropharmacology of psychostimulants. Repeated exposure to psychostimulants can lead to robust and enduring changes in neurobiological substrates and corresponding changes in sensitivity to acute drug effects on neurochemistry and behavior. It is important to emphasize that some neurobiological changes are not evident when drug administration is terminated but actually emerge during the period of drug withdrawal. Significant advances in the understanding of neurobiological mechanisms underlying psychostimulant abuse and dependence have guided pharmacological treatment strategies to improve clinical outcome. In particular, functional agonist treatments may be used effectively to stabilize neurochemistry and behavior. In addition, medications that target glutamatergic and GABAergic function are reasonable candidates that have received significant attention. However, additional clinical studies are required in order to identify safe and efficacious pharmacotherapies.

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

Cited by 58 publications

References 34 publications

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

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

Relationship between rate of drug uptake in brain and behavioral pharmacology of monoamine transporter inhibitors in rhesus monkeys

Psychostimulants

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