Self‐administration of cocaine and the cocaine analog RTI‐113: Relationship to dopamine transporter occupancy determined by PET neuroimaging in rhesus monkeys

Wilcox, Kristin M.; Lindsey, Kimberly P.; Votaw, John R.; Goodman, Mark M.; Martarello, Laurent; Carroll, F. Ivy; Howell, LL

doi:10.1002/syn.10018

Cited by 58 publications

(63 citation statements)

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“…In the present series of studies, the selective DAT inhibitors reliably maintained self-administration behavior in all subjects, consistent with results reported for phenyltropanes Wilcox et al, 2002;Lindsey et al, 2004; and phenylpiperazines (Bergman et al, 1989;Howell and Byrd, 1991;Lindsey et al, 2004) in nonhuman primates. However, the selective DAT inhibitors maintained lower rates of responding compared with cocaine across a broad range of doses, even though DAT occupancy was equal to or greater than that observed for cocaine Lindsey et al, 2004;.…”

Section: Discussionsupporting

confidence: 91%

“…Cocaine and selective DAT inhibitors exert similar effects on schedule-controlled behavior and are reliably self-administered in squirrel monkeys (Bergman et al, 1989;Howell & Byrd, 1991;Howell, Czoty, Kuhar, & Carroll, 2000;Kimmel, O'Connor, Carroll, & Howell, 2007) and rhesus monkeys (Nader, Grant, Davies, Mach, & Childers 1997;Lile et al, 2003;Lindsey et al, 2004;Wilcox et al, 2005Kimmel et al, 2008). Importantly, a variety of preclinical studies in nonhuman primates provide evidence that DAT inhibitors can effectively attenuate cocaine self-administration (Glowa et al, 1995;Nader et al, 1997;Howell et al, 2000;Wilcox et al, 2002;Lindsey et al, 2004;.The relevance of the DAT in the reinforcing effects of cocaine is supported further by human and nonhuman primate neuroimaging studies. In human cocaine users, a significant correlation was observed between the level of DAT occupancy and the magnitude of the subjective high reported following administration of cocaine (Volkow et al, 1997) or the behavioral stimulant methylphenidate (Volkow et al, 1999).…”

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confidence: 99%

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Nonhuman Primate Neuroimaging and Cocaine Medication Development

Howell¹

2008

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Given the important role of the dopamine transporter (DAT) in the addictive properties of cocaine, the development and use of compounds that target the DAT represents a reasonable approach for the pharmacological treatment of cocaine abuse. The present report describes a series of studies conducted in nonhuman primates that evaluated the effectiveness of DAT inhibitors in reducing cocaine self-administration. In addition, drug substitution studies evaluated the abuse liability of the DAT inhibitors. PET neuroimaging studies quantified DAT occupancy at behaviorally relevant doses, characterized the time-course of drug uptake in brain, and documented drug-induced changes in cerebral blood flow as a model of brain activation. Selective DAT inhibitors were effective in reducing cocaine use but high (>70%) levels of DAT occupancy were associated with significant reductions in cocaine self-administration. The selective DAT inhibitors were reliably self-administered but rates of responding were lower than those maintained by cocaine even at higher levels of DAT occupancy. A profile of slow rate of drug uptake in brain accompanied by a gradual increase in extracellular dopamine may account for the more limited reinforcing effectiveness of the DAT inhibitors. Selective serotonin transporter (SERT) inhibitors were also effective in reducing cocaine use and blocked cocaine-induced brain activation and increases in extracellular dopamine. Co-administration of SERT inhibitors with a selective DAT inhibitor was more effective than the DAT inhibitor administered alone, even at comparable levels of DAT occupancy. The results indicate that combined inhibition of DAT and SERT may be a viable approach to treat cocaine addiction. Keywords cocaine; dopamine transporter; serotonin transporter; PET imaging; nonhuman primates Despite extensive efforts directed toward the development of medications to treat cocaine abuse, no effective pharmacotherapy is currently in clinical use. Given the obvious importance of dopaminergic mechanisms in the addictive properties of cocaine, the development and use of compounds that target dopaminergic systems represents a reasonable approach for the pharmacological treatment of cocaine abuse. 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 & Negus, 1996;Carroll, Howell, & Kuhar, 1999;Howell & Wilcox, 2001; Corresponding author: Leonard L. Howell, Ph.D., Yerkes National Primate Research Center, Emory University, 954 Gatewood Road NE, Atlanta, GA 30329, lhowell@emory.edu, Phone: 404-727-7786, Fax: 404-727-1266. NIH P...

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Section: Discussionsupporting

confidence: 91%

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confidence: 99%

Nonhuman Primate Neuroimaging and Cocaine Medication Development

Howell¹

2008

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“…As previous studies have shown that 5-HT 2A receptor antagonism does not alter cocaine self-administration (Fantegrossi et al, 2002;Fletcher et al, 2002;Nic Dhonnchadha et al, 2009), this schedule was designed to elicit high and consistent rates of behavior, with the expectation that this would maximize our opportunity to observe any attenuation of cocaine selfadministration by M100907. Self-administration sessions were conducted in an operant test chamber with a controlled environment, as described previously (Wilcox et al, 2005). These sessions lasted 80 min and were typically conducted 5 d per week.…”

Section: Methodsmentioning

confidence: 99%

Serotonin 2A Receptors Differentially Contribute to Abuse-Related Effects of Cocaine and Cocaine-Induced Nigrostriatal and Mesolimbic Dopamine Overflow in Nonhuman Primates

Murnane¹,

Winschel²,

Schmidt³

et al. 2013

J. Neurosci.

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Two of the most commonly used procedures to study the abuse-related effects of drugs in laboratory animals are intravenous drug self-administration and reinstatement of extinguished behavior previously maintained by drug delivery. Intravenous selfadministration is widely accepted to model ongoing drug-taking behavior, whereas reinstatement procedures are accepted to model relapse to drug taking following abstinence. Previous studies indicate that 5-HT 2A receptor antagonists attenuate the reinstatement of cocaine-maintained behavior but not cocaine self-administration in rodents. Although the abuse-related effects of cocaine have been closely linked to brain dopamine systems, no previous study has determined whether this dissociation is related to differential regulation of dopamine neurotransmission. To elucidate the neuropharmacological and neuroanatomical mechanisms underlying this phenomenon, we evaluated the effects of the selective 5-HT 2A receptor antagonist M100907 on intravenous cocaine self-administration and drugand cue-primed reinstatement in rhesus macaques (Macaca mulatta). In separate subjects, we evaluated the role of 5-HT 2A receptors in cocaine-induced dopamine overflow in the nucleus accumbens (n ϭ 4) and the caudate nucleus (n ϭ 5) using in vivo microdialysis. Consistent with previous studies, M100907 (0.3 mg/kg, i.m.) significantly attenuated drug-and cue-induced reinstatement but had no significant effects on cocaine self-administration across a range of maintenance doses. Importantly, M100907 (0.3 mg/kg, i.m.) attenuated cocaine-induced (1.0 mg/kg, i.v.) dopamine overflow in the caudate nucleus but not in the nucleus accumbens. These data suggest that important abuse-related effects of cocaine are mediated by distinct striatal dopamine projection pathways.

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“…infusions of cocaine under a second-order schedule of reinforcement, as described previously (Wilcox et al, 2002). The training dose of cocaine was 0.1 mg/kg/infusion.…”

Section: Behavioral Methodsmentioning

confidence: 99%

“…Each subject was prepared with a chronic indwelling venous catheter under sterile surgical conditions using a technique described previously (Wilcox et al, 2002). Preoperative antibiotics (Rocephin, 25 mg/kg or Cefazolin, 25 mg/kg) were given on the day of surgery to help prevent infection.…”

Section: Surgerymentioning

confidence: 99%

Olanzapine-Induced Suppression of Cocaine Self-Administration in Rhesus Monkeys

Howell

Wilcox

Lindsey

et al. 2005

Neuropsychopharmacol

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The neuropharmacological profile of the atypical antipsychotic, olanzapine, is consistent with a potentially useful medication for cocaine abuse. The present study utilized an i.v. drug self-administration paradigm in nonhuman primates to obtain definitive evidence regarding the effectiveness of olanzapine to modulate the reinforcing effects of cocaine. The effects of olanzapine were compared directly to those of the neuroleptic, haloperidol. Rhesus monkeys (n ¼ 7) were trained to self-administer cocaine (0.03-0.3 mg/kg/injection) under a second-order, fixed-interval 600-s schedule with fixed ratio 20 components. Experimental sessions comprised five consecutive fixed intervals, each followed by a 1-min timeout. In drug-interaction experiments, a single dose of olanzapine (0.03-0.3 mg/kg) or haloperidol (0.01-0.03 mg/kg) was administered i.v. 15 min presession for at least three consecutive sessions. In drug-substitution experiments, different doses of olanzapine (0.01-0.1 mg/kg/injection) were substituted for cocaine until responding stabilized. Olanzapine caused doserelated decreases in cocaine self-administration at pretreatment doses that had no overt behavioral effects indicative of sedation. A dose of 0.1 mg/kg eliminated cocaine self-administration in all subjects. In contrast, doses of haloperidol that suppressed cocaine selfadministration induced marked sedation and catalepsy. Olanzapine failed to maintain self-administration behavior above saline extinction levels over a range of unit doses. In vivo microdialysis experiments in a second group of awake rhesus monkeys (n ¼ 3) confirmed previous reports in rodents that olanzapine effectively increases extracellular dopamine in ventral striatum. The dose of olanzapine that markedly suppressed cocaine self-administration behavior increased dopamine to approximately 190% of control values. Lastly, pretreatment with fluoxetine had no systematic effect on olanzapine-induced increases in striatal dopamine. The results indicate that olanzapine can effectively suppress cocaine self-administration behavior in nonhuman primates at doses that enhance dopamine release but do not maintain drug self-administration.

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Self‐administration of cocaine and the cocaine analog RTI‐113: Relationship to dopamine transporter occupancy determined by PET neuroimaging in rhesus monkeys

Cited by 58 publications

References 30 publications

Nonhuman Primate Neuroimaging and Cocaine Medication Development

Nonhuman Primate Neuroimaging and Cocaine Medication Development

Serotonin 2A Receptors Differentially Contribute to Abuse-Related Effects of Cocaine and Cocaine-Induced Nigrostriatal and Mesolimbic Dopamine Overflow in Nonhuman Primates

Olanzapine-Induced Suppression of Cocaine Self-Administration in Rhesus Monkeys

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