Methylphenidate and cocaine self‐administration produce distinct dopamine terminal alterations

Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston Salem, NC, USA Department of Pharmacology, University of Toronto, Toronto, Canada.
Addiction Biology (Impact Factor: 5.36). 03/2012; 19(2). DOI: 10.1111/j.1369-1600.2012.00456.x
Source: PubMed


Methylphenidate (MPH) is a commonly abused psychostimulant prescribed for the treatment of attention deficit hyperactivity disorder. MPH has a mechanism of action similar to cocaine (COC) and is commonly characterized as a dopamine transporter (DAT) blocker. While there has been extensive work aimed at understanding dopamine (DA) nerve terminal changes following COC self-administration, very little is known about the effects of MPH self-administration on the DA system. We used fast scan cyclic voltammetry in nucleus accumbens core slices from animals with a 5-day self-administration history of 40 injections/day of either MPH (0.56 mg/kg) or COC (1.5 mg/kg) to explore alterations in baseline DA release and uptake kinetics as well as alterations in the interaction of each compound with the DAT. Although MPH and COC have similar behavioral effects, the consequences of self-administration on DA system parameters were found to be divergent. We show that COC self-administration reduced DAT levels and maximal rates of DA uptake, as well as reducing electrically stimulated release, suggesting decreased DA terminal function. In contrast, MPH self-administration increased DAT levels, DA uptake rates and DA release, suggesting enhanced terminal function, which was supported by findings of increased metabolite/DA tissue content ratios. Tyrosine hydroxylase messenger RNA, protein and phosphorylation levels were also assessed in both groups. Additionally, COC self-administration reduced COC-induced DAT inhibition, while MPH self-administration increased MPH-induced DAT inhibition, suggesting opposite pharmacodynamic effects of these two drugs. These findings suggest that the factors governing DA system adaptations are more complicated than simple DA uptake blockade.

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Available from: Erin S Calipari, Nov 23, 2014
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    • "porter and elevate dopamine levels ( Ritz and Kuhar , 1989 ; Roberts et al . , 1977 ) . Further , changes in the NAc core have been shown to be directly associated with changes in reinforcement - related behaviors , where increased accumbal dopamine responses to cues or drugs result in increased in reinforcing efficacy / drug - seeking behaviors ( Calipari et al . , 2014a ; Saunders et al . , 2013 ; Graf et al . , 2013 ; Holmes and Fam , 2013 ) . This suggests that intermittent administration of MPH may lead to an increase in reward and reinforcement - related behaviors for amphetamines and other releasers , which could increase the abuse liability / addiction potential of these compounds . Although in t"
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    ABSTRACT: Long-access methylphenidate (MPH) self-administration has been shown to produce enhanced amphetamine potency at the dopamine transporter and concomitant changes in reinforcing efficacy, suggesting that MPH abuse may change the dopamine system in a way that promotes future drug abuse. While long-access self-administration paradigms have translational validity for cocaine, it may not be as relevant a model of MPH abuse, as it has been suggested that people often take MPH intermittently. Although previous work outlined the neurochemical and behavioral consequences of long-access MPH self-administration, it was not clear whether intermittent access (6 h session; 5min access/30min) would result in similar changes. For cocaine, long-access self-administration resulted in tolerance to cocaine's effects on dopamine and behavior while intermittent-access resulted in sensitization. Here we assessed the neurochemical consequences of intermittent-access MPH self-administration on dopamine terminal function. We found increased maximal rates of uptake, increased stimulated release, and subsensitive D2-like autoreceptors. Consistent with previous work using extended-access MPH paradigms, the potencies of amphetamine and MPH, but not cocaine, were increased, demonstrating that unlike cocaine, MPH effects were not altered by the pattern of intake. Although the potency results suggest that MPH may share properties with releasers, dopamine release was increased following acute application of MPH, similar to cocaine, and in contrast to the release decreasing effects of amphetamine. Taken together, these data demonstrate that MPH exhibits properties of both blockers and releasers, and that the compensatory changes produced by MPH self-administration may increase the abuse liability of amphetamines, independent of the pattern of administration.
    Full-text · Article · Mar 2014 · Neuropharmacology
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    • "Therefore, we determined how the potencies of methylphenidate (MPH; a dopamine uptake inhibitor) and amphetamine (a dopamine releaser) were affected by IntA, short-access (ShA), and LgA cocaine self-administration. Previously published work from our laboratory has shown that, although MPH is a DAT blocker, it is affected by changes at the DAT that alter releaser potency, possibly due to the amphetamine-like structure of the compound (Calipari et al., 2012, 2013b, 2014b; "
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    ABSTRACT: Previous literature investigating neurobiological adaptations following cocaine self-administration has shown that the development of pharmacodynamic tolerance, characterized by reduced cocaine potency at the dopamine transporter (DAT), results from high, continuous levels of intake (long-access; LgA), while sensitization of cocaine potency is caused by intermittent patterns of cocaine administration (intermittent-access; IntA). Here we aimed to determine if the changes observed following cocaine self-administration were specific to cocaine, or translated to other psychostimulants as well. Potency was assessed by fast scan cyclic voltammetry in brain slices containing the nucleus accumbens following control, IntA, short-access (ShA), and LgA. We assessed the potency of amphetamine, a releaser, and methylphenidate (MPH), a DAT blocker that is functionally similar to cocaine and structurally related to amphetamine. Changes in MPH potency can give information as to the importance of functional or structural aspects of compounds as related to the expression of tolerance/sensitization effects. MPH and amphetamine potencies were increased following IntA, while neither was changed following LgA. Here we demonstrate that while LgA-induced tolerance at the DAT is specific to cocaine, the sensitizing effects of IntA are conferred to cocaine, MPH, and amphetamine. The unchanged potency of MPH following LgA suggests that the expression of tolerance does not rely on the function of the compound as blocker/releaser. This demonstrates that the pattern with which cocaine is administered is important in determining the neurochemical consequences of not only cocaine effects, but cross-sensitization/cross-tolerance effects of other psychostimulants as well.
    Full-text · Article · Feb 2014 · Journal of Pharmacology and Experimental Therapeutics
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    • "This also suggests that differences in baseline DA functioning are not driving the cocaine tolerance , but rather they are completely dissociable. Only recently was it discovered that the effects of cocaine on the DAT were reduced following extended access cocaine self-administration (Ferris et al. 2011, 2012, 2013; Calipari et al. 2013a, b). Here, we replicate the reduced sensitivity of the DAT to cocaine, and demonstrate that this neurochemical tolerance at the DAT is also observed with DA overflow as measured by microdialysis, where cocaine's ability to increase DA levels following cocaine self-administration was reduced as compared to controls. "
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    ABSTRACT: Tolerance to the neurochemical and psychoactive effects of cocaine after repeated use is a hallmark of cocaine addiction in humans. However, comprehensive studies on tolerance to the behavioral, psychoactive, and neurochemical effects of cocaine following contingent administration in rodents are lacking. We outlined the consequences of extended access cocaine self-administration as it related to tolerance to the psychomotor activating, dopamine (DA) elevating, and DA transporter (DAT) inhibiting effects of cocaine. Cocaine self-administration (1.5 mg/kg/inj; 40 inj; 5 days), which resulted in escalation of first hour intake, caused reductions in evoked DA release and reduced maximal rates of uptake through the DAT as measured by slice voltammetry in the nucleus accumbens core. Further, we report reductions in cocaine-induced uptake inhibition as measured by fast scan cyclic voltammetry, and a corresponding increase in the dose of cocaine required for 50% inhibition of DA uptake (Ki ) at the DAT. Cocaine tolerance at the DAT translated to reductions in cocaine-induced DA overflow as measured by microdialysis. Additionally, cocaine-induced elevations in locomotor activity and stereotypy were reduced, while rearing behavior was enhanced in animals with a history of cocaine self-administration. Here we demonstrate both neurochemical and behavioral cocaine tolerance in an extended-access rodent model of cocaine abuse, which allows for a better understanding of the neurochemical and psychomotor tolerance that develops to cocaine in human addicts. This article is protected by copyright. All rights reserved.
    Full-text · Article · Sep 2013 · Journal of Neurochemistry
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