Cocaine reinforcement and extracellular dopamine overflow in rat nucleus accumbens: an in vivo microdialysis study.
ABSTRACT Addictive properties of cocaine have been suggested to be mediated by an interplay of depletion (craving) and re-elevation (reinforcement) of dopamine (DA) levels in limbic brain area. In this study, direct measurement of dopamine in the extracellular fluid of rats freely self-administering cocaine was evaluated using in vivo microdialysis. Acute cocaine administration was associated with enhanced accumulation of DA in the nucleus accumbens, correlated with enhanced locomotor activity. In contrast, the increased DA overflow observed in drug-naive animals was attenuated in animals self-administering cocaine who had previous regular repeated (9-day) exposure to the drug. The results suggest that the absolute amount of DA in the extracellular space is not the critical factor correlated with the self-administration behavior. Additionally, the results indicate that the reduced ability of cocaine to re-elevate DA to first-time drug use is not due to a reduction of DA in the tissue or reduced DA synthesis, but may instead be associated with alterations of release and reuptake processes.
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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.Neuropharmacology 03/2014; 82. DOI:10.1016/j.neuropharm.2014.02.021 · 4.82 Impact Factor
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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.Journal of Pharmacology and Experimental Therapeutics 02/2014; 349(2). DOI:10.1124/jpet.114.212993 · 3.86 Impact Factor
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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.Journal of Neurochemistry 09/2013; DOI:10.1111/jnc.12452 · 4.24 Impact Factor