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.
"2 , 2013a ; Calipari et al . , 2013b ) , here we expand and clarify this idea . First , until recently , sensitization and cross - sensitization have been phenomena pri - marily attributed to experimenter - delivered stimulant adminis - tration protocols , while self - administration of stimulants has repeatedly been shown to result in tolerance ( Hurd et al . , 1989 ; Calipari et al . , 2013b ; Calipari et al . , 2014a , b ; Ferris et al . , 2011 , 2012 , 2013a , b ) . Therefore , this is one of the first reports of stimu - lant self - administration resulting in the sensitization of the neurochemical effects of a drug . Second , we show that not only does cross - sensitization not occur for all sti"
[Show abstract][Hide abstract] 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.
"For example, we have previously demonstrated that the development of cocaine tolerance or sensitization at the DAT is a function of temporal pattern of administration (Calipari et al., 2013c). Long-access (LgA) self-administration results in high and sustained cocaine levels over daily 6-hour selfadministration sessions, and it is well documented that this pattern of cocaine exposure results in reduced potency of cocaine at the DAT (Mateo et al., 2005; Ferris et al., 2011, 2012; Calipari et al., 2012, 2013c, 2014a) and concomitant reductions in cocaine-induced increases in extracellular dopamine levels (Hurd et al., 1989; Ferris et al., 2011; Calipari et al., 2014a). Conversely, intermittent-access (IntA) self-administration, where animals are given time-outs to force self-administration patterns that result in sharp increases in cocaine levels followed by rapid decreases, results in sensitized cocaine potency at the DAT. "
[Show abstract][Hide abstract] 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 · 3.97 Impact Factor
"It has been reported that selective lesion of DA terminals with 6-hydroxy DA (6-OHDA), or with the neurotoxin kainic acid in the NAc significantly attenuates cocaine self-administration, supporting the hypothesis that the reinforcing effects of cocaine are dependent upon mesolimbic DA (Pettit et al., 1984; Zito et al., 1985; Caine and Koob, 1994). Consistent with these findings, in vivo microdialysis studies demonstrate that accumbal extrasynaptic DA levels are enhanced during cocaineself-administration in both the rat (Hurd et al., 1989; Pettit and Justice, 1989) and monkey (Czoty et al., 2000). Collectively, these findings suggest that enhanced DA transmission in the NAc plays a crucial role in cocaine self-administration behavior. "
[Show abstract][Hide abstract] ABSTRACT: Dopamine (DA) regulates emotional and motivational behavior through the mesolimbic dopaminergic pathway. Changes in DA mesolimbic neurotransmission have been found to modify behavioral responses to various environmental stimuli associated with reward behaviors. Psychostimulants, drugs of abuse, and natural reward such as food can cause substantial synaptic modifications to the mesolimbic DA system. Recent studies using optogenetics and DREADDs, together with neuron-specific or circuit-specific genetic manipulations have improved our understanding of DA signaling in the reward circuit, and provided a means to identify the neural substrates of complex behaviors such as drug addiction and eating disorders. This review focuses on the role of the DA system in drug addiction and food motivation, with an overview of the role of D1 and D2 receptors in the control of reward-associated behaviors.
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