Intermittent Cocaine Self-Administration Produces Sensitization of Stimulant Effects at the Dopamine Transporter

Abstract

Previous literature investigating neurobiological adaptations following cocaine self-administration has shown that high, continuous levels of cocaine intake (long access; LgA) results in reduced potency of cocaine at the dopamine transporter (DAT), whereas an intermittent pattern of cocaine administration (intermittent access; IntA) results in sensitization of cocaine potency at the DAT. Here, we aimed to determine whether these changes are specific to cocaine or translate to other psychostimulants. Psychostimulant potency was assessed by fast-scan cyclic voltammetry in brain slices containing the nucleus accumbens following IntA, short access, and LgA cocaine self-administration, as well as in brain slices from naive animals. We assessed the potency of amphetamine (a releaser), and methylphenidate (a DAT blocker, MPH). MPH was selected because it is functionally similar to cocaine and structurally related to amphetamine. We found that MPH and amphetamine potencies were increased following IntA, whereas neither was changed following LgA or short access cocaine self-administration. Therefore, whereas LgA-induced tolerance at the DAT is specific to cocaine as shown in previous work, the sensitizing effects of IntA apply to cocaine, MPH, and amphetamine. This demonstrates that the pattern with which cocaine is administered is important in determining the neurochemical consequences of not only cocaine effects but potential cross-sensitization/cross-tolerance effects of other psychostimulants as well.

How fast and how often: The pharmacokinetics of drug use are decisive in addiction

“…This is in agreement with studies using experimenter-administered drug and showing that intermittent access promotes sensitization of cocaine's effects on dopamine reuptake, while continuous access promotes tolerance Cox, 1990 andCox, 1992). The findings of Calipari et al, 2013 andCalipari et al, 2014 also concord with recent work showing that LgA rats show decreased phasic dopamine levels in the nucleus accumbens core (Willuhn et al, 2014).…”

“…They compared LgA rats to IntA rats. IntA rats developed sensitization to the ability of cocaine, methylphenidate and methamphetamine to inhibit the DAT within the nucleus accumbens, while LgA rats developed tolerance to cocaine's effects at the transporter (Calipari et al, 2013 andCalipari et al, 2014). This is in agreement with studies using experimenter-administered drug and showing that intermittent access promotes sensitization of cocaine's effects on dopamine reuptake, while continuous access promotes tolerance Cox, 1990 andCox, 1992).…”

“…Rather, they might voluntarily achieve intermittently rising brain levels of drug during a bout of intoxication (Beveridge et al, 2012), and also use intermittently over time Sas, 1994 andO'Brien, 2001). Moreover, work in animals shows that continuously high versus intermittently high brain levels of cocaine can produce opposite effects on DA system function for example (Calipari et al, 2013 andCalipari et al, 2014). This deserves research attention, as we want to be sure which model more closely captures the way humans take drugs.…”

“…This suggests that cocaine intake at short inter-infusion intervals promotes the ability of the prelimbic cortex to control drug use. Finally, Calipari et al, 2013 andCalipari et al, 2014 have assessed the influence of intermittent spikes in brain cocaine levels on the dopamine transporter (DAT). They compared LgA rats to IntA rats.…”

Effects of Cocaine Sensitization on Drug Self-Administration, Mesocorticolimbic SAPAP Levels, and Prefrontal Ionotropic Glutamate Receptors

“…Although desirable for testing the effects of "binge" cocaine exposure, a within-session model is maladapted to studies measuring the effectiveness of sensitization. This is because prolonged daily cocaine exposure has been reported to either artificially increase drug reinforcement [113], or induce short-term drug tolerance [114]. Because of this fact, studies designed to test acquisition and maintenance of cocaine responding can be hindered by within-session models.…”