Methylphenidate and cocaine self‐administration produce distinct dopamine terminal alterations

Abstract

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 five-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 mRNA, 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.

Temporal Pattern of Cocaine Intake Determines Tolerance vs Sensitization of Cocaine Effects at the Dopamine Transporter

“…The IntA results are opposite to the well-documented decrease in cocaine potency after LgA shown here and in previous research (Hurd et al, 1989;Ferris et al, 2011Ferris et al, , 2012Calipari et al, 2012). Although behavioral sensitization to cocaine has been reported previously (Schmidt and Pierce, 2010), to our knowledge, this is the first demonstration of a sensitized cocaine response directly at the DAT following cocaine self-administration.…”

“…The decreased cocaine potency following LgA is consistent with previous reports demonstrating similar changes following a number of different extended-access paradigms. In our hands and others, LgA results in neurobiological compensations characterized by decreased cocaine effects and blunted DA system function in the NAc (Hurd et al, 1989;Meil et al, 1995;Macey et al, 2004;Ferris et al, 2011Ferris et al, , 2012Calipari et al, 2012; but see Hooks et al, 1994;Zapata et al, 2003). Also, immediately following a 21-day LgA cocaine self-administration while cocaine is still present, there are decreases in functional activity in the ventral and dorsal striatum, as well as a number of other brain regions, indicating that cocaine is less efficacious at activating these circuits (Macey et al, 2004).…”

“…Animals that administered cocaine for only 1 day of 40 injections and animals that underwent extended-access self-administration for 5 days (40 inj. per day) both exhibited the same effects as LgA self-administration (Ferris et al, 2011Calipari et al, 2012). All of the previously tested procedures shared the property that animals could administer large amounts of cocaine for the duration of the session.…”

“…All of the previously tested procedures shared the property that animals could administer large amounts of cocaine for the duration of the session. Regardless of duration of testing, each of these groups that maintained high rates of responding over 5-to 6-h sessions showed neurochemical tolerance at the DAT when tested 24 h after the last self-administration session (Ferris et al, 2011Calipari et al, 2012). Although ShA animals have a similar pattern of self-administration and can administer large amounts of drug, they can only do so for 2 h. This results in significantly less drug consumption, leading to no change in cocaine potency.…”

“…Tolerance to the DA-elevating effects of cocaine, as measured by microdialysis (Hurd et al, 1989;Mateo et al, 2005;Lack et al, 2008;Ferris et al, 2011). It is possible that cocaine tolerance is due to a reduced ability of cocaine to inhibit the DAT, which has been reported in a number of paradigms where cocaine levels are high and sustained over daily extended-access self-administration sessions (Mateo et al, 2005;Ferris et al, 2011Ferris et al, , 2012Calipari et al, 2012).…”