Cocaine Self-Administration Produces Pharmacodynamic Tolerance: Differential Effects on the Potency of Dopamine Transporter Blockers, Releasers, and Methylphenidate

Abstract

The dopamine transporter (DAT) is the primary site of action for psychostimulant drugs such as cocaine, methylphenidate, and amphetamine. Our previous work demonstrated a reduced ability of cocaine to inhibit the DAT following high-dose cocaine selfadministration (SA), corresponding to a reduced ability of cocaine to increase extracellular dopamine. However, this effect had only been demonstrated for cocaine. Thus, the current investigations sought to understand the extent to which cocaine SA (1.5 mg/kg/inf  40 inf/ day  5 days) altered the ability of different dopamine uptake blockers and releasers to inhibit dopamine uptake, measured using fastscan cyclic voltammetry in rat brain slices. We demonstrated that, similar to cocaine, the DAT blockers nomifensine and bupropion were less effective at inhibiting dopamine uptake following cocaine SA. The potencies of amphetamine-like dopamine releasers such as 3,4-methylenedioxymethamphetamine, methamphetamine, amphetamine, and phentermine, as well as a non-amphetamine releaser, 4-benzylpiperidine, were all unaffected. Finally, methylphenidate, which blocks dopamine uptake like cocaine while being structurally similar to amphetamine, shared characteristics of both, resembling an uptake blocker at low concentrations and a releaser at high concentrations. Combined, these experiments demonstrate that after high-dose cocaine SA, there is cross-tolerance of the DAT to other uptake blockers, but not releasers. The reduced ability of psychostimulants to inhibit dopamine uptake following cocaine SA appears to be contingent upon their functional interaction with the DAT as a pure blocker or releaser rather than their structural similarity to cocaine. Further, methylphenidate's interaction with the DAT is unique and concentration-dependent.

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).…”

“…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).…”

Amphetamine Self-Administration Attenuates Dopamine D2 Autoreceptor Function

“…Control animals did not have sham surgery. Using the same treatment paradigm, we have repeatedly shown previously that there are no neurochemical differences in DA-related measurements such as DA uptake and release between animals with and without sham surgery for catheter implantation (Calipari et al, 2013a;Calipari et al, 2013b;Ferris et al, 2012).…”

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

“…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, 2011Ferris et al, , 2012Calipari et al, 2012Calipari et al, , 2013cCalipari et al, , 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.…”