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 self-administration (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 fast-scan 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.

Figure 1

(a, Left panel) Event record of a representative animal self-administering cocaine intravenously. Each horizontal line represents a daily self-administration (SA) session. Each vertical line represents an injection of cocaine (1.5 mg/kg/inj). The top line shows acquisition of cocaine SA, with the animal demonstrating regular inter-injection intervals by the end of the 6 h session. The animal showed escalation of drug intake by self-administering 40 injections each day in successively shorter time periods. (b, Right panel) Significant escalation in the rate of intake shown in a group of 29 animals (^**p<0.001, ^***p<0.0001).

Figure 2

Cocaine self-administration (SA) significantly reduces electrically stimulated dopamine (DA) release (a) and slows the maximal rate of DA uptake (b; V_max) in brain slices, as represented by the baseline means of all animals in the study acquired before drug application (^*p<0.05). The representative trace in a naïve animal (c; left panel) exemplifies the higher peak height and faster uptake in these animals relative to the cocaine SA animal (c; right panel). The color plots represent the voltammetric currents (encoded in color in the z axis) plotted against the applied potential (y axis) and time (x axis). The background-subtracted cyclic voltammograms indicative of DA are shown as insets to the upper right of the concentration–time plots. These curves identify the detected analyte as DA. The colour reproduction of the figure is available at the Neuropsychopharmacology journal online.

Figure 3

Cocaine self-administration (SA) significantly reduces the ability of multiple dopamine (DA) uptake blockers to inhibit DA uptake, with the exception of methylphenidate (MPH). The top row of graphs (a–d) demonstrates the effect of cocaine (a), nomifensine (b), bupropion (c), and MPH (d) on DA uptake, measured as apparent K_m (y axis scaling varies across panels). Note that uptake inhibition is significantly reduced in animals with a history of cocaine SA (green squares) when compared with naïve animals (black squares) in panels a–c (^**p<0.001; ^*p<0.05). When MPH is applied to the slice (d), however, the groups perfectly overlap, indicating no difference in the ability of MPH to inhibit DA uptake following cocaine SA. DA peak height for each concentration of cocaine (e), nomifensine (f), bupropion (g), and MPH (h), expressed as a percent of baseline peak height acquired before drug application. Blocker-induced increases in peak height (from baseline) are thought to largely represent increases in uptake inhibition when using brain slices. MPH, therefore, resembles cocaine in that normalized peak height (ie, uptake inhibition) at low concentrations is significantly higher in naïve animals (black squares) relative to cocaine SA animals (green squares), with no differences at higher concentrations. The colour reproduction of the figure is available at the Neuropsychopharmacology journal online.

Figure 4

Representative dopamine (DA) traces (matched peak height) demonstrating no effect of cocaine self-administration (SA) on the ability of methylphenidate (MPH) (10 μM) to inhibit DA uptake, similar to the lack of effect demonstrated by releasers (methamphetamine (30 μM)), but not blockers (cocaine (10 μM)). Note that the descending limb of DA curve from animals with a history of cocaine SA (green traces) is slower and shifted to the right relative to naïve (black traces) at baseline (a). In addition, the descending limb of DA curve from animals with a history of cocaine SA is substantially reduced relative to naïve for cocaine (b), but not for MPH (c) and methamphetamine (d). The colour reproduction of the figure is available at the Neuropsychopharmacology journal online.

Figure 5

Cocaine self-administration (SA) has no effect on the ability of multiple dopamine (DA) releasers to inhibit DA uptake. The top row of graphs (a–e) demonstrates the effect of 3,4-methylenedioxymethamphetamine (MDMA) (a), methamphetamine (b), phentermine (c), and amphetamine (d) and the non-amphetamine releaser 4-benzylpiperidine (BPP) (e) on DA uptake for both naïve (black squares) and cocaine SA animals (green squares), measured as apparent K_m (y axis scaling varies across panels). Normalized stimulated DA release (bottom row; f–j), measured across all concentrations of drugs, indicated no effect of a history of cocaine SA on the decline in stimulated DA release to increasing doses of releasers. The colour reproduction of the figure is available at the Neuropsychopharmacology journal online.