Self-administered heroin and cocaine combinations in the rat: additive reinforcing effects-supra-additive effects on nucleus accumbens extracellular dopamine

Abstract

The concurrent use of cocaine and opiate combinations (speedball) has increased since the 1970s and now represents a growing subset of intravenous drug abusers. An isobolographic analysis was applied to the ascending limb of the dose-effect curves for rat self-administration of cocaine, heroin, and their combination to determine the nature of the interaction. The addition of heroin to cocaine shifted the dose-effect curve for self-administration to the left, and the modulation in reinforcing efficacy of the combination of cocaine and heroin was found to be additive. A second experiment used microdialysis to determine the effects of this drug combination on nucleus accumbens (NAc) extracellular levels of dopamine ([DA](e)) in rats self-administering low doses of cocaine, heroin, or cocaine/heroin combinations. These doses of cocaine and cocaine/heroin combinations significantly increased NAc [DA](e), while heroin alone did not. The ratio of the % baseline of [DA](e) (or the dialysate concentrations of DA) to cocaine in the dialysate was higher during self-administration of cocaine/heroin combinations than with cocaine alone. These data indicate that although the interaction between cocaine and heroin in maintaining self-administration is additive, a potentiation of NAc dopaminergic neurotransmission is present, suggesting that NAc [DA](e) may not be a direct measure of reinforcing efficacy and/or it is not central to the mediation of the self-administration of this drug combination.

Figure 1

Dose–effect curves for cocaine, heroin, and cocaine/heroin combinations for six rats using a within session dose-intake procedure. The dose–effect curves were obtained by exposing each rat to three doses of drug in each session. The concentration of each drug was altered until complete dose-intake functions for each drug or combination were determined.

Figure 2

Isobolographic analysis of the self-administration of cocaine and heroin alone or in combination. The dose producing self-administration of 15 infusions on the ascending limb of the dose–effect curves (A_{15 infusion} (95% confidence limit)) for each drug presented alone are plotted on the X- (heroin) or Y- (cocaine) axis. The A_{15 infusion} (95% confidence limit) is plotted for the combination of cocaine/heroin in the middle portion of the graph.

Figure 3

Dose-intake relationship for the rats in the microdialysis experiments. Microdialysates from the NAc were collected during the self-administration of cocaine (N = 5), heroin (N = 6), and cocaine/heroin combinations (N = 6). The dose-intake values were obtained by exposing each rat to three doses of drug during each session.

Figure 4

Intake of three doses of heroin, cocaine, and cocaine/heroin combinations five sessions prior to and during the microdialysis session. Intake during the microdialysis session was not different at any of the three doses of the three drug conditions from the 5-day baseline. Points are means and error bars standard deviations for N = 6 at each point for heroin and cocaine/heroin combinations and N = 5 for cocaine. When no error bar is shown, error is less than the size of the data point.

Figure 5

NAc extracellular fluid levels of dopamine (circles) and cocaine (triangles) during self-administration of threshold levels of cocaine. Rats (N = 5) were trained to self-administer threshold doses of cocaine (166.5, 83.3, and 41.6 µg/infusion) in descending order and the levels of dopamine and cocaine measured in 10-min microdialysate samples from the nucleus accumbens. DA levels are expressed as a percentage of baseline and cocaine as micromoles in samples collected at 10-min intervals (error bars represent ± SEMs). Open symbols represent data for pre- and post-session and TO periods between doses. The infusions taken per component (mean ± SEM) are shown at the top of the figure. The extracellular fluid levels of dopamine were elevated at threshold doses of cocaine.

Figure 6

NAc extracellular fluid levels of dopamine (circles) during self-administration of threshold levels of heroin. Rats (N = 6) were trained to self-administer threshold doses of heroin (4.5, 2.3, and 1.1 µg/infusion) in descending order and the levels of dopamine measured in 10 min microdialysates of the NAC. DA levels are expressed as a percentage of baseline and cocaine as micromoles in samples collected at 10 min intervals (error bars represent ± SEMs). Open symbols represent data for pre- and post-session and TO periods between doses. The infusions taken per component (mean ± SEM) are shown at the top of the figure. The extracellular fluid levels of dopamine were marginally elevated at threshold self-administration doses of heroin.

Figure 7

NAc extracellular fluid levels of dopamine (circles) and cocaine/heroin combination (triangles) during self-administration of threshold levels of cocaine. Rats (N = 6) were trained to self-administer threshold doses of cocaine/heroin combination (cocaine/heroin—166.5/4.5, 83.3/2.3 and 41.6/1.1 µg/infusion) in descending order and the levels of dopamine and cocaine measured in 10-min microdialysates of the NAC. DA levels are expressed as a percentage of baseline and cocaine as micromoles in samples collected at 10-min intervals (error bars represent ± SEMs). Open symbols represent data for pre- and post-session and TO periods between doses. The infusions taken per component (mean ± SEM) are shown at the top of the figure. The extracellular fluid levels of dopamine were elevated at threshold doses of cocaine/heroin combination.

Figure 8

The percent increases in NAc extracellular dopamine above baseline per unit of cocaine in cocaine and cocaine/heroin combination self-administering rats. The drug intake between cocaine and cocaine/heroin combination self-administering rats was very different (Figures 1 and 3) as were the resulting cocaine levels in the microdialysates, yet the levels of dopamine were similar to the cocaine group. The levels of dopamine were corrected for those differences by calculating the percent dopamine increase per unit of cocaine in the microdialysate. A one-way ANOVA was used to analyze differences between the ratios of [DA]_e/cocaine concentration. Significant differences were: ^‡p <0.0001; ^†p <0.001. The potentiation by heroin of the effects of cocaine on extracellular dopamine is even more evident.

Figure 9

Location of the microdialysis probes in the NAc of cocaine, heroin, and cocaine/heroin combination self-administering rats. The loci for the microdialysis probes are indicated by the dark lines in the diagrams of the brain sections.