Influence of conditioned reinforcement on the response-maintaining effects of quinpirole in rats

Abstract

D2-like agonists, such as quinpirole, maintain responding in monkeys, rats, and mice when they are substituted for cocaine. This study examined the influence of operant history and cocaine-paired stimuli (CS) on quinpirole-maintained responding in rats trained to nose poke for cocaine. Upon acquisition of responding for cocaine, substitutions were performed in the presence or absence of injection-CS pairings. Although cocaine maintained responding regardless of whether injections were accompanied by CS, quinpirole maintained responding only when CS were paired with injections. To assess the influence of operant history, injections of cocaine, quinpirole, remifentanil, nicotine, or saline were made available on a previously inactive lever, while nose pokes continued to result in CS presentation. Although responding was reallocated from the nose poke to the lever when cocaine or remifentanil was available, lever presses remained low, and nose poking persisted when quinpirole or nicotine was made contingent upon lever presses. Finally, quinpirole pretreatments resulted in high rates of nose poking when nose pokes resulted in CS presentation alone, but failed to maintain nose poking when the CS was omitted. Taken together, these results suggest that the response-maintaining effects of quinpirole are primarily mediated by an enhancement of the conditioned reinforcing effects of earlier CS, rather than by a reinforcing effect of quinpirole.

Figure 1

Effects of the cocaine-paired CS on responding maintained by 0.56 mg/kg/inj cocaine (top panels), saline (middle panels), or 0.032 mg/kg/inj quinpirole (bottom panels). During the Baseline portions of each experimental condition nosepokes (black circles) resulted in 0.56 mg/kg/inj cocaine paired with CS presentation, and lever presses (open squares) were inactive. CS-NS Substitution; Left Panels) Nosepokes (gray dotted circles) resulted in the injection of cocaine (0.56 mg/kg/inj), saline, or quinpirole (0.032 mg/kg/inj) delivered in conjunction with the cocaine-paired CS (i.e., 0.5-sec illumination of a green LED above the nosepoke, followed by a 5-sec TO with a solid houselight). Lever presses (open dotted squares) resulted in NS presentation (i.e., a 0.5-sec illumination of a green, yellow, and red LED above the lever, followed by a 5-sec TO with a flashing houselight). No CS Substitution; Right Panels) Nosepokes (gray crossed circles) resulted in the injection of cocaine (0.56 mg/kg/inj), saline, or quinpirole (0.032 mg/kg/inj) but no CS presentation (i.e., a 5-sec unsignaled TO), whereas lever presses (open crossed squares) resulted in a 5-sec unsignaled TO. Responses represent the mean ± S.E.M. (n=6) number of nosepokes or lever presses made during the active portion of each 90-min session. ***, p<0.001; **,p<0.01; *, p<0.05; represents significant differences in the number of nosepokes during the substitution as compared to the number of nosepokes during the last baseline session as determined by one-way ANOVA with post hoc Dunnett's tests. +++, p<0.001; ++, p<0.01; +, p<0.05; represents significant differences in the number of lever presses during the substitution as compared to the number of lever presses during the last baseline session as determined by one-way ANOVA with post hoc Dunnett's tests.

Figure 2

Responding maintained during substitutions in which injections were paired with the NS, and delivered contingent upon a previously non-reinforced lever press response, whereas nosepoke responses continued to produce the cocaine-paired CS, but no longer resulted in injections. During the Baseline portions of each experimental condition nosepokes (black circles) resulted in 0.56 mg/kg/inj cocaine paired with CS presentation, and lever presses (open squares) were inactive. During the New Resp Sub, nosepokes (open dotted circles) resulted CS presentation, whereas lever presses (gray dotted squares) resulted in cocaine (0.56 mg/kg/inj), remifentanil (0.0032 mg/kg/inj), nicotine (0.064 mg/kg/inj), quinpirole (0.032 mg/kg/inj), or saline paired with NS presentation. Responses represent the mean ± S.E.M. (n=6) number of nosepokes or lever presses made during the active portion of each 90-min session. ***, p<0.001; **,p<0.01; *, p<0.05; represents significant differences in the number of nosepokes during the substitution as compared to the number of nosepokes during the last baseline session as determined by one-way ANOVA with post hoc Dunnett's tests. +++, p<0.001; ++, p<0.01; +, p<0.05; represents significant differences in the number of lever presses during the substitution as compared to the number of lever presses during the last baseline session as determined by one-way ANOVA with post hoc Dunnett's tests.

Figure 3

Nosepoke responses that resulted in CS presentation, as a function of the total self-administered dose of quinpirole resulting from lever presses during the New Resp Substitution. Data were fit with nonlinear regression using a variable slope sigmoid equation (GraphPad Prism).

Figure 4

Effects of pretreatment with cocaine (10.0 mg/kg; i.p.), quinpirole (0.56 mg/kg; s.c.), or saline on nosepoke responding for cocaine-paired CS presentation, and lever pressing for NS presentation. During the Baseline portions of each experimental condition nosepokes (black circles) resulted in 0.56 mg/kg/inj cocaine paired with CS presentation, and lever presses (open squares) were inactive. During the PT w/CS phase Left Panels) nosepokes (open dotted circles) resulted in presentation of the cocaine-paired CS, whereas lever presses (open dotted squares) resulted in NS presentation. During the PT No CS phase Right Panel) nosepokes (open crossed circles), and lever presses (open crossed squares) resulted in an unsignaled 5-sec TO, but no stimuli change. Responses represent the mean ± S.E.M. (n=6) number of nosepokes or lever presses made during the active portion of each 90-min session. ***, p<0.001; **,p<0.01; *, p<0.05; represents significant differences in the number of nosepokes during the pretreatment phase of the cocaine-, or quinpirole-treated groups as compared to the number of nosepokes during the pretreatment phase of the saline-treated group as determined by two-way repeated measures ANOVA with post hoc Bonferroni tests. +++, p<0.001; ++, p<0.01; +, p<0.05; represents significant differences in the number of lever presses during the pretreatment phase of the cocaine-, or quinpirole-treated groups as compared to the number of nosepokes during the pretreatment phase of the saline-treated group as determined by two-way repeated measures ANOVA with post hoc Bonferroni tests. #, p<0.05; represents significant differences in the number of nosepokes during the PT w/CS phase and PT No CS phase of the quinpirole-treated groups as determined by two-way repeated measures ANOVA with post hoc Bonferroni tests.

Figure 5

Effects of pretreatment with cocaine (10.0 mg/kg; i.p.), quinpirole (0.56 mg/kg; s.c.), or saline on nosepoke responding for food-paired CS presentation, and lever pressing for NS presentation. During the Baseline portions of each experimental condition nosepokes (black circles) resulted in 10-sec access to 50 μl of liquid food paired with CS presentation, and lever presses (open squares) were inactive. During the PT w/CS phase Left Panels) nosepokes (open dotted circles) resulted in presentation of the food-paired CS, whereas lever presses (open dotted squares) resulted in NS presentation. Responses represent the mean ± S.E.M. (n=6) number of nosepokes or lever presses made during the active portion of each 90-min session. ***, p<0.001; **,p<0.01; *, p<0.05; represents significant differences in the number of lever presses during the pretreatment phase of the cocaine-, or quinpirole-treated groups as compared to the number of nosepokes during the pretreatment phase of the saline-treated group as determined by two-way repeated measures ANOVA with post hoc Bonferroni tests.