Behavioral sensitization to cocaine in rats: evidence for temporal differences in dopamine D3 and D2 receptor sensitivity

Abstract

Rationale: Cocaine-induced changes in D(2) receptors have been implicated in the expression of sensitized behavioral responses and addiction-like behaviors; however, the influence of D(3) receptors is less clear.

Objectives: To characterize the effects of repeated cocaine administration on the sensitivity of rats to D(2)- and D(3)-mediated behaviors, as well as the binding properties of ventral striatal D(2)-like and D(3) receptors.

Methods: Pramipexole was used to assess the sensitivity of rats to D(3)/D(2) agonist-induced yawning, hypothermia, and locomotor activity, 24 h, 72 h, 10, 21, and 42 days after repeated cocaine or saline administration. The locomotor effects of cocaine (42 day) and the binding properties of ventral striatal D(2)-like and D(3) receptors (24 h and 42 days) were also evaluated.

Results: Cocaine-treated rats displayed an enhanced locomotor response to cocaine, as well as a progressive and persistent leftward/upward shift of the ascending limb (72 h-42 day) and leftward shift of the descending limb (42 days) of the pramipexole-induced yawning dose-response curve. Cocaine treatment also decreased B (max) and K (d) for D(2)-like receptors and increased D(3) receptor binding at 42 days. Cocaine treatment did not change pramipexole-induced hypothermia or locomotor activity or yawning induced by cholinergic or serotonergic agonists.

Conclusions: These studies suggest that temporal differences exist in the development of cocaine-induced sensitization of D(3) and D(2) receptors, with enhancements of D(3)-mediated behavioral effects observed within 72 h and enhancements of D(2)-mediated behavioral effects apparent 42 days after cocaine. These findings highlight the need to consider changes in D(3) receptor function when thinking about the behavioral plasticity that occurs during abstinence from cocaine use.

Figure 1

Locomotor activity induced by i.p. saline (Left) and 15.0 mg/kg; i.p. (Right) in cocaine- and saline-treated rats 42d after the cessation of repeated cocaine or saline administration. Data represent the mean ± S.E.M. (n=6 per group) of the total locomotor activity for each 5-min bin, and for each 60-min bin (inset panels) following administration of saline and cocaine. *,p<0.05; **,p<0.01. Significant differences in the amount of locomotor activity for cocaine- and saline-treated groups were determined by two-way, repeated-measures ANOVA with post-hoc Bonferroni tests (5-min bins) and by two-tailed, paired t-tests.

Figure 2

Dose-response curves for pramipexole-induced yawning in cocaine- and saline-treated rats as assessed 24hr, 72hr, 10d, 21d, and 42d after the cessation of repeated cocaine or saline administration. Data represent the mean ± S.E.M. (n=8 per group) number of yawns observed during the 30-minute period following each injection. *, p<0.05; ***, p<0.001. Significant effect of cocaine treatment on yawning compared to the saline-treated group at that particular time point as determined by two-way, repeated-measures ANOVA with post-hoc Bonferroni tests. +, p<0.05. Significant difference in the amount of yawning observed for the saline-treated group compared to the 24hr saline-treated time point as determined by two-way, repeated-measures ANOVA with post-hoc Bonferroni tests. ##, p<0.01; ###, p<0.001. Significant difference in the amount of yawning observed for the cocaine-treated group compared to the 24hr cocaine-treated time point as determined by two-way, repeated-measures ANOVA with post-hoc Bonferroni tests.

Figure 3

Dose-response curves for pramipexole-induced changes in core body temperature (Left Panels) and locomotor activity (Right Panels) in cocaine- and saline-treated rats as assessed 24hr, 72hr, 10d, and 21d after the cessation of repeated cocaine or saline administration. Data represent the mean ± S.E.M. (n=6 per group) change in core body temperature as measured 30 minutes after each injection compared to the core body temperature 1 minute prior to the first injection, and mean ± S.E.M. (n=6 per group) locomotor activity counts summed over the 30 minutes following each injection. +, p<0.05; ++,p<0.01. Significant difference in the change in core body temperature or locomotor activity for the saline-treated group compared to the 24hr saline-treated time point as determined by two-way, repeated-measures ANOVA with post-hoc Bonferroni tests. #,p<0.05; ##, p<0.01; ###, p<0.001. Significant difference in the change in core body temperature or locomotor activity for the cocaine-treated group compared to the 24hr cocaine-treated time point as determined by two-way, repeated-measures ANOVA with post-hoc Bonferroni tests.

Figure 4

Quantification of [3H]7-OH-DPAT bound to ventral striatal tissue collected from cocaine- and saline-treated rats 24hr and 42d after the cessation of repeated cocaine or saline administration. ***,p<0.001. Significant effect of treatment as determined by two-tailed paired t-tests.