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.2009 Oct;206(3):469-78.
doi: 10.1007/s00213-009-1624-2. Epub 2009 Jul 30.

Effects of adenosine A2A receptor stimulation on cocaine-seeking behavior in rats

Affiliations

Effects of adenosine A2A receptor stimulation on cocaine-seeking behavior in rats

Ryan K Bachtell et al. Psychopharmacology (Berl).2009 Oct.

Abstract

Rationale: Dopamine (DA) receptor stimulation in the nucleus accumbens (NAc) plays an important role in regulating cocaine-seeking behavior. Adenosine receptors antagonize the effects of DA receptor stimulation on intracellular signaling, neuronal output, and behavior.

Objectives: The goal of the present study is to determine the effects of adenosine A(2A) receptor stimulation on reinstatement of cocaine-seeking behavior in rats.

Methods: Rats were trained to lever press for cocaine in daily self-administration sessions on a fixed-ratio 1 schedule for 3 weeks. After 1 week of abstinence, lever pressing was extinguished in six daily extinction sessions. We subsequently assessed the effects of the adenosine A(2A) receptor agonist, CGS 21680, on cocaine-, quinpirole (D(2) agonist)-, and cue-induced reinstatement to cocaine seeking. We also assessed the effects of CGS 21680 on sucrose seeking in rats extinguished from sucrose self-administration.

Results: Pretreatment of CGS 21680 dose-dependently blunted cocaine-induced reinstatement (15 mg/kg, i.p.). Pretreatment with CGS 21680 (0.03 mg/kg, i.p.) also attenuated quinpirole- and cue-induced reinstatement. A minimally effective dose of CGS 21680 failed to alter cocaine-induced locomotor activity or sucrose seeking.

Conclusions: Stimulation of adenosine A(2A) receptors antagonizes reinstatement of cocaine seeking elicited by cocaine, DA D(2)-receptor stimulation, and cocaine-conditioned cues. These findings suggest that adenosine A(2A) receptor stimulation may oppose DA D(2) receptor signaling in the NAc that mediates cocaine relapse.

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Figures

Fig. 1
Fig. 1
Administration of the adenosine A2A receptor agonist CGS 21680 dose-dependently blocked cocaine-induced reinstatement. A) Number of cocaine infusions in each 4-hour session during the cocaine self-administration phase. B) Extinction training was performed in six daily sessions one week following the last self-administration session. Responses on the previously drug-paired lever were reduced to levels comparable to inactive lever responses. C) Cocaine-induced reinstatement testing conducted across five days following extinction training. Each reinstatement session included an initial extinction phase (2 hrs) that preceded the reinstatement phase. The A2A agonist, CGS 21680, dose-dependently reduced cocaine-induced drug-paired lever responding. The numbers of animals in each treatment group is as follows: 0 CGS/saline = 7, 0 CGS/cocaine = 10, 0.01 CGS/cocaine = 10, 0.03 CGS/cocaine = 14, 0.1 CGS/cocaine = 11, 0.3 CGS/cocaine = 4. * significant from vehicle (p < 0.05, Bonferroni's posttest), # significant from 15 mg/kg cocaine with 0 CGS 21680 pretreatment (p < 0.05, Bonferroni's posttest)2A
Fig. 2
Fig. 2
Cocaine-induced locomotor activity was unaltered by a pretreatment with CGS 21680. A) Time-course of locomotor activity illustrating the last 30 minutes of the habituation period (90-110 min) followed by the effects of 15 mg/kg cocaine (i.p.) with and without a pretreatment of 0.03 mg/kg CGS 21680 (i.p.). This dose was chosen since it was the lowest dose that was effective in reducing cocaine-induced reinstatement (Figure 1). B) Cocaine-induced locomotor activity over the first hour in animals pretreated with vehicle or 0.03 mg/kg CGS 21680 (i.p.). No significant changes in locomotor activity were observed, n = 12/group.
Fig. 3
Fig. 3
Administration of the adenosine A2A receptor agonist CGS 21680 blunted dopamine D2 receptor-induced reinstatement. Animals were trained to self-administer cocaine in 4-hour sessions over three weeks and extinguished following a week of abstinence. On the subsequent 5 days, animals were tested for D2 agonist (quinpirole)-induced reinstatement. As can be seen, pretreatment with 0.03 mg/kg CGS 21680 (i.p.) blunted quinpirole-induced reinstatement at the two highest doses. * significant main effect of the CGS 21680 pretreatment, n = 5-8/group
Fig. 4
Fig. 4
Administration of the adenosine A2A receptor agonist CGS 21680 blunted reinstatement induced by cocaine-associated cues. A) Number of cocaine infusions in each 4-hour session during the cocaine self-administration phase. B) Extinction training was performed in six daily sessions one week following the last self-administration session. Responses on the previously drug-paired lever (solid lines) were reduced to levels comparable to inactive lever responses (dotted lines). C) Cue-induced reinstatement testing was conducted in a 4-hr reinstatement session that included an initial extinction phase (3 hrs) that preceded the reinstatement phase (1 hr). Shown in the figure is the third hour of the extinction phase and the following hour of cue testing. The A2A agonist, CGS 21680, significantly reduced cue-induced drug-paired lever responding. * significant from extinction (p < 0.05, Bonferroni posttest), Bar- significant from 0 CGS 21680 pretreatment (t15 = 3.12, p < 0.01), Vehicle N = 8; CGS 21680 N = 9
Fig. 5
Fig. 5
Administration of the adenosine A2A receptor agonist CGS 21680 had no effect on sucrose seeking. A) Sucrose self-administration was conducted over three weeks. B) Extinction training was performed in six daily sessions one week following the last self-administration session. Responses on the previously sucrose-paired lever (solid line) were reduced to levels comparable to inactive lever responses (dotted line). C) Sucrose reinstatement testing was conducted in a 2-hr reinstatement session that included an initial extinction phase (1 hr) that preceded the reinstatement phase (1 hr). The A2A agonist, CGS 21680, failed to alter sucrose seeking despite significant responding on the lever previously paired with sucrose delivery. * significant from extinction (p < 0.05, Dunnett's Test), Vehicle N = 7, CGS 21680 N = 8
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