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, 102 (2), 257-63

Time and Sex-Dependent Effects of an Adenosine A2A/A1 Receptor Antagonist on Motivation to Self-Administer Cocaine in Rats

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Time and Sex-Dependent Effects of an Adenosine A2A/A1 Receptor Antagonist on Motivation to Self-Administer Cocaine in Rats

Susan E Doyle et al. Pharmacol Biochem Behav.

Abstract

Adenosine is an important neuromodulator, known to interact with both dopaminergic and glutamatergic systems to influence psychostimulant action. In the present study, we examined the effects of ATL444, a novel adenosine receptor antagonist, on motivation for cocaine in male and female rats. Adult male and female Sprague-Dawley rats were trained to self-administer cocaine (1.5mg/kg/infusion) on a fixed-ratio 1 schedule with a daily maximum of 20 infusions. Following 5 consecutive sessions during which all 20 available infusions were obtained, motivation for cocaine (0.5 mg/kg/infusion) was assessed under a progressive ratio (PR) schedule, and once responding stabilized, the effect of treatment with ATL444 (0, 15, and 30 mg/kg, i.p.) was examined. As a control, we also assessed its effects on PR responding for sucrose. Binding studies revealed that ATL 444 was 3-fold, 25-fold, and 400-fold more selective for the A2A receptor as compared to A1, A2B, and A3 receptors, respectively. ATL444 produced a significant increase in motivation for cocaine on the day of treatment in females with a trend for an increase in males. In addition, over the two PR sessions following ATL444 treatment a significant decrease in responding was observed in males but not females. Responding for sucrose was unaffected by ATL444 treatment. Our results reveal that adenosine receptor blockade may mediate both acute increases in the reinforcing effects of cocaine, and longer term inhibitory effects on cocaine reinforcement that differ according to sex.

Figures

Fig. 1
Fig. 1
Structure and synthetic scheme for ATL444. Top panel: Structure of ATL444. Middle and bottom panels: Outline of the general synthesis scheme for ATL444. Middle panel: Synthesis of the target 2,9-disubstituted adenine. Bottom panel: Alkyne synthesis.
Fig. 2
Fig. 2
Effect of ATL-444 on PR responding for cocaine. Top panels: mean (SEM) infusions and corresponding breakpoints observed for the baseline session (Base), the day of treatment (Treat) and the 3 post-treatment sessions that followed (P1, 2, 3) in males (left) and females (right). * indicates significant difference between vehicle and 15 mg/kg treatment group. ** indicates significant difference between vehicle and both 15 and 30 mg/kg treatment groups. Middle panels: mean (SEM) percent change from baseline number of cocaine infusions on the day of treatment (Treat) and for the 3 sessions that followed treatment (P1, 2, 3) with vehicle (left) or 15 mg/kg ATL-444 (right). * represents a significant difference between males and females. Lower left panel: individual female (left) and male (right) values for percent change from baseline number of cocaine infusions on the day of treatment with 15 mg/kg ATL444 (Treat) and for the 3 sessions that followed treatment (P1, 2, 3). Lower right panel: replicate of the effects of the 15 mg/kg dose of ATL444 in a representative male and female that received a repeat treatment with this same dose.

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