TY - JOUR
T1 - Time and sex-dependent effects of an adenosine A2A/A1 receptor antagonist on motivation to self-administer cocaine in rats
AU - Doyle, Susan E.
AU - Breslin, Florence J.
AU - Rieger, Jayson M.
AU - Beauglehole, Anthony
AU - Lynch, Wendy J.
N1 - Funding Information:
We would like to thank Robert Thompson for technical assistance. This work was supported by the NIDA grant R01 DA024716 (WJL) and SBIR grant 1R43DA022110-01 (JMR & AB). JMR and AB are employed by Dogwood Pharmaceuticals, Inc.
PY - 2012/8
Y1 - 2012/8
N2 - 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 (1.5 mg/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.
AB - 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 (1.5 mg/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.
KW - Adenosine receptors
KW - Cocaine
KW - Self-administration
KW - Sex difference
UR - http://www.scopus.com/inward/record.url?scp=84861449728&partnerID=8YFLogxK
U2 - 10.1016/j.pbb.2012.05.001
DO - 10.1016/j.pbb.2012.05.001
M3 - Article
C2 - 22579716
AN - SCOPUS:84861449728
SN - 0091-3057
VL - 102
SP - 257
EP - 263
JO - Pharmacology Biochemistry and Behavior
JF - Pharmacology Biochemistry and Behavior
IS - 2
ER -