A differential role for the adenosine A2A receptor in opiate reinforcement vs opiate-seeking behavior.
The adenosine A(2A) receptor is specifically enriched in the medium spiny neurons that make up the 'indirect' output pathway from the ventral striatum, a structure known to have a crucial, integrative role in processes such as reward, motivation, and drug-seeking behavior. In the present study we investigated the impact of adenosine A(2A) receptor deletion on behavioral responses to morphine in a number of reward-related paradigms. The acute, rewarding effects of morphine were evaluated using the conditioned place preference paradigm. Operant self-administration of morphine on both fixed and progressive ratio schedules as well as cue-induced drug-seeking was assessed. In addition, the acute locomotor response to morphine as well as sensitization to morphine was evaluated. Decreased morphine self-administration and breakpoint in A(2A) knockout mice was observed. These data support a decrease in motivation to consume the drug, perhaps reflecting diminished rewarding effects of morphine in A(2A) knockout mice. In support of this finding, a place preference to morphine was not observed in A(2A) knockout mice but was present in wild-type mice. In contrast, robust cue-induced morphine-seeking behavior was exhibited by both A(2A) knockout and wild-type mice after a period of withdrawal. The acute locomotor response to morphine in the A(2A) knockout was similar to wild-type mice, yet A(2A) knockout mice did not display tolerance to chronic morphine under the present paradigm. Both genotypes display locomotor sensitization to morphine, implying a lack of a role for the A(2A) receptor in the drug-induced plasticity necessary for the development or expression of sensitization. Collectively, these data suggest a differential role for adenosine A(2A) receptors in opiate reinforcement compared to opiate-seeking.
Brain Injury and Repair Group, Howard Florey Institute, University of Melbourne, Parkville, VIC, Australia.
Robyn Mary
RM
Brown
Jennifer Lynn
JL
Short
Michael Scott
MS
Cowen
Catherine
C
Ledent
Andrew John
AJ
Lawrence
D000704:Analysis of Variance; D000818:Animals; D016739:Behavior, Addictive / Q000378:metabolism*; D003216:Conditioning, Operant; D003463:Cues; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009020:Morphine / Q000008:administration & dosage*; D009021:Morphine Dependence / Q000378:metabolism*; D009043:Motor Activity / Q000187:drug effects; D043705:Receptor, Adenosine A2A / Q000235:genetics / Q000378:metabolism*; D012201:Reward; D012646:Self Administration; D013037:Spatial Behavior / Q000187:drug effects; D013395:Sucrose / Q000494:pharmacology
D043705:Receptor, Adenosine A2A; D013395:Sucrose; D009020:Morphine