Repeated cocaine administration changes the function and subcellular distribution of adenosine A1 receptor in the rat nucleus accumbens.
Adenosine A1 receptor (A1) protein and mRNA is increased in the nucleus accumbens following repeated cocaine treatment. In spite of this protein up-regulation, A1 agonist-stimulated [35S]GTPgammaS binding was attenuated in accumbens homogenates of rats withdrawn for 3 weeks from 1 week of daily cocaine injections. Cellular subfractionation revealed that the discrepancy between total A1 protein and G protein coupling resulted from a smaller proportion of receptors in the plasma membrane. The decrease in functional receptor in the plasma membrane was further indicated by diminished formation of heteromeric receptor complex consisting of A1 and dopamine D1A receptors. To explore the functional significance of the altered distribution of A1 receptors, at 3 weeks after discontinuing repeated cocaine or saline, animals were injected with cocaine and 45 min later the subcellular distribution of A1 receptors quantified. Whereas a cocaine challenge in repeated saline-treated animals induced a marked increase in membrane localization of the A1 receptor, the relative distribution of receptors in repeated cocaine rats was not affected by acute cocaine. These data suggest that the sorting and recycling of A1 receptors is dysregulated in the nucleus accumbens as the consequence of repeated cocaine administration.
Toda
Shigenobu
S
Physiology and Neuroscience, Medical University of South Carolina, Charleston, South Carolina 29425, USA. todas@musc.edu
Alguacil
Luis F
LF
Kalivas
Peter W
PW
D000818:Animals; D015153:Blotting, Western / Q000379:methods; D003042:Cocaine / Q000008:administration & dosage* / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000493:pharmacokinetics; D008297:Male; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism; D011233:Precipitin Tests / Q000379:methods; D011869:Radioligand Assay / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D043682:Receptor, Adenosine A1 / Q000378:metabolism*; D013347:Subcellular Fractions / Q000187:drug effects* / Q000378:metabolism; D013460:Sulfur Isotopes / Q000493:pharmacokinetics
D018765:Dopamine Uptake Inhibitors; D043682:Receptor, Adenosine A1; D013460:Sulfur Isotopes; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D003042:Cocaine