Increase in A2A receptors in the nucleus accumbens after extended cocaine self-administration and its disappearance after cocaine withdrawal.
Effects of extended cocaine self-administration and its withdrawal have been studied on A(2A) and D(2) receptor binding characteristics and expression in the nucleus accumbens and the anterior and posterior dorsal striatum of the rat (Rattus norvegicus). Biochemical binding techniques have been used with the D(2)-like receptor antagonist radioligand [(3)H]-Raclopride and the A(2A) receptor antagonist radioligand [(3)H]-ZM 241385 and immunoblots to study their expression. A substantial and significant increase in functional A(2A), but not in functional D(2) receptors, was observed in the nucleus accumbens immediately following 10 days of cocaine self-administration which returned to normal levels after 7 days of drug withdrawal. In contrast, in the posterior dorsal striatum significant reductions in A(2A) expression were observed immediately after cocaine self-administration which was associated with a trend for a reduction of the A(2A) receptor antagonist binding sites. In cocaine withdrawal groups, significant increases in the density and K(d) value of D(2)-like antagonist binding sites were observed in the nucleus accumbens in the absence of changes in D(2) expression, suggesting an up-regulation of D(3) receptors in this region after cocaine withdrawal. A(2A) receptor increases in the nucleus accumbens induced by cocaine may represent a compensatory up-regulation to counteract cocaine-induced increases in D(2) signaling and D(3) signaling which is in line with its disappearance in the 7-day withdrawal group displaying increased reinforcing efficacy of cocaine. A(2A) agonists may therefore represent cocaine antagonist drugs to be used in treatment of cocaine addiction acting inter alia by antagonizing signaling in accumbens A(2A)/D(2) and A(2A)/D(3) heteromers.
Marcellino
Daniel
D
Department of Neuroscience, Karolinska Institutet, 17177 Stockholm, Sweden. Daniel.Marcellino@ki.se
Roberts
David C S
DC
Navarro
Gemma
G
Filip
Malgorzata
M
Agnati
Luigi
L
Lluís
Carme
C
Franco
Rafael
R
Fuxe
Kjell
K
D000818:Animals; D001522:Behavior, Animal; D001667:Binding, Competitive / Q000187:drug effects; D003042:Cocaine / Q000008:administration & dosage*; D018492:Dopamine Antagonists / Q000493:pharmacokinetics; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D008297:Male; D009714:Nucleus Accumbens / Q000187:drug effects*; D020891:Raclopride / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D043705:Receptor, Adenosine A2A / Q000235:genetics / Q000378:metabolism*; D012055:Reinforcement Schedule; D012646:Self Administration; D013375:Substance Withdrawal Syndrome / Q000378:metabolism*; D013997:Time Factors; D014227:Triazines / Q000493:pharmacokinetics; D014230:Triazoles / Q000493:pharmacokinetics; D014316:Tritium / Q000493:pharmacokinetics
D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors; D043705:Receptor, Adenosine A2A; D014227:Triazines; D014230:Triazoles; C097270:ZM 241385; D014316:Tritium; D020891:Raclopride; D003042:Cocaine