Localization of dopamine receptor subtypes occupied by intra-accumbens antagonists that reverse cocaine-induced locomotion.
The purpose of this study was to examine whether blockade of either dopamine D1-like or D2-like receptors by selective antagonist administration into the nucleus accumbens (NAc) is sufficient to reverse cocaine-induced locomotion, and to develop a new technique that enables the population of receptors occupied by the antagonists to be quantified. Locomotor activity was assessed in rats that had received bilateral intra-accumbens injections of the D1-selective antagonist SCH-23390 (0-3.0 micrograms/0.5 microliters/side) or the D2/D3-selective antagonist sulpiride (0-1.0 micrograms/0.5 microliters/side), followed 15 min later by injections of saline or cocaine (15 mg/kg, i.p.). To assess receptor occupancy by the antagonists, 105 min prior to sacrifice the rats received intra-accumbens injections of the antagonist, followed 15 min later by an injection of the non-selective irreversible antagonist, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ; 10 mg/kg, i.p.). Receptors were labeled with [3H]SCH-23390 or [3H]sulpiride in sections containing the NAc, and the autoradiograms allowed quantitation of receptors occupied (i.e. protected from EEDQ) by the antagonist given in vivo. Only a dose of 3 micrograms/side SCH-23390 reversed cocaine-induced locomotion, whereas a dose of 0.5 microgram/side did not alter cocaine-induced locomotion despite occupying the same amount of [3H]SCH-23390 binding sites in the NAc. Intermediate doses of 0.1 and 0.3 microgram/side sulpiride reversed cocaine-induced locomotion, and also occupied the greatest number of [3H]sulpiride binding sites in the NAc. The results suggest that blockade of D2-like, but not D1-like, receptors in the NAc is sufficient to reverse cocaine-induced locomotion, and also demonstrate the importance of quantifying receptors occupied by drugs administered intracranially.
Neisewander
J L
JL
Department of Psychology, Arizona State University, Tempe 85287-1104, USA.
O'Dell
L E
LE
Redmond
J C
JC
D000818:Animals; D001345:Autoradiography; D001522:Behavior, Animal / Q000187:drug effects; D001552:Benzazepines / Q000008:administration & dosage / Q000494:pharmacology; D003042:Cocaine / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D007267:Injections; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D009714:Nucleus Accumbens / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism*; D011804:Quinolines / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011954:Receptors, Dopamine / Q000378:metabolism*; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D013469:Sulpiride / Q000008:administration & dosage / Q000494:pharmacology
D001552:Benzazepines; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D011804:Quinolines; D011954:Receptors, Dopamine; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; C000470:EEDQ; D013469:Sulpiride; D003042:Cocaine