Attenuation of relapse to cocaine seeking by dopamine D1 receptor agonists and antagonists in non-human primates.
BACKGROUND
Dopamine D(1) receptor agonists and antagonists attenuate reinstatement of cocaine seeking in a non-human primate model of relapse. The mechanisms by which these different classes of D(1) receptor drugs produce these similar effects on cocaine seeking are unknown.


OBJECTIVE
This study investigated how D(1) receptor agonists and antagonists alter the shape and position of the dose-response function for reinstatement of drug seeking induced by a cocaine prime accompanied by restoration of the cocaine-paired stimulus.


METHODS
Squirrel monkeys were given extensive histories of cocaine self-administration under a second-order fixed-interval, fixed-ratio schedule of i.v. drug injection. Drug seeking was then extinguished by replacing cocaine with vehicle and eliminating the cocaine-paired stimulus. In subsequent test sessions, in which the cocaine-paired stimulus was re-introduced, priming injections of cocaine alone or combined with the different D(1) receptor high- and low-efficacy agonists and antagonists (SKF 82958, SKF 81297, SKF 83959, ecopipam; n=3-4 per drug condition) were tested for their ability to reinstate extinguished cocaine seeking.


RESULTS
Cocaine priming accompanied by the restoration of the cocaine-paired stimulus induced a dose-dependent reinstatement of drug seeking. When combined with cocaine, all D(1) receptor agonists and antagonists produced rightward and downward shifts in the cocaine dose-response function. However, combined pretreatment of SKF81297 (agonist) and ecopipam (antagonist) inhibited cocaine seeking less than either drug individually.


CONCLUSIONS
These findings suggest that D(1) receptor high- and low-efficacy agonists as well as antagonists attenuate reinstatement of cocaine seeking in part via pharmacologically opposing actions at a common population of D(1) receptors.
Khroyan
Taline V
TV
SRI International, Center for Health Sciences, 333 Ravenswood Ave, Menlo Park, CA 94025, USA. Taline.Khroyan@sri.com.|New England Regional Primate Research Center, Harvard Medical School, Southborough, Massachusetts, USA. Taline.Khroyan@sri.com.
Platt
Donna M
DM
New England Regional Primate Research Center, Harvard Medical School, Southborough, Massachusetts, USA.
Rowlett
James K
JK
New England Regional Primate Research Center, Harvard Medical School, Southborough, Massachusetts, USA.
Spealman
Roger D
RD
New England Regional Primate Research Center, Harvard Medical School, Southborough, Massachusetts, USA.
D000818:Animals; D016739:Behavior, Addictive / Q000517:prevention & control* / Q000523:psychology; D003042:Cocaine / Q000008:administration & dosage*; D018491:Dopamine Agonists / Q000494:pharmacology / Q000627:therapeutic use*; D018492:Dopamine Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D008297:Male; D011323:Primates; D017447:Receptors, Dopamine D1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D012453:Saimiri; D055502:Secondary Prevention
D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D017447:Receptors, Dopamine D1; D003042:Cocaine