Attenuation of cocaine-induced reinstatement of drug seeking in squirrel monkeys: kappa opioid and serotonergic mechanisms.
BACKGROUND
Kappa agonists can attenuate reinstatement of cocaine-seeking behavior induced by cocaine priming. The mechanisms underlying this effect have not been characterized fully but may have a serotonergic component as kappa agonists also increase the release of serotonin (5-hydroxytryptamine, 5-HT).


OBJECTIVE
This study investigated the role of kappa opioid receptor and 5-HT mechanisms in kappa agonist-induced attenuation of cocaine priming in monkeys.


METHODS
Squirrel monkeys were trained to self-administer cocaine (0.18-0.3 mg/kg/injection) under a second-order schedule in which drug seeking was maintained jointly by cocaine injections and a cocaine-paired visual stimulus. In extinction sessions, saline was substituted for cocaine, and the cocaine-paired stimulus was omitted. During test sessions, only saline was available for self-administration, and response-contingent presentations of the cocaine-paired stimulus were restored.


RESULTS
Priming injections of cocaine (0.1-1.0 mg/kg) induced reinstatement of drug seeking. Maximal levels of responding were similar to those maintained by active cocaine self-administration. Pretreatment with the kappa agonists enadoline (0.01 mg/kg) and spiradoline (0.3 mg/kg) or the 5-HT transport inhibitors fluoxetine (5.6 mg/kg) and citalopram (10.0 mg/kg) attenuated the priming effects of cocaine, shifting the cocaine dose-response function rightward and downward. Inhibition of cocaine-induced reinstatement of drug seeking by spiradoline and fluoxetine was reversed by R(+)8-hydroxy-2-(di-n-propylamino)tetralin (0.03 mg/kg), a 5HT(1A) agonist that inhibits 5-HT release. The effects of spiradoline also were reversed by the kappa antagonist nor-binaltorphimine (10.0 mg/kg).


CONCLUSIONS
Results suggest that the capacity of kappa opioid agonists to increase extracellular 5-HT levels may at least partially underlie kappa agonist-induced modulation of cocaine seeking.
New England Primate Research Center, Harvard Medical School, One Pine Hill Drive, P.O. Box 9102, Southborough, MA 01772-9102, USA.
Daniela
D
Rüedi-Bettschen
James K
JK
Rowlett
Roger D
RD
Spealman
Donna M
DM
Platt
D000818:Animals; D001572:Benzofurans / Q000494:pharmacology / Q000627:therapeutic use; D015283:Citalopram / Q000494:pharmacology / Q000627:therapeutic use; D019970:Cocaine-Related Disorders / Q000188:drug therapy* / Q000523:psychology; D004305:Dose-Response Relationship, Drug; D005473:Fluoxetine / Q000494:pharmacology / Q000627:therapeutic use; D008024:Ligands; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology / Q000627:therapeutic use; D017473:Receptors, Opioid, kappa / Q000819:agonists* / Q000037:antagonists & inhibitors; D012453:Saimiri; D012646:Self Administration; D012701:Serotonin / Q000378:metabolism*; D058825:Serotonin 5-HT1 Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology / Q000627:therapeutic use
D001572:Benzofurans; D015283:Citalopram; D005473:Fluoxetine; D008024:Ligands; D009271:Naltrexone; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; D012701:Serotonin; D058825:Serotonin 5-HT1 Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors; C051844:norbinaltorphimine; C067110:enadoline; C051272:spiradoline