Depletion of serotonin decreases the effects of the kappa-opioid receptor agonist U-69593 on cocaine-stimulated activity.
Treatment with a kappa-opioid receptor agonist for 5 days decreases locomotor activity and reduces activity in response to a cocaine challenge 3 days later. In addition, chronic cocaine increases kappa-opioid receptor density, striatal dynorphin, and dynorphin gene expression in the striatum. The upregulation of kappa-opioid receptors after cocaine treatment occurs predominantly in brain regions that are highly innervated by serotonin. To determine if serotonin plays a role in the effects of kappa-opioid receptor agonists on cocaine-stimulated activity, parachloroamphetamine (PCA), which depleted serotonin by 53%-66%, or saline, was given prior to a five-day treatment with U-69593 or vehicle. Three days later each rat received a single injection of cocaine and locomotor activity was measured. Treatment with PCA had no effect on the ability of U-69593 alone to decrease locomotor activity. Thus, the behavioral effects of U-69593 alone were not dependent upon serotonin. In rats pretreated with saline, U-69593 treatment significantly blocked the locomotor-activating effects of cocaine. Following PCA pretreatment, however, there were no significant differences in locomotor activity in rats challenged with an injection of cocaine after treatment with U-69593 or vehicle. Thus, serotonin depletion prevented the long-lasting blockade of the locomotor-activating effects of cocaine subsequent to repeated administration of U-69593 but did not alter the effects of cocaine in rats that were treated with vehicle. Thus, the effects of PCA on U-69593 are not due to non-specific alterations in cocaine-induced locomotor activity. These findings suggest that serotonin plays an important role in mediating the effects of kappa-opioid receptor agonists on the behavioral response to cocaine.
Zakharova
Elena
E
University of Miami Miller School of Medicine, Department of Psychiatry and Behavioral Sciences, 1600 NW 10th Ave., Suite 4113A, (D-80), Miami, FL 33136, USA.
Collins
Stephanie L
SL
Aberg
Maria
M
Kumar
Adarsh
A
Fernandez
J B
JB
Izenwasser
Sari
S
D000818:Animals; D001345:Autoradiography; D044482:Benzeneacetamides / Q000494:pharmacology*; D001923:Brain Chemistry / Q000187:drug effects; D015283:Citalopram / Q000378:metabolism; D003042:Cocaine / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D012701:Serotonin / Q000378:metabolism / Q000502:physiology*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000378:metabolism
D044482:Benzeneacetamides; D015283:Citalopram; D003042:Cocaine; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; D012701:Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; C045444:U 69593