Depletion of serotonin decreases the effects of the kappa-opioid receptor agonist U-69593 on cocaine-stimulated activity

• Published in: European journal of pharmacology Vol. 586; no. 1; pp. 123 - 129
• Main Authors: Zakharova, Elena, Collins, Stephanie L., Åberg, Maria, Kumar, Adarsh, Fernandez, J.B., Izenwasser, Sari
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 31.05.2008; Elsevier
• Subjects: Animals; Autoradiography; Benzeneacetamides - pharmacology; Biological and medical sciences; Brain Chemistry - drug effects; Citalopram - metabolism; Cocaine; Cocaine - antagonists & inhibitors; Cocaine - pharmacology; Drug addictions; In Vitro Techniques; Kappa-opioid; Locomotor activity; Male; Medical sciences; Motor Activity - drug effects; PCA; Pharmacology. Drug treatments; Pyrrolidines - pharmacology; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa - agonists; Selective Serotonin Reuptake Inhibitors - metabolism; Sensitization; Serotonin; Serotonin - metabolism; Serotonin - physiology; Serotonin Plasma Membrane Transport Proteins - drug effects; Serotonin Plasma Membrane Transport Proteins - metabolism; Toxicology; Kappa-opioid; Cocaine; Sensitization; Serotonin; Locomotor activity; PCA; Agonist; CNS stimulant; Psychotropic; Opiates; κ Opioid receptor; Opioid peptide; Local anesthetic; Ester; Locomotion; Depletion; Neurotransmitter; Drug of abuse
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2008.02.065

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.