Background
Increasing evidence indicates that brain kappa-opioid receptors (KORs) are involved
in regulation of mood states. In animal models often used to study psychiatric illness,
KOR agonists produce depressive-like effects (e.g., anhedonia), whereas KOR antagonists
produce antidepressant- and anxiolytic-like effects. The ability of KOR agonists to
produce anhedonia-like signs in laboratory animals raises the possibility that this
class of drugs might be useful to ameliorate states characterized by excess reward
or motivation, such as mania or stimulant intoxication.
Methods
We examined how the selective KOR agonist U69,593 affects cocaine-induced facilitation
of intracranial self-stimulation (ICSS), a model of the abnormally increased reward
function that characterizes mania and stimulant intoxication. Rats with stimulating
electrodes implanted in the medial forebrain bundle (MFB) were tested with intraperitoneal
injections of U69,593 (.063–.5 mg/kg) alone, cocaine (1.25–10 mg/kg) alone, and combinations
of the drugs.
Results
Cocaine dose-dependently decreased ICSS thresholds, indicating that it enhanced the
rewarding impact of MFB stimulation. In contrast, U69,593 dose-dependently increased
ICSS thresholds, indicating that it decreased the rewarding impact of the stimulation.
Pretreatment with U69,593 blocked cocaine-induced decreases in ICSS thresholds at
doses that had negligible effects on their own.
Conclusions
Activation of KORs reduces the reward-related effects of cocaine. Inasmuch as cocaine-induced
behavioral stimulation in rodents may model key aspects of enhanced mood in humans,
these findings raise the possibility that KOR agonists might ameliorate symptoms of
conditions characterized by increased motivation and hyperfunction of brain reward
systems, such as mania and stimulant intoxication.
Key Words
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Article info
Publication history
Published online: July 21, 2008
Accepted:
May 14,
2008
Received in revised form:
April 21,
2008
Received:
December 6,
2007
Identification
Copyright
© 2008 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
