Effects of kappa opioid receptor agonists on attention as assessed by a 5-choice serial reaction time task in rats.
In humans, kappa opioid receptor agonists produce, among other effects, sedation and difficulty concentrating, suggesting that they may disrupt attention. The purpose of the present studies was therefore to evaluate the effects of kappa opioid receptor agonists on attention as assessed by a 5-choice serial reaction time task in rats. The kappa opioid receptor agonists (+)-U69,593 (0.1-0.56mg/kg), (+/-)-U50,488 (1.0-5.6mg/kg) and racemic GR89,696 (0.0003-0.01mg/kg) all produced dose-related decreases in the percentage of trials terminated by a correct or incorrect response and increases in the percentage of omissions. In contrast, the peripherally restricted opioid agonist ICI-204,448 was ineffective (1.0-10mg/kg). Moreover, the effects of GR89,696 were stereoselective in that (R)-GR89,696 was approximately equipotent to racemic GR89,696 and approximately 100-fold more potent than (S)-GR89,696. The opioid receptor antagonist naltrexone (0.3-3mg/kg) administered alone had no effects on performance. However, naltrexone, over the dose-range of 0.03-1.0mg/kg, produced a dose-related antagonism of the disruption produced by U69,593 (0.56mg/kg). In contrast, naltrexone, over the dose-range of 0.01-0.3mg/kg produced a dose-related antagonism of morphine (5.6mg/kg). Recent evidence has suggested that kappa opioid receptor agonists decrease dopaminergic and noradrenergic neurotransmission in prefrontal cortex and locus coeruleus. Together with previous findings, the present data indicate that kappa opioid receptor agonists disrupt performance of this attention task by decreasing the probability of responding by specific actions at central kappa opioid receptors, perhaps by decreasing dopaminergic and noradrenergic neurotransmission.
Shannon
Harlan E
HE
Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. shannon_harlan_e@lilly.com
Eberle
Elizabeth L
EL
Mitch
Charles H
CH
McKinzie
David L
DL
Statnick
Michael A
MA
D000700:Analgesics / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D001288:Attention / Q000187:drug effects*; D001522:Behavior, Animal / Q000187:drug effects; D002755:Choice Behavior / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D008297:Male; D009271:Naltrexone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D010775:Photic Stimulation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects*; D017473:Receptors, Opioid, kappa / Q000819:agonists* / Q000378:metabolism
D000700:Analgesics; D009292:Narcotic Antagonists; D017473:Receptors, Opioid, kappa; D009271:Naltrexone