Kappa opioid receptor activation disrupts prepulse inhibition of the acoustic startle in rats.
BACKGROUND
Compelling evidence indicates that kappa opioid receptor (KOR) agonists produce perceptual distortions in animals and humans, yet the mechanism of action and clinical relevance of such effects remain unclear. Since abnormalities in preattentional functions and informational processing are hypothesized to underlie psychotic disorders, the present study has been designed to assess the role of KOR on sensorimotor gating.


METHODS
The effects of the selective KOR agonist U50488 were evaluated on the behavioral paradigm of prepulse inhibition (PPI) of the acoustic startle reflex (ASR).


RESULTS
U50488 (1.25, 2.5, and 5 mg/kg, subcutaneous [SC]) induced a dose-dependent reduction of PPI, which was efficiently prevented by the selective KOR antagonist norbinaltorphimine (nor-BNI, 10 mg/kg, SC), as well as by the atypical antipsychotic clozapine (5, 8 mg/kg, intraperitoneal [IP]) but not by the typical antipsychotic haloperidol (.1, .5 mg/kg, IP). Conversely, nor-BNI (10 mg/kg, SC) failed to reverse the PPI disruption mediated by both apomorphine (.25 mg/kg, SC) and dizocilpine (.1 mg/kg, SC).


CONCLUSIONS
Our results support a pivotal role of KOR in the regulation of preattentional functions and sensorimotor gating, pointing to these receptors as a possible neurobiological substrate especially relevant to the clusters of psychosis unresponsive to typical antipsychotics.
Bortolato
Marco
M
Department of Psychiatry and Human Behavior, University of California, Irvine, California, USA. bortolam@uci.edu
Aru
Gian Nicola
GN
Frau
Roberto
R
Orrù
Marco
M
Fà
Mauro
M
Manunta
Mario
M
Puddu
Mara
M
Mereu
Giampaolo
G
Gessa
Gian Luigi
GL
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology; D000161:Acoustic Stimulation / Q000379:methods*; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D001058:Apomorphine / Q000494:pharmacology; D003024:Clozapine / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018491:Dopamine Agonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004347:Drug Interactions; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology; D007266:Inhibition, Psychological; D008297:Male; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D051381:Rats; D017473:Receptors, Opioid, kappa / Q000502:physiology*; D013216:Reflex, Startle / Q000187:drug effects / Q000502:physiology*
D018712:Analgesics, Non-Narcotic; D014150:Antipsychotic Agents; D018491:Dopamine Agonists; D018691:Excitatory Amino Acid Antagonists; D009292:Narcotic Antagonists; D017473:Receptors, Opioid, kappa; C051844:norbinaltorphimine; D009271:Naltrexone; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D016291:Dizocilpine Maleate; D003024:Clozapine; D006220:Haloperidol; D001058:Apomorphine