The effects of kappa-opioid receptor ligands on prepulse inhibition and CRF-induced prepulse inhibition deficits in the rat.
BACKGROUND
Kappa-opioid receptor (KOR) agonists produce dysphoria and psychotomimesis in humans. KORs are enriched in the prefrontal cortex and other brain regions that regulate mood and cognitive function. Dysregulation of the dynorphin/KOR system has been implicated in the pathogenesis of schizophrenia, depression, and bipolar disorder. Prepulse inhibition of the acoustic startle reflex (PPI), a sensorimotor gating process, is disrupted in many psychiatric disorders.


OBJECTIVE
The present study determined whether KOR ligands alter PPI in rats.


RESULTS
Utilizing a range of doses of the synthetic KOR agonists (+/-) U50,488, (-) U50,488, and U69,593 and the naturally occurring KOR agonist, Salvinorin A, we demonstrate that KOR activation does not alter PPI or startle reactivity in rats. Similarly, selective KOR blockade using the long-acting antagonist nor-binaltorphimine (nor-BNI) was without effect. In contrast to KOR ligands, MK-801 and quinpirole produced deficits in PPI. Stress and corticotropin-releasing factor (CRF) decrease PPI levels. The dynorphin/KOR system has been suggested to be a key mediator of various behavioral effects produced by stress and CRF. We therefore examined the contribution of KORs to CRF-induced alterations in PPI. Intracerebroventricular infusion of CRF decreased PPI. Administration of nor-BNI failed to affect the CRF-evoked disruption in PPI.


CONCLUSIONS
Together, these results provide no evidence of a link between the dynorphin/KOR system and deficits in sensory gating processes. Additional studies, however, examining whether dysregulation of this opioid system contributes to cognitive deficits and other behavioral abnormalities associated with psychiatric disorders are warranted.
Tejeda
Hugo A
HA
Integrative Neuroscience Section, Integrative Neuroscience Branch, National Institute on Drug Abuse, National Institutes of Health, NIDA/IRP 333 Cassell Dr., Baltimore, MD 21224, USA.
Chefer
Vladimir I
VI
Zapata
Agustin
A
Shippenberg
Toni S
TS
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology; D000818:Animals; D044482:Benzeneacetamides / Q000494:pharmacology; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology*; D045785:Diterpenes, Clerodane / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D008024:Ligands; D008297:Male; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009433:Neural Inhibition; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000819:agonists* / Q000037:antagonists & inhibitors; D013216:Reflex, Startle / Q000187:drug effects*
D044482:Benzeneacetamides; D045785:Diterpenes, Clerodane; D008024:Ligands; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; C051844:norbinaltorphimine; D009271:Naltrexone; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D003346:Corticotropin-Releasing Hormone; C045444:U 69593; C090499:salvinorin A