The effects of kappa-opioid receptor ligands on prepulse inhibition and CRF-induced prepulse inhibition deficits in the rat

Abstract

Rationale: 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.

Objectives: 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.

Fig. 1

MK-801 and quinpirole decrease PPI levels and alter startle reactivity. a, c PPI is expressed as a percentage of “prepulse plus pulse” trials of “pulse alone” trials. b, d Startle magnitude levels in rats treated with vehicle, MK-801, or quinpirole. Each bar represents the mean±SEM of five to six rats. One and two asterisks reflect a significant difference relative to vehicle-treated animals (p<0.01 and p<0.001, respectively)

Fig. 2

Influence of kappa-opioid receptor (KOR) agonists on PPI and startle reactivity. The KOR agonists (±) U50,488, (−) U50,488, U69,593, and Salvinorin A did not alter PPI or startle levels at any of the doses tested. a, c, e, g PPI is expressed as a percentage of “prepulse plus pulse” trials of “pulse alone” trials in rats treated with (±) U50,488 (0–7.5 mg/kg), (−) U50,488 (0–5.0 mg/kg), U69,593 (0–0.32 mg/kg), and Salvinorin A (0–2.0 mg/kg). b, d, f, h Data reflect startle magnitude levels for rats treated with (±) U50,488, (−) U50,488, U69,593, and Salvinorin A, respectively, or their corresponding vehicle. Each bar represents the mean±SEM of seven to 12 rats

Fig. 3

Influence of the kappa-opioid receptor antagonist, nor-binaltorphimine (nor-BNI), on PPI and startle reactivity. a PPI is expressed as a percentage of “prepulse plus pulse” trials of “pulse alone” trials for rats treated with vehicle or nor-BNI (10 mg/kg). b Data reflect startle magnitude levels for rats treated with vehicle or nor-BNI. Each bar represents the mean±SEM of seven rats

Fig. 4

Influence of kappa-opioid receptor blockade on corticotropin-releasing factor (CRF)-induced deficits in PPI. a PPI is expressed as a percentage of “prepulse plus pulse” trials of “pulse alone” trials for rats pretreated with vehicle or nor-binaltorphimine (nor-BNI; 10 mg/kg) 24 h prior to testing. On the test day, either saline or CRF (3 µg) was microinjected into the lateral ventricle prior to testing. b Startle magnitude levels during the test session. Each bar represents the mean±SEM of eight rats. An asterisk reflect a significant main effect of treatment (CRF) indicating that CRF decreased PPI levels regardless of pretreatment (nor-BNI)