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.

Association of In Vivo κ-Opioid Receptor Availability and the Transdiagnostic Dimensional Expression of Trauma-Related Psychopathology

“…On the basis of preclinical data suggesting that cortisol levels may mediate the relation between KOR availability in this circuit and the behavioral expression of threat and loss symptoms, 27,28 we then examined the potential role of 24-hour urinary cortisol levels in mediating this association in humans. Given that PET imaging with the KOR-selective radioligand [ 11 C]LY2795050 allows one to assess KOR availability brain-wide, we additionally examined how [ 11 C]LY2795050 values in regions outside the amygdala-anterior cingulate cortexventral striatal neural circuit were related to threat and loss symptoms.…”

The dynorphin/κ-opioid receptor system and its role in psychiatric disorders

“…Bortolato et al [412] demonstrated that U50,488 disrupted PPI of the acoustic startle in rats, an effect reversed by atypical, but not typical, antipsychotic pretreatment. However, using various synthetic KOR agonists and salvinorin A, we found no effect of KOR activation on PPI [413]. Furthermore, KOR blockade did not alter basal PPI levels.…”

Kappa opioid receptor signaling in the brain: Circuitry and implications for treatment

“…The interactions between the KOR and CRF systems have been investigated heavily (Koob 2013, Land et al 2008, Tejeda et al 2010). The KOR and CRF systems have long been thought to interact in order to orchestrate anxiety-like responses.…”