Activation of Nociceptin/Orphanin FQ Peptide Receptors Disrupts Visual but Not Auditory Sensorimotor Gating in BALB/cByJ Mice: Comparison to Dopamine Receptor Agonists

Abstract

Nociceptin/orphanin FQ (N/OFQ) peptide and its receptor (NOP receptor) have been implicated in a host of brain functions and diseases, but the contribution of this neuropeptide system to behavioral processes of relevance to psychosis has not been investigated. We examined the effect of the NOP receptor antagonists, Compound 24 and J-113397, and the synthetic agonist, Ro64-6198, on time function (2-2000 ms prepulse-pulse intervals) of acoustic (80 dB/10 ms prepulse) and visual (1000 Lux/20 ms prepulse) prepulse inhibition of startle reflex (PPI), a preattentive sensory filtering mechanism that is central to perceptual and mental integration. The effects of the dopamine D1-like receptor agonist, SKF-81297, the D2-like receptor agonist, quinelorane, and the mixed D1/D2 agonist, apomorphine, were studied for comparison. When acoustic stimulus was used as prepulse, BALB/cByJ mice displayed a monotonic time function of PPI, and consistent with previous studies, apomorphine and SKF-81279 induced PPI impairment, whereas quinelorane had no effect. None of the NOP receptor ligands was effective on acoustic PPI. When flash light was used as prepulse, BALB/cByJ mice displayed a bell-shaped time function of PPI and all dopamine agonists were active. Ro64-6198 was also effective in reducing visual PPI. NOP receptor antagonists showed no activity but blocked disruptive effect of Ro64-6198. Finally, coadministration of the typical antipsychotic, haloperidol, attenuated PPI impairment induced by Ro64-6198, revealing involvement of a dopaminergic component. These findings show that pharmacological stimulation of NOP or dopamine D2-like receptors is more potent in disrupting visual than acoustic PPI in mice, whereas D1-like receptor activation disrupts both. They further suggest that dysfunction of N/OFQ transmission may be implicated in the pathogenesis of psychotic manifestations.

The nociceptin orphanin FQ peptide receptor agonist, Ro64-6198, impairs recognition memory formation through interaction with glutamatergic but not cholinergic receptor antagonists

“…During the acquisition session, Ro64-6198 increased the time spent exploring the object, an effect that seems to reflect a psychomotor stimulant rather than an anxiolytic-like action of this compound (Ces et al, 2012;Goeldner et al, 2008). Such increase in exploratory activity cannot account for the memory deficit.…”

GPR88 in A2A receptor‐expressing neurons modulates locomotor response to dopamine agonists but not sensorimotor gating

“…The pattern of deficits obtained with visual PPI also argues against an impairment of the visual prepulse detection. As demonstrated by previous studies, decrement in visual sensitivity or visual prepulse strength causes a delay in the onset of PPI: a shift of the bell‐shaped curve to the right (Aubert et al ., ; Ces et al ., ). However, no shift in the onset of PPI was detected in KO mice.…”

“…The absence of effect on acoustic PPI is somewhat not surprising knowing that D1R rather than D2R plays a prominent role in the modulation of acoustic PPI in mice. Indeed, several research groups, including our, showed that direct stimulation of D1R but not D2R produces disruption of acoustic PPI in mice, a pharmacological profile opposite to that obtained in rats (Ralph‐Williams et al ., ; Ralph & Caine, ; Geyer, ; Ces et al ., ). Our data therefore extend these mouse studies by showing that genetic deletion of GPR88 activity in striatal D2R‐MSNs is ineffective on acoustic PPI.…”

“…In the present study, we confirm the acoustic PPI impairment reported in total GPR88 KO mice and further demonstrate that sensorimotor gating deficit generalizes to visual stimuli. The presentation of the flash light at varying intervals before the pulse produced the typical temporal profile of visual PPI in wild-type and KO mice: a bell-shaped curve with a sharp peak of inhibition occurring at short (20 ms) lead time interval (Aubert et al, 2006;Ces et al, 2012). Interestingly, KO mice displayed a poor performance at lead time intervals starting from 20 to 100 ms, a temporal window corresponding to the effective startle inhibition.…”

“…Our data therefore extend these mouse studies by showing that genetic deletion of GPR88 activity in striatal D2R-MSNs is ineffective on acoustic PPI. To unravel a possible impact of the mutation on sensorimotor gating, we used visual PPI, which is highly sensitive to D2R perturbations (Ces et al, 2012). However, no deficit in visual PPI was detected in Gpr88 A2AR-Cre mice as compared to the control mice.…”