Blockade of growth hormone secretagogue receptor 1A signaling by JMV 2959 attenuates the NMDAR antagonist, phencyclidine-induced impairments in prepulse inhibition.

Jörgen A Engel,Roy G Smith,Lennart Svensson,Elisabet Jerlhag,Emil Egecioglu

doi:10.1007/s00213-015-4054-3

Jörgen A Engel, Roy G Smith + Show 3 more

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https://doi.org/10.1007/s00213-015-4054-3

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Abstract

RationaleSchizophrenic-spectrum patients commonly display deficits in preattentive information processing as evidenced, for example, by disrupted prepulse inhibition (PPI), a measure of sensorimotor gating. Similar disruptions in PPI can be induced in rodents and primates by the psychotomimetic drug phencyclidine (PCP), a noncompetitive inhibitor of the NMDA receptor. Mounting evidence suggests that the hunger hormone ghrelin and its constitutively active receptor influences neuronal circuits involved in the regulation of mood and cognition.ObjectivesIn the present series of experiments, we investigated the effects of ghrelin and the growth hormone secretagogue receptor (GHS-R1A) neutral antagonist, JMV 2959, on acoustic startle responses (ASR), PPI, and PCP-induced alterations in PPI.ResultsIntraperitoneal (i.p.) administration of ghrelin (0.033, 0.1, and 0.33 mg/kg) did not alter the ASR or PPI in rats. Conversely, i.p. injection of JMV 2959 (1, 3, and 6 mg/kg), dose dependently decreased the ASR and increased PPI. Pretreatment with JMV 2959 at a dose with no effect on ASR or PPI per se, completely blocked PCP-induced (2 mg/kg) deficits in PPI while pretreatment with the highest dose of ghrelin did not potentiate or alter PPI responses of a sub-threshold dose of PCP (0.75 mg/kg).ConclusionThese findings indicate that the GHS-R1A is involved in specific behavioral effects of PCP and may have relevance for patients with schizophrenia.

Highlights

The growth hormone secretagogue receptor (GHS-R1A), initially an orphan receptor activated by growth hormonereleasing peptides and nonpeptidyl ligands such as GHRP-6 and MK-0677, is expressed in discrete areas throughout the central nervous system (Howard et al 1996; Guan et al 1997)
We show that modulation of the GHS-R1A alter acoustic startle responses (ASR) as well as prepulse inhibition
Peripheral treatment with ghrelin did not have any effect on ASR or prepulse inhibition (PPI) and did not potentiate psychotomimetic drug phencyclidine (PCP)-induced effects on PPI

Summary

Introduction

The growth hormone secretagogue receptor (GHS-R1A), initially an orphan receptor activated by growth hormonereleasing peptides and nonpeptidyl ligands such as GHRP-6 and MK-0677, is expressed in discrete areas throughout the central nervous system (Howard et al 1996; Guan et al 1997). There has been an increasing interest in the modulatory effect of ghrelin and the GHS-R1A on central dopamine and glutamate signaling (Abizaid et al 2006; Jerlhag et al 2006, 2011a, b; Jiang et al 2006; Kern et al 2012; Goshadrou et al 2013; Ghersi et al 2014). Alterations in PPI responses has been demonstrated following the administration of various psychotomimetic drugs affecting central dopaminergic and glutamatergic signaling, such as amphetamine in humans and rodents (Mansbach et al 1988; Hutchison and Swift 1999) or the N-methyl-D-aspartate (NMDA)-receptor antagonists phencyclidine (PCP) in monkeys and rodents (Bakshi et al 1994; Javitt and Lindsley 2001). PCPinduced deficit in sensorimotor gating has been shown to be antagonized by both atypical antipsychotics such as clozapine (Bakshi et al 1994) and recently by the new dopamine stabilizer aripirazole (Fejgin et al 2007), underlining the interaction between dopaminergic and glutamatergic signaling in schizophrenia

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