title: Effects of the psychotomimetic benzomorphan N-allylnormetazocine (SKF 10,047) on prepulse inhibition of startle in mice.
abstract: N-allylnormetazocine (NANM; SKF 10,047) is a benzomorphan opioid that produces psychotomimetic effects. (+)-NANM is the prototypical agonist for the sigma-1 (σ1) receptor, and there is a widespread belief that the hallucinogenic effects of NANM and other benzomorphan derivatives are mediated by interactions with σ1 sites. However, NANM is also an agonist at the κ opioid receptor (KOR) and binds to the PCP site located within the channel pore of the NMDA receptor, interactions that could potentially contribute to the effects of NANM. NMDA receptor antagonists such as phencyclidine (PCP) and ketamine are known to disrupt prepulse inhibition (PPI) of acoustic startle, a measure of sensorimotor gating, in rodents. We recently found that racemic NANM disrupts PPI in rats, but it is not clear whether the effect is mediated by blockade of the NMDA receptor, or alternatively whether interactions with KOR and σ1 receptors are involved. The present studies examined whether NANM and its stereoisomers alter PPI in C57BL/6J mice, and tested whether the effects on PPI are mediated by KOR or σ1 receptors. Racemic NANM produced a dose-dependent disruption of PPI (3-30mg/kg SC). (+)-NANM also disrupted PPI, whereas (-)-NANM was ineffective. Pretreatment with the selective KOR antagonist nor-binaltorphimine (10mg/kg SC) or the selective σ1 antagonist NE-100 (1mg/kg IP) failed to attenuate the reduction in PPI produced by racemic NANM. We also found that the selective KOR agonist (-)-U-50,488H (10-40mg/kg SC) had no effect on PPI. These findings confirm that NANM reduces sensorimotor gating in rodents, and indicate that the effect is mediated by interactions with the PCP receptor and not by activation of KOR or σ1 receptors. This observation is consistent with evidence indicating that the σ1 receptor is not linked to hallucinogenic or psychotomimetic effects.
authors.affiliation: Department of Psychiatry, University of California San Diego, La Jolla, CA, United States; Research Service, VA San Diego Healthcare System, San Diego, CA, United States. Electronic address: ahalbers@ucsd.edu.
authors.forename: Adam L
authors.initials: AL
authors.lastname: Halberstadt
authors.affiliation: Department of Psychiatry, University of California San Diego, La Jolla, CA, United States.
authors.forename: James
authors.initials: J
authors.lastname: Hyun
authors.affiliation: Department of Psychiatry, University of California San Diego, La Jolla, CA, United States.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Ruderman
authors.affiliation: Department of Psychiatry, University of California San Diego, La Jolla, CA, United States; Research Service, VA San Diego Healthcare System, San Diego, CA, United States.
authors.forename: Susan B
authors.initials: SB
authors.lastname: Powell
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology; D000818:Animals; D000840:Anisoles / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006213:Hallucinogens / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D010620:Phenazocine / Q000031:analogs & derivatives* / Q000494:pharmacology; D065808:Prepulse Inhibition / Q000187:drug effects* / Q000502:physiology; D011437:Propylamines / Q000494:pharmacology; D017473:Receptors, Opioid, kappa / Q000819:agonists; D017478:Receptors, Phencyclidine / Q000502:physiology; D017480:Receptors, sigma / Q000819:agonists; D013216:Reflex, Startle / Q000187:drug effects; D013237:Stereoisomerism; D000097605:Sigma-1 Receptor
chemical_list: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000840:Anisoles; D006213:Hallucinogens; D009271:Naltrexone; D010620:Phenazocine; D011437:Propylamines; D017473:Receptors, Opioid, kappa; D017478:Receptors, Phencyclidine; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C083832:N,N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy)phenyl)ethylamine monohydrochloride; C051844:norbinaltorphimine; C012134:SK&F 10047
keywords: Dissociative; Hallucinogen; Kappa receptor; Mice; Prepulse inhibition; Psychotomimetic; Sigma receptor