doi:10.1016/j.peptides.2008.04.004
Copyright © 2008 Elsevier Inc. All rights reserved.
GABAA signalling is involved in N/OFQ anxiolytic-like effects but not in nocistatin anxiogenic-like action as evaluated in the mouse elevated plus maze
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Elaine C. Gaviolia, Filipe S. Duarteb, Remo Guerrinic, Girolamo Calod, Giles A. Raeb and Thereza C. M. De Limab, 
, 
aPrograma de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica da Saúde, Universidade do Extremo Sul Catarinense, 88806-000 Criciúma, Brazil
bDepartment of Pharmacology, CCB, Federal University of Santa Catarina, 88049-900 Florianópolis, Brazil
cDepartment of Pharmaceutical Sciences and Biotechnology Center, University of Ferrara, 44100 Ferrara, Italy
dDepartment of Experimental and Clinical Medicine, Section of Pharmacology, and Neuroscience Center, University of Ferrara, 44100 Ferrara, Italy
Received 3 March 2008;
revised 7 April 2008;
accepted 8 April 2008.
Available online 17 April 2008.
Abstract
Nociceptin/orphanin FQ (N/OFQ) and nocistatin are two neuropeptides originated from the same precursor prepronociceptin/orphanin FQ (ppN/OFQ). N/OFQ is the endogenous ligand of the NOP receptor, while the target of action of nocistatin is still unknown. N/OFQ modulates various biological functions, including anxiety. Conversely, nocistatin either behaves as a functional N/OFQ antagonist or evokes per se effects opposite to those of N/OFQ. Here we investigated the interaction between the anxiolytic-like effects of N/OFQ and the anxiogenic-like action of nocistatin with those evoked by GABAA receptor ligands in the mouse elevated plus maze. The anxiogenic-like effects of the GABAA receptor antagonist pentylenetetrazol (20 mg/kg; intraperitoneal, i.p.) were abolished by the co-treatment with N/OFQ (10 pmol; intracerebroventricular, i.c.v.) while potentiated by the administration of nocistatin (0.01 pmol; i.c.v.). The anxiolytic-like effects of the benzodiazepine receptor agonist diazepam (0.75 mg/kg, i.p.) were reversed by nocistatin (0.1 pmol; i.c.v.), whereas signs of sedation were observed when mice were co-treated with diazepam and N/OFQ (3 pmol). Interesting enough, the i.p. treatment with flumazenil (1 mg/kg) blocked the anxiolytic-like effects of N/OFQ (10 pmol; i.c.v.), but not the anxiogenic effect elicited by nocistatin. Collectively, our findings suggest that the effects on anxiety elicited by pentylenetetrazol and diazepam can be counteracted or potentiated in the presence of N/OFQ and nocistatin. In addition, the effects on anxiety of N/OFQ, but not nocistatin, appear to be dependent on the benzodiazepine site of the GABAA receptor.
Keywords: Anxiety; Nociceptin/orphanin FQ; Nocistatin; NOP receptor; GABAA receptor ligands; Mouse
Abbreviations: N/OFQ, nociceptin/orphanin FQ; ppN/OFQ, prepronociceptin/orphanin FQ; i.p., intraperitoneal; i.c.v., intracerebroventricular
Fig. 1. Effects of N/OFQ (10 pmol, i.c.v.; top panels) or NST-C6 (0.01 pmol, i.c.v.; bottom panels) 15 min after the pre-treatment with pentylenetetrazol (PTZ 20 mg/kg, i.p.) on the time spent in (A and C) and on the frequency of entries (B and D) into open arms of the elevated plus maze (EPM) in mice. Each value represents the mean ± S.E.M. *P < 0.05 compared to the control group (Saline + PBS) and #P < 0.05 compared to N/OFQ 10 pmol (Saline + NOF/Q 10 pmol) or NST-C6 0.01 pmol (Saline + NST-C6 0.01 pmol) groups (two-way ANOVA followed by Student Newman–Keuls’ test).
Fig. 2. Effects of N/OFQ (3 pmol, i.c.v.; top panels) or NST-C6 (0.1 pmol, i.c.v.; bottom panels) 15 min after the pre-treatment with diazepam (DZP 0.75 mg/kg, i.p.) on the time spent in (A and C) and on the frequency of entries (B and D) into open arms of the elevated plus maze (EPM) in mice. Each value represents the mean ± S.E.M. *P < 0.05 compared to the control group (Saline + PBS) and #P < 0.05 compared to NST-C6 0.1 pmol (Saline + NST-C6 0.01 pmol) group (two-way ANOVA followed by Student Newman–Keuls’ test).
Fig. 3. Effects of N/OFQ (10 pmol, i.c.v.; medium panels) and NST-C6 (0.1 pmol, i.c.v.; bottom panels) 15 min after the pre-treatment with flumazenil (FMZ 1 mg/kg, i.p.) on the time spent in (C and E) and frequency of entries (D and F) into open arms of the elevated plus maze (EPM) in mice. Diazepam (0.75 mg/kg, i.p.; top panels), used as positive control drug, was administered 15 min after an i.p. injection of saline or flumazenil (1 mg/kg) (A and B). Each value represents the mean ± S.E.M. *P < 0.05 compared to the respective control group (Saline + Saline or Saline + PBS groups) and #P < 0.05 compared to DZP 0.75 mg/kg (Saline + DZP 0.75 mg/kg) or N/OFQ 10 pmol (Saline + N/OFQ 10 pmol) groups (two-way ANOVA followed by Student Newman–Keuls’ test).
Table 1.
Effects of central administration of N/OFQ (3–10 pmol) or NST-C6 (0.01–0.1 pmol), 15 min after the intraperitoneal injection of pentylenetetrazol (PTZ 20 mg/kg), flumazenil (FMZ 1 mg/kg), diazepam (DZP 0.75 mg/kg) or saline, in mice evaluated in the elevated plus maze (EPM)
Each value represents the mean ± S.E.M. *P < 0.05 compared to Saline + PBS group; #P < 0.05 compared to Saline + N/OFQ 10 pmol or DZP 0.75 mg/kg + PBS groups; ##P < 0.05 compared to Saline + DZP 0.75 mg/kg group; §P < 0.05 compared to Saline + Saline group (two-way ANOVA followed by Student Newman–Keuls’ test). Abbreviations: EEA, entries on enclosed arms; SAP, stretch-attend postures; HD, head-dipping; REA, rearing.
Corresponding author at: Department of Pharmacology, Room 308, Block D, CCB, Universidade Federal de Santa Catarina, Florianópolis, SC 88049-900, Brazil. Tel.: +55 48 3721 9491x225; fax: +55 48 3337 5479.
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