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The NOP (ORL1) receptor antagonist Compound B stimulates mesolimbic dopamine release and is rewarding in mice by a non‐NOP‐receptor‐mediated mechanism
Author(s) -
Koizumi Miwako,
Sakoori Kazuto,
Midorikawa Naoko,
Murphy Niall P
Publication year - 2004
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0705906
Subject(s) - nop , nociceptin receptor , microdialysis , chemistry , agonist , receptor , pharmacology , mesolimbic pathway , receptor antagonist , conditioned place preference , nucleus accumbens , antagonist , dopamine , endocrinology , medicine , ventral tegmental area , opioid , dopaminergic , biology , opioid peptide , biochemistry , extracellular
Compound B (1‐[(3 R , 4 R )‐1‐cyclooctylmethyl‐3‐hydroxymethyl‐4‐piperidyl]‐3‐ethyl‐1,3‐dihydro‐2H‐benzimidazol‐2‐one, CompB) is a nociceptin/orphanin FQ (N/OFQ) antagonist showing high selectivity for the NOP (ORL1) receptor over classical opioid receptors. We studied the effect of subcutaneous CompB administration on the release of mesolimbic dopamine (DA) and the expression of hedonia in mice. CompB (0.3–30 mg kg −1 ) dose dependently stimulated mesolimbic DA release as measured by in vivo freely moving microdialysis, without any change in locomotor activity. However, intracerebroventricular administered N/OFQ (endogenous agonist of the NOP receptor, 6 nmol) did not influence CompB‐ (10 mg kg −1 ) induced DA release, despite clearly suppressing release when administered alone. Studies using NOP receptor knockout mice and no‐net‐flux microdialysis revealed mildly, but not statistically significantly higher endogenous DA levels in mice lacking the NOP receptor compared to wild‐type mice. Administration of CompB (10 mg kg −1 ) induced identical increases in mesolimbic DA release in wild‐type and NOP receptor knockout mice. CompB was rewarding in approximately the same dose range in which CompB induced major increases in mesolimbic DA release when assayed using a conditioned place preference paradigm. The rewarding effect of CompB (30 mg kg −1 ) was maintained in NOP receptor knockout mice. These results show that CompB stimulates mesolimbic DA release and is rewarding by an action independent of the NOP receptor, the precise site of which is unclear. Consequently, caution should be exercised when interpreting the results of studies using this drug, particularly when administered by a peripheral route.British Journal of Pharmacology (2004) 143 , 53–62. doi: 10.1038/sj.bjp.0705906