A selective sigma‐2 receptor ligand antagonizes cocaine‐induced hyperlocomotion in mice. Issue 2 (24th October 2013)

• Record Type: Journal Article
• Authors: Lever, John R.; Miller, Dennis K.; Green, Caroline L.; Fergason‐cantrell, Emily A.; Watkinson, Lisa D.; Carmack, Terry L.; Fan, Kuo‐hsien; Lever, Susan Z.
• Is Part Of: Synapse. Volume 68:Issue 2(2014:Feb.)
• Page Start: 73
• Page End: 84
• Publication Date: 2013-10-24
• Subjects: Synapses -- Periodicals; 612
• DOI: 10.1002/syn.21717
• Languages: English
• ISSNs: 0887-4476

Abstract

<abstract abstract-type="main"> <title>ABSTRACT</title> <p>Cocaine functions, in part, through agonist actions at sigma‐1 (σ<sub>1</sub>) receptors, while roles played by sigma‐2 (σ<sub>2</sub>) receptors are less established. Attempts to discriminate σ<sub>2</sub> receptor‐mediated effects of cocaine in locomotor hyperactivity assays have been hampered by the lack of potent and selective antagonists. Certain tetrahydroisoquinolinyl benzamides display high σ<sub>2</sub> receptor affinity, and excellent selectivity for binding to σ<sub>2</sub> over σ<sub>1</sub> receptors. The behavioral properties of this structural class of σ ligands have not yet been investigated. The present study evaluated 5‐bromo‐<italic>N</italic>‐[4‐(6, 7‐dimethoxy‐3, 4‐dihydro‐1H‐isoquinolin‐2‐yl)‐butyl)]‐2, 3‐dimethoxy‐benzamide, <bold>1</bold>, a ligand shown by others to bind preferentially to σ<sub>2</sub> over σ<sub>1</sub> receptors, as well as dopamine <italic>D</italic><sub>2</sub> and <italic>D</italic><sub>3</sub> sites. First, we determined binding to monoamine transporters and opioid receptors, and noted 57‐fold selectivity for σ<sub>2</sub> receptors over the serotonin transporter, and >800‐fold selectivity for σ<sub>2</sub> receptors over the other sites tested. We then examined <bold>1</bold> in locomotor activity studies using male CD‐1® mice, and saw no alteration of basal activity at doses up to 31.6 µmol/kg. Cocaine produced a fivefold increase in locomotor activity, which was attenuated by 66% upon pretreatment of mice with <bold>1</bold> at 31.6 µmol/kg. In vivo radioligand binding studies also were performed, and showed no occupancy of σ<sub>1</sub> receptors or the dopamine transporter by <bold>1</bold>, or its possible metabolites, at the 31.6 µmol/kg dose. Thus, ligand <bold>1</bold> profiles behaviorally as a σ<sub>2</sub> receptor‐selective antagonist that is able to counteract cocaine's motor stimulatory effects. <bold>Synapse 68:73–84, 2014</bold>. © 2013 Wiley Periodicals, Inc.</p> </abstract>