A selective sigma‐2 receptor ligand antagonizes cocaine‐induced hyperlocomotion in mice

Abstract

Cocaine functions, in part, through agonist actions at sigma-1 (σ1 ) receptors, while roles played by sigma-2 (σ2 ) receptors are less established. Attempts to discriminate σ2 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 σ2 receptor affinity, and excellent selectivity for binding to σ2 over σ1 receptors. The behavioral properties of this structural class of σ ligands have not yet been investigated. The present study evaluated 5-bromo-N-[4-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-butyl)]-2,3-dimethoxy-benzamide, 1, a ligand shown by others to bind preferentially to σ2 over σ1 receptors, as well as dopamine D2 and D3 sites. First, we determined binding to monoamine transporters and opioid receptors, and noted 57-fold selectivity for σ2 receptors over the serotonin transporter, and >800-fold selectivity for σ2 receptors over the other sites tested. We then examined 1 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 1 at 31.6 µmol/kg. In vivo radioligand binding studies also were performed, and showed no occupancy of σ1 receptors or the dopamine transporter by 1, or its possible metabolites, at the 31.6 µmol/kg dose. Thus, ligand 1 profiles behaviorally as a σ2 receptor-selective antagonist that is able to counteract cocaine's motor stimulatory effects.

Relationship between Cerebral Sigma-1 Receptor Occupancy and Attenuation of Cocaine’s Motor Stimulatory Effects in Mice by PD144418

“…Animals were euthanized, and tissue radioactivity was determined 30 minutes after intravenous administration of [ 125 I]E-IA-DM-PE-PIPZE. As expected from previous work (Lever et al, 2012(Lever et al, , 2014, significant blockade of uptake by BD1063 (5.0 mmol/kg i.v.) in brain (84%), heart (58%), spleen (70%), and lung (68%) was observed.…”

“…PD144418 displayed an ED 50 of 0.22 mmol/kg in whole mouse brain, and ED 50 values ranging from 0.08 to 0.39 mmol/kg in heart, lung, and spleen. In a directly comparable study (Lever et al, 2014), BD1063 administered intraperitoneal gave an ED 50 of 0.62 mmol/kg in mouse brain, with ED 50 values between 0.14 and 1.47 mmol/kg for the heart, lung, and spleen.…”

“…To define the interactions of PD144418 with s 1 receptors in vivo, a series of binding studies were performed in male CD-1 mice using the selective s 1 receptor radioligand [ (Lever et al, 2012(Lever et al, , 2014. The effects of pretreatments with PD144418 and the s 1 receptor antagonist BD1063 on radioligand uptake in mouse whole brain and peripheral organs are shown in Fig.…”

“…Thus, small molecule s 1 receptor antagonists are under study for pharmacotherapy of psychostimulant abuse (Robson et al, 2012). Cocaine is also a s 2 receptor agonist (Garcés-Ramírez et al, 2011), and selective s 2 receptor antagonists can also inhibit cocaine-induced hyperactivity (Lever et al, 2014). Roles played by s 2 receptors in cocaine's behavioral effects, however, are less well defined than those for s 1 receptors.…”

Novel Treatment Strategies for Cocaine and Opioid Abuse

“…Several studies have shown that cocaine preferentially exert its psychostimulant effect by binding to sigma-1 receptors. It is believed that, sigma-1 receptors influence the actions of cocaine through three different mechanisms, 1) direct binding to the receptors, 2) modulation of other neurotransmitter systems, and 3) alterations in gene expression [34,35]. Matsumoto et al confirmed that low doses of novel sigma receptor antagonists could notably inhibit convulsions and lethality induced by toxic doses of cocaine.…”