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

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. Synapse 68:73–84, 2014 . © 2013 Wiley Periodicals, Inc.     

The Endocannabinoid System and the Neuroendocrine Control of Hydromineral Balance

Endocannabinoids (ECBs) are ubiquitous lipophilic agents, and this characteristic is consistent with the wide range of homeostatic functions attributed to the ECB system. There is an increasing number of studies showing that the ECB system affects neurotransmission within the hypothalamic neurohypophyseal system. We provide an overview of the primary roles of ECBs in the modulation of neuroendocrine function and, specifically, in the control of hydromineral homeostasis. Accordingly, the general aspects of ECB‐mediated signalling, as well as the specific contributions of the central component of the ECB system to the integration of behavioural and endocrine responses that control body fluid homeostasis, are discussed.