MK-7128, a novel CB1 receptor inverse agonist, improves scopolamine-induced learning and memory deficits in mice

Abstract

Cannabinoid receptors (CBRs) play an important role in a variety of physiological functions and have been considered drug targets for obesity and psychiatric disorders. In particular, the CB1R is highly expressed in brain regions crucial to learning and memory processes, and several lines of evidence indicate that pharmacological blockade of this receptor could have therapeutic applications in the treatment of cognitive disorders. In this study, we investigated whether MK-7128 (0.1, 0.3, and 1 mg/kg, orally), a novel and selective CB1R inverse agonist, could improve learning and memory deficits induced by scopolamine (1 mg/kg, subcutaneously) in mice. The investigators also assessed CB1R occupancy in the brain to ensure target engagement of MK-7128, and showed that MK-7128 significantly improved both Y-maze spontaneous alternation and object habituation performance in scopolamine-treated mice and inhibits the binding of radioiodinated AM251 in murine cortex and hippocampus. These data indicate that MK-7128 improves cognitive performance in a model of cholinergic hypofunction and suggest that efficacy is achieved at relatively low levels of CB1R occupancy in the brain. Our results extend earlier findings suggesting a role of CB1Rs in the modulation of memory processes and a potential therapeutic application for CB1R inverse agonists in cognitive disorders.

How Ligands Illuminate GPCR Molecular Pharmacology

“…The models further predict that so-called neutral antagonists are likely to be rare, as any ligand will bias the ensemble of spontaneously arising conformations at least to some extent. The predictions that antagonists are actually inverse agonists have been extensively validated in recombinant systems in vitro (Chidiac et al, 1993) and in vivo (Dillon et al, 2011). These models also predict that the active states stabilized by agonist (R*L) might differ conformationally from ternary signaling complexes (R*GL; R*AL).…”

The Behavioral and Neurochemical Changes Induced by Boldenone and/or Tramadol in Adult Male Rats

“…YMT depends on native tendency of rats to explore the new arm of the maze rather than return to the same arm they previously visited [47]. The cerebral cortex is one of the brain regions contributing potentially in this task [48] that can assess cognitive deficits and drug effects on cognition [49]. In addition, the present elevated plus maze test (EPMT) analyses showed a decrease in the time spent by rats treated with boldenone in the open arm.…”

“…This test evaluates both the exploratory and cognitive behaviors associated with spatial learning and memory using the spontaneous alternation behavior as an indicator of spatial working memory, a form of short-term memory [ 46 ].YMT depends on native tendency of rats to explore the new arm of the maze rather than return to the same arm they previously visited [ 47 ]. The cerebral cortex is one of the brain regions contributing potentially in this task [ 48 ] that can assess cognitive deficits and drug effects on cognition [ 49 ]. In addition, the present elevated plus maze test (EPMT) analyses showed a decrease in the time spent by rats treated with boldenone in the open arm.…”

Diet‐dependent modulation of hippocampal expression of endocannabinoid signaling‐related proteins in cannabinoid antagonist‐treated obese rats

“…Taking together the effect of high levels of plasmatic triglycerides on long‐term synaptic potentiation and the effect of CB1 activation on long‐term depression, both caused by a HFD‐induced obesity, we can expect an important neuronal dysfunction in the hippocampus of obese animals. Previous studies showed that treatment with CB1 receptor antagonists/inverse agonists not only reduced body weight, increased hippocampal neurogenesis and down‐regulated ECS (Rivera et al ., ; present study), but also enhanced cognitive performance (Terranova et al ., ; Wolff & Leander, ; Takahashi et al ., ; Dillon et al ., ). From this perspective, we can suggest that an excess of CB1 receptors and endocannabinoid synthesis activated by a HFD can lead to obesity, which in turn increases the synthesis of endocannabinoids and, probably, the desensitization of the CB1 receptor.…”