PRE-084, a σ selective PCP derivative, attenuates MK-801-induced impairment of learning in mice

Abstract

-084, a aselectivePCPderivative, attenuates MK-8Ol-induced impairment of learning in mice. PHARMACOL BIOCHEM BEHAV 49(4) [859][860][861][862][863][864][865][866][867][868][869] 1994.-We investigated the effect of the tr selective PCP derivative PRE-084 on the impairment of learning induced in mice by the noncompetitive NMDA antagonist MK-801. Learning capacities were evaluated using the spontaneous alternation in a Y-maze test for spatial working memory, the step-down passive avoidance and the elevated plus-maze test for long-term memory. At doses about 1 mg/kg IP, PRE-084 significantly attenuated MK-801 (0.2 mg/kg IP) induced impairment of learning. The dose-response curve was bell-shaped which is typical for cognition enhancers. The effect of PRE-084 was antagonized by BMY-14802 (10 mg/kg IP) and suppressed by a chronic treatment with haloperidol (4 mg/kg/day SC for 7 days). Furthermore, PRE-084 did not affect scopolamine (1 mg/kg SC) induced amnesia but significantly attenuated mecamylamine (10 mg/kg IP) induced amnesia. These results show that a sites mediate a modulation of the NMDA receptor complex-dependent learning processes and may similarly affect the cholinergic nicotinic memory processes. Moreover, the PCP derivative PRE-084, acting selectively at a sites, reverses the amnesia induced by a drug acting at the PCP site. , and dextrometorphan bind with a high affinity and stereoselectivity, and the a2 site, which has lower affinity and is not stereoselective for these ligands. Both 1,3-di-(2-tolyl)guanidine (DTG) and haloperidol are nonselective drugs and bind with a similar high affinity to the two classes of sites (25,34,42). Further, it has been shown that haloperidol, rimcazole, o~-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazinebutanol (BMY-14802) and N,N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy)phenyl)-ethylamine hydrochloride (NE-100) appear to act as antagonists in several behavioralTo whom request for reprints should be addressed.tests (23,35,36). On the other hand, it is now clear that these sites are different entities from opiate receptors, for which they were initially classified, and from the high affinity phencyclidine (PCP) binding site (26). The PCP site is located inside the ion channel associated with the N-methyl-Daspartate (NMDA) type of glutamate receptor. Drugs, such as PCP, its more selective derivative TCP, or MK-801, bind with high affinity to this site and lead to a noncompetitive antagonism of the NMDA type of glutamatergic neurotransmission (1,18).Although the pharmacological roles of cr sites are not yet well understood, evidences indicate that they may have several biological functions (32,41). Among them, a facilitatory role 859

The effects of sigma (σ1) receptor‐selective ligands on muscarinic receptor antagonist‐induced cognitive deficits in mice

“…Ligands selective for σ1 receptors have been reported to exert antidepressant-like, anxiolytic and analgesic actions in preclinical studies (Hayashi et al, 2011). In addition, σ1 receptor occupation has been linked to neurorestorative effects and has been suggested as a novel therapeutic target for the treatment of cognition deficit (Maurice et al, 1994;Urani et al, 1998;Maurice, 2002;Espallergues et al, 2007;Antonini et al, 2011;van Waarde et al, 2011;Kourrich et al, 2012).…”

“…Ligands selective for σ1 receptors have been reported to exert antidepressant-like, anxiolytic and analgesic actions in preclinical studies (Hayashi et al, 2011). In addition, σ1 receptor occupation has been linked to neurorestorative effects and has been suggested as a novel therapeutic target for the treatment of cognition deficit (Maurice et al, 1994;Urani et al, 1998;Maurice, 2002;Espallergues et al, 2007;Antonini et al, 2011;van Waarde et al, 2011;Kourrich et al, 2012).Our laboratory previously reported on the neuroprotective properties of the σ1 receptor ligand, LS-1-137, which is a novel N-(benzylpiperidin)phenylacetamide that binds to the σ1 receptor with high affinity (Ki value = 3.2 nM) and exhibits 80-fold binding selectivity for the σ1, over the σ2 receptor . LS-1-137 was found to protect HT-22 neuronal cells from glutamate-induced cell death and LS-1-137 was found in vivo to significantly reduce the ischaemic lesion volume in rats using a transient middle cerebral artery occlusion model of stroke (Luedtke et al, 2012).…”

Purification, molecular cloning, and expression of the mammalian sigma1-binding site.

“…Endogenous sigma-ligands are not known, although progesterone has been suggested to be one of them (7)(8)(9). Possible sigma-site-mediated drug effects include modulation of glutamate receptor function, neurotransmitter response, neuroprotection, behavior, and cognition (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22). Most of these studies implied that sigma-binding sites are plasmalemmal elements of the signal transduction cascade.…”

Cav2.2-mediated NMDA receptor signaling in short-term memory

“…Pharmacological studies have showed that NMDA receptor antagonists impair the cognitive functions [21][22][23] and that NMDA receptor agonists enhance memory tasks [24]. Previous studies have demonstrated that systemic injection of CPP dose-dependently inhibited spatial short-term memory in the Y maze test [17].…”