Decreasing nicotinic receptor activity and the spatial learning impairment caused by the NMDA glutamate antagonist dizocilpine in rats

Abstract

Nicotinic systems have been shown by a variety of studies to be involved in cognitive function. Nicotinic receptors have an inherent property to become desensitized after activation. The relative role of nicotinic receptor activation vs. net receptor inactivation by desensitization in the cognitive effects of nicotinic drugs remains to be fully understood. In these studies, we tested the effects of the α7 nicotinic receptor antagonist methyllycaconitine (MLA), the α4β2 nicotinic receptor antagonist dihydro-β-erythroidine (DHβE), the nonspecific nicotinic channel blocker mecamylamine and the α4β2 nicotinic receptor desensitizing agent sazetidine-A on learning in a repeated acquisition test. Adult female Sprague-Dawley rats were trained on a repeated acquisition learning procedure in an 8-arm radial maze. MLA (1–4 mg/kg), DHβE (1–4 mg/kg), mecamylamine (0.125–0.5 mg/kg) or sazetidine-A (1 and 3 mg/kg) were administered in four different studies either alone or together with the NMDA glutamate antagonist dizocilpine (0.05 and 0.10 mg/kg). MLA significantly counteracted the learning impairment caused by dizocilpine. The overall choice accuracy impairment caused by dizocilpine was significantly attenuated by co-administration of DHβE. Low doses of the non-specific nicotinic antagonist mecamylamine also reduced dizocilpine-induced repeated acquisition impairment. Sazetidine-A reversed the accuracy impairment caused by dizocilpine. These studies provide evidence that a net decrease in nicotinic receptor activity can improve learning by attenuating learning impairment induced by NMDA glutamate blockade. This adds to evidence in cognitive tests that nicotinic antagonists can improve cognitive function. Further research characterizing the efficacy and mechanisms underlying nicotinic antagonist and desensitization induced cognitive improvement is warranted.

A novel nicotinic mechanism underlies β-amyloid-induced neurotoxicity

“…Another possibility is that the internalization of Ab is facilitated by its high-affinity binding to the a7-nAChRs on neuronal cell surfaces, followed by endocytosis of the resulting complex and its intracellular accumulation that provokes neurotoxicity (Nagele et al, 2002). Interestingly, recent studies also reported that blockade of nicotinic receptors can effectively attenuate the attentional impairments (Burke et al, 2014;Levin et al, 2013). Our results suggest that deletion or inhibition of the a7 nAChR subtype prevents Ab-induced cytotoxicity, which are consistent with these findings.…”

Galantamine anti-colitic effect: Role of alpha-7 nicotinic acetylcholine receptor in modulating Jak/STAT3, NF-κB/HMGB1/RAGE and p-AKT/Bcl-2 pathways

“…In the second set of experiment, rats (n = 36) were allocated equally into 2 control groups (normal and TNBS), one reference group (Sulfz), one treated with blocker alone (methylcaconitine citrate [MLA], 5.6 mg/kg, i.p; Tocris Bioscience, Bristol, UK) and 2 treated with Galan 10 , with and without MLA. The blocker was administered 15 min before Galan 10 and was dissolved immediately before injection in saline solution 23 , 24 . Animals were subjected to TNBS-induced colitis as mentioned before, except for the normal control group.…”

Is Memantine Effective as an NMDA Receptor Antagonist in Adjunctive Therapy for Schizophrenia?

“…The IC 50 values were approximately two-fold higher compared to the therapeutically relevant serum concentrations (around 1 μM), suggesting that the effects of adjunctive administration of memantine on negative symptoms does not seem to derive mainly from its 5-HT 3 receptor antagonist activity. Memantine has complex actions on α4β2, α7, and other nicotinic cholinergic receptors [ 90 ], and these actions may be related to the amelioration of cognitive impairments in schizophrenia [ 90 , 92 ]. However, it was reported that memantine inhibits α4β2 responses with an IC 50 of 6.6 or 11.3 μM; these concentrations are much higher than the therapeutic concentrations (around 1 μM) [ 55 ].…”