Competitive and noncompetitive NMDA antagonist effects in rats trained to discriminate lever-press counts

Memantine Blocks α7* Nicotinic Acetylcholine Receptors More Potently Than N-Methyl-D-aspartate Receptors in Rat Hippocampal Neurons

“…Taking these facts into account, memantine-induced ␣7* nAChR inhibition could explain the report that in healthy, young human subjects memantine impairs eyeblink conditioning (Schugens et al, 1997), a response that is modulated by the cholinergic system and is known to discriminate between aging related and probable AD cognitive deficits (Woodruff-Pak, 2001). It could also underlie the impairment of short-term memory processing observed in rats treated with memantine (Willmore et al, 2001). Thus, ␣7* nAChR inhibition by memantine could be counterproductive to its effectiveness in AD, particularly at early stages of the disease, when deterioration of cognitive functions correlates well with the degree of nicotinic cholinergic dysfunction (Francis et al, 1985;Perry et al, 2000;Nordberg, 2001;Sabbagh et al, 2001); the benefit of inhibiting excessive tonic NMDA receptor activity with memantine could be counteracted and eventually outweighed by the concomitant ␣7* nAChR inhibition.…”

“…In contrast, in placebo-controlled studies of patients with mild-to-moderate vascular dementia, a complex disorder in which the cholinergic system is also compromised (Gratham and Geerts, 2002), memantine caused a small, albeit significant, cognitive improvement that was not clinically perceived, given that it was not accompanied by amelioration of the global clinical impression of change (Wilcock, 2003). Furthermore, there is evidence that, resembling nicotinic antagonists (Levin, 2002), memantine impairs cognition in laboratory animals (Willmore et al, 2001) and healthy human subjects (Schugens et al, 1997). In particular, a single dose of memantine (30 mg) administered orally to young, healthy humans impairs the eyeblink classical conditioning (Schugens et al, 1997), a form of associative learning that is modulated by the nicotinic cholinergic system and differentiates cognitive deficits in normal aging and probable AD (Woodruff-Pak, 2001).…”

Comments on “Memantine Blocks α7* Nicotinic Acetylcholine Receptors More Potently Than N-Methyl-d-aspartate Receptors in Rat Hippocampal Neurons”

“…using a 4-week up-titration scheme starting at 5 mg once daily (Reisberg et al, 2003). Aracava et al (2005) also state that memantine can impair short-term memory processing in rats since memantine reduced accuracy in fixed consecutive number tasks (Willmore et al, 2001). However, the cited study also states that memantine reduced the accuracy in the above task only at doses that reduced response rates, indicating that this was a nonspecific effect of memantine, and at high doses that are not clinically relevant.…”

Response: Comments on “Memantine Blocks α7* Nicotinic Acetylcholine Receptors More Potently Than N-Methyl-d-aspartate Receptors in Rat Hippocampal Neurons”

“…However, as the authors pointed out in their comments, the reduction of accuracy by memantine cannot be unambiguously attributed to memory impairment, because at the doses that memantine reduced response accuracy, it also decreased response rates (Willmore et al, 2001). Nevertheless, memantine decreased task accuracy with ED 50 values ranging from 4.2 to 12.0 mg/kg (Willmore et al, 2001); these doses are significantly lower than those used experimentally to ameliorate memory impairment induced by excessive glutamatergic activation in rats (Misztal et al, 1996) and those recommended clinically for AD treatment (Reisberg et al, 2003). Identifying the doses at which memantine selectively decreases response accuracy in this test would probably depend on increasing the complexity of the task (Willmore, 2003).…”

“…The clinical relevance of the finding that memantine reduces the accuracy and rate of response of rats in a fixed consecutive number task (Willmore et al, 2001) has been questioned by Banerjee et al In general, a decreased performance in fixed consecutive number tasks is indicative of disruption of working memory (Sanger, 1992). However, as the authors pointed out in their comments, the reduction of accuracy by memantine cannot be unambiguously attributed to memory impairment, because at the doses that memantine reduced response accuracy, it also decreased response rates (Willmore et al, 2001).…”