The Effects of Memantine on Prepulse Inhibition

Abstract

Background Reduced prepulse inhibition (PPI) of startle provides evidence of deficient sensorimotor gating in several disorders, including schizophrenia. The role of NMDA neurotransmission in the regulation of PPI is unclear, due to cross-species differences in the effects of NMDA antagonists on PPI. Recent reports suggest that drug effects on PPI differ in subgroups of normal humans that differ in levels of baseline PPI or specific personality domains; here, we tested the effects of these variables on the sensitivity of PPI to the NMDA antagonist, memantine. Methods PPI was measured in male Sprague-Dawley rats, after treatment with memantine (0, 10 or 20 mg/kg, sc). Baseline PPI was then measured in 37 healthy adult men. Next, subjects were tested twice, in a double-blind crossover design, comparing either: 1) placebo vs. 20 mg of the NMDA antagonist memantine (n=19), or 2) placebo vs. 30 mg memantine (n=18). Tests included measures of acoustic startle amplitude, PPI, autonomic indices and subjective self-rating scales. Results Memantine had dose- and interval-dependent effects on PPI in rats: compared to vehicle, 10 mg/kg increased short-interval (10-20 ms) PPI, and 20 mg/kg decreased long-interval (120 ms) PPI. In humans, memantine caused dose-dependent effects on psychological and somatic measures: 20 mg was associated with increased ratings of happiness, and 30 mg was associated with increased ratings of dizziness. PPI at the 120 ms prepulse interval was increased by 20 mg but not 30 mg of memantine. Subgroups most sensitive to the PPI-enhancing effects of memantine were those with low baseline PPI, or with personality scale scores suggestive of high novelty seeking, high sensation seeking, or high disinhibition. Conclusion NMDA blockade with memantine appears to have dose- and interval-dependent effects on sensorimotor gating in rats and humans, particularly among specific subgroups of normal human subjects. These findings are discussed as they relate to consistencies across other studies in humans, as well as apparent inconsistencies in the NMDA regulation of PPI across species.

Animal Models of Deficient Sensorimotor Gating in Schizophrenia: Are They Still Relevant?

“…Based on this PPI enhancement, and reports of PPI-enhancing effects of ketamine and amantadine in healthy subjects (HS), we speculated that memantine would potentiate PPI in HS. Indeed, we reported that 20 mg memantine (po) enhanced PPI modestly across all HS (Swerdlow et al 2009) and that this effect was most robust among HS with low basal PPI levels (Fig. 1a), and among HS scoring high on personality scales for novelty seeking, sensation seeking, and disinhibition.…”

“…While NMDA antagonists are generally reported to disrupt PPI in rodents, PPI is actually increased in healthy subjects (HS) by NMDA antagonists such as ketamine (Duncan et al 2001;Abel et al 2003) and by the mixed NMDA antagonist/dopamine agonist, amantadine (Swerdlow et al 2002). In intact rats, we detected PPI-enhancing effects of memantine, using relatively short (10-30 ms) prepulse intervals (Swerdlow et al 2009). Based on this PPI enhancement, and reports of PPI-enhancing effects of ketamine and amantadine in healthy subjects (HS), we speculated that memantine would potentiate PPI in HS.…”

“…Conceivably, this plasticity may represent a neural resource that could be engaged in a therapeutic capacity, Fig. 1 a PPI in healthy subjects (HS) tested in a double-blind, placebo-controlled study of memantine (0 vs. 20 mg po), reported in Swerdlow et al (2009). Data from all subjects are at left; at right, results are divided to show individuals with low versus high baseline PPI (grouped based on a median split).…”

Memantine Effects On Sensorimotor Gating and Mismatch Negativity in Patients with Chronic Psychosis

“…Interestingly, whereas NMDA systems have been implicated in the regulation of both PPI and MMN, the evidence linking reduced NMDA activity to deficits in PPI and/or MMN is not entirely straightforward. Thus, PPI is actually increased in healthy subjects (HS) by NMDA antagonists such as ketamine (Duncan et al, 2001;Abel et al, 2003), the low-to moderate-affinity NMDAreceptor antagonist, memantine (Swerdlow et al, 2009), and by the mixed NMDA antagonist/dopamine agonist, amantadine (Swerdlow et al, 2002b). Although MMN has been reported to be reduced in HS by ketamine (Umbricht et al, 2000;Umbricht et al, 2002), it has also been shown to be increased by memantine (Korostenskaja et al, 2007).…”

“…Memantine does not cause the sensory or dissociative symptoms produced by ketamine (Duncan et al, 2001;Abel et al, 2003;Umbricht et al, 2002), which might complicate the interpretation of changes in PPI and MMN. Doses (10 and 20 mg, po) were selected based on published reports in HS, which noted dizziness and other mild adverse reactions at higher doses (Swerdlow et al, 2009).…”