Symptomatological Effects of Memantine

Long-Term Potentiation Recording electrode Stimulating electrode DG CA3 CA1 Technique in hippocampal slices Frankiewicz & Parsons, Neuropharmacology 1999

% Control EPSP Amplitude Time (min) Memantine completely restored LTP Stimulation (100 Hz) Control LTP Memantine Counteracted Deficits in LTP Induced by Low Mg 2+ MK-801 failed to restore LTP Deficit in LTP after Mg 2+ removal

Habituation Day 1 Start box (light) Choice box (light) Choice box (dark) Training Day 2 Test Parameters The latency to enter the dark box Retention Test Day 3 Passive Avoidance Learning: Experimental Setting Reinforcement 2 shocks when entering the dark box Zajaczkowski et al. Neuropharmacology 1997 injection

Zajaczkowski et al. Neuropharmacology 1997 Memantine Attenuated Learning Deficits Induced by NMDA Passive avoidance learning Latency to enter the dark box (% of control) * p < 0.05 versus NMDA NMDA 25 mg/kg NMDA + Memantine 1,25 mg/kg NMDA + Memantine 2,5 mg/kg NMDA + Memantine 5 mg/kg ** Control (300 sec)

Quinolinic acid lesion of the entorhinal cortex 4 days Radial maze learning 4 trials/day for 12 days Zajaczkowski et al., Eur J Pharmacol 1996 Symptomatological effects Implantation of mini-pump/ Infusion of memantine (s.c. 20 mg/kg/day) 1 week Memantine in an Animal Model for Neurodegenerative Dementia

Memantine in an animal model for neurodegenerative dementia Memantine Did Not Restore Working Memory 0,4 0,3 0,2 0,1 0 Blocks of 2 days Zajaczkowski et al., Eur J Pharmacol 1996 * p < 0.05 versus sham operated for the whole learning period 0,4 0,3 0,2 0,1 0 * * Frequency of working memory errors Sham operated Lesion Lesion + memantine

Memantine in an animal model for neurodegenerative dementia Memantine Restored Reference Memory Zajaczkowski et al., Eur J Pharmacol 1996 * p < 0.05 versus lesion for the whole learning period 0,50 0,45 0,40 0,35 0,30 0, * Blocks of 2 days Frequency of reference memory errors Sham operated Lesion Lesion + memantine

Summary Long term potentiation is an in vitro correlate for memory formation. Memantine counteracted a deficit of long term potentiation induced by tonic NMDA receptor activation (increased background noise) Memantine counteracted amnestic effects of continuous NMDA receptor stimulation (increased background noise) in the passive avoidance task Memantine infusion (20 mg/kg/day, therapeutic serum levels) restored reference memory in rats with entorhinal cortex lesion Conclusion Clinically relevant doses of memantine may produce symptomatological improvements in learning and memory under conditions of tonic NMDA receptor activation and neurodegeneration (e.g. in Alzheimer´s Disease)