Figure 4

Lack of effect of NitroMemantine on EPSCs, LTP and Morris water maze.

(a) Whole-cell recordings of evoked EPSCs from hippocampal autapses. The NMDAR-mediated component of the EPSC was blocked to a lesser extent by 10 μM NitroMemantine YQW-036 than by 10 μM memantine. The AMPA component of the EPSC has been blocked with 20 μM CNQX. As a control, 50 μM (2R)-amino-5-phosphonopentanoate (d-AP5), a competitive antagonist of the glutamate binding site, completely blocked the NMDAR component of the EPSC. (b) The degree of blockade of the EPSC did not significantly increase with repeated electrical stimulation (pulses 1–10) in the presence of NitroMemantine YQW-036. (c) The inhibitory effect of memantine was use-dependent with the 10^th-elicited EPSC being blocked more than the 1^st. Hence, equimolar memantine blocks neurotransmission to a greater degree than NitroMemantine. For each panel, data are representative from n ≥ 4 patch-clamp recordings. (d) Neuroprotective dose of NitroMemantine (NitroMem, 10 μM) did not inhibit LTP in hippocampal CA1 induced by high-frequency burst in rat hippocampal slices. (e) As a control in the LTP experiments, MK-801 (equimolar, 10 μM) completely inhibited LTP induction (n ≥ 4 slices for panels d and e). (f) Lack of effect of NitroMemantine on Morris water maze performance. Water-maze testing of adult male spontaneously hypertensive rats (SHR) treated with NitroMemantine or vehicle. Rats were acclimated to the water maze on day 1 and then tested on the following 4 days, with 6 trials/day for a total of 24 trials. The platform position was changed every day and release points for each trial varied in a pseudorandom manner. All values are mean ± s.e.m.; n = 5 for each group. The peaks at trials 7 and 13 represent the result of the first trial on days 2 and 3 of testing and indicate that the animals exhibited some degree of ‘forgetfulness’ for the task overnight and had to re-learn. By day 4 (trial 19), the animals learned the new position of the platform more rapidly.