EFFECTS OF NMDA-R1 ANTISENSE OLIGODEOXYNUCLEOTIDE ADMINISTRATION - BEHAVIORAL AND RADIOLIGAND BINDING-STUDIES

The effects of an antisense phosphodiester oligodeoxynucleotide (ODN) directed to the NR1 subunit of the NMDA receptor mRNA and of its corre sponding sense ODN were investigated in mice, Treatment with the antis ense ODN significantly increased the time mice spent in the open arms of an elevated maze while the total number of arm entries was unaltere d. Furthermore, seizure latencies after the administration of an ED100 dose of NMDA (150 mg/kg) were significantly higher in antisense treat ed animals compared to vehicle controls. At the same time, treatment w ith NR1 antisense ODN significantly reduced the B-max of [H-3]CGS-1975 5 binding (2101 fmol/mg protein) compared to both vehicle (2787 fmol/m g protein) and sense (2832+/-39 fmol/mg protein) controls without any significant change in K-D (33 nM). A corresponding reduction of [H-3]C GP-39653 binding was also observed after treatment with NR1 antisense compared to both sense and vehicle controls. In contrast, neither anti sense nor sense ODNs altered the proportion of high affinity glycine s ites or the potency of glycine at either high or low affinity glycine binding sites to inhibit [H-3]CGP-39653 binding. These results show th at in vivo treatment with NR1 antisense ODNs to the NMDA receptor comp lex reduces antagonist binding al NMDA receptors and has pharmacologic al effects similar to those observed with some NMDA receptor antagonis ts. These results also suggest that treatment with antisense ODNs may provide another means to investigate allosteric modulation of receptor subtypes in vivo.