Are the disparate pharmacological profiles of competitive and un-competitive NMDA antagonists due to different baseline activities of distinct glutamatergic pathways? (Hypothesis).

Corticostriatal glutamatergic neurons impinging on the so-called "direct" striato-thalamic pathways appear to act as a driving force with respect to psychomotor functions, whereas corticostriatal glutamatergic neurons projecting to the "indirect" striato-thalamic route appear to mediate inhibition of the thalamus and thus act as a "brake" with respect to psychomotor functions. The GABAergic striatal projection neurons pertaining to the "direct" pathway mediating behavioural stimulation appear to be phasically activated, whereas GABAergic striatal projection neurons pertaining to the "indirect" pathway mediating suppression of behaviour must be assumed to display a high tonic activity. Such an organization could explain some of the behavioural differences between competitive and un-competitive NMDA antagonists, since the binding of competitive NMDA antagonists is inhibited by glutamate, whereas the binding of un-competitive NMDA antagonists is enhanced by the presence of NMDA receptor agonists, a phenomenon called use/agonist dependence.