DUAL EFFECTS OF ANANDAMIDE ON NMDA RECEPTOR-MEDIATED RESPONSES AND NEUROTRANSMISSION

Anandamide is an endogenous ligand of cannabinoid receptors that induc es pharmacological responses in animals similar to those of cannabinoi ds such as Delta(9)-tetrahydrocannabinol (THC). Typical pharmacologica l effects of cannabinoids include disruption of pain, memory formation , and motor coordination, systems that all depend on NMDA receptor med iated neurotransmission, We investigated whether anandamide can influe nce NMDA receptor activity by examining NMDA-induced calcium flux (Del ta Ca-NMDA(2+)) in rat brain slices, The presence of anandamide reduce d Delta Ca-NMDA(2+) and the inhibition was disrupted by cannabinoid re ceptor antagonist, pertussis toxin treatment, and agatoxin (a calcium channel inhibitor), Whereas these treatments prevented anandamide inhi biting Delta Ca-NMDA(2+), they also revealed another, underlying mecha nism by which anandamide influences Delta Ca-NMDA(2+). In the presence of cannabinoid receptor antagonist, anandamide potentiated Delta Ca-N MDA(2+) in cortical, cerebellar, and hippocampal slices, Anandamide (b ut not THC) also augmented NMDA-stimulated currents in Xenopus oocytes expressing cloned NMDA receptors, suggesting a capacity to directly m odulate NMDA receptor activity, In a similar manner, anandamide enhanc ed neurotransmission across NMDA receptor-dependent synapses in hippoc ampus in a manner that was not mimicked by THC and was unaffected by c annabinoid receptor antagonist, These data demonstrate that anandamide can modulate NMDA receptor activity in addition to its role as a cann abinoid receptor ligand.