THE ROLE OF NITRIC OXIDE IN ANTIDEPRESSANT ACTIVITY

University Of Mississippi Medical Center, Jackson MS

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Abstract

GRANT=6673590;P20RR Numerous laboratories have published evidence for a significant role of intracellular calcium homeostasis in major depressive disorders. Recent data implicates excitatory amino acid (EAA) neurotransmission in major depression and antidepressant activity. Synaptic activation at EAA receptive neurons is often mediated by the calcium-calmodulin-nitric oxide synthase-guanylyl cyclase cascade. We have recently demonstrated that antagonists of the several isoforms of nitric oxide synthase are as efficacious as imipramine in preclinical behavioral and biochemical screening procedures sensitive to antidepressants. We hypothesize that neuronal NOS inhibitors will produce antidepressant-like effects on behaviors and neurobiological sites know to be affected by antidepressants. Conversely, we hypothesize that the effects of clinically active SRI antidepressants on these behaviors and neurobiological sites is dependent upon their ability to inhibit neocortical NO production by NOS. Our SPECIFIC AIM 1 is to determine whether selective inhibition of nNOS will have antidepressant-like effects in mice. By extension of the central hypothesis, we predict that inhibition of neuronal NOS is absolutely required to produce the selective effects of antidepressants on behavior and neurobiological sites. Our SPECIFIC AIM 2 is to determine whether cotreatment with the nNOS substrate L-arginine will disrupt the effects of known antidepressants on behavior and neurobiological adaptation. SPECIFIC AIM 3 will determine whether the effects of known antidepressants can proceed in mice lacking the nNOS isoform. Conversely, we hypothesize that lesion of monoaminergic neurons which modulate EAA signaling in forebrain will disrupt the ability of classical antidepressant but not neuronal NOS inhibitors to produce antidepressant-like effects in mice. Our SPECIFIC AIM 4 is to determine whether functional monoaminergic neurotransmitter systems are required for the antidepressant-like effects of NOS inhibitors. Finally, we hypothesize that antidepressant treatments will produce an adaptive response in EAA-receptive neurons utilizing nNOS as a subcellular messenger. Our SPECIFIC AIM 5 is to determine whether desensitization of neuronal NOS is produced by antidepressant treatments. We will test these hypotheses by examining the antidepressant-like effects of these treatments: (1) in acute behavioral tests and; (2) on neuronal substrates after chronic treatment.