Figure 1.

Role of nNOS in TDS stress. Immediately after an acute stress, NO is released via the action of adrenal glucocorticoids and the sequential release of glutamate in the hippocampus, activation of NMDA receptors, and the influx of Ca²⁺ leading to the activation of nNOS. 5HT released as a consequence of stress acts on 5HT2 receptors activating constitutive nNOS via the protein kinase C (PKC) pathway. NO then exerts various neuromodulatory effects (Prast and Phillippu 2001) as well as promotes the cellular processes of plasticity and memory either via itself, or by the synthesis of its second messenger, cGMP. However, NO prevents this cascade from progressing indefinitely by inhibiting its own synthesis (nNOS), inhibiting NMDA receptor function, promoting GABA release that further attenuates glutamate activity and by inhibiting the expression of iNOS. 5HT also inhibits guanylate cyclase-cGMP, thereby also effectively down-regulating the NO-pathway. Raised glucocorticoids inhibit cytokine release preventing any possible mobilization of iNOS. Shortly after the immediate response to a stressful event, glucorticoids then shut down the cortisol response by feedback inhibition of the HPA axis. Solid lines indicate activation; broken lines indicate inhibition. (Abbreviations are listed at the end of the paper.)