POSTSYNAPTIC SEROTONIN RECEPTORS
Biochemical hypotheses of schizophrenia
The role of 5-HT in stimulating the HPA axis encompasses effects on CRH by activation of 5-HT and 5-HT/5-HT receptors and on AVP by activation of 5-HT receptors (5, 18). Recently, it has been demonstrated that serotonergic structures may modify glucocorticoid negative-feedback effects on HPA-axis function. Seckl and Fink (65) found that depletion of 5-HT in hippocampal structures may attenuate the negative-feedback effects of glucocorticoids on the HPA axis through reduced expression of GR or MR. In depression, a significant negative correlation between plasma TRP availability and baseline cortisoladjusted post-DST cortisol values was found, suggesting that lower presynaptic 5-HT activity is related to escape of negative-feedback inhibition (44). This suggests the possibility that a diminished central 5-HT neurotransmission in major depression may attenuate the hippocampal negative-feedback control over the HPA axis, thus inducing excessive corticosteroid secretion. Treatment with TRP (3.5 to 7 g/day) for 1 to 2 weeks has been shown to improve DST nonsuppression in depressed subjects (59). Therefore, it may be hypothesized that TRP treatment may have restored the serotonergic deficit in the hippocampus, thus increasing the negative feedback over the HPA axis. Treatment with fluoxetine and imipramine may also increase the level of MR messenger ribonucleic acid (mRNA), thus increasing the efficacy of the negative feedback on hypothalamic CRH mRNA (4). Other results may indicate that upregulation of postsynaptic 5-HT receptors in major depression is related to escape of ACTH/cortisol secretion from negative-feedback effects; compared with patients who had minor depression, those with a diagnosis of major depression exhibited a significant enhancing effect of 5-HTP (125 to 200 mg) on post-DST ACTH or cortisol values, although 5-HTP converted DST cortisol or ACTH suppression into nonsuppression in some major depressed subjects (40).
Basis of classical dopamine hypothesis of schizophrenia
The hippocampus has been demonstrated to be a site of serotonergic innervation associated with CNS control of the HPA-axis. A good correlation exists between the concentrations of cellular receptors for 5-HT and glucocorticoids. There is now compelling evidence that glucocorticoids may accelerate 5-HT synthesis and turnover in the brain of rodents (8). Increased central 5-HT turnover is, in part, caused by glucocorticoid or CRH-mediated induction of tryptophan hydroxylase (68). In humans, glucocorticoids may also augment central 5-HT turnover; some groups found that TRP-induced prolactin responses were significantly higher after dexamethasone administration and found increased levels of CSF 5-HIAA after administration of dexamethasone in a group of psychiatric patients (71).