all cases of schizophrenia share the same single major locus (SML).

Using nonspecific probes for the whole GluR1 family, Kerwin et al. () found reductions in mRNA GluR1 levels in CA3 regions in hippocampi of schizophrenics (). Investigations by the same group with more specific probes (i.e., GluR1, GluR2, GluR6&7 and KA 1&2) showed that all of these were significantly reduced in schizophrenics (). Similarly, Collinge and Curtis () observed a dramatic loss of mRNA AMPA receptors in the hippocampus of schizophrenics, compared with controls. Eastwood et al. (), using hybridization histochemistry with probes specific for two non-NMDA (AMPA) receptor subtypes (GluR1 and GluR2, showed that mRNAs for GluR1 and GluR2 were regionally decreased in dentate gyrus, CA4, CA3 and subiculum, while GluR2 mRNA was reduced in the parahippocampal gyrus. Breese et al. (8) measured antibodies to functional AMPA/kainate (GluR1-3) sites and to kainate binding sites (GluR5-7) in the hippocampi and cingulate cortex of schizophrenic subjects and non-psychotic controls (normals and subjects with a previous history of alcohol abuse). No significant differences were found for any of the GluR receptor subtypes in schizophrenics, compared with only the normal controls.


Dopamine plays a key role in biochemical hypotheses of schizophrenia.

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).

Dopamine hypothesis of schizophrenia - ScienceDaily

by proposing “a noradrenaline hypothesis of schizophrenia

The dopamine hypothesis is schizophrenia’s most venerable (see ), and was initially based on the observation that antipsychotic drugs are dopamine antagonists. The hypothesis posits that hyperactive dopamine signaling in subcortical brain regions is responsible for the positive symptoms of the illness, and has been bolstered by findings of increased striatal D2/3 receptor density and dopamine in postmortem tissue (), and elevations in cerebrospinal fluid (CSF) dopamine levels (). Positron emission tomography (PET) and single-photon emission computerized tomography (SPECT) studies have enabled the in-vivo measurement of dopamine function in the illness, and the large number of these studies affords the opportunity for meta-analysis.

Dopamine, schizophrenia, mania, and depression: …

the impact of norepinephrine in both schizophrenia and ..

The identification of glycine transport inhibitors provided a new and exciting approach to the development of alternative antipsychotic compounds (). Two classes of glycine transporters have been cloned and identified. These are GlyT1 and related subunits (GlyT1a-c), which are present in forebrain and colocalize with NMDA-R, and Gly T2, found in spinal cord and brain stem, and which colocalizes with strychnine-sensitive glycine receptors. The glycine transporters are high-affinity and regulate extracellular glycine. Inhibitors to the Gly transporters have been identified. Of these, the most potent is TxRx 5311 which is active at the GlyT1c receptors. experiments in rats showed that the GlyT1 transport inhibitors decreased PCP-induced increases in locomotor activity. Research data suggests that these compounds are selective for NMDA-R channel activity, the site where PCP is active (). These substrates may be more effective than glycine in the treatment of schizophrenia (). Since schizophrenic patients with low pretreatment glycine levels are the most likely to respond to glycine agonists (), this subgroup of patients may be particularly good responders to treatment with glycine transport inhibitors.

Dopamine Hypothesis of Schizophrenia Revisited | …

Dopamine Hypothesis of Schizophrenia Revisited

The principal assumption is that normal brain development is disrupted in specific ways at critical periods and the resulting lesion produces the symptoms of schizophrenia only through interaction with the normal maturation processes in the brain, which occur in late adolescence or early adulthood.