Findings of increased Gsα levels and forskolin‐stimulated adenylyl cyclase activity in selective cerebral cortical postmortem brain regions in bipolar affective disorder (BD) implicate increased cyclic AMP (cAMP)‐mediated signaling in this illness. Accumulating evidence suggests that intracellular levels of cAMP modulate the abundance and disposition of the regulatory subunits of cAMP‐dependent protein kinase (cAMP‐dPK). Thus, in the present study, we tested further whether hyperfunctional Gsα‐linked cAMP signaling occurs in BD by determining [3H]cAMP binding, a measure of the levels of regulatory subunits of cAMP‐dPK, in cytosolic and membrane fractions from discrete brain regions of postmortem BD brain. Specific [3H]cAMP (5 nM) binding was determined in autopsied brain obtained from 10 patients with DSM‐III‐R diagnoses of BD compared with age‐ and postmortem delay‐matched controls. [3H]cAMP binding was significantly reduced across all brain regions in cytosolic fractions of BD frontal (−22%), temporal (−23%), occipital (−22%) and parietal (−15%) cortex, cerebellum (−36%), and thalamus (−13%) compared with controls, but there were no differences in [3H]cAMP binding in the membrane fractions from these same regions. These results suggest that changes occur in the cAMP‐dPK regulatory subunits in BD brain, possibly resulting from increased cAMP signaling. The possibility that antemortem lithium and/or other mood stabilizer treatment may contribute to the above changes, however, cannot be ruled out.
Until recently, research on the neurochemical basis of affective disorders (AD) and schizophrenia (SCZ) focused on detecting postulated disturbances in presynaptic neurotransmitter release and metabolism, or postsynaptic receptor function. New insights into the molecular mechanisms involved in the propagation of neurotransmitter signals across biological membranes and in the regulation of neuronal responses have allowed the development of novel hypotheses, which may explain the altered postsynaptic neuroreceptor responsivity thought to be integral to the pathophysiology of these disorders. In this review we evaluate evidence from both basic science and clinical research implicating disturbances in postreceptor signal transduction in the pathophysiology and pharmacotherapy of AD and SCZ. Specific findings regarding potential postreceptor sites of pathophysiology are highlighted in each of these disorders, together with the growing body of data on the possible postreceptor loci of psychotropic drug action, especially lithium and antidepressants.
] B (n = 6) (−59%, P = 0.0004). A significant negative correlation was observed between IMPA2 mRNA levels and [Ca 2+ ] B in BLCLs from male (P = 0.046), but not female BD-I patients. Sex-dependent differences were also evident in postmortem temporal cortex IMPA2 mRNA levels which, in contrast to BLCLs, were significantly higher in male BD-I subjects compared with male controls (P = 0.025, n = 4/group). Collectively, these observations suggest a potential sex-dependent link between abnormalities in IMPA2 expression and calcium homeostasis in the pathophysiology of BD. Molecular Psychiatry (2001) 6, 678-683.
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