Our findings are consistent with a selective reduction in DARPP-32 levels in schizophrenic subjects. This may be involved in the prefrontal dysfunction associated with schizophrenia.

No abstract

Isoflurane is an effective neuroprotective drug in a canine cardiac arrest model in terms of both functional and biochemical criteria.

Halothane acutely stimulated basal protein kinase C activity in synaptosomes when assayed with endogenous nerve terminal substrates, lipids, and protein kinase C. This effect appeared to be selective for protein kinases C, because two other structurally similar second messenger-regulated protein kinases were not affected. Direct determinations of anesthetic effects on endogenous protein kinase C activation, translocation, and/or down-regulation are necessary to determine the ultimate effect of anesthetics on the protein kinase C signaling pathway in intact cells.

Protein kinase C (PKC) is a key regulatory enzyme that has been implicated as a molecular target for the action of general anaesthetics. We have determined the effects of halothane on the translocation and down-regulation of conventional PKC (cPKC) by analysing the subcellular distribution of PKC activity, [3H]phorbol-12,13-dibutyrate ([3H]PDBu) binding and PKC immunoreactivity in intact rat cerebrocortical synaptosomes, a subcellular fraction that contains functional nerve terminals. Halothane alone (2.4 vol%) reduced membrane-associated (P < 0.05) and increased cytosol (P < 0.01) PKC activity, while phorbol-12-myristate, 13-acetate (PMA) 0.1 mumol litre-1, a metabolically stable activator of PKC, reduced membrane (P < 0.01) without altering cytosol PKC activity. Halothane and PMA in combination reduced membrane PKC activity to undetectable levels and reduced cytosol PKC activity (P < 0.01). Halothane alone had no significant effects on the distribution of [3H]PDBu binding, while PMA alone significantly reduced both membrane and cytosol [3H]PDBu binding (P < 0.01). Halothane and PMA in combination reduced membrane and cytosol [3H]PDBu binding further, but this effect was not significantly different from the effect of PMA alone. Experiments using isoform-selective antibodies to PKC alpha, PKC beta or PKC gamma demonstrated synergistic interactions between halothane and PMA in promoting translocation of the three conventional PKC isoforms from the cytosol to the membrane fraction of synaptosomes and down-regulation of their immunoreactivity. Halothane and PMA together reduced cytosol PKC alpha/beta/gamma immunoreactivity significantly more (P < 0.05) than PMA alone. Halothane thus has two distinct actions on PKC in synaptosomes: activation of endogenous PKC activity and potentiation of activation-induced cPKC translocation and down-regulation. These potentially competing effects may underlie some of the conflicting results obtained with halothane on PKC-mediated processes in intact cells.