Signal Transduction from Synapse to Nucleus
Most psychotherapeutic drugs (eg, antidepressants, antipsychotic drugs, lithium) require long-term administration to be optimally effective. Apparently, acute interaction at various steps in the agonist-receptor-mediated transduction cascades is not directly responsible for their therapeutic effects. The activation of intracellular messenger pathways and the regulation of neuronal gene expression appear to play a central role in long-term adaptive changes in neuronal function. By altering programs of gene expression, the CNS adapts to conditions that threaten the physical and psychic emotional well-being of the organism. Ultimately changes in programs of gene expression determine the intensities of incoming signals; the sensitivities of neuronal systems to those signals; and the nature, amplitude, and duration of CNS responses (ie, the plasticity of the CNS). In this way, the clinically important actions of psychotropic drugs can be viewed as the restoration of neural plasticity, a plasticity that appears to be impaired in patients with affective or cognitive disorders.
Changes in gene expression in the brain have been reported following long-term administration of antidepressants and antipsychotic drugs. Of particular interest is the role of transcription factors in the neural plasticity restored by psychotropic drugs. Transcription factors are proteins that bind to specific sequences in the promoter regions of genes and thereby increase or decrease the rate at which those genes are transcribed. Transcription factors of particular interest in neuropharmacology are steroid and thyroid hormone receptors, the cyclic adenosine monophosphate responsive element-binding -protein- (CREB)/ATF family and the family of immediate early gene products (eg, cFos, cJun). The regulation of transcription factors and their importation from the cytoplasm into the nucleus fine-tunes gene expression. It is of neurobiological and clinical interest that the density of glucocorticoid (GRII) receptors and their mRNA are increased following extended treatment with some antidepressants. The increase in GRII receptors following antidepressant treatment could be responsible—via feedback inhibition—for the normalization of the hyperactive hypothalamic-pituitary-adrenal axis often associated with depression. The long-term administration of several antidepressants, such as norepinephrine and 5-HT reuptake inhibitors, increases the expression of CREB in the rat hippocampus. The CREB transcription factor could be an intracellular target for antidepressants. Researchers have analyzed the expression of Fos-like transcription factors after the administration of antipsychotic drugs. Several clinically effective typical antipsychotics induce cfos in the striatum and nucleus accumbens, whereas clozapine increases fos levels in the prefrontal cortex and nucleus accumbens but not in the striatum. Although the target genes regulated by GRII, Fos, and CREB in brain are largely unknown, these transcription factors play a critical role in the regulation of genes and their products during long-term adaptive responses to antidepressants and other psychotropic drugs. Because most, if not all, transcription factors are phosphoproteins, phosphorylation by protein kinases and dephosphorylation by protein phosphatases play critical roles in changing transcription factor protein conformation into an active-inactive DNA-binding structure. Thus psychotropic drugs could directly or indirectly modify both transcription factor and DNA-binding activity by phosphorylation via PKA, PKC, or calcium/calmodulin-dependent protein kinases, activated via aminergic-receptor-mediated signal transduction pathways (target 5 in Figure 3-8).
