Peptide signaling paths related to intoxication, memory and addiction

Many peptides bind to G protein-coupled receptors and activate intracellula r signaling paths for adaptive cellular responses. The components of these paths can be affected by signals from other neurotransmitters to produce ov erall integrated results not easily predicted from customary a priori consi derations. This intracellular cross-talk among signaling paths provides a " filter" through which long-term tonic signals affect short-term phasic sign als as they progress toward the nucleus and induce long-term adaptation of gene expression which provide enduring attributes of acquired memories and addictions. Peptides of the PACAP family provide intracellular signaling th at involves kinases, scaffolding interactions, Ca2+ mobilization, and gene expression to facilitate development of tolerance to alcohol and developmen t of associative memories. The peptide-induced enhancement of NMDA receptor responses to extracellular glutamate also may increase behavioral sensitiz ation to the low doses of alcohol that occur at the onset of each bout of d rinking. Because many gene products participate in each signaling path, eac h behavioral response to alcohol is a polygenic process of many steps with no single gene product sufficient to interpret fully the adaptive response to alcohol. Different susceptibility of individuals to alcohol addiction ma y be a cumulative result of small differences among the many signaling comp onents. Understanding this network of signals may help interpret future "ma gic bullets" proposed to treat addiction.