The "ups and downs" of signaling cascades in addiction.
Drug addiction is a chronic disease characterized by compulsive drug use despite the severe negative consequences associated with it. Repeated exposure to drugs of abuse results in molecular adaptations in neuronal signaling pathways, which eventually manifest in the complex behavioral alterations that characterize addiction. These include tolerance, sensitization, dependence, drug craving, and relapse. In this Review, we focus on recent studies highlighting signaling cascades initiated by cocaine, as a representative of a drug of abuse with a defined site of action, and alcohol, as a drug with an undefined primary site of action. Specifically, we describe recent studies that emphasize the role of protein-protein interactions, phosphorylation, and compartmentalization in the molecular mechanisms that result in the cellular and behavioral adaptations that underlie addiction. Signaling cascades that contribute to addiction, as well as those that protect or delay the development of addiction, are presented.
Ron
Dorit
D
Ernest Gallo Clinic and Research Center, University of California San Francisco, Emeryville, CA 94608, USA. dorit@itsa.ucsf.edu
Jurd
Rachel
R
D000437:Alcoholism / Q000503:physiopathology; D000818:Animals; D002352:Carrier Proteins / Q000502:physiology; D003042:Cocaine / Q000009:adverse effects / Q000494:pharmacology / Q000633:toxicity; D019970:Cocaine-Related Disorders / Q000503:physiopathology; D000242:Cyclic AMP / Q000502:physiology; D004298:Dopamine / Q000502:physiology; D050483:Dopamine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors; D000431:Ethanol / Q000009:adverse effects / Q000494:pharmacology / Q000633:toxicity; D020730:Guanine Nucleotide Dissociation Inhibitors; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology; D008032:Limbic System / Q000503:physiopathology; D051379:Mice; D034521:Nuclear Matrix-Associated Proteins / Q000502:physiology; D009714:Nucleus Accumbens / Q000503:physiopathology; D010766:Phosphorylation; D017397:Prefrontal Cortex / Q000503:physiopathology; D011494:Protein Kinases / Q000502:physiology; D011499:Protein Processing, Post-Translational; D020710:RGS Proteins / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000502:physiology; D012201:Reward; D015398:Signal Transduction / Q000502:physiology*; D019966:Substance-Related Disorders / Q000503:physiopathology*; D014158:Transcription, Genetic; D017557:Ventral Tegmental Area / Q000503:physiopathology
D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; C498915:Gpsm1 protein, mouse; D020730:Guanine Nucleotide Dissociation Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D034521:Nuclear Matrix-Associated Proteins; D020710:RGS Proteins; D043562:Receptors, G-Protein-Coupled; C116925:regulator of g-protein signaling 9; D000431:Ethanol; D000242:Cyclic AMP; D011494:Protein Kinases; D003042:Cocaine; D004298:Dopamine