Molecular mechanisms of drug addiction: adaptations in signal transduction pathways

Despite staggering advances in the neurosciences over the past decade, detailed knowledge of the pathophysiology and pathogenesis of psychiatric disorders remains severely limited. Similarly, the mechanisms by which long-term exposure to psychotropic drugs leads to their clinically relevant actions are not yet known. This relative lack of progress in psychiatric research is due in part to the extraordinary complexity of the brain and the difficulties inherent in studying central nervous system pathology. However, the lack of progress is also due to the limited scope of psychiatric neuroscience, which remains focused to a great extent on traditional neurotransmitters and their receptors as the site of pathophysiological lesions in a disease state and as the ultimate targets for pharmacological treatments of these disorders. This limited focus persists despite our current knowledge that such neurotransmitters and receptors are truly the tip of the iceberg of the brain's complex inter- and intraneuronal regulatory machinery. The goal of this review is to illustrate how our rapidly evolving knowledge of neuronal regulatory mechanisms can be used as a template within which to delineate more complete models of the molecular mechanisms of psychotropic drug action, as well as the role of genetic and environmental factors in determining individual differences in drug responsiveness. The focus of the review is on drug addiction. Repeated exposure to drugs of abuse has been shown to elicit long-term adaptations in post-receptor second messenger and protein phosphorylation pathways in specific brain regions. There is increasing evidence that these adaptations are part of the molecular basis of an addictive state. Individual differences in some of these same signaling proteins also may contribute to individual differences in vulnerability for drug addiction. More recent research has demonstrated that drug-induced adaptations occur in other, non-second messenger-related, post-receptor signaling pathways, specifically, those influenced by neurotrophic factors. Together, these studies provide insight into the complex mechanisms that must be considered in understanding the brain's adaptations to chronic perturbations in general as well as the formation of a neuropsychiatric disorder and its treatment.