Initiation and adaptation: a paradigm for understanding psychotropic drug action.
OBJECTIVE
This article describes a paradigm--initiation and adaptation--within which to conceptualize the drug-induced neural plasticity that underlies the long-term actions of psychotropic drugs in the brain.


METHODS
Recent advances in neurobiology are reviewed.


RESULTS
Recent developments in cellular and molecular neurobiology provide new conceptual and experimental tools for understanding the mechanisms by which psychotropic drugs produce long-lived alterations in brain function. Because of the availability of more robust animal models, the mechanisms by which drugs of abuse produce dependence are better understood than the mechanisms by which antidepressants, antipsychotics, and lithium produce their therapeutic effects. Nonetheless, the fundamental types of mechanisms appear to be similar: chronic drug administration drives the production of adaptations in postreceptor signaling pathways, including regulation of neural gene expression. Whether the results are deleterious or therapeutic depends on the precise neural systems targeted by a particular drug.


CONCLUSIONS
Biological investigation in psychiatry has often focused too narrowly on synaptic pharmacology, especially on neurotransmitter turnover and neurotransmitter receptors. This review focuses on molecular and cellular changes in neural function that are produced as adaptations to chronic administration of addictive drugs such as psychostimulants and therapeutic drugs such as antidepressants. To understand normal brain function, psychopathology, and the actions of psychiatric treatments, and to exploit the eventual findings of psychiatric genetics, psychiatric research must now extend its efforts beyond the synapse, to an understanding of cellular and molecular neurobiology (in particular, postreceptor signal transduction) as well as to a better understanding of the architecture and function of neural systems. A paradigm is presented to help understand the long-term effects of psychotropic drugs, including the latency in onset of their therapeutic actions.
Hyman
S E
SE
Department of Psychiatry, Massachusetts General Hospital, Charlestown 02129, USA.
Nestler
E J
EJ
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D001689:Biological Psychiatry; D001921:Brain / Q000187:drug effects* / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008094:Lithium / Q000494:pharmacology / Q000627:therapeutic use; D001523:Mental Disorders / Q000188:drug therapy / Q000378:metabolism; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology; D011619:Psychotropic Drugs / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017981:Receptors, Neurotransmitter / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D019966:Substance-Related Disorders / Q000209:etiology / Q000534:rehabilitation; D009435:Synaptic Transmission / Q000187:drug effects
D000928:Antidepressive Agents; D011619:Psychotropic Drugs; D017981:Receptors, Neurotransmitter; D008094:Lithium