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Am J Psychiatry 1996; 153:151-162
Copyright © 1996 by American Psychiatric Association
Initiation and adaptation: a paradigm for understanding psychotropic drug action
SE Hyman and EJ Nestler
Department of Psychiatry, Massachusetts General Hospital, Charlestown 02129, USA.
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. METHOD:
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.
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