Depression and antidepressant therapy: receptor dynamics.
1. The classical norepinephrine (NE) and serotonin (5-HT) theories of depression have been abandoned in light of recent chronic antidepressant drug studies. 2. The new NE and 5-HT theories of depression focus on the dynamics of receptor subtypes in depression and chronic antidepressant treatments. 3. Recent studies in molecular genetics suggest a reclassification of monoamine receptors based on receptor structural homologies in DNA and amino acid sequences rather than receptor affinity for ligands. 4. Electrophysiologic studies in rats suggest that 5-HT1 receptor function is facilitated by chronic antidepressant treatment. 5. Preclinical studies employing a range of 5-HT1 mediated behavioral models also suggest that chronic antidepressant treatment facilitates transmission at central 5-HT1 receptors. 6. Patient studies, employing a 5-HT1 mediated neuroendocrine model, suggest that depression is associated with decreased transmission at CNS 5-HT1 receptors; and that chronic antidepressant treatment facilitates 5-HT1 receptor responsiveness in depressed patients. 7. New 5-HT1 selective agonists have been developed and found to be clinically effective antidepressants. 8. The above clinical and preclinical data suggest that some forms of depression are related to a decreased responsiveness of 5-HT1 receptors which is reversed by chronic antidepressant treatment. 9. Beta adrenergic and NE-stimulated cyclic AMP studies suggest that chronic antidepressant treatment decreases the responsiveness of central beta-adrenergic receptors, particularly beta-1 receptors. 10. A novel approach to antidepressant drug development focuses on identifying centrally active beta-1 agonists, which like clinically proven antidepressants, decrease beta-1 receptor responsiveness with chronic treatment. 11. 5-HT2 receptor binding studies and initial studies of 5-HT2 receptor coupled PI turnover suggest that chronic antidepressant treatment decreases 5-HT2 receptor number and function. 12. The development of new atypical antidepressants with 5-HT2 receptor related mechanisms of action suggest that 5-HT2 receptors may be associated with certain types of depression and their clinical treatment.
Zemlan
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FP
Department of Psychiatry, School of Medicine, University of Cincinnati, Ohio.
Garver
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DL
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D003866:Depressive Disorder / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism
D000928:Antidepressive Agents; D011943:Receptors, Adrenergic, beta; D011956:Receptors, Cell Surface; D011985:Receptors, Serotonin