5-HT receptors as targets for the development of novel anxiolytic drugs: models, mechanisms and future directions

5-HT receptors as targets for the development of novel anxiolytic drugs: models, mechanisms and... 213 112 112 1 1 James E. Barrett Kimberly E. Vanover Central Nervous System Research Department Medical Research Division, Lederle Laboratories, American Cyanamid Co. 10965 Pearl River NY USA Abstract The introduction of buspirone for the treatment of anxiety, together with the eventual suggestion of a mode of action involving the serotonin (5-HT) 1A receptor subtype, has generated considerable research activity and renewed interest in the potential role of 5-HT in anxiety. The further identification of multiple 5-HT 1 receptors, coupled with the possibility that these subtypes potentially are involved in discrete biobehavioral regulation and pathophysiological conditions, has greatly expanded the search for tools capable of probing these receptors and has raised hopes for a new generation of more specific compounds to treat other disorders associated with the 5-HT system such as depression, aggression, and sleep and eating disturbances. The involvement of 5-HT in anxiety has prompted a careful reevaluation of several traditional areas of research. This has included those methods used in the in vivo evaluation of drugs in preclinical animal test procedures used to assess potential anxiolytic activity, as well as the mechanisms associated with adaptive changes occurring during long-term drug administration. The proliferation of various procedures for studying the anxiolytic effects of 5-HT drugs has not always been accompanied by systematic behavioral and pharmacological validation. At the present time, this area of research is characterized by numerous inconsistent findings. Procedures that are objective and impartial to the behavioral effects of drugs provide distinct advantages for addressing some of these issues, as will the results from carefully controlled clinical studies. The main objective of this article is to provide an overview of the recent developments in research involving the 5-HT system and anxiety. The emphasis will be on the 5-HT 1 receptor system and a review of the results in the predominant animal models used to evaluate these drugs, as well as an overview of the mechanisms currently believed to be responsible for the therapeutic activity of this class of compounds. Studies with the pigeon are reviewed, since this species appears distinctly sensitive to the anxiolytic-like effects of 5-HT 1A drugs in conflict procedures. Although chronic administration of 5-HT 1A drugs appears necessary for clinical anxiolytic and antidepressant activity, the most noteworthy neuropharmacological effects in animals seem to occur in 5-HT 2 and, perhaps, 5-HT 3 receptors which are downregulated. Studies summarizing the activity of drugs interacting with 5-HT 1C/2 and 5-HT 3 receptor sites are also discussed as they too may be involved in anxiety or the actions of anxiolytic drugs. The growing evidence suggesting an interaction between 5-HT receptor types, particularly between 5-HT 1A and 5-HT 1C/2 receptors, is reviewed, since drugs with these combined properties appear to be particularly efficacious in animal models of anxiety and warrant further detailed analyses. The development of drugs targeted specifically at multiple receptors may provide distinct therapeutic advantages for disorders such as anxiety and depression that appear to involve multiple neurotransmitter systems. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Psychopharmacology Springer Journals

5-HT receptors as targets for the development of novel anxiolytic drugs: models, mechanisms and future directions

Psychopharmacology, Volume 112 (1) – Aug 1, 1993

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Publisher
Springer Journals
Copyright
Copyright © 1993 by Springer-Verlag
Subject
Biomedicine; Pharmacology/Toxicology; Psychiatry
ISSN
0033-3158
eISSN
1432-2072
DOI
10.1007/BF02247357
Publisher site
See Article on Publisher Site

Abstract

213 112 112 1 1 James E. Barrett Kimberly E. Vanover Central Nervous System Research Department Medical Research Division, Lederle Laboratories, American Cyanamid Co. 10965 Pearl River NY USA Abstract The introduction of buspirone for the treatment of anxiety, together with the eventual suggestion of a mode of action involving the serotonin (5-HT) 1A receptor subtype, has generated considerable research activity and renewed interest in the potential role of 5-HT in anxiety. The further identification of multiple 5-HT 1 receptors, coupled with the possibility that these subtypes potentially are involved in discrete biobehavioral regulation and pathophysiological conditions, has greatly expanded the search for tools capable of probing these receptors and has raised hopes for a new generation of more specific compounds to treat other disorders associated with the 5-HT system such as depression, aggression, and sleep and eating disturbances. The involvement of 5-HT in anxiety has prompted a careful reevaluation of several traditional areas of research. This has included those methods used in the in vivo evaluation of drugs in preclinical animal test procedures used to assess potential anxiolytic activity, as well as the mechanisms associated with adaptive changes occurring during long-term drug administration. The proliferation of various procedures for studying the anxiolytic effects of 5-HT drugs has not always been accompanied by systematic behavioral and pharmacological validation. At the present time, this area of research is characterized by numerous inconsistent findings. Procedures that are objective and impartial to the behavioral effects of drugs provide distinct advantages for addressing some of these issues, as will the results from carefully controlled clinical studies. The main objective of this article is to provide an overview of the recent developments in research involving the 5-HT system and anxiety. The emphasis will be on the 5-HT 1 receptor system and a review of the results in the predominant animal models used to evaluate these drugs, as well as an overview of the mechanisms currently believed to be responsible for the therapeutic activity of this class of compounds. Studies with the pigeon are reviewed, since this species appears distinctly sensitive to the anxiolytic-like effects of 5-HT 1A drugs in conflict procedures. Although chronic administration of 5-HT 1A drugs appears necessary for clinical anxiolytic and antidepressant activity, the most noteworthy neuropharmacological effects in animals seem to occur in 5-HT 2 and, perhaps, 5-HT 3 receptors which are downregulated. Studies summarizing the activity of drugs interacting with 5-HT 1C/2 and 5-HT 3 receptor sites are also discussed as they too may be involved in anxiety or the actions of anxiolytic drugs. The growing evidence suggesting an interaction between 5-HT receptor types, particularly between 5-HT 1A and 5-HT 1C/2 receptors, is reviewed, since drugs with these combined properties appear to be particularly efficacious in animal models of anxiety and warrant further detailed analyses. The development of drugs targeted specifically at multiple receptors may provide distinct therapeutic advantages for disorders such as anxiety and depression that appear to involve multiple neurotransmitter systems.

Journal

PsychopharmacologySpringer Journals

Published: Aug 1, 1993

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