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

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-HT1 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-HT1 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-HT1A drugs in conflict procedures. Although chronic administration of 5-HT1A drugs appears necessary for clinical anxiolytic and antidepressant activity, the most noteworthy neuropharmacological effects in animals seem to occur in 5-HT2 and, perhaps, 5-HT3 receptors which are downregulated. Studies summarizing the activity of drugs interacting with 5-HT1C/2 and 5-HT3 receptor sites are also discussed as they too may be involved in anxiety or the actions of anxiolytic drugs.(ABSTRACT TRUNCATED AT 400 WORDS)

Effects of sertindole on sleep-wake states, electroencephalogram, behavioral patterns, and epileptic activity of rats

“…Despite numerous studies, the role of the serotonergic system in the mediation of anxiety remains unclear (2,16,19). The best evidence for an anxiolytic effect are those drugs having agonistic properties at S-HT,, receptors, such as buspirone and ipsapirone (14).…”

Stereochemistry of serotonin receptor ligands from crystallographic data. Crystal structures of NAN-190.HBr, 1-phenylbiguanide, MDL 72222 and mianserin.HCl and selectivity criteria towards 5-HT1, 5-HT2 and 5-HT3 receptor subtypes

“…In particular, 5-HT~A and 5-HT~ receptor subtypes have been well characterized by radioligand binding assays by Pazos & Palacios (1985). The former selectively binds the agonist 8-OH-DPAT [8-hydroxy-2-(di-npropylamino)tetralin (Middlemiss & Sozard, 1983)] and it is generally accepted that these receptors are involved in psychiatric disorders such as depression (Fuller & Robertson, 1991) and anxiety (Barrett & Vanover, 1993). Although three 5-HT2 receptor subtypes have been proposed, only one (5-HT2A) has been well typified by its pharmacological profile, that is by the specific binding of the antagonist ketanserin {3-[2-[4-(4-fluorobenzoyl)-lpiperdinyl]ethyl]-2,4(1H,3H)-quinazolinedione (Leysen, Niemegeers, Van Nueten & Laudron, 1982)}.…”

Perospirone, a Novel Antipsychotic Agent, Hyperpolarizes Rat Dorsal Raphe Neurons via 5-HT1A Receptor

“…Although 5-HT 1A -receptor agonists are commonly used as antianxiety drugs (15), these agonists clearly antagonize the catalepsy induced by a DA-receptor antagonist in rats (16). Furthermore, 5-HT 1A agonists consistently increase dopamine release in the prefrontal cortex in rodents.…”