Is there a role for 5-HT(1A) agonists
in the treatment of depression?

by
Blier P, Ward NM.
Departments of Psychiatry and Neuroscience,
University of Florida Brain Institute,
Gainesville, Florida, USA
Biol Psychiatry 2003 Feb 1;53(3):193-2036


ABSTRACT

The role of serotonin (5-hydroxytryptamine; 5-HT) in the treatment of depressive and anxiety disorders is underscored by the therapeutic action of selective 5-HT reuptake inhibitors acting to enhance the degree of activation of various 5-HT receptor subtypes. The 5-HT(1A) receptors are particularly relevant to the antidepressant and anxiolytic responses in human beings. They are located presynaptically in the raphe nuclei, where they act as cell body autoreceptors to inhibit the firing rate of 5-HT neurons, and are located postsynaptically in limbic and cortical regions, where they also attenuate firing activity. The azapirones are full agonists at 5-HT(1A) autoreceptors and are generally, but not exclusively, partial agonists at postsynaptic 5-HT(1A) receptors. Some of these drugs, including gepirone and other 5-HT(1A) agonists such as buspirone, have been reported to exert anxiolytic and antidepressive activity in double-blind, placebo-controlled, and comparative trials. Their delayed therapeutic activity is believed to result from increased activation of postsynaptic 5-HT(1A) receptors occurring only after 5-HT neurons regain their normal firing activity. The recovery of this parameter, which is attributable to 5-HT(1A) autoreceptor desensitization, also restores 5-HT release. At this point, the summed effects of a normalized level of synaptic 5-HT and the exogenous 5-HT(1A) agonist can be exerted on postsynaptic 5-HT(1A) receptors. The widespread recognition of the clinical efficacy of such agents has largely been hampered by their undesirable pharmacokinetic properties. Most 5-HT(1A) agonists are indeed readily absorbed but are also rapidly eliminated, thereby often producing either suboptimal therapeutic responses at low doses, or cumbersome adverse effects at higher doses. Extended-release formulations allow once-daily dosing regimens, thus avoiding sharp peak plasma concentrations. This improves compliance and permits the use of higher dosages, which may be associated with enhanced efficacy and better tolerability relative to the immediate-release formulations. In sum, 5-HT(1A) receptor agonism represents a valuable and efficacious therapeutic approach to major depression.
5-HT2
5-HT3
5-HT1a
5-HT1b
5-HT1d
5-HT2a
5-HT2c
F11440
MKC-242
Buspirone
Mirtzapine
Flibanserin
Eltoprazine
Aggression
Knockout mice
5-HT2c/5-HT2b
5-HT1a v 5-HT1b
MDMA and 5-HT1a
Suicide and 5-HT1a
5-HT1a and F11440
5-HT1a and anxiety
Anxious 5-HT1a kockout mice
Genomics and mood disorders
A rheostat in the brain for emotion?
The serotonin 5-HT(1a) agonist F 13640


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