5-HT1A Receptors in Psychopharmacology

Authors:  Kiran Panesar, BPharm, MRPharmS, RPh, CPh and Flavio Guzman, MD


The 5-HT1A receptor is a subtype of serotonin receptor located in presynaptic and postsynaptic regions. Activation of this receptor has been involved in the mechanism of action of anxiolytic, antidepressant and antipsychotic medications.

General features

Serotonin is a monoamine neurotransmitter that interacts with 14 serotonin (5-HT) receptors that can be subdivided into 7 classes [1]. Specifically, the 5-HT1A receptors are G-protein coupled receptors that exert their effects through Gi/o proteins to inhibit adenylyl cyclase, as well as other second messenger cascades such as MAPK pathways and NMDA receptor channels [2].

5HT1A-G-protein

Location

5-HT1A receptors can be found in the brain as:

  • Presynaptic autoreceptors on serotonergic cell bodies in the raphe nuclei. Upon stimulation, these receptors inhibit firing of 5-HT neurons [3,4].

Presynaptic_5HT1A_receptors

 

  • Postsynaptic heteroreceptors in the limbic system, including the hippocampus, septum, amygdala and entorhinal cortex as well as the hypothalamus, cortex and dorsal horn [1,3,5]

Postsynaptic_5HT1A
Abundant 5-HT1A receptors are also expressed on astrocytes and other glia where they are thought to be involved in mood control [1].

The 5-HT1A receptor in psychiatric disorders

Postsynaptic 5-HT1A receptors are found in those regions of the brain that are implicated in the control of mood, cognition and memory. It has become clear that these receptors can be a useful target in the management of various neuropsychiatric disorders [6].

The effect of drug molecules that act on 5-HT1A receptors seems to vary with the location of the receptor, possibly due to a difference in regional receptor reserve [1]. It is therefore crucial to achieve the right balance of agonism at both pre and post synaptic 5HT1A receptors in order to obtain the desired effect [1].

The Role of 5-HT1A receptors in anxiety

The role of 5-HT in anxiety is well established. Recently, an animal study demonstrated increased anxiety behaviors in knockout mice bred without 5-HT1A receptors in the cerebral cortex and limbic system, suggesting a key role specifically for 5-HT1A in this respect [7].

A study conducted on human subjects using neuroendocrine testing showed that panic disorder patients have impaired 5-HT1A receptor function [8]. Furthermore, two functional imaging studies also conducted in humans revealed decreased 5-HT1A binding in patients with untreated panic disorder [7,9].

The mechanism of action of buspirone

Buspirone is an azapirone that was originally thought to achieve its anxiolytic effects solely through D2 receptor antagonistic mechanisms. It was later discovered that buspirone specifically displaces 8- OH-DPAT from 5-HT1A receptor binding sites, in addition to some D2 receptor antagonist activity [1].

Further investigation has revealed that buspirone acts at both:

  • Presynaptic receptors (somatodendritic region) , where it  behaves as a full agonist inhibiting the synthesis of neuronal 5-HT and firing.
  • Postsynaptic receptors in the hippocampus and cortex as a partial agonist [1].

buspirone-mechanism-of-action

The role of 5-HT1A receptors in antidepressant effects

The role of 5-HT1A receptors in depression has been demonstrated through various studies.

Firstly, antidepressants such as MAOIs and TCAs, SSRIs, lithium, valproate, all increase postsynaptic 5-HT1A signaling, either through direct or indirect mechanisms in humans [10].

Secondly, reduced numbers of 5-HT1A receptors have been found in suicide patients following post mortem studies and a reduced binding affinity of 5-HT1A receptors has been demonstrated using the same post mortem studies as well as PET scanning analysis [10].

Lastly, genetic studies on both humans and 5-HT1A receptor knockout mice have led to the postulation that 5-HT1A receptor dysfunction may be an underlying mechanism in depressive disorders [10]. These findings lead to the theory that 5-HT receptors may play a role in the alleviating depression, specifically through the desensitization of 5-HT1A autoreceptors [1,2]

View a related video: The Mechanism of Action of SSRIs

Proposed mechanism of action of vilazodone

Vilazodone, is thought to exert its antidepressant effect through the combined effect of serotonin reuptake inhibition and partial agonism at 5-HT1A receptors [4].

5-HT1A receptors in schizophrenia

Schizophrenia is associated with positive symptoms including hallucinations and delusions, and negative symptoms such as flattened affect, loss of sense or pleasure, loss of will or drive (avolition) and social withdrawal [6].

Recently it has been shown that compounds possessing balanced 5-HT1A receptor agonism and D2 antagonism are efficacious antipsychotics that have a low propensity to elicit EPS or metabolic dysfunction. These agents, known as “selectively non-selective drugs”, might achieve the desired therapeutic benefit by targeting the sites responsible for the required effect but avoid the sites that are responsible for side effects [6].

Further research into this area has been prompted by a number of factors:

  • 5-HT1A receptor activation is required for the cortical DA release by antipsychotics- confirmed through studies on knockout mice; this effect is regionally selective and is only seen in frontocortical regions, but not the nucleus accumbens or striatum [6].
  • 5-HT1A receptor agonists such as 8-OH-DPAT eliminates catalepsy caused by typical antipsychotics in rats [11].
  • 5-HT1A receptors are upregulated in patients with schizophrenia.
  • Buspirone and tandospirone that act as partial agonists at 5-HT1A receptors reduce negative symptoms in schizophrenics treated with haloperidol [6]

Clinically relevant 5-HT1A partial agonists

DrugTrade name
Antianxiety agent
BuspironeBuspar
Second-generation (atypical) antipsychotics
ClozapineClozaril
Ziprasidone
Geodon
AripiprazoleAbilify
Antidepressant
VilazodoneViibryd

5HT1A partial agonists vilazodone aripiprazole clozapine ziprasidone buspirone

Video: biased agonism at serotonin 5-HT1A receptors


It has been shown that optimal therapeutic benefit from targeting 5-HT1A receptors can be obtained with the use of “biased agonists“ or “functionally selective agonists”. These activate receptors that mediate therapeutic activity but avoid those that control other effects and result in unwanted effects. Biased agonists present an novel opportunity to manage psychiatric disorders that are associated with 5HT1A receptors [3].

Note: Thanks to Drs. Farid Shagiakhmetov and Janice Downey for their valuable contributions.

References

  1. Schatzberg AF, Nemeroff CB. The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Ed. Apr 2009, American Psychiatric Publishing Inc.
  2. Drago A, Ronchi DD, Serretti A. 5-HT1A gene variants and psychiatric disorders: a review of current literature and selection of SNPs for future studies. Int J Neuropsychopharmacol. 2008;11(5):701-21.
  3. Newman-Tancredi. Biased agonism at serotonin 5-HT1A receptors: preferential postsynaptic activity for improved therapy of CNS disorders. Neuropsychiatry. 2011;1(2):149-164.
  4. Kalia R, Mittal M S, and Preskorn S H:Vilazodone for major depressive disorder. Current Psychiatry. 2011;10(4): 84-88.
  5. Rang H, Ritter J. Dale M, et al. Pharmacology. 3rd Ed. Churchill Livingstone, UK.
  6. Newman-Tancredi A, Kleven MS. Comparative pharmacology of antipsychotics possessing combined dopamine D2 and serotonin 5-HT1A receptor properties.
  7. Nash JR, Sargent PA, Rabiner EA, et al. Serotonin 5-HT1A receptor binding in people with panic disorder: positron emission tomography study. Br J Psychiatry. 2008 Sep;193(3):229-34.
  8. Lesch KP, Wiesmann M, Hoh A, et al. 5-HT1A receptor-effector system responsivity in panic disorder. Psychopharmacology (Berl). 1992;106(1):111-7.
  9. Neumeister A, Bain E, Nugent AC, et al. Reduced serotonin type 1A receptor binding in panic disorder. J Neurosci. 2004;24(3):589-91.
  10. Savitz J, Lucki I, Drevets WC. 5-HT(1A) receptor function in major depressive disorder. Prog Neurobiol. 2009;88(1):17-31.
  11. Newman-Tancredi. The importance of 5-HT1A receptor agonism in antipsychotic drug action: rationale and perspectives. Curr Opin Investig Drugs. 2010;11(7):802-12.