What is 5 ht 1a

Conversely, global over-expression of the 5-HT1A receptor or enhancement of its post-synaptic signalling decreases anxiety [ 96 , ]. Rescue of post-synaptic 5-HT1A receptor expression in early postnatal forebrain restores a normal anxiety phenotype, while its inhibition from postnatal day induces anxiety in the adult, suggesting it has a role in development of the anxiety phenotype [ , ].

Hence, reduced activity of post-synaptic 5-HT1A receptors is implicated in anxiety, while an increased transcription of 5-HT1A autoreceptors associates with depression and resistance to chronic SSRI treatment [ ].

Because acute desensitization uncoupling and internalization occurs rapidly sec-min and is rapidly reversible [ , ], we postulated that reduced transcription of 5-HT1A autoreceptors could account for the three-week delay in clinical response following antidepressant treatment [ , , ]. In characterizing the 5-HT1A promoter, we have uncovered a number of important regulators at the minimal promoter, upstream repressor and enhancer regions, as well as at a C G polymorphism, that could affect 5-HT1A autoreceptor expression Figure 4.

The location of identified DNA elements on the 5-HT1A 5' regions flanking the start of translation bold arrow are shown figuratively. Identified activators arrows or repressors bars of transcription are also shown. Hes and Deaf1 proteins repress the 5-HT1A promoter at the C allele, while in serotonin neurons Pet-1 exerts strong enhancer activity.

To examine the transcriptional regulation of the 5-HT1A receptor gene, the promoter region has been characterized using transcriptional reporter assays in cultured cell lines [ 99 , , ]. Most non-neuronal cell lines and tissues express low or undetectable levels of 5-HT1A receptors [ 61 ], while some neuronal cell lines express endogenous 5-HT1A receptors. Nevertheless, the minimal promoter located within bp upstream of the intronless coding sequence is highly conserved.

This minimal promoter is typical of a "housekeeping" promoter and consists of a series of GC-rich enhancer elements recognized by the ubiquitous factors MAZ1 and Sp1 [ ] that drive non-selective expression of the gene in all cell types, whether they express endogenous 5-HT1A receptors or not [ 99 ]. NFkB is observed in several types of immune cells including B- and T-lymphocytes, neutrophils and macrophages in which basal 5-HT1A receptor levels are very low, but can be greatly induced by mitogenic stimulation to augment the mitogenic response [ — ].

Finally, there is evidence that suppression of 5-HT1A receptor expression by glucocorticoids is mediated by inhibitory actions on the minimal promoter via Sp1 and NFkB elements [ ].

Located upstream from the minimal promoter is a series of repressor elements that silence 5-HT1A expression in non-neuronal cells, but also repress 5-HT1A transcription in neuronal cell lines that express 5-HT1A receptors [ , ]. Importantly these elements are conserved between human, rat and mouse genes and are functional. REST has been shown to be crucial for silencing neuronal gene expression in neural stem cells or progenitors and non-neuronal cells, but is down-regulated upon neuronal differentiation, allowing for expression of neuronal genes.

However, the 5-HT1A receptor is not expressed in all neuronal subtypes, hence additional repressors are required to restrict its expression to appropriate neurons.

Freud-1 and Freud-2 are colocalized with 5-HT1A receptors in neurons, where they play complementary roles to regulate the level of 5-HT1A receptor expression. In particular, Freud-1, but not Freud-2, is strongly expressed and colocalized with 5-HT and 5-HT1A receptors in raphe nuclei, while both Freud-1 and Freud-2 are colocalized with the receptor in post-synaptic areas such as cortex and hippocampus [ , ].

Together, Freud-1 and Freud-2 mediate dual repression of 5-HT1A receptor expression in most cell types including many post-synaptic neurons to restrict 5-HT1A receptor expression to appropriate neurons. However, it is possible that in mental illness, other repressors may play a role. For example, REST expression is up-regulated in serotonergic raphe cells from depressed suicide as compared to control brains, and may restrain over-expression of 5-HT1A autoreceptors observed in these subjects [ ].

Located between the minimal promoter and the upstream DRE is a region that exhibits both enhancer and repressor activities Figure 4. Within this region, a novel type of negative glucocorticoid response element nGRE , composed of two GRE half-sites separated by 6 nucleotides rather than 3 nucleotides as for a typical consensus GRE [ ] was identified.

The nGRE is conserved between human, mouse and rat, although its function has only been demonstrated for the rat nGRE thus far. The 5-HT1A nGRE mediates synergistic repression by both high and low affinity glucocorticoid receptors MR and GR , suggesting a key role in repression of 5-HT1A receptors in the hippocampus, in which both these receptors are present [ ]. In the raphe, only GR has been detected, and it appears to have a relatively weaker ability to suppress 5-HT1A receptor expression compared to hippocampus [ — ].

Conversely, knockdown of GR abrogates the down-regulation of 5-HT1A autoreceptors induced by chronic mild stress in mice [ ].

Since glucocorticoids are dys-regulated in depression, the chronic elevation of cortisol may ultimately desensitize GR and could contribute to increase 5-HT1A autoreceptor expression in depression.

Since the C G polymorphism is located in a bp palindrome, we addressed whether this palindrome could bind protein in nuclear extracts of raphe RN46A cells, and showed a specific complex that preferentially recognized the C-allele over the G-allele. Deaf1 Deformed autoregulatory factor-1 binds to a minimal TCG consensus sequence [ ] present in the human, rat and mouse 5-HT1A genes [ ] and can act as a repressor or enhancer [ , ].

By supershift analysis, Deaf1 was detected as a major component of the RN46A nuclear protein C-allele palindrome-binding complex. However, unlike Freud-1, while mutation of the palindrome blocked Deaf1 repression, it did not de-repress basal 5-HT1A transcription compared to mutation of the FRE, suggesting that Freud-1 is the predominant repressor of the autoreceptor in RN46A cells.

In the adult rat and human brain, Deaf1 is colocalized with 5-HT1A receptors, and in the raphe nuclei it is also colocalized with 5-HT [ , ]. The Hes proteins, which also preferentially recognize the HTR1A C allele, appear to play an important role in regulating early induction of the 5-HT1A autoreceptor. Hes5, and especially Hes1, repress neuronal gene expression in neural precursor cells and are down-regulated upon neuronal differentiation [ ].

We therefore addressed whether Hes1 can repress 5-HT1A receptor expression, and found that Hes1 exerts even stronger repression than either Hes5 or Deaf1. However, Deaf1 appears to be the dominant factor when the two are co-expressed [ ]. Thus, reduction in repression by both Deaf1 and Hes proteins at the G-allele of the 5-HT1A promoter could lead to upregulation of 5-HT1A autoreceptor expression beginning in early serotonergic differentiation and extending to adulthood.

The expression of Deaf1, Freud-1 and Freud-2 also appears to be dys-regulated in human depression in a region-specific manner [ , , , ].

Hence, despite compensatory upregulation of repressors, there appears to be a general upregulation of 5-HT1 autoreceptor expression on serotonergic neurons. In addition to repression, 5-HT1A autoreceptor expression is subject to regulation by enhancers, the most important of which appears to be Pet Hence we addressed whether Pet-1 regulates 5-HT1A receptor gene transcription [ ].

Consistent with a role for Pet-1 in regulation of 5-HT1A autoreceptor expression in vivo , the Pet-1 knockout mice demonstrated a nearly complete loss of 5-HT1A RNA and protein specifically in the raphe [ — ], while at post-synaptic target tissues 5-HT1A expression was modestly affected [ ]. Thus, Pet-1 functions as a major enhancer of 5-HT1A autoreceptor expression. However, since Pet-1 is also required for TPH2 expression, blocking Pet-1 would actually reduce 5-HT neurotransmission as shown in the Pet-1 knockout mice, which leads to an anxious and aggressive behavioral phenotype [ ].

Given the role of 5-HT1A autoreceptors in regulation of the serotonin system and the importance of 5-HT in clinical depression, several approaches have addressed whether 5-HT1A receptor expression is altered in depression. In depressed subjects, the observed increases in 5-HT1A autoreceptors could be due to increased 5-HT1A autoreceptor transcription, while region-specific reductions in post-synaptic 5-HT1A receptors could result from reduced transcription in these regions.

These changes in 5-HT1A receptors would result in a global reduction in 5-HT neurotransmission, and predisposition to depression Figure 5. In agreement with this idea, the G 5-HT1A allele, which leads to increased 5-HT1A autoreceptor transcription, has been associated with major depression and suicide [ ], and this association has been replicated and extended in most [ , , , — ], but not all studies [ ]. The 5-HT1A G allele has also been associated with anxiety [ — ].

These results suggest that although the G-allele may promote higher expression of 5-HT1A autoreceptors Figure 5 , normal subjects are able to compensate for the effect of the G allele, while depressed patients are not.

For example, the absolute level of 5-HT1A receptors may differ between depressed and normal subjects due to differences in the regulation of 5-HT1A expression e. An increase in 5-HT1A autoreceptor levels delays or prevents antidepressant response [ ] and 3 weeks of treatment with antidepressants is required for clinical improvement, due to recurrent inhibition of raphe activity by the 5-HT1A autoreceptor Figure 2.

One strategy to overcome negative feedback by 5-HT1A autoreceptor has been to use 5-HT1A partial agonists such as pindolol or buspirone, to block or desensitize the autoreceptor and accelerate SSRI action [ — ]. However, these compounds have insufficient specificity since they affect both pre-and post-synaptic receptors, and display only partial specificity for 5-HT1A autoreceptors [ , ].

We and others have found that the G allele associates with reduced antidepressant response [ , — ], suggesting that regulation by Deaf1 could facilitate antidepressant response. Successful treatment of panic disorder patients with chronic SSRIs correlates with a normalization of pre- and post-synaptic 5-HT1A receptors, suggesting that down-regulation of pre-synaptic receptors concomitant with an up-regulation of post-synaptic 5-HT1A receptors may be critical for treatment response [ 45 , ].

Among the transcriptional regulators of the 5-HT1A promoter, Deaf1 is of particular interest since it displays repressor activity on 5-HT1A autoreceptor expression, but enhancer activity on post-synaptic 5-HT1A receptors, a combination of activities that would normalize pre- and post-synaptic 5-HT1A receptor levels to enhance serotonergic neurotransmission. In conclusion, since dys-regulation of the 5-HT1A autoreceptor has the potential to affect the activity of the entire 5-HT system, it is critical to identify the transcriptional mechanisms underlying its long-term regulation.

Understanding the transcription factors involved may provide important clues to the molecular mechanisms responsible for 5-HT1A receptor dys-regulation in mental illness.

Transcriptional regulators of the 5-HT1A autoreceptor may also constitute important targets to restore normal levels of the receptor and improve treatment outcome for depression and related mental illnesses.

Nat Med. Google Scholar. PLoS Med. Br J Psychiatry. N Engl J Med. Am J Psychiatry. PubMed Google Scholar. J Clin Psychiatry. Anguelova M, Benkelfat C, Turecki G: A systematic review of association studies investigating genes coding for serotonin receptors and the serotonin transporter: I.

Affective disorders. Mol Psychiatry. J Psychiatr Res. Duman RS: Role of neurotrophic factors in the etiology and treatment of mood disorders. Neuromolecular Med. Biol Psychiatry. Blier P: The pharmacology of putative early-onset antidepressant strategies. Eur Neuropsychopharmacol. Trends Pharmacol Sci. Millan MJ: The role of monoamines in the actions of established and "novel" antidepressant agents: a critical review.

Eur J Pharmacol. Nat Rev Drug Discov. J Pharmacol Exp Ther : 81— Neuropsychopharmacology 4 : — CAS Google Scholar. Hillegaart V. Hjorth S. J Neural Transm 61 : — Hjorth S, Auerbach SB. Neuropharmacology 33 : — Article Google Scholar. Brain Res : 62— Pharmacol Biochem Behav 54 : — J Psychiatr Neurosci 19 : 63— Eur J Pharmacol : 1—8.

Kreiss DS, Lucki I. J Pharmacol Exp Ther : — Biol Psychiatry 26 : — Eur J Clin Pharmacol 39 : 17— J Clin Endocrinol Metab 70 : — Life Sciences 46 : — Biol Psychiatry 28 : — Brain Res : — Biol Psychiat 36 : — Biol Psychiatry 31 : — Psychopharmacology : 73— Maj J, Moryl E. J Neural Transm 88 : — Neuropsychopharmacology 17 : 1— Meltzer HY, Maes M.

Biol Psychiatry 38 : — Arch Gen Psychiatr 41 : — Brain Res Review 23 : — Newman ME, Lerer B. Europ J Pharmacol : — J Pharmacol Exp Ther : 16— Peroutka SJ. Trends Neurosci 11 : — Pol J Pharmacol Pharm 41 : 63— Neurosci Lett : — Spitzer RL, Endicott J.

Psychopharmacology : 83— Traber J, Glaser T. Trends Pharmacol Sci 8 : — Synapse 4 : — Download references. The authors thank Dr. Michael Franklin, University Department of Psychiatry, Warneford Hospital, Oxford for measurement of plasma growth hormone, ipsapirone, and fluoxetine levels. Ipsapirone tablets were supplied by Tropon, Bayer.

You can also search for this author in PubMed Google Scholar. Reprints and Permissions. Lerer, B. Neuropsychopharmacol 20, — Download citation. Received : 15 May Accepted : 25 August Issue Date : June Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative. Neuropsychopharmacology Molecular Psychiatry Psychopharmacology European Archives of Psychiatry and Clinical Neuroscience Advanced search. Skip to main content Thank you for visiting nature. Download PDF. Abstract Serotonergic receptors of the 5-HT 1A subtype have been suggested to play a pivotal role in the mechanism of action of antidepressant drugs, including specific serotonin reuptake inhibitors SSRIs.

Main There is considerable interest in the role of serotonergic 5-HT receptors of the 5-HT 1A subtype in the therapeutic action of antidepressant drugs. Fluoxetine Administration The protocol for fluoxetine administration was as follows: Subjects received one capsule per day for 10 weeks, containing placebo for the first 2 weeks, 10 mg fluoxetine for the next week, 20 mg fluoxetine for the following 5 weeks and placebo for the last 2 weeks.

Challenge Procedure The subjects underwent ipsapirone challenge on the last or second last day of the initial two week placebo period, before beginning to receive active fluoxetine. Statistical Analysis Pre- and post-fluoxetine temperature and hormone responses to ipsapirone were compared by analysis of variance ANOVA with repeated measures with Greenhouse Geisser Correction , after normalization of the distribution by log E transformation, if indicated.

RESULTS Baseline Temperature and Hormone Levels Table 1 shows the baseline temperature and hormone levels of the 15 subjects on each of the challenge days—after two weeks of placebo pre-fluoxetine and after four weeks of fluoxetine administration post-fluoxetine. Figure 1. Full size image. Figure 2.

Figure 3. Figure 4. Figure 5. References American Psychiatric Association. Acknowledgements The authors thank Dr. View author publications. Rights and permissions Reprints and Permissions. About this article Cite this article Lerer, B. Copy to clipboard. Further reading Slow-release delivery enhances the pharmacological properties of oral 5-hydroxytryptophan: mouse proof-of-concept Jacob P.

The human raphe nuclei and the serotonergic system. Hsiung, S. Jaworski, J. Kim, I. Extracellular signal-regulated kinases regulate dendritic growth in rat sympathetic neurons. Kobe, F. Stimulation- and palmitoylation-dependent changes in oligomeric conformation of serotonin 5-HT 1A receptors. Acta , — Kumar, V. Lauder, J. Neurotransmitters as growth regulatory signals: role of receptors and second messengers. Trends Neurosci.

Leemhuis, J. Rho GTPases and phosphoinositide 3-kinase organize formation of branched dendrites. Liu, Y. Gi subtype specificity of the 5-HT 1A receptor.

Fluorescence studies of homooligomerization of adenosine A2A and serotonin 5-HT 1A receptors reveal the specificity of receptor interactions in the plasma membrane. Mattson, M. Milligan, G. G protein-coupled receptor dimerisation: molecular basis and relevance to function. Mogha, A. Psychiatry 2:e Papaioannou, A.

Effects of neonatal handling on basal and stress-induced monoamine levels in the male and female rat brain. Patel, T. Ontogeny of 5-HT 1A receptor expression in the developing hippocampus. Polter, A. Glycogen synthase kinase-3 is an intermediate modulator of serotonin neurotransmission. Functional significance of glycogen synthase kinase-3 regulation by serotonin. Renner, U. Heterodimerization of serotonin receptors 5-HT 1A and 5-HT 7 differentially regulates receptor signalling and trafficking.

Cell Sci. Riad, M. Somatodendritic localization of 5-HT 1A and preterminal axonal localization of 5-HT 1B serotonin receptors in adult rat brain.

Agonist-induced internalization of serotonin-1a receptors in the dorsal raphe nucleus autoreceptors but not hippocampus heteroreceptors. Rojas, P. Ruat, M. Molecular cloning, characterization, and localization of a high-affinity serotonin receptor 5-HT7 activating cAMP formation.

U S A 90, — Salgado-Commissariat, D. Serotonin inhibits epileptiform discharge by activation of 5-HT 1A receptors in CA1 pyramidal neurons.

Neuropharmacology 36, — Schmitz, D. Serfaty, C. Nutritional tryptophan restriction and the role of serotonin in development and plasticity of central visual connections. Neuroimmunomodulation 15, — Sprouse, J. Neuropharmacology 46, 52— Tada, K.

Endogenous 5-HT inhibits firing activity of hippocampal CA1 pyramidal neurons during conditioned fear stress-induced freezing behavior through stimulating 5-HT 1A receptors. Hippocampus 14, — Tokarski, K. Comparison of the effects of 5-HT 1A and 5-HT 4 receptor activation on field potentials and epileptiform activity in rat hippocampus.

Turner, J. Calmodulin interacts with the third intracellular loop of the serotonin 5-hydroxytryptamine1A receptor at two distinct sites: putative role in receptor phosphorylation by protein kinase C. Varrault, A.

Vizi, E. Neurochemistry and pharmacology of the major hippocampal transmitter systems: synaptic and nonsynaptic interactions. Hippocampus 8, — Winter, C. Prenatal immune activation leads to multiple changes in basal neurotransmitter levels in the adult brain: implications for brain disorders of neurodevelopmental origin such as schizophrenia.

Woehler, A. Specific oligomerization of the 5-HT 1A receptor in the plasma membrane.