Lerer B, Macciardi
F, Segman RH, Adolfsson R, Blackwood D, Blairy S, Del Favero J, Dikeos DG, Kaneva
R, Lilli R, Massat I, Milanova V, Muir W, Noethen M, Oruc L, Petrova T, Papadimitriou
GN, Rietschel M, Serretti A, Souery D, Van Gestel S, Van Broeckhoven C, Mendlewicz
Variability of 5-HT2C receptor cys23ser polymorphism among European
populations and vulnerability to affective disorder.
Psychiatry 2001 Sep;6(5):579-85
"We examined a structural variant of
the serotonin 2C (5-HT2C) receptor gene (HTR2C) that gives rise to a cysteine
to serine substitution in the N terminal extracellular domain of the receptor
protein (cys23ser),5 in 513 patients with recurrent major depression (MDD-R),
649 patients with bipolar (BP) affective disorder and 901 normal controls. The
subjects were drawn from nine European countries participating in the European
Collaborative Project on Affective Disorders. There was significant variation
in the frequency of the HT2CR ser23 allele among the 10 population groups included
in the sample (from 24.6% in Greek control subjects to 9.2% in Scots, 2 = 20.9,
df 9, P = 0.01). Logistic regression analysis demonstrated that over and above
this inter-population variability, there was a significant excess of HT2CR ser23
allele carriers in patients compared to normal controls that was demonstrable
for both the MDD (2 = 7.34, df 1, P = 0.006) and BP (2 = 5.45, df 1, P = 0.02)
patients. These findings support a possible role for genetically based structural
variation in 5-HT2C receptors in the pathogenesis of major affective disorder."
Gutierrez B, Fananas L, Arranz MJ, Valles
V, Guillamat R, van Os J, Collier D.
Allelic association analysis
of the 5-HT2C receptor gene in bipolar affective disorder.
Lett 1996 Jul 5;212(1):65- 7
"These results suggest that the ser23 allele
may increase susceptibility to bipolar affective disorder in women." [Abstract]
B, Arias B, Papiol S, Rosa A, Fananas L.
Association study between
novel promoter variants at the 5-HT2C receptor gene and human patients with bipolar
Neurosci Lett. 2001 Aug 24;309(2):135-7.
recently described adjacent DNA polymorphisms [(GT)12-18 and (CT)4-5] in the 5'-regulatory
region of 5-HT2C receptor gene were analysed in a sample of 88 bipolar patients
and 162 controls, all of Spanish origin. Statistical analyses revealed no overall
allele or genotype associations with the disease. A haplotype analyses between
the (GT)12-18/(CT)4-5 motif and a Cys23Ser variant of the 5-HT2C gene (which had
previously been genotyped in the same sample) showed similar distributions between
cases and controls. Only a slight increase of s-Ser23 haplotype was found in the
subgroup of bipolar women with family history of psychiatric illness (OR=1.24
[95%CI: 1.12-1.38]). [Abstract]
J, Saam W, Mossner R, Cangir O, Ortega GR, Tatschner T, Riederer P, Wienker TF,
Evolutionary conserved microsatellites in the promoter
region of the 5-hydroxytryptamine receptor 2C gene (HTR2C) are not associated
with bipolar disorder in females.
J Neural Transm. 2002
Two polymorphic dinucleotide repeats separated by a short
spacer are localized in the promoter region of the serotonin receptor 2C gene
( HTR2C). One of the repeats was found to be evolutionary conserved between humans
and rhesus monkeys. Although promoter-associated microsatellites have previously
been shown to regulate expression of different genes, we did not find any significant
influence of distinct HTR2C promoter microsatellite alleles on transcriptional
efficiency as measured by luciferase activity and receptor availability as assayed
by [(3)H]-mesulergine binding. Furthermore, no association of specific alleles
with bipolar disorder was found. These results indicate that the HTR2C promoter
polymorphism does not contribute significantly to the etiopathogenesis of bipolar
disorder in females. [Abstract]
K, Kato T.
RNA editing of serotonin 2C receptor in human postmortem
brains of major mental disorders.
Neurosci Lett. 2003 Aug
"The importance of serotonin 2C receptor (HTR2C) in mental
disorders has been implicated by studies of HTR2C-deficient mice and linkage and
association studies. Recent studies have revealed that RNA editing of HTR2C is
involved in mental disorders. Here we examined RNA editing efficiencies of site
A and D of HTR2C in the prefrontal cortex samples of patients with bipolar disorder,
schizophrenia, and major depression as well as control subjects by using primer
extension combined with denaturing high performance liquid chromatography. Postmortem
samples were donated by the Stanley Foundation Brain Collection. We could not
find significant alterations of RNA editing efficiencies of these sites in patients.
However, we found trends for increased RNA editing efficiencies of site D in depressive
patients (P=0.08) and site A in suicide victims (P=0.07). These findings are in
accordance with the previous findings, and suggest that altered RNA editing of
HTR2C may have some significance in major depression and suicide." [Abstract]
CM, Herrick-Davis K, Dilley GE, Meltzer HY, Overholser JC, Stockmeier CA, Emeson
RB, Sanders-Bush E.
RNA editing of the human serotonin 5-HT2C receptor.
alterations in suicide and implications for serotonergic pharmacotherapy
Neuropsychopharmacology 2001 May;24(5):478-91 .
examination of the efficiencies of RNA editing of the 5-HT(2C)R in prefrontal
cortex of control individuals vs. subjects diagnosed with schizophrenia or major
depressive disorder revealed no significant differences in RNA editing among the
three populations. However, subjects who had committed suicide (regardless of
diagnosis) exhibited a statistically significant elevation of editing at the A-site,
which is predicted to change the amino acid sequence in the second intracellular
loop of the 5-HT(2C)R. These findings suggest that alterations in RNA editing
may contribute to or complicate therapy in certain psychiatric disorders."
I, Tamir H, Arango V, Dwork AJ, Mann JJ, Schmauss C.
of serotonin 2C receptor pre-mRNA in the prefrontal cortex of depressed suicide
Neuron. 2002 Apr 25;34(3):327-8.
adenosines within the coding sequence of the serotonin 2C receptor (5-HT2C) pre-mRNA
are converted to inosines by RNA editing (named A, B, C' (E), C, and D sites).
In human prefrontal cortex (PFC), the most abundant 5-HT2C mRNA sequences result
from editing at the A site, or from the editing combinations AC'C, ABCD, and ABD.
In suicide victims with a history of major depression, C' site editing is significantly
increased, D site editing is significantly decreased, and the C site shows a trend
toward increased editing. Treatment of mice with the antidepressant drug fluoxetine
(Prozac) causes changes in C', C, and D site editing that are exactly opposite
to those seen in suicide victims. Thus, one outcome of fluoxetine treatment may
be to reverse the abnormalities in 5-HT2C pre-mRNA editing seen in depressed suicide
I, Englander MT, Adlersberg M, Siegal NB, Schmauss C.
of serotonin 2C receptor editing by sustained changes in serotonergic neurotransmission.
Neurosci 2002 Dec 15;22(24):10529-32
"Serotonin 2C (5-HT2C) receptor pre-mRNA
is a substrate for RNA editing enzymes that convert five adenosines (named A,
B, C', C, and D editing sites) to inosines. Editing of two of these sites (C'
and C) is crucial for decreasing the efficiency of the receptor to activate G-protein.
Nucleotide sequence analysis of mouse forebrain neocortical 5-HT2C mRNA isoforms
revealed that editing at these two sites is regulated in a serotonin-dependent
manner. In serotonin-depleted mice, C'- and C-site editing is significantly decreased.
This results in an increased expression of 5-HT2C mRNA isoforms encoding receptors
with higher sensitivity to serotonin. In contrast, a 4 d treatment with the 5-HT2A/2C
agonist (+/-)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane significantly increases
the editing frequency at the C' site and leads to increased expression of 5-HT2C
mRNA isoforms encoding receptors that activate G-protein least efficiently. None
of the drug treatments led to alterations in cytoplasmic 5-HT2C mRNA levels. These
data indicate that editing of 5-HT2C pre-mRNA is a mechanism that retains basic
response properties of 5-HT2C receptors in the face of changing synaptic input
to keep receptor activation within an optimal range for information processing."
Brian D., Clarke, William P., Berg, Kelly A.
of the Serotonin2C Receptor System: Effector Pathway and Agonist Dependence
J Pharmacol Exp Ther 2002 302: 957-962
"The serotonin2C (5-HT2C) receptor
couples to multiple effector mechanisms, including phospholipase A2-mediated arachidonic
acid (AA) release and phospholipase C-mediated production of inositol phosphates
(IP). Agonist relative efficacy differs depending upon which response (AA release
or IP accumulation) is measured. In this study, we investigated the characteristics
and agonist dependence of rapid desensitization of 5-HT2C receptor-mediated AA
release and IP accumulation measured simultaneously from the same cell population.
Pretreatment with 5-HT reduced the ability of a maximal concentration of 5-HT
to elicit AA release and IP accumulation by about 60%; however, the AA response
desensitized more rapidly (t1/2 = 1.3 min) than the IP response (t1/2 = 6.9 min).
In addition, desensitization of the IP response was more sensitive (occurred at
lower receptor occupancy levels) than the AA response. Moreover, in response to
submaximal 5-HT concentrations, after an initial transient desensitization, the
AA response was enhanced by up to ~250%. After maximal desensitization, both responses
recovered, but recovery of the AA response was complete and faster than that for
IP. Desensitization of both responses was also agonist-dependent, and the capacity
of agonists to elicit desensitization was not related to their efficacy to activate
signaling. These data suggest that desensitization of the 5-HT2C receptor system
is both agonist- and effector pathway-dependent and underscore the need to study
multiple cellular responses to multiple agonists to understand receptor-mediated
signaling systems." [Abstract]
On site link: 5-HT2C Receptor
On site link: Bipolar
Disorder Genetic Research
Oruc L, Verheyen GR, Furac
I, Jakovljevic M, Ivezic S, Raeymaekers P, Van Broeckhoven C.
analysis of the 5-HT2C receptor and 5-HT transporter genes in bipolar disorder.
Am J Med Genet 1997 Sep 19;74(5):504-6
"We selected 42
patients with bipolar disorder type I (BPI) and 40 healthy controls for genetic
analysis of DNA polymorphisms in the serotonin receptor 2c (5-HTR2c) and serotonin
transporter (5-HTT) genes. No significant associations were found in the total
patient sample. However, when the individuals were divided according to gender,
trends for association with both polymorphisms (P = 0.051 for 5-HTR2c and P =
0.049 for 5-HTT) in female patients were observed. These results suggest that
variations in these genes may be responsible for a minor increase in susceptibility
for bipolar disorder in women." [Abstract]
Lindberg N, Virkkunen M, Tani P, Appelberg B, Virkkala J,
Rimon R, Porkka-Heiskanen T.
Effect of a single-dose of olanzapine
on sleep in healthy females and males.
Int Clin Psychopharmacol
"The difference between the sexes could not be
explained by differences in body mass index. Olanzapine affects sleep probably
through 5-HT2C receptors. The receptor gene is located on the X-chromosome, inducing
an allelic difference between the females and males. This difference may contribute
to the different effects of olanzapine on sleep." [Abstract]
Berg, KA, Maayani, S, Clarke, WP
receptor activation inhibits 5- hydroxytryptamine1B-like receptor function via
arachidonic acid metabolism
Mol Pharmacol 1996 50: 1017-1023
"Consistent with our previous report and in contrast to activation of 5-HT2C
or purinergic receptors, activation of 5-HT2A receptors had no effect on CHO/5-HT1B
receptor function, although 5-HT2A receptor-mediated activation of PLA2 was measured.
Interestingly, purinergic receptor-mediated inhibition of CHO/5-HT1B receptor
function was blocked when 5-HT2A receptors were activated simultaneously. These
data suggest that the lack of 5-HT2A mediated regulation of CHO/5-HT1B receptors
may be due to activation of a third pathway (in addition to PLC and PLA2 pathways),
which results in the inhibition of the production or the actions of a cyclooxygenase-
dependent arachidonic acid metabolite." [Abstract]
LK, Tecott LH.
A paradoxical locomotor response in serotonin 5-HT(2C)
receptor mutant mice.
J Neurosci 2000 Apr 15;20(8):RC71
"We report that a single receptor gene mutation produces a paradoxical response
to the nonspecific serotonin receptor agonist m-chlorophenylpiperazine (mCPP).
Although this compound normally suppresses locomotion, it produces hyperactivity
in mice bearing a targeted mutation of the 5-HT(2C) receptor gene. This effect
was blocked by pretreatment with a 5-HT(1B) receptor antagonist, indicating that
the behavioral consequences of mCPP-induced 5-HT(1B) receptor stimulation are
unmasked in animals devoid of 5-HT(2C) receptor function." [Abstract]
J, Reeves B, Platt H, Leibenau A, Goldman D, Jefferson K, Nutt D.
serotonin genes and repetition of deliberate self-harm (DSH).
Med 2000 Nov;30(6):1327-34
"Males with the 5-HT2c serine variant were
more impulsive than those with the cysteine variant (039 standardized units, P
= 0.041, 95% CI 0.017 to 0.076)." [Abstract]