5-HT2A Receptor Research -- Neurotransmitter.net

(Updated 12/02)

Hanley, Nicole R. Sullivan, Hensler, Julie G.
Mechanisms of Ligand-Induced Desensitization of the 5-Hydroxytryptamine2A Receptor
J Pharmacol Exp Ther 2002 300: 468-477
"[In C6 glioma cells] 5-HT-induced desensitization of the 5-HT2A receptor involved receptor internalization through a clathrin- and dynamin-dependent process because it was prevented by concanavalin A, monodansylcadaverine, and by expression of the dominant negative mutants beta-arrestin (319-418) and dynamin K44A. Although short-term (i.e., 10 min) 5-HT and ketanserin exposure resulted in the same degree of desensitization, ketanserin-induced desensitization was not prevented by these agents and did not involve receptor internalization. In contrast, prolonged ketanserin exposure (i.e., 2 h) resulted in 5-HT2A receptor internalization through a clathrin- and dynamin-dependent process, as was observed after agonist treatment. Inhibitors of protein kinase C or calcium-calmodulin kinase II did not attenuate or prevent 5-HT-induced desensitization of the receptor. 5-HT2A receptor desensitization induced by 5-HT and prolonged ketanserin treatment, but not by short-term ketanserin treatment, was prevented by the expression of the dominant negative mutant of G protein-coupled receptor kinase (GRK)2, GRK2-K220R, and by an anti-GRK2/3 antibody." [Abstract]

Anji, Antje, Sullivan Hanley, Nicole R., Kumari, Meena, Hensler, Julie G.
The role of protein kinase C in the regulation of serotonin-2A receptor expression
J Neurochem 2001 77: 589-597
"Comparison of the time-courses of agonist-induced downregulation of receptor number and mRNA indicate that a decrease in the number of 5-HT2A receptor binding sites in response to serotonin (5-HT) treatment is preceded by a decrease in 5-HT2A receptor mRNA."
...
"Taken together, our results implicate PKC{alpha} and/or PKC{gamma} in the regulation of 5-HT2A mRNA receptor and binding sites in response to agonist treatment [in C6 glioma cells]." [Abstract]

Berg, KA, Clarke, WP, Chen, Y, Ebersole, BJ, McKay, RD, Maayani, S
5-Hydroxytryptamine type 2A receptors regulate cyclic AMP accumulation in a neuronal cell line by protein kinase C-dependent and calcium/calmodulin-dependent mechanisms
Mol Pharmacol 1994 45: 826-836
"In conclusion, these data suggest that 5-HT2A receptor activation can amplify cAMP formation in A1A1 cells by two distinct pathways coupled to the hydrolysis of inositol phosphates, i.e., PKC and calcium/calmodulin." [Abstract]

Arvanov VL, Liang X, Russo A, Wang RY.
LSD and DOB: interaction with 5-HT2A receptors to inhibit NMDA receptor-mediated transmission in the rat prefrontal cortex.
Eur J Neurosci 1999 Sep;11(9):3064-72
"We conclude that phenethylamine and indoleamine hallucinogens may exert their hallucinogenic effect by interacting with 5-HT2A receptors via a Ca2+/CaM-KII-dependent signal transduction pathway as partial agonists and modulating the NMDA receptors-mediated sensory, perceptual, affective and cognitive processes." [Abstract]

Berg, KA, Maayani, S, Clarke, WP
5-hydroxytryptamine2C 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]

Muraoka S, Kamei K, Muneoka K, Takigawa M.
Chronic imipramine administration amplifies the serotonin2A receptor-induced intracellular Ca2+ mobilization in C6 glioma cells through a calmodulin-dependent pathway.
J Neurochem 1998 Oct;71(4):1709-18
"Imipramine, desipramine, clomipramine, and maprotiline amplified the 5-HT response at 48, but not at 2, h. Imipramine increased the maximum response to 5-HT without altering the EC50 of the dose-response curve. This effect was time dependent and cycloheximide blocked the maximal induction, suggesting an essential role for protein synthesis in this process."

"Taken together, these results suggest that imipramine has a modulatory effect on the 5-HT2A receptor-coupled intracellular Ca2+ in C6 cells through a calmodulin-dependent pathway, possibly involving Ca2+/calmodulin kinase activation." [Abstract]

Vaidya, Vidita A., Marek, Gerard J., Aghajanian, George K., Duman, Ronald S.
5-HT2A Receptor-Mediated Regulation of Brain-Derived Neurotrophic Factor mRNA in the Hippocampus and the Neocortex
J. Neurosci. 1997 17: 2785-2795
"In the hippocampus, the 5-HT2A /2C receptor agonist significantly decreased BDNF mRNA expression in the dentate gyrus granule cell layer but did not influence expression of the neurotrophin in the CA subfields. In parietal cortex and other neocortical areas, but not piriform cortex, the 5-HT2A /2C receptor agonist dramatically increased the expression of BDNF mRNA. The effect of the 5-HT2A /2C receptor agonist on BDNF mRNA in both the hippocampus and the neocortex was blocked by pretreatment with a selective 5-HT2A, but not 5-HT2C, receptor antagonist. The expression of BDNF mRNA in the hippocampus is reported to be decreased by stress, raising the possibility that the 5-HT2A receptor mediates this effect." [Full Text]

Shirayama, Yukihiko, Chen, Andrew C.-H., Nakagawa, Shin, Russell, David S., Duman, Ronald S.
Brain-Derived Neurotrophic Factor Produces Antidepressant Effects in Behavioral Models of Depression
J. Neurosci. 2002 22: 3251-3261
"A single bilateral infusion of BDNF into the dentate gyrus of hippocampus produced an antidepressant effect in both the LH and FST that was comparable in magnitude with repeated systemic administration of a chemical antidepressant. These effects were observed as early as 3 d after a single infusion of BDNF and lasted for at least 10 d. Similar effects were observed with neurotrophin-3 (NT-3) but not nerve growth factor." [Abstract]

Sibille, Etienne, Sarnyai, Zoltan, Benjamin, Daniel, Gal, Judit, Baker, Harriet, Toth, Miklos
Antisense Inhibition of 5-Hydroxytryptamine2a Receptor Induces an Antidepressant-Like Effect in Mice
Mol Pharmacol 1997 52: 1056-1063
"The antidepressant-like effect induced by AS oligonucleotide injection in mice is consistent with the beneficial effect of pharmacological blockade of the 5-HT2A receptor in dysthymic disorders." [Full Text]

Smith RL, Canton H, Barrett RJ, Sanders-Bush E.
Agonist properties of N,N-dimethyltryptamine at serotonin 5-HT2A and 5-HT2C receptors.
Pharmacol Biochem Behav 1998 Nov;61(3):323-30 [Abstract]

Williams, Graham V., Rao, Srinivas G., Goldman-Rakic, Patricia S.
The Physiological Role of 5-HT2A Receptors in Working Memory
J. Neurosci. 2002 22: 2843-2854 [Abstract]

Koskinen, Tiina
Activation of 5-HT2A receptors impairs response control of rats in a five-choice serial reaction time task
NEUROPHARMACOLOGY , 39(3):471-481 2000
"These data suggest that the overactivation of 5-HT2A receptors impairs response control in a 5-CSRT task, whereas the overactivation of 5-HT2C receptors can affect behavioral activity and/or arousal state of the animals for this food rewarded task." [Abstract]

Shen, Roh-Yu, Andrade, Rodrigo
5-Hydroxytryptamine2 Receptor Facilitates GABAergic Neurotransmission in Rat Hippocampus
J Pharmacol Exp Ther 1998 285: 805-812 [Full Text]

Roger M. Nitsch, Meihua Deng, John H. Growdon, and Richard J. Wurtman
Serotonin 5-HT2a and 5-HT2c Receptors Stimulate Amyloid Precursor Protein Ectodomain Secretion
J. Biol. Chem. 271: 4188-4194, February 23, 1996. [Full Text]

Cornea-Hebert V, Riad M, Wu C, Singh SK, Descarries L.
Cellular and subcellular distribution of the serotonin 5-HT2A receptor in the central nervous system of adult rat.
J Comp Neurol 1999 Jun 28;409(2):187-209
"It was concluded that the 5-HT2A receptor is mostly intracellular and transported in dendrites and axons, but does not reach into dendritic spines or axon terminals. Because it has previously been shown that this serotonin receptor is transported retrogradely as well as anterogradely, activates intracellular transduction pathways and intervenes in the regulation of the expression of many genes, it is suggested that one of its main functions is to participate in retrograde signaling systems activated by serotonin." [Abstract]

Ozaki, N, Manji, H, Lubierman, V, Lu, SJ, Lappalainen, J, Rosenthal, NE, Goldman, D
A naturally occurring amino acid substitution of the human serotonin 5- HT2A receptor influences amplitude and timing of intracellular calcium mobilization.
J Neurochem 1997 68: 2186-2193 [Abstract]

Johnson, Robert G., Stevens, Karen E., Rose, Gregory M.
5-Hydroxytryptamine2 Receptors Modulate Auditory Filtering in the Rat
J Pharmacol Exp Ther 1998 285: 643-650 [Full Text]

Jorgensen H, Knigge U, Kjaer A, Warberg J.
Serotonergic involvement in stress-induced vasopressin and oxytocin secretion.
Eur J Endocrinol 2002 Dec;147(6):815-824
"OBJECTIVE: To investigate the involvement of serotonin (5-hydroxytryptamine - 5-HT) receptors in mediation of stress-induced arginine vasopressin (AVP) and oxytocin (OT) secretion in male rats. DESIGN: Experiments on laboratory rats with control groups. METHODS: Different stress paradigms were applied after pretreatment with intracerebroventricular infusion of saline or different 5-HT antagonists. RESULTS: Restraint stress (5 min), hypotensive hemorrhage or dehydration for 24 h increased AVP secretion fivefold and OT secretion threefold. Swim stress for 3 min had no effect on AVP secretion, but increased OT secretion threefold. Ether vapor or hypoglycemia had no effect on AVP or OT secretion. The restraint stress-induced AVP response was inhibited by pretreatment with the 5-HT(2A+2C) antagonists ketanserin (KET) and LY-53857 (LY) and the 5-HT(3+4) antagonist ICS-205930 (ICS), whereas the 5-HT(1A) antagonist WAY-100635 (WAY) had no effect. The OT response to restraint stress was inhibited by WAY, KET and LY but not by ICS. KET and LY inhibited OT response to dehydration, and LY inhibited OT response to hemorrhage. Neither of the antagonists affected AVP responses to dehydration or hemorrhage, nor the swim stress-induced OT response. CONCLUSION: 5-HT(2A), 5-HT(2C) and possibly 5-HT(3) and 5-HT(4) receptors, but not 5-HT(1A) receptors, are involved in the restraint stress-induced AVP secretion. 5-HT does not seem to be involved in the dehydration- or hemorrhage-induced AVP response. The restraint stress-induced OT response seems to be mediated via 5-HT(1A), 5-HT(2A) and 5-HT(2C) receptors. The dehydration and hemorrhage-induced OT responses are at least mediated by the 5-HT(2A) and 5-HT(2C) receptors. The 5-HT(3) and 5-HT(4) receptors are not involved in stress-induced OT secretion." [Abstract]

Y Zhang, D K Raap, L D van de Kar, A Javed, T S Gray, F Serres
5-Ht2a receptors stimulate acth, corticosterone, oxytocin, renin, and prolactin release and activate hypothalamic crf and oxytocin-expressing cells
JOURNAL OF NEUROSCIENCE: THE OFFICIAL JOURNAL OF THE SOCIETY FOR NEUROSCIENCE, THE , 21(10):3572-3579 2001
"MDL 100,907 produced a dose-dependent inhibition (ED(50) congruent with 0.001 mg/kg) of the effect of DOI on plasma levels of ACTH, corticosterone, oxytocin, prolactin, and renin without altering basal hormone levels." [Full Text]

Apfelbaum ME.
Role of vasoactive intestinal peptide and 5-HT2 receptor subtype in serotonin stimulation of basal and thyrotropin-releasing-hormone-induced prolactin release in vitro from rat pituitary cells.
Neuroendocrinology 1998 Jan;67(1):45-50 [Abstract]

Juan Pablo Huidobro-Toro, and R. Adron Harris
Brain lipids that induce sleep are novel modulators of 5-hydroxytryptamine receptors
PNAS 93: 8078-8082, July 23, 1996. [Abstract/Full Text]

Rosmond, Roland, Bouchard, Claude, Bjorntorp, Per
5-HT2A Receptor Gene Promoter Polymorphism in Relation to Abdominal Obesity and Cortisol
Obes Res 2002 10: 585-589 [Abstract]

Y Zhang, D D'Souza, D K Raap, F Garcia, G Battaglia, N A Muma, L D van de Kar
Characterization of the functional heterologous desensitization of hypothalamic 5-ht1a receptors after 5-ht2a receptor activation
JOURNAL OF NEUROSCIENCE: THE OFFICIAL JOURNAL OF THE SOCIETY FOR NEUROSCIENCE, THE , 21(20):7919-7927 2001
"In conclusion, the activation of 5-HT(2A) receptors induces a transient functional desensitization of 5-HT(1A) receptor signaling in the hypothalamus, which may occur distal to the 5-HT(1A) receptor-G(z)-protein interface." [Abstract]

V L Arvanov, P Magro, R Roberts, R Y Wang
A pre- and postsynaptic modulatory action of 5-HT and the 5-HT2A, 2C receptor agonist DOB on NMDA-evoked responses in the rat medial prefrontal cortex
EUROPEAN JOURNAL OF NEUROSCIENCE , 11(8):2917-2934 1999
"Indeed, the selective PKC inhibitor chelerythrine and the Ca2+/CaM-KII inhibitor KN-93 prevented the facilitating and inhibitory action of DOB, respectively." [Abstract]

David A. Shapiro, Kurt Kristiansen, David M. Weiner, Wesley K. Kroeze, and Bryan L. Roth
Evidence for a Model of Agonist-induced Activation of 5-Hydroxytryptamine 2A Serotonin Receptors That Involves the Disruption of a Strong Ionic Interaction between Helices 3 and 6
J. Biol. Chem. 277: 11441-11449, March 29, 2002. [Abstract]

Gelber, Edward I., Kroeze, Wesley K., Willins, David L., Gray, John A., Sinar, Christine A., Hyde, Edward G., Gurevich, Vsevolod, Benovic, Jeffrey, Roth, Bryan L.
Structure and Function of the Third Intracellular Loop of the 5-Hydroxytryptamine2A Receptor: The Third Intracellular Loop Is {alpha}-Helical and Binds Purified Arrestins
J Neurochem 1999 72: 2206-2214 [Abstract]

Berg, Kelly A., Stout, Brian D., Maayani, Saul, Clarke, William P.
Differences in Rapid Desensitization of 5-Hydroxytryptamine2A and 5-Hydroxytryptamine2C Receptor-Mediated Phospholipase C Activation
J Pharmacol Exp Ther 2001 299: 593-602
"Agonist-induced desensitization of the 5-HT2A, but not the 5-HT2C, receptor system was reduced by the PKC inhibitors staurosporine and bisindolylmaleimide, and by down-regulation of PKC. In addition, inhibitors of calmodulin (W-7) or of calmodulin-dependent protein kinase II, reduced 5-HT2A, but not 5-HT2C, desensitization. Desensitization of the 5-HT2C, but not the 5-HT2A, receptor system was dependent on G protein receptor kinase activity." [Abstract]

Anushree Bhatnagar, David L. Willins, John A. Gray, Jason Woods, Jeffrey L. Benovic, and Bryan L. Roth
The Dynamin-dependent, Arrestin-independent Internalization of 5-Hydroxytryptamine 2A (5-HT2A) Serotonin Receptors Reveals Differential Sorting of Arrestins and 5-HT2A Receptors during Endocytosis
J. Biol. Chem. 276: 8269-8277, November 7, 2000.
"The major findings of this study are that 1) agonist- and antagonist-induced internalization of 5-HT2A receptors in HEK-293 cells are dynamin-dependent and arrestin-independent and 2) the agonist-induced internalization of 5-HT2A receptors leads to a differential sorting of 5-HT2A receptors and beta-arrestin-1 (Arr-2) and beta-arrestin-2 (Arr-3) into distinct plasma membrane and intracellular compartments. These results demonstrate that novel sorting pathways exist for arrestins and 5-HT2A receptors. Additionally, since 5-HT2A receptor activation leads to a redistribution of Arr-2 and Arr-3, our findings imply that internalization-independent functions exist for Arr-2 and Arr-3." [Full Text]

Gray, John A., Sheffler, Douglas J., Bhatnagar, Anushree, Woods, Jason A., Hufeisen, Sandra J., Benovic, Jeffrey L., Roth, Bryan L.
Cell-Type Specific Effects of Endocytosis Inhibitors on 5-Hydroxytryptamine2A Receptor Desensitization and Resensitization Reveal an Arrestin-, GRK2-, and GRK5-Independent Mode of Regulation in Human Embryonic Kidney 293 Cells
Mol Pharmacol 2001 60: 1020-1030 [Abstract]

McKune, C. M., Watts, S. W.
Characterization of the Serotonin Receptor Mediating Contraction in the Mouse Thoracic Aorta and Signal Pathway Coupling
J Pharmacol Exp Ther 2001 297: 88-95
"We conclude that contraction to 5-HT in the mouse aorta is mediated primarily by a 5-HT2A receptor and is coupled to L-type calcium channels, PLC, and tyrosine kinases." [Full Text]

Jasjit S. Grewal, Yurii V. Mukhin, Maria N. Garnovskaya, John R. Raymond, and Eddie L. Greene
Serotonin 5-HT2A receptor induces TGF-beta1 expression in mesangial cells via ERK: proliferative and fibrotic signals
Am J Physiol Renal Physiol 276: F922-F930, June 1999. [Full Text]

Eddie L. Greene, Odette Houghton, Georgiann Collinsworth, Maria N. Garnovskaya, Toshio Nagai, Tahir Sajjad, Venugopala Bheemanathini, Jasjit S. Grewal, Richard V. Paul, and John R. Raymond
5-HT2A receptors stimulate mitogen-activated protein kinase via H2O2 generation in rat renal mesangial cells
Am J Physiol Renal Physiol 278: F650-F658, April 2000. [Full Text]

Blakley, Gregory G., Pohorecky, Larissa A., Benjamin, Daniel
Bidirectional Changes in Ethanol Consumption in Rats with Site-Specific Antisense Down-Regulation of 5-Hydroxytryptamine2A Receptors in Brain
J Pharmacol Exp Ther 2001 299: 277-289 [Abstract]

Kasho M, Sakai M, Sasahara T, Anami Y, Matsumura T, Takemura T, Matsuda H, Kobori S, Shichiri M.
Serotonin enhances the production of type IV collagen by human mesangial cells.
Kidney Int 1998 Oct;54(4):1083-92 [Abstract]

Florian, Jennifer A., Watts, Stephanie W.
Integration of Mitogen-Activated Protein Kinase Kinase Activation in Vascular 5-Hydroxytryptamine2A Receptor Signal Transduction
J Pharmacol Exp Ther 1998 284: 346-355 [Full Text]

Banes, A., Florian, J. A., Watts, S. W.
Mechanisms of 5-Hydroxytryptamine2A Receptor Activation of the Mitogen-Activated Protein Kinase Pathway in Vascular Smooth Muscle
J Pharmacol Exp Ther 1999 291: 1179-1187 [Full Text]

Takayuki Ito, Uichi Ikeda, Masahisa Shimpo, Keiji Yamamoto, and Kazuyuki Shimada
Serotonin Increases Interleukin-6 Synthesis in Human Vascular Smooth Muscle Cells
Circulation 102: 2522-2527, 2000. [Full Text]

Szabo, Steven T., Blier, Pierre
Effects of Serotonin (5-Hydroxytryptamine, 5-HT) Reuptake Inhibition Plus 5-HT2A Receptor Antagonism on the Firing Activity of Norepinephrine Neurons
J Pharmacol Exp Ther 2002 302: 983-991 [Abstract]

Scruggs, Jennifer L., Patel, Sachin, Bubser, Michael, Deutch, Ariel Y.
DOI-Induced Activation of the Cortex: Dependence on 5-HT2A Heteroceptors on Thalamocortical Glutamatergic Neurons
J. Neurosci. 2000 20: 8846-8852
"Our findings provide a mechanism for understanding how 5-HT2A antagonists and suppression of glutamate transmission may be useful in treating schizophrenia." [Full Text]

Lambe, Evelyn K., Aghajanian, George K.
The Role of Kv1.2-Containing Potassium Channels in Serotonin-Induced Glutamate Release from Thalamocortical Terminals in Rat Frontal Cortex
J. Neurosci. 2001 21: 9955-9963
"These results indicate that blockade of Kv1.2-containing potassium channels is part of the mechanism underlying 5-HT-induced glutamate release from thalamocortical terminals." [Abstract]

Michelle Day, Patricia A. Olson, Josef Platzer, Joerg Striessnig, and D. James Surmeier
Stimulation of 5-HT2 Receptors in Prefrontal Pyramidal Neurons Inhibits Cav1.2 L-Type Ca2+ Currents Via a PLC/IP3/Calcineurin Signaling Cascade
J Neurophysiol 87: 2490-2504, 2002.
"There is growing evidence linking alterations in serotonergic signaling in the prefrontal cortex to the etiology of schizophrenia. Prefrontal pyramidal neurons are richly innervated by serotonergic fibers and express high levels of serotonergic 5-HT(2)-class receptors. It is unclear, however, how activation of these receptors modulates cellular activity. To help fill this gap, whole cell voltage-clamp and single-cell RT-PCR studies of acutely isolated layer V-VI prefrontal pyramidal neurons were undertaken. The vast majority (>80%) of these neurons had detectable levels of 5-HT(2A) or 5-HT(2C) receptor mRNA. Bath application of 5-HT(2) agonists inhibited voltage-dependent Ca(2+) channel currents. L-type Ca(2+) channels were a particularly prominent target of this signaling pathway. The L-type channel modulation was blocked by disruption of G(alphaq) signaling or by inhibition of phospholipase Cbeta. Antagonism of intracellular inositol trisphosphate signaling, chelation of intracellular Ca(2+), or depletion of intracellular Ca(2+) stores also blocked this modulation. Inhibition of the Ca(2+)-dependent phosphatase calcineurin prevented receptor-mediated modulation of L-type currents. Last, the 5-HT(2) receptor modulation was robustly expressed in neurons from Ca(v)1.3 knockout mice. These findings argue that 5-HT(2) receptors couple through G(alphaq) proteins to trigger a phospholipase Cbeta/inositol trisphosphate signaling cascade resulting in the mobilization of intracellular Ca(2+), activation of calcineurin, and inhibition of Ca(v)1.2 L-type Ca(2+) currents. This modulation and its blockade by atypical neuroleptics could have wide-ranging effects on synaptic integration and long-term gene expression in deep-layer prefrontal pyramidal neurons." [Abstract]

Marek, Gerard J., Wright, Rebecca A., Schoepp, Darryle D., Monn, James A., Aghajanian, George K.
Physiological Antagonism between 5-Hydroxytryptamine2A and Group II Metabotropic Glutamate Receptors in Prefrontal Cortex
J Pharmacol Exp Ther 2000 292: 76-87
"These findings suggest a close coupling between mGlu2/3 and 5-HT2A receptors in the prefrontal cortex that may be relevant for novel therapeutic approaches in the treatment of neuropsychiatric syndromes such as depression and schizophrenia." [Full Text]

Jalonen TO, Margraf RR, Wielt DB, Charniga CJ, Linne ML, Kimelberg HK.
Serotonin induces inward potassium and calcium currents in rat cortical astrocytes.
Brain Res 1997 May 30;758(1-2):69-82
"Ca2+ imaging and patch-clamp techniques were used to study the effects of serotonin (5-HT) on ionic conductances in rat cortical astrocytes. 1 and 10 microM serotonin caused a transient increase in intracellular calcium (Ca(i)) levels in fura-2AM-loaded cultured astrocytes and in astrocytes acutely isolated and then cultured in horse serum-containing medium for over 24 h. However, the acutely isolated (less than 6 h from isolation) astrocytes, as well as acutely isolated astrocytes cultured in serum-free media, failed to respond to 5-HT by changes in Ca(i). Coinciding with the changes in Ca(i) levels, inward currents were activated by 10 microM 5-HT in cultured, but not in acutely isolated astrocytes. Two separate types of serotonin-induced, small-conductance inward single-channel currents were found. First, in both Ca2+-containing and Ca2+-free media serotonin transiently activated a small-conductance apamin-sensitive channel. Apamin is a specific blocker of the small-conductance Ca2+-activated K+ channel (sK(Ca)) When cells were pre-treated with phospholipase C inhibitor U73122 no 5-HT-induced sK(Ca) channel openings were seen, indicating that this channel was activated by Ca2+ released from intracellular stores via IP3. A second type of small inward channel activated later, but only in the presence of external Ca2+. It was inhibited by the L-type Ca2+ channel blockers, nimodipine and nifedipine. Both types of channel activity were inhibited by ketanserin, indicating activation of the 5-HT2A receptor." [Abstract]

Katagiri H, Kagaya A, Nakae S, Morinobu S, Yamawaki S.
Modulation of serotonin2A receptor function in rats after repeated treatment with dexamethasone and L-type calcium channel antagonist nimodipine.
Prog Neuropsychopharmacol Biol Psychiatry 2001 Aug;25(6):1269-81
"1. It has been conceivable that the hypothalamic-pituitary-adrenal (HPA) axis hyperactivity plays an important role in the pathophysiology of depression. In the present study, we have investigated the effect of repeated treatment with dexamethasone on serotonin (5-HT) 1A, 5-HT2A and alpha1-adrenergic receptors in the rat frontal cortex. Moreover, several studies have suggested the effectiveness of L-type calcium channel antagonist nimodipine for the treatment of depression. We also investigated the effect of repeated treatment with nimodipine on 5-HT2A receptor in rats with repeated dexamethasone treatment. 2. Repeated treatment with dexamethasone (1 mg/kg/day for 14 days) increased the density of 5-HT2A receptor, but not 5-HT1A and alpha1-adrenergic receptors in the rat frontal cortex. 3. The density of 5-HT2A receptor in the rat frontal cortex was significantly increased 1 day after repeated treatment with dexamethasone, but was not increased 7 or 14 days after repeated treatment. Wet dog shakes (WDS) induced by (+/-)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane hydrochloride (DOI), a 5-HT2A receptor agonist, in rats were significantly enhanced 1, 7 and 14 days after repeated treatment with dexamethasone, although the frequency of WDS gradually decreased after repeated treatment. 4. Repeated treatment with nimodipine (5 mg/kg/day for 14 days) attenuated DOI-induced WDS enhanced by repeated treatment with dexamethasone (1 mg/kg/day for 14 days), however, it did not change the density of 5-HT2A receptor. Repeated treatment with dexamethasone decreased locomotor activity and body weight, but repeated treatment with nimodipine did not recover these parameters. 5. The results of the present study suggest that repeated treatment with dexamethasone may selectively increase the 5-HT2A receptor in the rat frontal cortex and affect 5-HT2A receptor-mediated signal transduction. In addition, the intracellular calcium homeostasis by blocking calcium influx through L-type calcium channel may play an important role in the regulation of the 5-HT2A receptor function by dexamethasone." [Abstract]

Hasuo, Hiroshi, Matsuoka, Toshimasa, Akasu, Takashi
Activation of Presynaptic 5-Hydroxytryptamine 2A Receptors Facilitates Excitatory Synaptic Transmission via Protein Kinase C in the Dorsolateral Septal Nucleus
J. Neurosci. 2002 22: 7509-7517
"These results suggest that 5-HT enhances the EPSP by increasing the release of glutamate via presynaptic 5-HT2A receptors that link with PKC in rat DLSN neurons." [Abstract]

Zhou, Fu-Ming, Hablitz, John J.
Activation of Serotonin Receptors Modulates Synaptic Transmission in Rat Cerebral Cortex
J Neurophysiol 1999 82: 2989-2999
"We found that 5-HT, through activation of 5-HT2A receptors, induced a massive enhancement of spontaneous inhibitory postsynaptic currents (sIPSCs) in pyramidal neurons, lasting for ~6 min. In interneurons, this 5-HT-induced enhancement of sIPSCs was much weaker. Activation of 5-HT2A receptors also increased spontaneous excitatory postsynaptic currents (sEPSCs) in pyramidal neurons. This response desensitized less and at a slower rate." [Full Text]

Feng, Jian, Cai, Xiang, Zhao, Jinghui, Yan, Zhen
Serotonin Receptors Modulate GABAA Receptor Channels through Activation of Anchored Protein Kinase C in Prefrontal Cortical Neurons
J. Neurosci. 2001 21: 6502-6511 [Full Text]

Aloyo, Vincent J., Dave, Kuldip D., Rahman, Tariq, Harvey, John A.
Selective and Divergent Regulation of Cortical 5-HT2A Receptors in Rabbit
J Pharmacol Exp Ther 2001 299: 1066-1072 [Abstract]

Araneda R, Andrade R.
5-Hydroxytryptamine2 and 5-hydroxytryptamine 1A receptors mediate opposing responses on membrane excitability in rat association cortex.
Neuroscience 1991;40(2):399-412 [Abstract]

McMahon, Lance R., Cunningham, Kathryn A.
Antagonism of 5-Hydroxytryptamine2A Receptors Attenuates the Behavioral Effects of Cocaine in Rats
J Pharmacol Exp Ther 2001 297: 357-363
"These results suggest that the 5-HT2AR plays an important role in the behavioral effects of cocaine and that 5-HT2AR should be considered a viable target for analysis in the search for pharmacotherapies for the treatment of cocaine dependence, particularly in light of a potentially more acceptable side effect profile presented by M100907 than DA receptor antagonists." [Full Text]

Schmidt CJ, Fadayel GM, Sullivan CK, Taylor VL.
5-HT2 receptors exert a state-dependent regulation of dopaminergic function: studies with MDL 100,907 and the amphetamine analogue, 3,4-methylenedioxymethamphetamine.
Eur J Pharmacol 1992 Nov 13;223(1):65-74
"The results suggest a permissive role for 5-HT2 receptors in the activation of the dopamine system which occurs during states of high serotonergic activity or during conditions of elevated dopamine efflux with high D2 receptor occupancy." [Abstract]

Lucas, Guillaume, Spampinato, Umberto
Role of Striatal Serotonin2A and Serotonin2C Receptor Subtypes in the Control of In Vivo Dopamine Outflow in the Rat Striatum
J Neurochem 2000 74: 693-701
"These results indicate that striatal 5-HT2A receptors, probably through activation of DA synthesis, positively modulate DA outflow only under activated conditions. In contrast, striatal 5-HT2C receptors exert a facilitatory control on basal DA efflux, which appears to be both tonic and phasic." [Abstract]

McMahonLance R, LR McMahon, M Filip, KA Cunningham
Differential regulation of the mesoaccumbens circuit by serotonin 5-hydroxytryptamine (5-ht)2a and 5-ht2c receptors
JOURNAL OF NEUROSCIENCE: THE OFFICIAL JOURNAL OF THE SOCIETY FOR NEUROSCIENCE, THE , 21(19):7781-7787 2001
"These findings are the first to demonstrate that the behavioral effects of cocaine are generated in part by activation of 5-HT(2A)Rs in the VTA and by activation of 5-HT(2C)Rs in the NAc shell." [Abstract]

Nocjar C, Roth BL, Pehek EA.
Localization of 5-HT(2A) receptors on dopamine cells in subnuclei of the midbrain A10 cell group.
Neuroscience 2002;111(1):163-76
"Interestingly, 5-HT(2A) receptors were expressed on dopamine neurons in several A10 subnuclei that project to mesolimbic forebrain regions implicated in drug addiction, and recent evidence indicates that ventral tegmental area 5-HT(2A) receptor activation may modulate reward-related behavior in rodents."
[Abstract]

Ikemoto K, Nishimura A, Okado N, Mikuni M, Nishi K, Nagatsu I.
Human midbrain dopamine neurons express serotonin 2A receptor: an immunohistochemical demonstration.
Brain Res 2000 Jan 24;853(2):377-80
"Double immunohistochemistry of 5-HT2A receptor and tyrosine hydroxylase (TH) revealed many neurons doubly labeled by 5-HT2A receptor and TH in the VTA and SN. It is suggested that activity of human midbrain dopaminergic neurons might be strongly regulated via 5-HT2A receptors at the level of their originating nuclei." [Abstract]

Deurwaerdère, Philippe De, Spampinato, Umberto
Role of Serotonin2A and Serotonin2B/2C Receptor Subtypes in the Control of Accumbal and Striatal Dopamine Release Elicited In Vivo by Dorsal Raphe Nucleus Electrical Stimulation
J Neurochem 1999 73: 1033-1042
"In summary, our results show that 5-HT2A and 5-HT2C receptors differentially contribute in the control of the mesolimbic and the nigrostriatal DA pathway activity. Whereas 5-HT2C receptors exert a tonic inhibitory control on both accumbal and striatal DA release, 5-HT2A receptors phasically stimulate DA release in the NAC only." [Abstract]

YATHAM, LAKSHMI N., LIDDLE, PETER F., SHIAH, I-SHIN, LAM, RAYMOND W., ADAM, MICHAEL J., ZIS, ATHANASIOS P., RUTH, THOMAS J.
Effects of rapid tryptophan depletion on brain 5-HT2 receptors: a PET study
Br J Psychiatry 2001 178: 448-453
"Taken together, these observations may indicate that reduced 5-HT2 receptor density may be potentially a critical event in the prevention and relief of depressive symptoms." [Full Text]

Peroutka, SJ, Snyder, SH
Regulation of serotonin2 (5-HT2) receptors labeled with [3H]spiroperidol by chronic treatment with the antidepressant amitriptyline
J Pharmacol Exp Ther 1980 215: 582-587
"The properties of 5-HT2 receptor reduction after chronic antidepressant treatment indicate that this alteration could be associated with therapeutic response." [Abstract]

Pandey, Ghanshyam N., Dwivedi, Yogesh, Rizavi, Hooriyah S., Ren, Xinguo, Pandey, Subhash C., Pesold, Christine, Roberts, Rosalinda C., Conley, Robert R., Tamminga, Carol A.
Higher Expression of Serotonin 5-HT2A Receptors in the Postmortem Brains of Teenage Suicide Victims
Am J Psychiatry 2002 159: 419-429
"The authors observed significantly higher [125I]LSD binding in the prefrontal cortex and greater protein expression and mRNA levels in the prefrontal cortex and hippocampus but not in the nucleus accumbens of suicide victims, compared with normal subjects. Greater protein expression was localized on pyramidal cells in cortical layer V but not in other cortical layers or in the surrounding neuropil of the prefrontal cortex of teenage suicide victims." [Abstract]

Audenaert K, Van Laere K, Dumont F, Slegers G, Mertens J, van Heeringen C, Dierckx RA.
Decreased frontal serotonin 5-HT 2a receptor binding index in deliberate self-harm patients.
Eur J Nucl Med 2001 Feb;28(2):175-82

Robert L. Jakab, and Patricia S. Goldman-Rakic
5-Hydroxytryptamine2A serotonin receptors in the primate cerebral cortex: Possible site of action of hallucinogenic and antipsychotic drugs in pyramidal cell apical dendrites
PNAS 95: 735-740, January 20, 1998.
"Clozapine's capability to deplete 5-HT2A receptors from apical dendrites or to slow the transport of the receptor from the soma to the dendritic tree may normalize the gating function of apical dendritic ion channels, and this effect may specifically contribute to the drug's clinical effectiveness in the treament of schizophrenia." [Full Text]

Schmidt CJ, Sorensen SM, Kehne JH, Carr AA, Palfreyman MG.
The role of 5-HT2A receptors in antipsychotic activity.
Life Sci 1995;56(25):2209-22
"We have used the highly selective 5-HT2A antagonist MDL 100,907 to explore the contribution of 5-HT2A receptor blockade to antipsychotic activity. Biochemical, electrophysiological and behavioral studies reveal that selective 5HT2A receptor antagonists have the preclinical profile of an atypical antipsychotic. The limited clinical evidence available also suggests that compounds producing 5-HT2A receptor blockade are effective, in particular, against the negative symptoms of schizophrenia." [Abstract]

Egan, Christina T., Herrick-Davis, Katharine, Teitler, Milt
Creation of a Constitutively Activated State of the 5-Hydroxytryptamine2A Receptor by Site-Directed Mutagenesis: Inverse Agonist Activity of Antipsychotic Drugs
J Pharmacol Exp Ther 1998 286: 85-90 [Full Text]

Willins, David L., Meltzer, Herbert Y.
Direct Injection of 5-HT2A Receptor Agonists into the Medial Prefrontal Cortex Produces a Head-Twitch Response in Rats
J Pharmacol Exp Ther 1997 282: 699-706 [Full Text]

de Angelis L.
5-HT2A antagonists in psychiatric disorders.
Curr Opin Investig Drugs 2002 Jan;3(1):106-12 [Abstract]

Fay R, Kubin L.
Pontomedullary distribution of 5-HT2A receptor-like protein in the rat.
Comp Neurol 2000 Mar 13;418(3):323-45 [Abstract]

Weiner, D. M., Burstein, E. S., Nash, N., Croston, G. E., Currier, E. A., Vanover, K. E., Harvey, S. C., Donohue, E., Hansen, H. C., Andersson, C. M., Spalding, T. A., Gibson, D. F. C., Krebs-Thomson, K., Powell, S. B., Geyer, M. A., Hacksell, U., Brann, M. R.
5-Hydroxytryptamine2A Receptor Inverse Agonists as Antipsychotics
J Pharmacol Exp Ther 2001 299: 268-276
"Detailed profiling of 40 antipsychotics confirmed that as expected, most of these agents are potent competitive antagonists of the dopamine D2 receptor. Surprisingly, this analysis also revealed that most are potent and fully efficacious 5-hydroxytryptamine (5-HT)2A receptor inverse agonists. No other molecular property was shared as universally by this class of compounds. Furthermore, comparisons of receptor potencies revealed that antipsychotics with the highest extrapyramidal side effects (EPS) liability are significantly more potent at D2 receptors, the EPS-sparing atypical agents had relatively higher potencies at 5-HT2A receptors, while three were significantly more potent at 5-HT2A receptors." [Abstract]

Schreiber, R, Brocco, M, Audinot, V, Gobert, A, Veiga, S, Millan, MJ
(1-(2,5-dimethoxy-4 iodophenyl)-2-aminopropane)-induced head-twitches in the rat are mediated by 5-hydroxytryptamine (5-HT) 2A receptors: modulation by novel 5-HT2A/2C antagonists, D1 antagonists and 5-HT1A agonists
J Pharmacol Exp Ther 1995 273: 101-112 [Abstract]

Levitan R, Masellis M, Basile V, Lam R, Jain U, Kaplan A, Kennedy S, Siegel G, Walker M, Vaccarino F, Kennedy J.
Polymorphism of the serotonin-2A receptor gene (HTR2A) associated with childhood attention deficit hyperactivity disorder (ADHD) in adult women with seasonal affective disorder.
J Affect Disord 2002 Sep;71(1-3):229
"LIMITATIONS: The current sample size is small, and childhood ADHD diagnoses were based on retrospective recall. CONCLUSION: These preliminary results suggest a possible association between variation in HTR2A, childhood ADHD, and the later development of SAD in women." [Abstract]

Coccaro EF, Kavoussi RJ, Oakes M, Cooper TB, Hauger R.
5-HT2a/2c receptor blockade by amesergide fully attenuates prolactin response to d-fenfluramine challenge in physically healthy human subjects.
Psychopharmacology (Berl) 1996 Jul;126(1):24-30 [Abstract]

Knowles ID, Ramage AG.
Evidence for a role for central 5-HT2B as well as 5-HT2A receptors in cardiovascular regulation in anaesthetized rats.
Br J Pharmacol 1999 Oct;128(3):530-42
"The data indicate that cardiovascular responses caused by i.c.v. quipazine and DOI are primarily due to activation of central 5-HT2A receptors, which causes the release of vasopressin and a tachycardia. This released vasopressin appears to suppress a 5-HT2A receptor-evoked central increase in sympathetic outflow, which involves the activation of central 5-HT2B receptors indirectly by the released vasopressin." [Abstract]

->Back to Home<-

Recent 5-HT2A Receptor Research
1) Niebert M, Vogelgesang S, Koch UR, Bischoff AM, Kron M, Bock N, Manzke T
Expression and Function of Serotonin 2A and 2B Receptors in the Mammalian Respiratory Network.
PLoS One. 2011;6(7):e21395.
Neurons of the respiratory network in the lower brainstem express a variety of serotonin receptors (5-HTRs) that act primarily through adenylyl cyclase. However, there is one receptor family including 5-HT(2A), 5-HT(2B), and 5-HT(2C) receptors that are directed towards protein kinase C (PKC). In contrast to 5-HT(2A)Rs, expression and function of 5-HT(2B)Rs within the respiratory network are still unclear. 5-HT(2B)R utilizes a Gq-mediated signaling cascade involving calcium and leading to activation of phospholipase C and IP3/DAG pathways. Based on previous studies, this signal pathway appears to mediate excitatory actions on respiration. In the present study, we analyzed receptor expression in pontine and medullary regions of the respiratory network both at the transcriptional and translational level using quantitative RT-PCR and self-made as well as commercially available antibodies, respectively. In addition we measured effects of selective agonists and antagonists for 5-HT(2A)Rs and 5-HT(2B)Rs given intra-arterially on phrenic nerve discharges in juvenile rats using the perfused brainstem preparation. The drugs caused significant changes in discharge activity. Co-administration of both agonists revealed a dominance of the 5-HT(2B)R. Given the nature of the signaling pathways, we investigated whether intracellular calcium may explain effects observed in the respiratory network. Taken together, the results of this study suggest a significant role of both receptors in respiratory network modulation. [PubMed Citation] [Order full text from Infotrieve]

2) Amireault P, Hatia S, Bayard E, Bernex F, Collet C, Callebert J, Launay JM, Hermine O, Schneider E, Mallet J, Dy M, C�t� F
Ineffective erythropoiesis with reduced red blood cell survival in serotonin-deficient mice.
Proc Natl Acad Sci U S A. 2011 Jul 25;
Serotonin (5-HT) has long been recognized as a neurotransmitter in the central nervous system, where it modulates a variety of behavioral functions. Availability of 5-HT depends on the expression of the enzyme tryptophan hydroxylase (TPH), and the recent discovery of a dual system for 5-HT synthesis in the brain (TPH2) and periphery (TPH1) has renewed interest in studying the potential functions played by 5-HT in nonnervous tissues. Moreover, characterization of the TPH1 knockout mouse model (TPH1(-/-)) led to the identification of unsuspected roles for peripheral 5-HT, revealing the importance of this monoamine in regulating key physiological functions outside the brain. Here, we present in vivo data showing that mice deficient in peripheral 5-HT display morphological and cellular features of ineffective erythropoiesis. The central event occurs in the bone marrow where the absence of 5-HT hampers progression of erythroid precursors expressing 5-HT(2A) and 5-HT(2B) receptors toward terminal differentiation. In addition, red blood cells from 5-HT-deficient mice are more sensitive to macrophage phagocytosis and have a shortened in vivo half-life. The combination of these two defects causes TPH1(-/-) animals to develop a phenotype of macrocytic anemia. Direct evidence for a 5-HT effect on erythroid precursors is provided by supplementation of the culture medium with 5-HT that increases the proliferative capacity of both 5-HT-deficient and normal cells. Our thorough analysis of TPH1(-/-) mice provides a unique model of morphological and functional aberrations of erythropoiesis and identifies 5-HT as a key factor for red blood cell production and survival. [PubMed Citation] [Order full text from Infotrieve]

3) Huot P, Fox SH, Newman-Tancredi A, Brotchie JM
Anatomically-selective 5-HT1A and 5-HT2A therapies for Parkinson's disease - an approach to reducing dyskinesia without exacerbating parkinsonism?
J Pharmacol Exp Ther. 2011 Jul 22;
L-3,4-dihydroxyphenylalanine (L-DOPA) remains the most effective treatment for Parkinson's disease (PD). However, long-term administration of L-DOPA is compromised by complications, particularly dyskinesia. Serotonergic type 1A (5-HT1A) receptor agonists and serotonergic type 2A (5-HT2A) receptor antagonists were, until recently, considered to be promising therapies against dyskinesia. However, there have been some recent, high profile failures in clinical trials, notably with sarizotan, and it appears that these classes of drug might also impair L-DOPA anti-parkinsonian efficacy. A simple explanation for loss of anti-parkinsonian benefit might be lack of good selectivity of these compounds for their respective targets, particularly with respect to off-target actions on dopaminergic receptors or poor dose selection in clinical studies. However, such explanations do not hold broadly when considering the actions of all compounds studied to date, whether in animal models or clinical trials. Here, we review 5-HT1A and 5-HT2A receptor function in PD and provide an anatomically-based rationale as to why in some instances 5-HT1A- and 5-HT2A-modulating drugs might worsen parkinsonism, in addition to reducing dyskinesia. We propose that, in addition to selectivity for specific receptor subtypes, to target 5-HT1A and 5-HT2A receptors to alleviate dyskinesia, without worsening parkinsonism, it will be necessary to develop compounds which display anatomical selectivity, targeting corticostriatal transmission, avoiding 5-HT receptors on ascending serotonergic and dopaminergic inputs from the raphe and substantia nigra respectively. [PubMed Citation] [Order full text from Infotrieve]

4) Talbot PS, Slifstein M, Hwang DR, Huang Y, Scher E, Abi-Dargham A, Laruelle M
Extended characterisation of the serotonin 2A (5-HT(2A)) receptor-selective PET radiotracer (11)C-MDL100907 in humans: Quantitative analysis, test-retest reproducibility, and vulnerability to endogenous 5-HT tone.
Neuroimage. 2011 Jul 19;
INTRODUCTION: Scanning properties and analytic methodology of the 5-HT(2A) receptor-selective positron emission tomography (PET) tracer (11)C-MDL100907 have been partially characterised in previous reports. We present an extended characterisation in healthy human subjects. METHODS: 64 (11)C-MDL100907 PET scans with metabolite-corrected arterial input function were performed in 39 healthy adults (18-55years). 12 subjects were scanned twice (duration 150min) to provide data on plasma analysis, model order estimation, and stability and test-retest characteristics of outcome measures. All other scans were 90min duration. 3 subjects completed scanning at baseline and following 5-HT(2A) receptor antagonist medication (risperidone or ciproheptadine) to provide definitive data on the suitability of the cerebellum as reference region. 10 subjects were scanned under reduced 5-HT and control conditions using rapid tryptophan depletion to investigate vulnerability to competition with endogenous 5-HT. 13 subjects were scanned as controls in clinical protocols. Pooled data were used to analyse the relationship between tracer injected mass and receptor occupancy, and age-related decline in 5-HT(2A) receptors. RESULTS: Optimum analytic method was a 2-tissue compartment model with arterial input function. However, basis function implementation of SRTM may be suitable for measuring between-group differences non-invasively and warrants further investigation. Scan duration of 90min achieved stable outcome measures in all cortical regions except orbitofrontal which required 120min. Binding potential (BP(P) and BP(ND)) test-retest variability was very good (7-11%) in neocortical regions other than orbitofrontal, and moderately good (14-20%) in orbitofrontal cortex and medial temporal lobe. Saturation occupancy of 5-HT(2A) receptors by risperidone validates the use of the cerebellum as a region devoid of specific binding for the purposes of PET. We advocate a mass limit of 4.6?g to remain below 5% receptor occupancy. (11)C-MDL100907 specific binding is not vulnerable to competition with endogenous 5-HT in humans. Paradoxical decreases in BP(ND) were found in right prefrontal cortex following reduced 5-HT, possibly representing receptor internalisation. Mean age-related decline in brain 5-HT(2A) receptors was 14.0�5.0% per decade, and higher in prefrontal regions. CONCLUSIONS: Our data confirm and extend support for (11)C-MDL100907 as a PET tracer with very favourable properties for quantifying 5-HT(2A) receptors in the human brain. [PubMed Citation] [Order full text from Infotrieve]

5) Renoir T, Zajac MS, Du X, Pang TY, Leang L, Chevarin C, Lanfumey L, Hannan AJ
Sexually Dimorphic Serotonergic Dysfunction in a Mouse Model of Huntington's Disease and Depression.
PLoS One. 2011;6(7):e22133.
Depression is the most common psychiatric disorder in Huntington's disease (HD) patients. In the general population, women are more prone to develop depression and such susceptibility might be related to serotonergic dysregulation. There is yet to be a study of sexual dimorphism in the development and presentation of depression in HD patients. We investigated whether 8-week-old male and female R6/1 transgenic HD mice display depressive-like endophenotypes associated with serotonergic impairments. We also studied the behavioral effects of acute treatment with sertraline. We found that only female HD mice exhibited a decreased preference for saccharin as well as impaired emotionality-related behaviors when assessed on the novelty-suppressed feeding test (NSFT) and the forced-swimming test (FST). The exaggerated immobility time displayed by female HD in the FST was reduced by acute administration of sertraline. We also report an increased response to the 5-HT(1A) receptor agonist 8-OH-DPAT in inducing hypothermia and a decreased 5-HT(2A) receptor function in HD animals. While tissue levels of serotonin were reduced in both male and female HD mice, we found that serotonin concentration and hydroxylase-2 (TPH2) mRNA levels were higher in the hippocampus of males compared to female animals. Finally, the antidepressant-like effects of sertraline in the FST were blunted in male HD animals. This study reveals sex-specific depressive-related behaviors during an early stage of HD prior to any cognitive and motor deficits. Our data suggest a crucial role for disrupted serotonin signaling in mediating the sexually dimorphic depression-like phenotype in HD mice. [PubMed Citation] [Order full text from Infotrieve]

6) Blier P, Briley M
The noradrenergic symptom cluster: clinical expression and neuropharmacology.
Neuropsychiatr Dis Treat. 2011;7(Suppl 1):15-20.
Signs and symptoms of depression can be linked to one or more monoaminergic systems, specifically the norepinephrine (NE), the dopamine (DA), and the serotonin (5-HT) systems. In particular, the modulation of energy, vigilance, and arousal can be directly linked to the NE system. There is, however, a great deal of overlap in the modulation of the symptoms of depression between these monoaminergic systems. There are considerable reciprocal interactions between the NE, DA, and the 5-HT systems. When using a selective serotonin reuptake inhibitor (SSRI), for example, 5-HT transmission is enhanced, but at the same time there is a dampening of the activity of NE and DA neurons through inhibitory 5-HT(2A) and 5-HT(2C) receptors, respectively. This could explain the residual symptoms of fatigue, lack of energy, and anhedonia, often seen after patients present an overall positive response to a SSRI. Using a dual 5-HT and NE reuptake inhibitor (SNRI), such as milnacipran, would result in an additional increase in NE activity. Futhermore, inhibiting NE reuptake increases DA availability in the frontal cortex since DA is mainly cleared by the NE transporters in several brain regions. A risk inherent in increased NE activity is that of provoking anxiety. This is avoided however by the attenuation of the phasic reactivity of the firing of NE neurons through prolonged administration of SSRI and SNRI. [PubMed Citation] [Order full text from Infotrieve]

7) Riss PJ, Hong YT, Williamson D, Caprioli D, Sitnikov S, Ferrari V, Sawiak SJ, Baron JC, Dalley JW, Fryer TD, Aigbirhio FI
Validation and quantification of [(18)F]altanserin binding in the rat brain using blood input and reference tissue modeling.
J Cereb Blood Flow Metab. 2011 Jul 13;
The 5-hydroxytryptamine type 2a (5-HT(2A)) selective radiotracer [(18)F]altanserin has been subjected to a quantitative micro-positron emission tomography study in Lister Hooded rats. Metabolite-corrected plasma input modeling was compared with reference tissue modeling using the cerebellum as reference tissue. [(18)F]altanserin showed sufficient brain uptake in a distribution pattern consistent with the known distribution of 5-HT(2A) receptors. Full binding saturation and displacement was documented, and no significant uptake of radioactive metabolites was detected in the brain. Blood input as well as reference tissue models were equally appropriate to describe the radiotracer kinetics. [(18)F]altanserin is suitable for quantification of 5-HT(2A) receptor availability in rats.Journal of Cerebral Blood Flow & Metabolism advance online publication, 13 July 2011; doi:10.1038/jcbfm.2011.94. [PubMed Citation] [Order full text from Infotrieve]

8) Ebdrup BR, Rasmussen H, Arnt JR, Glenth J B
Serotonin 2A receptor antagonists for treatment of schizophrenia.
Expert Opin Investig Drugs. 2011 Jul 8;
Introduction: All approved antipsychotic drugs share an affinity for the dopamine 2 (D(2)) receptor; however, these drugs only partially ameliorate the symptoms of schizophrenia. It is, therefore, of paramount importance to identify new treatment strategies for schizophrenia. Areas covered: Preclinical, clinical and post-mortem studies of the serotonin 5-HT(2A) system in schizophrenia are reviewed. The implications of a combined D(2) and 5-HT(2A) receptor blockade, which is obtained by several current antipsychotic drugs, are discussed, and the rationale for the development of more selective 5-HT(2A) receptor antagonists is evaluated. Moreover, the investigational pipeline of major pharmaceutical companies is examined and an Internet search conducted to identify other pharmaceutical companies investigating 5-HT(2A) receptor antagonists for the treatment of schizophrenia. Expert opinion: 5-HT(2A) receptor antagonists appear to assume an intermediate position by being marginally superior to placebo but inferior to conventional antipsychotic drugs. Three previous 5-HT(2A) receptor antagonists have been discontinued after Phase II or III trials, and available Phase IIa data on the remaining 5-HT(2A) receptor antagonist will need substantial additional validation to be approved as a new treatment strategy against schizophrenia. [PubMed Citation] [Order full text from Infotrieve]

9) Yadav PN, Kroeze W, Farrell M, Roth BL
ANTAGONIST FUNCTIONAL SELECTIVITY: 5-HT2A SEROTONIN RECEPTOR ANTAGONISTS DIFFERENTIALLY REGULATE 5-HT2A RECEPTOR PROTEIN LEVEL IN VIVO.
J Pharmacol Exp Ther. 2011 Jul 7;
Dysregulation of the serotonin2A (5-HT2A) receptor is implicated in both the etiology and treatment of schizophrenia. Although the essential role of 5-HT2A receptors in atypical antipsychotic drug actions is widely accepted, the contribution of 5-HT2A down-regulation to their efficacy is not known. We hypothesized that down-regulation of cortical 5-HT2A receptors contributes to the therapeutic action of atypical antipsychotic drugs. To test this hypothesis, we assessed the effect of chronically administered antipsychotics (clozapine, olanzapine, and haloperidol), and several 5-HT2A antagonists (ketanserin, altanserin, M100907, M11939, SR46349B and pimavanserin), on the phencyclidine (PCP)-induced hyperlocomotor response and cortical 5-HT2A receptor levels in C57BL/6J mice. Clozapine and olanzapine, but not haloperidol, induced receptor down-regulation and attenuated PCP-induced locomotor responses. Of the selective 5-HT2A antagonists tested, only ketanserin caused significant receptor protein down-regulation, whereas SR46349B up-regulated 5-HT2A receptors and potentiated PCP-hyperlocomotion; the other 5-HT2A receptor antagonists were without effect. The significance of these findings with respect to atypical antipsychotic drug action is discussed. [PubMed Citation] [Order full text from Infotrieve]

10) Underwood MD, Kassir SA, Bakalian MJ, Galfalvy H, Mann JJ, Arango V
Neuron density and serotonin receptor binding in prefrontal cortex in suicide.
Int J Neuropsychopharmacol. 2011 May 9;:1-13.
Although serotonin receptor and cytoarchitectonic alterations are reported in prefrontal cortex (PFC) in suicide and depression, no study has considered binding relative to neuron density. Therefore, we measured neuron density and serotonin transporter (SERT), 5-HT1A and 5-HT2A binding in matched suicides and controls. Suicides and normal controls (n=15 matched pairs) were psychiatrically characterized. Neuron density and binding were determined in dorsal [Brodmann area (BA) 9] and ventral (BA 47) PFC by stereology and quantitative autoradiography in near-adjacent sections. Binding index was defined as the ratio of receptor binding to neuron density. Suicides had lower neuron density in the gyrus of both areas. The binding index was lower for SERT in BA 47 but not in BA9; the 5-HT1A binding index was higher in BA 9 but not in BA 47, while the 5-HT2A binding index was not different between groups. SERT binding was lower in suicides in BA 47 but not BA 9, while 5-HT1A binding was higher in BA 9 but not BA 47. SERT binding negatively correlated with 5-HT1A binding in BA 47 in suicides. Neuron density decreased with age. The 5-HT1A binding index was higher in females than males. We found lower neuron density and lower SERT binding index in both PFC regions in suicides. More 5-HT1A binding with less SERT binding and the negative correlation in depressed suicides suggests post-synaptic receptor up-regulation, and it is independent of the difference in neuron density. Thus, abnormalities in both cortical neurons and in their serotonergic innervation are present in suicides and future studies will need to determine whether cortical changes reflect the trophic effect of altered serotonin innervation. [PubMed Citation] [Order full text from Infotrieve]

11) Gong P, Zheng Z, Chi W, Lei X, Wu X, Chen D, Zhang K, Zheng A, Gao X, Zhang F
An Association Study of the Genetic Polymorphisms in 13 Neural Plasticity-Related Genes with Semantic and Episodic Memories.
J Mol Neurosci. 2011 Jul 5;
Semantic and episodic memories were two different attributes of long-term memory. In the past few years, plenty of physiological evidence has indicated that neural plasticity is involved in the formation of long-term memory. In the present study, we hypothesized that some functional variants of neural plasticity-related genes were related to episodic and semantic memories. To confirm this hypothesis, we examined the relationship of 13 plasticity-related genes with episodic and semantic memories. The results indicated that there was a statistically significant difference in semantic memory scores among the three genotype groups of T267C in 5-HT ( 6 ) (? (2)?=?16.638, p?=?0.0002). However, the functional variations in BDNF, COMT, DBH, DRD ( 2 ), DRD ( 3 ), DRD ( 4 ), MAOA, TPH ( 2 ), 5-HT ( 2A ), GRM ( 1 ), and GRIN2B had no observable effects on the memories. Our preliminary results confirm the hypothesis that a small number of functional variants of the neural plasticity-related genes, such as T267C in 5-HT ( 6 ), play important roles in human specific memory. [PubMed Citation] [Order full text from Infotrieve]

12) Hautzel H, M�ller HW, Herzog H, Grandt R
Cognition-induced modulation of serotonin in the orbitofrontal cortex: A controlled cross-over PET study of a delayed match-to-sample task using the 5-HT2a receptor antagonist [(18)F]altanserin.
Neuroimage. 2011 Jun 17;
Behavioral and cellular studies indicate that serotonin interacting with the 5-HT2a receptor (5-HT2aR) is involved in cognitive processes supporting working memory (WM). However, 5-HT receptor neuroimaging studies directly relating WM-induced neuronal activations to concomitant changes in the availability of 5-HT receptors as a functional measure for serotonin release are lacking. This controlled cross-over PET study aimed to identify brain regions with WM-induced changes in the binding potential (BP(nd)) of the 5-HT2aR antagonist [(18)F]altanserin. Ten young males underwent a delayed match-to-sample task using photographs of faces and a control task. The BP(nd)s for both conditions were calculated by applying Ichise's noninvasive plot. Statistics were performed with the SPM toolbox statistical nonparametric mapping (SnPM3) particularly suited for analyzing whole-brain PET data in an exploratory way. A higher BP(nd) for [(18)F]altanserin during WM versus control was found in the orbitofrontal cortex (OFC) pointing towards an increased [(18)F]altanserin/5-HT2aR interaction in OFC while BP(nd) decreases during WM were not found. Furthermore, no BP(nd) changes in regions known from functional neuroimaging studies to be more specifically involved in WM were identified. These findings may suggest that the increased [(18)F]altanserin BP(nd) under WM challenge and hence the increased availability of 5-HT2aR reflects a decrease in local OFC serotonin. As the OFC plays a prominent role in decision-making and supports cognitive processes related to the central executive functions of WM it might be modulated by the serotoninergic system via the 5-HT2aR in order to support and optimize basic cognitive functions. [PubMed Citation] [Order full text from Infotrieve]

13) Renoir T, Pang TY, Zajac MS, Chan G, Du X, Leang L, Chevarin C, Lanfumey L, Hannan AJ
Treatment of depressive-like behaviour in Huntington's disease mice by chronic sertraline and exercise.
Br J Pharmacol. 2011 Jun 30;
Background and purpose:? Depression is the most common psychiatric disorder in Huntington's disease (HD) patients. Women are more prone to develop depression and such susceptibility might be related to serotonergic dysregulation. Experimental approach:? We performed tests of depression-related behaviors on female R6/1 HD mice that had been chronically treated with sertraline or provided with running-wheels. Functional assessments of 5-HT(1A) and 5-HT(2A) receptors were performed by measuring behavioral and physiological responses following administration of specific agonists, in combination with analysis of hippocampal gene expression. Finally we assessed the effect of exercise on hippocampal cell proliferation. Key results:? Female HD mice recorded increased immobility time in the forced-swimming test, reduced saccharin preference and a hyperthermic response to stress compared to wild-type animals. These alterations were improved by chronic sertraline treatment. Wheel-running also resulted in similar improvements with the exception of saccharin preference while failing to correct the hippocampal cell proliferation deficits displayed by HD mice. The benefits of sertraline treatment and exercise involved altered 5-HT(1A) autoreceptor function as demonstrated by modulation of the exaggerated 8-OH-DPAT-induced hypothermia exhibited by female HD mice. On the other hand, sertraline treatment was unable to rescue the reduced 5-HT(1A) and 5-HT(2) heteroceptor function observed in HD animals. Conclusions and implications:? We report for the first time a crucial role for 5-HT(1A) autoreceptor function in mediating the sex-specific depressive-like phenotype of female R6/1 HD mice. Our data further supports a differential effect of chronic sertraline treatment and exercise on hippocampal cell proliferation despite common behavioral benefits. [PubMed Citation] [Order full text from Infotrieve]

14) Ansah TA, Ferguson MC, Nayyar T
The 5-HT(2A) Receptor Antagonist M100907 Produces Antiparkinsonian Effects and Decreases Striatal Glutamate.
Front Syst Neurosci. 2011;5:48.
5-HT plays a regulatory role in voluntary movements of the basal ganglia and has a major impact on disorders of the basal ganglia such as Parkinson's disease (PD). Clinical studies have suggested that 5-HT(2) receptor antagonists may be useful in the treatment of the motor symptoms of PD. We hypothesized that 5-HT(2A) receptor antagonists may restore motor function by regulating glutamatergic activity in the striatum. Mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) exhibited decreased performance on the beam-walking apparatus. Peripheral administration of the 5-HT(2A) receptor antagonist M100907 improved performance of MPTP-treated mice on the beam-walking apparatus. In vivo microdialysis revealed an increase in striatal extracellular glutamate in MPTP-treated mice and local perfusion of M100907 into the dorsal striatum significantly decreased extracellular glutamate levels in saline and MPTP-treated mice. Our studies suggest that blockade of 5-HT(2A) receptors may represent a novel therapeutic target for the motor symptoms of PD. [PubMed Citation] [Order full text from Infotrieve]

15) Varela MJ, Brea J, Loza MI, Maldonado R, Robledo P
Sensitization to MDMA locomotor effects and changes in the functionality of 5-HT2A and D2 receptors in mice.
Behav Pharmacol. 2011 Aug;22(4):362-9.
The behavioral and neurochemical adaptations related to chronic 3,4-methylenedioxymethamphetamine (MDMA) treatment are largely unknown. In this study, we assessed whether repeated administration of MDMA would induce (a) context-dependent locomotor sensitization in mice and (b) changes in serotonin 5-HT2A and dopamine D2 receptor functionality as measured by [S]GTP?S binding. Mice were treated with MDMA (10 mg/kg, intraperitoneally) or saline every other day for 11 days either in their home cages or in the environment where locomotor activity was measured. After a 10-day withdrawal period, mice were challenged with MDMA (5 and 10 mg/kg) and saline before locomotor activity measurements. During repeated MDMA treatment, locomotion was progressively enhanced, indicating the development of behavioral sensitization. The MDMA challenge at a dose of 5 mg/kg increased locomotor activity to a greater extent in mice pretreated with MDMA in the testing apparatus than in mice pretreated in the home cages, revealing that contextual cues paired with repeated drug exposure can enhance the expression of behavioral sensitization to MDMA. In contrast, a challenge administration of MDMA at 10 mg/kg induced similar locomotor sensitization in mice pretreated in both environments. An increase in the functionality of cortical 5-HT2A receptors was observed in mice pretreated with MDMA compared with mice pretreated with saline, but this activation was significantly greater in mice pretreated in the locomotor environment. In contrast, the functional activity of striatal D2 receptors was significantly decreased only in mice pretreated with MDMA in the testing apparatus. These results reveal neuroadaptations in cortical 5-HT2A and striatal D2 receptors after MDMA-induced behavioral sensitization in mice. [PubMed Citation] [Order full text from Infotrieve]

16) Murphy TM, Ryan M, Foster T, Kelly C, McClelland R, O'Grady J, Corcoran E, Brady J, Reilly M, Jeffers A, Brown K, Maher A, Bannan N, Casement A, Lynch D, Bolger S, Tewari P, Buckley A, Quinlivan L, Daly L, Kelleher C, Malone KM
Risk and protective genetic variants in suicidal behaviour: association with SLC1A2, SLC1A3, 5-HTR1B &NTRK2 polymorphisms.
Behav Brain Funct. 2011;7:22.
[PubMed Citation] [Order full text from Infotrieve]

17) Klempan T, Hudon-Thibeault AA, Oufkir T, Vaillancourt C, Sanderson JT
Stimulation of serotonergic 5-HT(2A) receptor signaling increases placental aromatase (CYP19) activity and expression in BeWo and JEG-3 human choriocarcinoma cells.
Placenta. 2011 Jun 23;
It is known that serotonin can influence the production and function of sex hormones, such as estrogens. Estrogens are critical for maintenance of pregnancy and regulate placental and fetal development. The key enzyme controlling estrogens synthesis during pregnancy is placental aromatase (CYP19). To better understand the regulation of placental aromatase, this study determined whether serotonin is involved in the regulation of this enzyme. BeWo and JEG-3 choriocarcinoma cells were used as models of the human placental trophoblast to evaluate the effects of serotonin and selective 5-HT(2A) receptor agonists on CYP19 activity and expression. Serotonin and selective 5-HT(2A) receptor agonists as well as PKC activation increased aromatase activity and expression in BeWo and JEG-3 cells. Dexamethasone, which regulates aromatase expression via JAK/STAT activation in certain tissues, had no effect. Increased CYP19 gene transcription by 5-HT(2A) receptor and PKC stimulation was mediated by activation of the placental I.1 aromatase promoter. This study shows that the serotonergic system modulates placental aromatase expression, which would result in altered estrogens biosynthesis in trophoblast cells. Future detailed studies of serotonin-estrogen interactions in placenta are crucial for an improved understanding of the endo-, para- and autocrine role of serotonin during pregnancy and fetal development. [PubMed Citation] [Order full text from Infotrieve]

18) Nascimento EB, Seniuk JG, Godin AM, Ferreira WC, Dutra MB, Oliveira AC, Bastos LF, Fiebich BL, Coelho MM
Peripheral 5-HT(1B) and 5-HT(2A) receptors mediate the nociceptive response induced by 5-hydroxytryptamine in mice.
Pharmacol Biochem Behav. 2011 Jun 16;99(4):598-603.
While the role of 5-hydroxytryptamine (5-HT, serotonin) in the nociceptive processing has been widely investigated in the central nervous system, information regarding its role in peripheral tissues is still lacking. Noteworthy, 5-HT induces phenotypic changes of nociceptors and peripheral injection induces pain in humans and nociceptive response in rodents. However, local receptors involved in 5-HT effects are not well characterized. Thus, we aimed to investigate the role of 5-HT and some of its receptors in the peripheral nociceptive processing in mice. Intraplantar injection of 5-HT (10, 20 or 40?g) into the hind-paw of mice induced paw licking behavior, which was inhibited by previous intraplantar treatment with cyproheptadine (5-HT(1) and 5-HT(2) antagonist; 0.5 or 5?g), mianserin (5-HT(2) and 5-HT(6) antagonist; 0.1?g), isamoltane (5-HT(1B) antagonist; 0.5 or 5?g) and ketanserin (5-HT(2A) antagonist; 0.1 or 1?g), but not by BRL 15572 (5-HT(1D) antagonist; 1 or 10?g), ondansetron (5-HT(3) antagonist; 1, 5, 10 or 20?g) and SB 269970 (5-HT(7) antagonist; 2.5 and 25?g). Altogether, these results indicate the local involvement of 5-HT(1), 5-HT(2) and 5-HT(6), especially 5-HT(1B) and 5-HT(2A), in the nociceptive response induced by 5-HT in mice, thus contributing to a better understanding of 5-HT role in the peripheral nociceptive processing. In addition, they also point to important species differences and the need of a wide evaluation of the peripheral nociceptive processing in mice as these animals have been increasingly used in studies investigating the cellular and molecular mechanisms mediating the nociceptive response. [PubMed Citation] [Order full text from Infotrieve]

19) Nagao Y, Akahoshi T, Kamori M, Uehara H, Hashimoto N, Kinjo N, Shirabe K, Taketomi A, Tomikawa M, Hashizume M, Maehara Y
Liver regeneration is promoted by increasing serotonin content in rat liver with secondary biliary cirrhosis.
Hepatol Res. 2011 Jun 23;
Aim:? Liver cirrhosis clinically shows thrombocytopenia and hypersplenism. Although splenectomy is performed to achieve higher platelet count and better hemostasis, the effect of splenectomy for liver cirrhosis remains unclear. The aim of the present study that was focused on serotonin was to investigate the relationship between splenectomy and liver regeneration in rats with secondary biliary cirrhosis. Methods:? Liver cirrhosis was induced in Sprague-Dawley rats by bile duct ligation (BDL). In addition, splenectomy and administration of ketanserin, which selectively antagonizes 5-HT2A and 2B serotonin receptors, were performed. Three weeks after the interventions, whole blood, plasma, serum, and liver specimens were obtained for the following studies: peripheral platelet counts, hemodynamics of serotonin, histopathological examination, immunostaining, and quantification of mRNA expression. Results:? Splenectomy induced thrombocytosis, and increased serotonin content in cirrhotic liver. Stimulation of liver regeneration was indicated by the following parameters: hepatocyte ratio to the entire liver area, Ki67-positive hepatocyte count, and expression of phosphorylated extracellular signal-regulated kinases. This enhancement of liver regeneration was negated by ketanserin. Conclusion:? Our results showed that splenectomy promoted liver regeneration by increasing serotonin content in liver even under cirrhotic conditions. [PubMed Citation] [Order full text from Infotrieve]

20) Homberg JR
Serotonin and decision making processes.
Neurosci Biobehav Rev. 2011 Jun 12;
Serotonin (5-HT) is an important player in decision making. Serotonergic antidepressant, anxiolytic and antipsychotic drugs are extensively used in the treatment of neuropsychiatric disorders characterized by impaired decision making, and exert both beneficial and harmful effects in patients. Detailed insight into the serotonergic mechanisms underlying decision making is needed to strengthen the first and weaken the latter. Although much remains to be done to achieve this, accumulating studies begin to deliver a coherent view. Thus, high central 5-HT levels are generally associated with improved reversal learning, improved attentional set shifting, decreased delay discounting, and increased response inhibition, but a failure to use outcome representations. Based on 5-HT's evolutionary role, I hypothesize that 5-HT integrates expected, or changes in, relevant sensory and emotional internal/external information, leading to vigilance behaviour affecting various decision making processes. 5-HT receptor subtypes play distinctive roles in decision making. 5-HT(2A) agonists and 5-HT2c antagonists decrease compulsivity, whereas 5-HT(2A) antagonists and 5-HT(2C) agonists decrease impulsivity. 5-HT(6) antagonists univocally affect decision making processes. [PubMed Citation] [Order full text from Infotrieve]