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]

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Recent 5-HT2A Receptor Research
1) Moreno JL, Holloway T, Umali A, Rayannavar V, Sealfon SC, Gonz�lez-Maeso J
Persistent effects of chronic clozapine on the cellular and behavioral responses to LSD in mice.
Psychopharmacology (Berl). 2012 Jul 28;
RATIONALE: In schizophrenia patients, optimal treatment with antipsychotics requires weeks to months of sustained drug therapy. However, single administration of antipsychotic drugs can reverse schizophrenia-like behavioral alterations in rodent models of psychosis. This raises questions about the physiological relevance of such antipsychotic-like activity. OBJECTIVE: This study evaluates the effects of chronic treatment with clozapine on the cellular and behavioral responses induced by the hallucinogenic serotonin 5-HT(2A) receptor agonist lysergic acid diethylamide (LSD) as a mouse model of psychosis. METHOD: Mice were treated chronically (21�days) with 25�mg/kg/day clozapine. Experiments were conducted 1, 7, 14, and 21�days after the last clozapine administration. [(3)H]Ketanserin binding and 5-HT ( 2A ) mRNA expression were determined in mouse somatosensory cortex. Head-twitch behavior, expression of c-fos, which is induced by all 5-HT(2A) agonists, and expression of egr-1 and egr-2, which are LSD-like specific, were assayed. RESULTS: Head-twitch response was decreased and [(3)H]ketanserin binding was downregulated in 1, 7, and 14�days after chronic clozapine. 5-HT ( 2A ) mRNA was reduced 1�day after chronic clozapine. Induction of c-fos, but not egr-1 and egr-2, was rescued 7�days after chronic clozapine. These effects were not observed after short treatment (2�days) with clozapine or chronic haloperidol (1�mg/kg/day). CONCLUSION: Our findings provide a murine model of chronic atypical antipsychotic drug action and suggest downregulation of the 5-HT(2A) receptor as a potential mechanism involved in these persistent therapeutic-like effects. [PubMed Citation] [Order full text from Infotrieve]

2) Anneken JH, Gudelsky GA
MDMA produces a delayed and sustained increase in the extracellular concentration of glutamate in the rat hippocampus.
Neuropharmacology. 2012 Jul 25;
The neurochemical effects of MDMA (3,4-methylenedioxymethamphetamine) on monoaminergic and cholinergic systems in the rat brain have been well documented. However, little is known regarding the effects of MDMA on glutamatergic systems in the brain. In the present study the effects of multiple injections of MDMA on extracellular concentrations of glutamate in the striatum, prefrontal cortex, and dorsal hippocampus were examined. Two or four, but not one, injections of MDMA (10�mg/kg, i.p. at 2�h intervals) resulted in a 2-3 fold increase in the extracellular concentration of glutamate in the hippocampus; no increase was evident in the striatum or prefrontal cortex. Reverse dialysis of MDMA (100�?M) into the hippocampus also elicited an increase in extracellular glutamate. Treatment with the 5-HT reuptake inhibitor fluoxetine prevented the increase in extracellular glutamate in the hippocampus following the systemic administration of MDMA, as did treatment with the serotonin 5-HT2A/C receptor antagonist ketanserin. Moreover, reverse dialysis of the sodium channel blocker tetrodotoxin did not prevent the increase in extracellular glutamate in the hippocampus. These data support the view that stimulation of 5-HT2A/2C receptors on non-neuronal cells by 5-HT released by MDMA promotes glutamate efflux in the hippocampus. [PubMed Citation] [Order full text from Infotrieve]

3) Franklin JM, Vasiljevik T, Prisinzano TE, Carrasco GA
Cannabinoid 2 receptor- and beta Arrestin 2-dependent upregulation of serotonin 2A receptors.
Eur Neuropsychopharmacol. 2012 Jul 27;
Recent evidence suggests that cannabinoid receptor agonists may regulate serotonin 2A (5-HT(2A)) receptor neurotransmission in the brain, although no molecular mechanism has been identified. Here, we present experimental evidence that sustained treatment with a non-selective cannabinoid agonist (CP55,940) or selective CB2 receptor agonists (JWH133 or GP1a) upregulate 5-HT(2A) receptors in a neuronal cell line. Furthermore, this cannabinoid receptor agonist-induced upregulation of 5-HT(2A) receptors was prevented in cells stably transfected with either CB2 or ?-Arrestin 2 shRNA lentiviral particles. Additionally, inhibition of clathrin-mediated endocytosis also prevented the cannabinoid receptor-induced upregulation of 5-HT(2A) receptors. Our results indicate that cannabinoid agonists might upregulate 5-HT(2A) receptors by a mechanism that requires CB2 receptors and ?-Arrestin 2 in cells that express both CB2 and 5-HT(2A) receptors. 5-HT(2A) receptors have been associated with several physiological functions and neuropsychiatric disorders such as stress response, anxiety and depression, and schizophrenia. Therefore, these results might provide a molecular mechanism by which activation of cannabinoid receptors might be relevant to some cognitive and mood disorders in humans. [PubMed Citation] [Order full text from Infotrieve]

4) Maguire DR, Li JX, Koek W, France CP
Effects of 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) and quipazine on heroin self-administration in rhesus monkeys.
Psychopharmacology (Berl). 2012 Jul 27;
RATIONALE: The serotonin (5-HT) system is involved in pain modulation, and 5-HT receptor agonists can enhance antinociceptive effects of mu opioid receptor agonists. Less is known about the actions of 5-HT receptor agonists on other effects of opioids. OBJECTIVE: This study examined the effects of non-contingent and contingent administration of the 5-HT(2A) receptor agonists DOM and quipazine on i.v. heroin self-administration in rhesus monkeys. RESULTS: Heroin (0.0001-0.1�mg/kg/infusion) generated an inverted U-shaped dose-response function. Non-contingent administration of DOM (0.1-0.32�mg/kg) flattened the dose-response function in three monkeys and eliminated heroin self-administration in a fourth monkey. Contingent DOM (0.0032-0.032�mg/kg/infusion) alone did not maintain responding above that maintained by saline, and, when added to self-administered heroin, monkeys responded less than for the same unit doses of heroin alone. Non-contingent (0.32-3.2�mg/kg) and contingent (0.0032-0.56�mg/kg/infusion) administration of quipazine flattened the dose-response function in two monkeys, increasing responding maintained by small unit doses of heroin and saline, but failed to enhance responding for heroin in two other monkeys. CONCLUSION: This study shows that DOM does not enhance, and might attenuate, the positive reinforcing effects of the mu opioid receptor agonist heroin. Quipazine increased responding for saline and small doses of heroin; those effects were modest and observed in only two subjects. Taken together, these data suggest that 5-HT(2A) receptor agonists do not significantly enhance the reinforcing effectiveness of mu opioid receptor agonists and support the view that administering 5-HT drugs in combination with opioids to treat pain might not enhance abuse liability. [PubMed Citation] [Order full text from Infotrieve]

5) Rylands AJ, Hinz R, Jones M, Holmes SE, Feldmann M, Brown G, McMahon AW, Talbot PS
Pre- and Postsynaptic Serotonergic Differences in Males with Extreme Levels of Impulsive Aggression Without Callous Unemotional Traits: A Positron Emission Tomography Study Using (11)C-DASB and (11)C-MDL100907.
Biol Psychiatry. 2012 Jul 24;
BACKGROUND: Impulsive aggression (IA) in adults is associated with brain serotonin (5-HT) system abnormalities and is more common following childhood adversity. Within aggressive behavior, IA and callous unemotional (CU) traits are core components of differentiable factors with opposing 5-HT abnormalities. We aimed to investigate 5-HT abnormalities in IA and potential correlations with severity of childhood adversity while controlling for confounding 5-HT effects of high CU traits and mental disorders. METHODS: Healthy male subjects (mean age 34 � 9 years) without high CU traits were recruited with IA ratings in the high (n = 14) and low (n = 13) population extremes. Serotonin transporter (SERT) and 5-HT(2A) receptor availability was measured in multiple brain regions using positron emission tomography with (11)C-DASB and (11)C-MDL100907, respectively, and compared between high-IA and low-IA groups. Correlations were measured between SERT and 5-HT(2A) receptor availability, impulsivity and aggression, and childhood adversity. RESULTS: Compared with the low-IA group, SERT were significantly higher in brainstem regions in the high-IA group (by 29.0% � 11.4%) and modestly lower across cortical regions (by 11.1% � 6.0%), whereas 5-HT(2A) receptors were also modestly lower (by 8.6% � 4.0%). Across all subjects, brainstem SERT were significantly positively correlated with impulsivity, aggression, and childhood trauma ratings. Within the high-IA group, higher brainstem SERT was most strongly predicted by severity of childhood trauma (r = .76 in midbrain). CONCLUSIONS: Pre-and postsynaptic 5-HT differences are present in men with high levels of IA and are strongly suggestive of a persisting effect of childhood adversity on serotonergic neurodevelopment and emotional-behavioral control. [PubMed Citation] [Order full text from Infotrieve]

6) Kozaka T, Uno I, Kitamura Y, Miwa D, Ogawa K, Shiba K
Syntheses and in vitro evaluation of decalinvesamicol analogues as potential imaging probes for vesicular acetylcholine transporter (VAChT).
Bioorg Med Chem. 2012 Jun 29;
A series of vesamicol analogues, o-iodo-trans-decalinvesamicol (OIDV) or o-bromo-trans-decalinvesamicol (OBDV), were synthesized and their affinities to vesicular acetylcholine transporter (VAChT) and ? receptors (?-1, ?-2) were evaluated by in vitro binding assays using rat cerebral or liver membranes. OIDV and OBDV showed greater binding affinity to VAChT (K(i)=20.5�5.6 and 13.8�1.2nM, respectively) than did vesamicol (K(i)=33.9�18.1nM) with low affinity to ? receptors. A saturation binding assay in rat cerebral membranes revealed that [(125)I]OIDV had a single high affinity binding site with a K(d) value of 1.73nM and a B(max) value of 164.4fmol/mg protein. [(125)I]OIDV revealed little competition with inhibitors, which possessed specific affinity to each ? (?-1 and ?-2), serotonin (5-HT(1A) and 5-HT(2A)), noradrenaline, and muscarinic acetylcholine receptors. In addition, BBB penetration of [(125)I]OIDV was verified in in vivo. The results of the binding studies indicated that OIDV and OBDV had great potential to be VAChT imaging probes with high affinity and selectivity. [PubMed Citation] [Order full text from Infotrieve]

7) da Silva Lopes L, Marques RB, Fernandes HB, da Silva Pereira S, Ayres MC, Chaves MH, Almeida FR
Mechanisms of the antinociceptive action of (-) Epicatechin obtained from the hydroalcoholic fraction of Combretum leprosum Mart & Eic in rodents.
J Biomed Sci. 2012 Jul 25;19(1):68.
ABSTRACT: BACKGROUND: The mechanisms of the antinociceptive activity of () epicatechin (EPI), a compound isolated from the hydroalcoholic fraction of Combreum leprosum Mart & Eicher. METHODS: were assessed in the model of chemical nociception induced by glutamate (20 mumol/paw). To evaluate the mechanisms involved, the animals , male Swiss mice (25-30 g), received EPI (50 mg/kg p.o.) after pretreatment with naloxone (2 mg/kg s.c. opioid antagonist), glibenclamide (2 mg/kg s.c. antagonist K + channels sensitive to ATP), ketanserin (0.3 mg/kg s.c. antagonist of receptor 5-HT2A), yoimbine (0.15 mg/kg s.c. alpha2 adrenergic receptor antagonist), pindolol (1 mg/kg s.c. 5-HT1a/1b receptor antagonist), atropine (0.1 mg/kg s.c. muscarinic antagonist) and caffeine (3 mg/kg s.c. adenosine receptor antagonist), ondansetron (0.5 mg/kg s.c. for 5-HT3 receptor) and L-arginine (600 mg/kg i.p.). RESULTS: The antinociceptive effect of EPI was reversed by pretreatment with naloxone and glibenclamide, ketanserin, yoimbine, atropine and pindolol, which demonstrates the involvement of opioid receptors and potassium channels sensitive to ATP, the serotoninergic (receptor 5HT1A and 5HT2A), adrenergic (receptor alpha 2) and cholinergic (muscarinic receptor) systems in the activities that were observed. The effects of EPI, however, were not reversed by pretreatment with caffeine, L-arginine or ondansetron, which shows that there is no involvement of 5HT3 receptors or the purinergic and nitrergic systems in the antinociceptive effect of EPI. In the Open Field and Rotarod test, EPI had no significant effect, which shows that there was no central nervous system depressant or muscle relaxant effect on the results. CONCLUSIONS: This study demonstrates that the antinociceptive activity of EPI in the glutamate model involves the participation of the opioid system, serotonin, adrenergic and cholinergic. [PubMed Citation] [Order full text from Infotrieve]

8) Risbood V, Lee JR, Roche-Desilets J, Fuller MA
Lurasidone: an atypical antipsychotic for schizophrenia.
Ann Pharmacother. 2012 Jul;46(7-8):1033-46.
[PubMed Citation] [Order full text from Infotrieve]

9) Serres F, Rodriguez M, Rivet JM, Galizzi JP, Lockhart B, Sharp T, Millan MJ
Blockade of α(2)-adrenoceptors induces Arc gene expression in rat brain in a glutamate receptor-dependent manner: A combined qPCR, in situ hybridisation and immunocytochemistry study.
Neuropharmacology. 2012 Jul 22;
Studies of 5-HT-glutamate interactions suggest that activation of brain 5-HT(2A) receptors leads to an AMPA receptor-mediated induction of the immediate early (activity-dependent) gene, Arc (Arg3.1). In this respect, noradrenaline-glutamate interactions are poorly characterised. Here we investigated the influence on regional brain Arc gene expression of selective blockade of ?(2)-adrenoceptors in rats. Several complementary techniques were used: qPCR (mRNA, discrete tissue punches), in situ hybridisation (mRNA, sections) and immunocytochemistry. The ?(2)-adrenoceptor antagonist, RX 821002, dose-dependently and time-dependently (maximal effect 2�h) increased Arc mRNA levels as demonstrated both by qPCR and in situ hybridisation. The ?(2)-adrenoceptor antagonist, atipamezole, also increased Arc mRNA in in situ hybridisation studies. Changes in Arc mRNA after RX 8210002 were of similar magnitude in punches and intact tissue sections and region-specific, with effects being most pronounced in parietal cortex and caudate putamen, less robust in frontal cortex, and not detectable in hippocampal sub-regions. Both qPCR and in situ hybridisation studies demonstrated that RX 821002-induced Arc mRNA was blocked by the AMPA antagonist, GYKI 52466. Pretreatment with the NMDA antagonist MK 801 also prevented RX 821002-induced Arc mRNA, as did the mGluR5 antagonist MPEP, whilst the mGluR2/3 antagonist, LY341495, had no effect. Finally, immunocytochemical studies showed that RX 821002 increased Arc-immunoreactivity in cells in close apposition to ?(2)-adrenoceptor-positive processes. Thus, employing three complementary techniques, these observations demonstrate that blockade of ?(2)-adrenoceptors triggers brain expression of the immediate early gene, Arc, and that this effect involves the recruitment of AMPA, NMDA and mGluR5 but not mGluR2/3 glutamatergic receptors. [PubMed Citation] [Order full text from Infotrieve]

10) Gacs�lyi I, Nagy K, Pallagi K, M�ricz K, Kert�sz S, Varga P, Haller J, Gigler G, Sz�n�si G, Bark�czy J, B�r� J, Spedding M, Antoni FA
Egis-11150: A candidate Antipsychotic compound with Procognitive efficacy in Rodents.
Neuropharmacology. 2012 Jul 20;
Classical antipsychotics, e.g. haloperidol, chlorpromazine, are potent at controlling the positive symptoms of schizophrenia but frequently elicit extrapyramidal motor side-effects. The introduction of atypical antipsychotics such as risperidone, olanzapine and clozapine has obviated this problem, but none of the current drugs seem to improve the cognitive deficits accompanying schizophrenia. Thus there is an unmet need for agents that not only suppress the psychotic symptoms but also ameliorate the impairment of cognition. Here, we report the preclinical properties of a candidate antipsychotic, Egis-11150, that shows marked pro-cognitive efficacy. Egis-11150 displayed high affinity for adrenergic ?(1), ?(2c), 5-HT(2A) 5-HT(7), moderate affinity for adrenergic ?(2a) and D(2) receptors. It was a functional antagonist on all of the above receptors, with the exception of 5-HT(7) receptors, where it was an inverse agonist. Phencyclidine-induced hypermotility in mice and inhibition of conditioned avoidance response in rats were assessed to estimate efficacy against the positive and social withdrawal test in rats was used to predict efficacy against the negative symptoms of schizophrenia. Passive-avoidance learning, novel object recognition and radial maze tests in rats were used to assess pro-cognitive activity, while phencyclidine-induced disruption of prepulse inhibition in mice was examined to test for effects on attention. Egis-11150 (0.01-0.3 mg/kg,ip.) was effective in all of the preclinical models of schizophrenia examined. Moreover, a robust pro-cognitive profile was apparent. In summary, work in preclinical models indicates that Egis-11150 is a potential treatment for controlling the psychosis as well as the cognitive dysfunction in schizophrenia. [PubMed Citation] [Order full text from Infotrieve]

11) Wen YG, Ni XJ, Zhang M, Liu X, Shang DW
Simultaneous determination of blonanserin and its metabolite in human plasma and urine by liquid chromatography-tandem mass spectrometry: Application to a pharmacokinetic study.
J Chromatogr B Analyt Technol Biomed Life Sci. 2012 Jul 4;
Blonanserin is a novel atypical antipsychotic with highly selective receptor antagonist activity to dopamine D(2) and 5-HT(2A). N-desethyl blonanserin (blonanserin C) is its major active metabolite in human plasma. Herein we report a new highly sensitive, selective, and rapid liquid chromatography-tandem mass spectrometry method to determine blonanserin and blonanserin C simultaneously in human plasma and urine, with N-desethyl-chlor-blonanserin (blonanserin D) as internal standard (IS). Blonanserin and blonanserin C were extracted from aliquots of plasma and urine with ethyl acetate and dichloromethane (4:1) as the solvent and chromatographic separation was performed using an Agilent Eclipse Plus C(18) column. The mobile phase was composed of: acetonitrile and ammonium formate-formic acid buffer containing 5mM ammonium formate and 0.1% formic acid (87:13, v/v). To quantify blonanserin, blonanserin C, and blonanserin D, respectively, multiple reaction monitoring (MRM) transition of m/z 368.2?297.2, m/z 340.2?297.1, and m/z 356.2?313.3 was performed in positive mode. The analysis time was about 5.5min. The calibration curve was linear in the concentration range of 0.01-2ng/ml. The lower limit of quantification reached 0.01ng/ml. The intra and inter-day precision and relative errors were less than 8.0% and 6.6% for three QC levels in plasma and urine. The current LC-MS/MS method was validated as simple, sensitive, and accurate and has been successfully applied to investigate the pharmacokinetics of blonanserin and blonanserin C in humans. [PubMed Citation] [Order full text from Infotrieve]

12) Baptista D, Nunes-de-Souza RL, Canto-de-Souza A
Activation of 5-HT(2C) receptors in the dorsal periaqueductal gray increases antinociception in mice exposed to the elevated plus-maze.
Behav Brain Res. 2012 Jul 16;
Several findings have pointed to the role of the dorsal periaqueductal gray (dPAG) serotonin 5-HT(1A) and 5-HT(2A-C) receptor subtypes in the modulation of defensive behavior in animals exposed to the elevated plus-maze (EPM). Besides displaying anxiety-like behavior, rodents also exhibit antinociception in the EPM. This study investigated the effects of intra-dPAG injections of 5-HT(1A) and 5-HT(2B/2C) receptor ligands on EPM-induced antinociception in mice. Male Swiss mice received 0.1?l intra-dPAG injections of vehicle, 5.6 and 10nmol of 8-OHDPAT, a 5-HT(1A) receptor agonist (Experiment 1), or 0.01, 0.03 and 0.1nmol of mCPP, a 5-HT(2B/2C) receptor agonist (Experiment 2). Five minutes later, each mouse received an intraperitoneal injection of 0.6% acetic acid (0.1ml/10g body weight; nociceptive stimulus) and was individually confined in the open (OA) or enclosed (EA) arms of the EPM for 5min, during which the number of abdominal writhes induced by the acetic acid was recorded. While intra-dPAG injection of 8-OHDPAT did not change open-arm antinociception (OAA), mCPP (0.01nmol) enhanced it. Combined injections of ketanserin (10nmol/0.1?l), a 5-HT(2A/2C) receptor antagonist, and 0.01nmol of mCPP (Experiment 3), selectively and completely blocked the OAA enhancement induced by mCPP. Although intra-dPAG injection of mCPP (0.01nmol) also produced antinociception in EA-confined mice (Experiment 2), this effect was not confirmed in Experiment 3. Moreover, no other compound changed the nociceptive response in EA-confined animals. These results suggest that the 5-HT(2C) receptors located within the PAG play a role in this type of environmentally induced pain inhibition in mice. [PubMed Citation] [Order full text from Infotrieve]

13) Franklin JM, Carrasco GA
Cannabinoid-induced enhanced interaction and protein levels of serotonin 5-HT2A and dopamine D2 receptors in rat prefrontal cortex.
J Psychopharmacol. 2012 Jul 11;
Recent evidence suggests that non-selective cannabinoid receptor agonists may regulate serotonin 2A (5-HT(2A)) receptor neurotransmission in brain. The molecular mechanisms of this regulation are unknown, but could involve cannabinoid-induced enhanced interaction between 5-HT(2A) and dopamine D2 (D(2)) receptors. Here, we present experimental evidence that Sprague-Dawley rats treated with a non-selective cannabinoid receptor agonist (CP55,940, 50 �g/kg, 7 days, i.p.) showed enhanced co-immunoprecipitation of 5-HT(2A) and D(2) receptors and enhanced membrane-associated expression of D(2) and 5-HT(2A) receptors in prefrontal cortex (PFCx). Furthermore, 5-HT(2A) receptor mRNA levels were increased in PFCx, suggesting a cannabinoid-induced upregulation of 5-HT(2A) receptors. To date, two cannabinoids receptors have been found in brain, CB1 and CB2 receptors. We used selective cannabinoid agonists in a neuronal cell line to study mechanisms that could mediate this 5-HT(2A) receptor upregulation. We found that selective CB2 receptor agonists upregulate 5-HT(2A) receptors by a mechanism that seems to involve activation of Gai G-proteins, ERK1/2, and AP-1 transcription factor. We hypothesize that the enhanced cannabinoid-induced interaction between 5-HT(2A) and D(2) receptors and in 5-HT(2A) and D(2) receptors protein levels in the PFCx might provide a molecular mechanism by which activation of cannabinoid receptors might be contribute to the pathophysiology of some cognitive and mood disorders. [PubMed Citation] [Order full text from Infotrieve]

14) Savli M, Bauer A, Mitterhauser M, Ding YS, Hahn A, Kroll T, Neumeister A, Haeusler D, Ungersboeck J, Henry S, Isfahani SA, Rattay F, Wadsak W, Kasper S, Lanzenberger R
Normative database of the serotonergic system in healthy subjects using multi-tracer PET.
Neuroimage. 2012 Jul 10;63(1):447-459.
The highly diverse serotonergic system with at least 16 different receptor subtypes is implicated in the pathophysiology of most neuropsychiatric disorders including affective and anxiety disorders, obsessive compulsive disorder, post-traumatic stress disorder, eating disorders, sleep disturbance, attention deficit/hyperactivity disorder, drug addiction, suicidal behavior, schizophrenia, Alzheimer, etc. Alterations of the interplay between various pre- and postsynaptic receptor subtypes might be involved in the pathogenesis of these disorders. However, there is a lack of comprehensive in vivo values using standardized procedures. In the current PET study we quantified 3 receptor subtypes, including the major inhibitory (5-HT(1A) and 5-HT(1B)) and excitatory (5-HT(2A)) receptors, and the transporter (5-HTT) in the brain of healthy human subjects to provide a database of standard values. PET scans were performed on 95 healthy subjects (age=28.0�6.9years; 59% males) using the selective radioligands [carbonyl-(11)C]WAY-100635, [(11)C]P943, [(18)F]altanserin and [(11)C]DASB, respectively. A standard template in MNI stereotactic space served for region of interest delineation. This template follows two anatomical parcellation schemes: 1) Brodmann areas including 41 regions and 2) AAL (automated anatomical labeling) including 52 regions. Standard values (mean, SD, and range) for each receptor and region are presented. Mean cortical and subcortical binding potential (BP) values were in good agreement with previously published human in vivo and post-mortem data. By means of linear equations, PET binding potentials were translated to post-mortem binding (provided in pmol/g), yielding 5.89pmol/g (5-HT(1A)), 23.5pmol/g (5-HT(1B)), 31.44pmol/g (5-HT(2A)), and 11.33pmol/g (5-HTT) being equivalent to the BP of 1, respectively. Furthermore, we computed individual voxel-wise maps with BP values and generated average tracer-specific whole-brain binding maps. This knowledge might improve our interpretation of the alterations taking place in the serotonergic system during neuropsychiatric disorders. [PubMed Citation] [Order full text from Infotrieve]

15) Russo E, Citraro R, Davoli A, Gallelli L, Donato Di Paola E, De Sarro G
Ameliorating effects of aripiprazole on cognitive functions and depressive-like behavior in a genetic rat model of absence epilepsy and mild-depression comorbidity.
Neuropharmacology. 2012 Jul 2;
Aripiprazole (APZ) is regarded as a first-line atypical antipsychotic used for the treatment of first and multiple episodes of schizophrenia to improve positive- and negative-symptoms. Its therapeutic indications were extended to acute manic and mixed episodes associated with bipolar disorder. In addition, APZ was approved as an adjunct therapy for major depressive disorder in 2007. Compared to other antipsychotic drugs, APZ has a unique pharmacological profile. It is a partial agonist at D(2) dopamine receptors and serotonin 5-HT(1A) and 5-HT(7) receptors, whereas it is an antagonist at serotonin 5-HT(2A) and 5-HT(6) receptors. Since epilepsy is often accompanied with neurological comorbidities such as depression, anxiety and cognitive deficits caused by both the disease and/or drug treatment, we wished to examine the effects of a sub-chronic treatment (>14 consecutive days) with APZ (0.3, 1 and 3�mg/kg; i.p.) on both absence seizures and WAG/Rij rat's behavior using different standard paradigms: Open field (OF) test, elevated plus maze (EPM) test, forced swimming (FS) test, sucrose consumption (SC) test and Morris water maze (MWM). WAG/Rij rats represent a validated genetic animal model of absence epilepsy with mild-depression comorbidity, also including other behavioral alterations. APZ treatment showed some anti-absence properties and regarding the behavioral comorbidity in this rat strain, we observed that APZ possesses clear antidepressant effects in the FS and SC tests also increasing memory/learning function in the Morris water maze test. In the two anxiety models used, APZ showed only minor effects. In conclusion, our results indicate that APZ might actually have a potential in treating absence seizures or as add-on therapy but more interestingly, these effect might be accompanied by positive modulatory actions on depression, anxiety and memory which might be also beneficial in other epileptic syndromes. This article is part of a Special Issue entitled 'Cognitive Enhancers'. [PubMed Citation] [Order full text from Infotrieve]

16) Martins LC, Rocha NP, Torres KC, Dos Santos RR, Fran�a GS, de Moraes EN, Mukhamedyarov MA, Zefirov AL, Rizvanov AA, Kiyasov AP, Vieira LB, Guimar�es MM, Yalva� ME, Teixeira AL, Bicalho MA, Janka Z, Romano-Silva MA, Palot�s A, Reis HJ
Disease-specific expression of the serotonin-receptor 5-HT(2C) in natural killer cells in Alzheimer's dementia.
J Neuroimmunol. 2012 Jul 3;
Alzheimer's dementia (AD) is a degenerative brain disorder characterized mainly by cholinergic failure, but other neuro-transmitters are also deficient especially at late stages of the disease. Misfolded ?-amyloid peptide has been identified as a causative agent, however inflammatory changes also play a pivotal role. Even though the most prominent pathology is seen in the cognitive functions, specific abnormalities of the central nervous system (CNS) are also reflected in the periphery, particularly in the immune responses of the body. The aim of this study was to characterize the dopaminergic and serotonergic systems in AD, which are also markedly disrupted along with the hallmark acetyl-choline dysfunction. Peripheral blood mono-nuclear cells (PBMCs) from demented patients were judged against comparison groups including individuals with late-onset depression (LOD), as well as non-demented and non-depressed subjects. Cellular sub-populations were evaluated by mono-clonal antibodies against various cell surface receptors: CD4/CD8 (T-lymphocytes), CD19 (B-lymphocytes), CD14 (monocytes), and CD56 (natural-killer (NK)-cells). The expressions of dopamine D(3) and D(4), as well as serotonin 5-HT(1A), 5-HT(2A), 5-HT(2B) and 5-HT(2C) were also assessed. There were no significant differences among the study groups with respect to the frequency of the cellular sub-types, however a unique profound increase in 5-HT(2C) receptor exclusively in NK-cells was observed in AD. The disease-specific expression of 5-HT(2C), as well as the NK-cell cyto-toxicity, has been linked with cognitive derangement in dementia. These changes not only corroborate the existence of bi-directional communication between the immune system and the CNS, but also elucidate the role of inflammatory activity in AD pathology, and may serve as potential biomarkers for less invasive and early diagnostic purposes as well. [PubMed Citation] [Order full text from Infotrieve]

17) Price DL, Bonhaus DW, McFarland K
Pimavanserin, a 5-HT2A receptor inverse agonist, reverses psychosis-like behaviors in a rodent model of Alzheimer's disease.
Behav Pharmacol. 2012 Aug;23(4):426-33.
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive deterioration in cognitive functioning. Overall, 25-50% of patients with AD also show symptoms of psychosis including hallucinations and delusions. As all available antipsychotic drugs have a 'black-box' warning for use in these patients because of increased mortality, no appropriate treatment for psychotic symptoms in AD currently exists. In the present study, we examined whether selective antagonism of 5-HT2A serotonin receptors has antipsychotic-like activity in an animal model of AD. Mice receiving an intracerebroventricular infusion of the amyloid ?25-35 peptide fragment showed AD-like histopathology and a psychosis-related behavioral phenotype with enhanced responses to the psychostimulants 2,5-dimethoxy-4-iodoamphetamine hydrochloride and amphetamine as well as disrupted prepulse inhibition. Treatment with pimavanserin, a selective serotonin 5-HT2A receptor inverse agonist, prevented 2,5-dimethoxy-4-iodoamphetamine hydrochloride-induced head twitches, reversed the augmented locomotor response to amphetamine, and normalized prepulse inhibition in mice with amyloid pathology. These data suggest that an infusion of amyloid ? might induce alterations in serotonergic function that underlie a psychosis-like phenotype that can be normalized by treatment with a 5-HT2A inverse agonist. This in turn suggests that 5-HT2A inverse agonists, such as pimavanserin, might have therapeutic benefits in the treatment of psychosis in AD patients. [PubMed Citation] [Order full text from Infotrieve]

18) Qian W, Lu W, Sun H, Li Z, Zhu L, Zhao R, Zhang L, Zhou S, Zhou Y, Jiang H, Zhen X, Liu H
Design, synthesis, and pharmacological evaluation of novel tetrahydroprotoberberine derivatives: Selective inhibitors of dopamine D(1) receptor.
Bioorg Med Chem. 2012 Aug 1;20(15):4862-71.
A series of new tetrahydroprotoberberine (THPB) derivatives were designed, synthesized, and tested for their binding affinity towards dopamine (D(1) and D(2)) and serotonin (5-HT(1A) and 5-HT(2A)) receptors. Many of the THPB compounds exhibited high binding affinity and activity at the dopamine D(1) receptor, as well as high selectivity for the D(1) receptor over the D(2), 5-HT(1A), and 5-HT(2A) receptors. Among these, compound 19c exhibited a promising D(1) receptor binding affinity (K(i)=2.53nM) and remarkable selectivity versus D(2)R (inhibition=81.87%), 5-HT(1A)R (inhibition=61.70%), and 5-HT(2A)R (inhibition=24.96%). Compared with l-(S)-stepholidine (l-SPD) (D(1)K(i)=6.23nM, D(2)K(i)=56.17nM), compound 19c showed better binding affinity for the D(1) receptor (2.5-fold higher) and excellent D(2)/D(1) selectivity. Functional assays found compounds 18j, 18k, and 19c are pure D(1) receptor antagonists. These results indicate that removing the C10 hydroxy group and introducing a methoxy group at C11 of the pharmacophore of l-SPD can reverse the function of THPB compounds at the D(1) receptor. These results are in accord with molecular docking studies. [PubMed Citation] [Order full text from Infotrieve]

19) Stefano GB, Kr�l�čkov� M, Ptacek R, Kuzelova H, Esch T, Kream RM
Low dose morphine adjuvant therapy for enhanced efficacy of antipsychotic drug action: Potential involvement of endogenous morphine in the pathophysiology of schizophrenia.
Med Sci Monit. 2012 Jun 28;18(7):HY23-26.
Major thematic threads linking extensive preclinical and clinical efforts have established a working mechanistic scheme whereby atypical antipsychotic drugs ameliorate negative DSM IV diagnostic criteria by effecting relatively potent blockade of serotonin (5-HT)(2A) receptors coupled with weaker antagonism of dopamine D(2) receptors in frontal cortical areas. These contentions are more or less supported by in vitro binding experiments employing cloned receptors on cultured cells, although significant functional involvement of 5-HT(2C) receptors has also been proposed. It is interesting that a key statistical analysis indicates a major shift in usage back to typical antipsychotic agents for management of schizophrenia from 1995-2008, whereas off-label usage of atypical antipsychotic agents was markedly increased or expanded for bipolar affective disorder. Importantly, meta-analyses generally did not support efficacy differences between the other atypical antipsychotics compared with the older typical agents. A critical examination of putative functional linkages of morphine and its type-selective mu opioid receptor to higher order cortical regulation of cognitive processes may provide novel insights into human behavioral processes that are severely impaired in schizophrenia spectrum disorders.
[PubMed Citation] [Order full text from Infotrieve]

20) Horiguchi M, Hannaway KE, Adelekun AE, Jayathilake K, Meltzer HY
Prevention of the Phencyclidine-Induced Impairment in Novel Object Recognition in Female Rats by Co-Administration of Lurasidone or Tandospirone, a 5-HT(1A) Partial Agonist.
Neuropsychopharmacology. 2012 Jun 27;
Hypoglutamatergic function may contribute to cognitive impairment in schizophrenia (CIS). Subchronic treatment with the N-methyl-D-aspartate receptor antagonist, phencyclidine (PCP), induces enduring deficits in novel object recognition (NOR) in rodents. Acute treatment with atypical antipsychotic drugs (APDs), which are serotonin (5-HT)(2A)/dopamine D(2) antagonists, but not typical APDs, eg, haloperidol, reverses the PCP-induced NOR deficit in rats. We have tested the ability of lurasidone, an atypical APD with potent 5-HT(1A) partial agonist properties, tandospirone, a selective 5-HT(1A) partial agonist, haloperidol, a D(2) antagonist, and pimavanserin, a 5-HT(2A) inverse agonist, to prevent the development of the PCP-induced NOR deficit. Rats were administered lurasidone (0.1 or 1?mg/kg), tandospirone (5?mg/kg), pimavanserin (3?mg/kg), or haloperidol (1?mg/kg) b.i.d. 30?min before PCP (2?mg/kg, b.i.d.) for 7 days (day1-7), followed by a 7-day washout (day8-14). Subchronic treatment with PCP induced an enduring NOR deficit. Lurasidone (1?mg/kg) but not 0.1?mg/kg, which is effective to acutely reverse the deficit due to subchronic PCP, or tandospirone, but not pimavanserin or haloperidol, significantly prevented the PCP-induced NOR deficit on day 15. The ability of lurasidone co-treatment to prevent the PCP-induced NOR deficit was enduring and still present at day 22. The preventive effect of lurasidone was blocked by WAY100635, a selective 5-HT(1A) antagonists, further evidence for the importance of 5-HT(1A) receptor stimulation in the NOR deficit produced by subchronic PCP. Further study is needed to determine whether these results concerning mechanism and dosage can be the basis for prevention of the development of CIS in at risk populations.Neuropsychopharmacology advance online publication, 27 June 2012; doi:10.1038/npp.2012.64. [PubMed Citation] [Order full text from Infotrieve]