5-HT1A Receptor Research -- Neurotransmitter.net

(Updated 3rd or 4th quarter 2002)

Jordan S, Koprivica V, Chen R, Tottori K, Kikuchi T, Altar CA.
The antipsychotic aripiprazole is a potent, partial agonist at the human 5-HT(1A) receptor.
Eur J Pharmacol 2002 Apr 26;441(3):137-40
"Aripiprazole, 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butyloxy]-3,4-dihydro-2(1H)-quinolinone, a novel antipsychotic with partial agonist activity at dopamine D2 receptors, bound with high affinity to recombinant human 5-HT(1A) receptors (h5-HT(1A)) in Chinese hamster ovary cell membranes and displayed potent, partial agonism at 5-HT(1A) receptors in a guanosine-5'-O-(3-[(35)S]thio)-triphosphate ([(35)S]GTP gamma S)-binding assay that was blocked completely by a selective 5-HT(1A) receptor antagonist. An interaction with 5-HT(1A) receptors may contribute to the overall efficacy of aripiprazole against symptoms of schizophrenia, including anxiety, depression, cognitive and negative symptoms, and to its favorable side-effect profile. Combined with previous studies demonstrating the potent partial agonism of aripiprazole at dopamine D2 receptors, this study suggests aripiprazole is the first dopamine-serotonin system stabilizer." [Abstract]

Ichikawa J, Li Z, Dai J, Meltzer HY.
Atypical antipsychotic drugs, quetiapine, iloperidone, and melperone, preferentially increase dopamine and acetylcholine release in rat medial prefrontal cortex: role of 5-HT(1A) receptor agonism.
Brain Res 2002 Nov 29;956(2):349-57
"Preferential increases in both cortical dopamine (DA) and acetylcholine (ACh) release have been proposed to distinguish the atypical antipsychotic drugs (APDs) clozapine, olanzapine, risperidone and ziprasidone from typical APDs such as haloperidol. Although only clozapine and ziprasidone are directly acting 5-HT(1A) agonists, WAY100635, a selective 5-HT(1A) antagonist, partially attenuates these atypical APD-induced increases in cortical DA release that may be due to combined 5-HT(2A) and D(2) blockade. However, WAY100635 does not attenuate clozapine-induced cortical ACh release. The present study determined whether quetiapine, iloperidone and melperone, 5-HT(2A)/D(2) antagonist atypical APDs, also increase cortical DA and ACh release, and whether these effects are related to 5-HT(1A) agonism. Quetiapine (30 mg/kg), iloperidone (1-10 mg/kg), and melperone (3-10 mg/kg) increased DA and ACh release in the medial prefrontal cortex (mPFC). Iloperidone (10 mg/kg) and melperone (10 mg/kg), but not quetiapine (30 mg/kg), produced an equivalent or a smaller increase in DA release in the nucleus accumbens (NAC), respectively, compared to the mPFC, whereas none of them increased ACh release in the NAC. WAY100635 (0.2 mg/kg), which alone did not affect DA or ACh release, partially attenuated quetiapine (30 mg/kg)-, iloperidone (10 mg/kg)- and melperone (10 mg/kg)-induced DA release in the mPFC. WAY100635 also partially attenuated quetiapine (30 mg/kg)-induced ACh release in the mPFC, but not that induced by iloperidone (10 mg/kg) or melperone (10 mg/kg). These results indicate that quetiapine, iloperidone and melperone preferentially increase DA release in the mPFC, compared to the NAC via a 5-HT(1A)-related mechanism. However, 5-HT(1A) agonism may be important only for quetiapine-induced ACh release." [Abstract]

Ichikawa, Junji, Ishii, Hideo, Bonaccorso, Stefania, Fowler, Wiley L., O'Laughlin, Ian A., Meltzer, Herbert Y.
5-HT2A and D2 receptor blockade increases cortical DA release via 5-HT1A receptor activation: a possible mechanism of atypical antipsychotic-induced cortical dopamine release
J Neurochem 2001 76: 1521-1531
"Atypical antipsychotic drugs (APDs), all of which are relatively more potent as serotonin (5-HT)2A than dopamine D2 antagonists, may improve negative symptoms and cognitive dysfunction in schizophrenia, in part, via increasing cortical dopamine release. 5-HT1A agonism has been also suggested to contribute to the ability to increase cortical dopamine release. The present study tested the hypothesis that clozapine, olanzapine, risperidone, and perhaps other atypical APDs, increase dopamine release in rat medial prefrontal cortex (mPFC) via 5-HT1A receptor activation, as a result of the blockade of 5-HT2A and D2 receptors. M100907 (0.1 mg/kg), a 5-HT2A antagonist, significantly increased the ability of both S(–)-sulpiride (10 mg/kg), a D2 antagonist devoid of 5-HT1A affinity, and R(+)-8-OH-DPAT (0.05 mg/kg), a 5-HT1A agonist, to increase mPFC dopamine release. These effects of M100907 were abolished by WAY100635 (0.05 mg/kg), a 5-HT1A antagonist, which by itself has no effect on mPFC dopamine release. WAY100635 (0.2 mg/kg) also reversed the ability of clozapine (20 mg/kg), olanzapine (1 mg/kg), risperidone (1 mg/kg), and the R(+)-8-OH-DPAT (0.2 mg/kg) to increase mPFC dopamine release. Clozapine is a direct acting 5-HT1A partial agonist, whereas olanzapine and risperidone are not. These results suggest that the atypical APDs via 5-HT2A and D2 receptor blockade, regardless of intrinsic 5-HT1A affinity, may promote the ability of 5-HT1A receptor stimulation to increase mPFC DA release, and provide additional evidence that coadministration of 5-HT2A antagonists and typical APDs, which are D2 antagonists, may facilitate 5-HT1A agonist activity." [Abstract]

Serres, F., Li, Q., Garcia, F., Raap, D. K., Battaglia, G., Muma, N. A., Van de Kar, L. D.
Evidence That Gz-Proteins Couple to Hypothalamic 5-HT1A Receptors In Vivo
J. Neurosci. 2000 20: 3095-3103 [Full Text]

Storring, John M., Charest, Alain, Cheng, Peihua, Albert, Paul R.
TATA-Driven Transcriptional Initiation and Regulation of the Rat Serotonin 5-HT1A Receptor Gene
J Neurochem 1999 72: 2238-2247 [Abstract]

Christopher L. Parks, and Thomas Shenk
The Serotonin 1a Receptor Gene Contains a TATA-less Promoter that Responds to MAZ and Sp1
J. Biol. Chem. 271: 4417-4430, February 23, 1996. [Full Text]

Xiao-Ming Ou, Hamed Jafar-Nejad, John M. Storring, Juan-Hong Meng, Sylvie Lemonde, and Paul R. Albert
Novel Dual Repressor Elements for Neuronal Cell-specific Transcription of the Rat 5-HT1A Receptor Gene
J. Biol. Chem. 275: 8161-8168, March 17, 2000. [Full Text]

D A Bayliss, M Umemiya, A J Berger
Inhibition of N- and P-type calcium currents and the after-hyperpolarization in rat motoneurones by serotonin
JOURNAL OF PHYSIOLOGY -LONDON THEN CAMBRIDGE- , 485 ( Pt 3)():635-647 1995 [Abstract]

Yasuno F, Suhara T, Nakayama T, Ichimiya T, Okubo Y, Takano A, Ando T, Inoue M, Maeda J, Suzuki K.
Inhibitory effect of hippocampal 5-HT1A receptors on human explicit memory.
Am J Psychiatry 2003 Feb;160(2):334-40 [Abstract]

Monckton, James E., McCormick, David A.
Neuromodulatory Role of Serotonin in the Ferret Thalamus
J Neurophysiol 2002 87: 2124-2136
"The magnitude of the hyperpolarizing response decreased with age and varied greatly across and somewhat within nuclei maintaining the following relationship (in descending order of magnitude): lateral posterior, lateral dorsal, pulvinar, mediodorsal, center median, anteroventral, central lateral, ventral basal, and medial geniculate. This hyperpolarization is elicited through two mechanisms: one direct and the other via local interneurons. The direct action occurs through an increase in potassium conductance mediated through the 5-HT1A receptor."
[Abstract]

Lora K. Heisler, Hung-Ming Chu, Thomas J. Brennan, Jean A. Danao, Preetpaul Bajwa, Loren H. Parsons, and Laurence H. Tecott
Elevated anxiety and antidepressant-like responses in serotonin 5-HT1A receptor mutant mice
PNAS 95: 15049-15054, December 8, 1998. [Full Text]

Greenwood BN, Foley TE, Day HE, Campisi J, Hammack SH, Campeau S, Maier SF, Fleshner M.
Freewheel running prevents learned helplessness/behavioral depression: role of dorsal raphe serotonergic neurons.
J Neurosci. 2003 Apr 1;23(7):2889-98.
"Serotonin (5-HT) neurons in the dorsal raphe nucleus (DRN) are implicated in mediating learned helplessness (LH) behaviors, such as poor escape responding and expression of exaggerated conditioned fear, induced by acute exposure to uncontrollable stress. DRN 5-HT neurons are hyperactive during uncontrollable stress, resulting in desensitization of 5-HT type 1A (5-HT1A) inhibitory autoreceptors in the DRN. 5-HT1A autoreceptor downregulation is thought to induce transient sensitization of DRN 5-HT neurons, resulting in excessive 5-HT activity in brain areas that control the expression of learned helplessness behaviors. Habitual physical activity has antidepressant/anxiolytic properties and results in dramatic alterations in physiological stress responses, but the neurochemical mediators of these effects are unknown. The current study determined the effects of 6 weeks of voluntary freewheel running on LH behaviors, uncontrollable stress-induced activity of DRN 5-HT neurons, and basal expression of DRN 5-HT1A autoreceptor mRNA. Freewheel running prevented the shuttle box escape deficit and the exaggerated conditioned fear that is induced by uncontrollable tail shock in sedentary rats. Furthermore, double c-Fos/5-HT immunohistochemistry revealed that physical activity attenuated tail shock-induced activity of 5-HT neurons in the rostral-mid DRN. Six weeks of freewheel running also resulted in a basal increase in 5-HT1A inhibitory autoreceptor mRNA in the rostral-mid DRN. Results suggest that freewheel running prevents behavioral depression/LH and attenuates DRN 5-HT neural activity during uncontrollable stress. An increase in 5-HT1A inhibitory autoreceptor expression may contribute to the attenuation of DRN 5-HT activity and the prevention of LH in physically active rats." [Abstract]

Wu X, Kushwaha N, Albert PR, Penington NJ.
A critical protein kinase C phosphorylation site on the 5-HT(1A) receptor controlling coupling to N-type calcium channels.
J Physiol 2002 Jan 1;538(Pt 1):41-51 [Abstract]

Kellett, Elaine, Carr, I. Craig, Milligan, Graeme
Regulation of G Protein Activation and Effector Modulation by Fusion Proteins between the Human 5-Hydroxytryptamine1A Receptor and the alpha Subunit of Gi1alpha : Differences in Receptor-Constitutive Activity Imparted by Single Amino Acid Substitutions in Gi1alpha
Mol Pharmacol 1999 56: 684-692 [Full Text]

Xiang Cai, Zhenglin Gu, Ping Zhong, Yong Ren, and Zhen Yan
Serotonin 5-HT1A receptors regulate AMPA receptor channels through inhibiting CaMKII in prefrontal cortical pyramidal neurons
JBC Papers in Press published on July 30, 2002 as 10.1074/jbc.M203752200 [Abstract/Full Text]

Pan L, Gilbert F.
Activation of 5-HT1A receptor subtype in the paraventricular nuclei of the hypothalamus induces CRH and ACTH release in the rat.
Neuroendocrinology 1992 Dec;56(6):797-802 [Medline]

Becker C, Hamon M, Benoliel JJ.
Prevention by 5-HT1A receptor agonists of restraint stress- and yohimbine-induced release of cholecystokinin in the frontal cortex of the freely moving rat.
Neuropharmacology 1999 Apr;38(4):525-32
"In line with the idea that cholecystokinin (CCK) is involved in anxiety-related behaviours, previous investigations showed that stressful conditions and an 'anxiogenic' drug, yohimbine, increased the cortical release of CCK like-material (CCKLM) in awake rats, and that this effect could be prevented by diazepam. Here, we investigated whether other anxiolytic drugs such as 5-HT1A receptor agonists could also affect cortical CCKLM release. Indeed, neither buspirone (1 mg/kg i.p.), alnespirone (1 mg/kg i.p.) nor lesopitron (3 mg/kg i.p.) affected, on their own, CCKLM release. However, pretreatment with the latter drugs completely abolished the stimulatory effect of restraint stress on the peptide outflow. As expected of the involvement of 5-HT1A receptors, tertatolol (10 mg/kg i.p) markedly reduced the inhibitory effect of buspirone on restraint stress-evoked CCKLM overflow. On the other hand, pretreatment with buspirone, alnespirone or lesopitron also inhibited the stimulatory effect of yohimbine (5 mg/kg i.p.) on cortical CCKLM outflow. These data support the idea that the anxiolytic action of 5-HT1A receptor agonists could be mediated, at least partly, through their inhibitory influence on cortical CCK-ergic systems." [Abstract]

Meltzer HY, Maes M.
Effects of ipsapirone on plasma cortisol and body temperature in major depression.
Biol Psychiatry 1995 Oct 1;38(7):450-7 [Abstract]

Riedel W.J., Klaassen T, Honig A, Van Praag, H.M.
5-HT Challenge and cognition in major depression and healthy control subjects
Experimental Psychopharmacology Unit Universiteit Maastricht [Poster]

Xiao-Ming Ou, John M. Storring, Neena Kushwaha, and Paul R. Albert
Heterodimerization of Mineralocorticoid and Glucocorticoid Receptors at a Novel Negative Response Element of the 5-HT1A Receptor Gene
J. Biol. Chem. 276: 14299-14307, April 27, 2001. [Full Text]

Watanabe_K_-I, Ashby_C_R_Jr, Katsumori_H, Minabe_Y, Watanabe, K. I., Ashby Jr., C. R., Katsumori, H., Minabe, Y.
The effect of the acute administration of various selective 5-HT receptor antagonists on focal hippocampal seizures in freely-moving rats
European journal of pharmacology, 398(2):239-246 2000 [Abstract]

Mohamed Abdouh, John M. Storring, Mustapha Riad, Yves Paquette, Paul R. Albert, Elliot Drobetsky, and Edouard Kouassi
Transcriptional Mechanisms for Induction of 5-HT1A Receptor mRNA and Protein in Activated B and T Lymphocytes
J. Biol. Chem. 276: 4382-4388, February 9, 2001. [Full Text]

Wu, X., Kushwaha, N., Albert, P. R., Penington, N. J.
A critical protein kinase C phosphorylation site on the 5-HT1A receptor controlling coupling to N-type calcium channels
J Physiol (Lond) 2002 538: 41-51 [Abstract]

Li, Qian, Wichems, Christine, Heils, Armin, Lesch, Klaus-Peter, Murphy, Dennis L.
Reduction in the Density and Expression, But Not G-Protein Coupling, of Serotonin Receptors (5-HT1A) in 5-HT Transporter Knock-Out Mice: Gender and Brain Region Differences
J. Neurosci. 2000 20: 7888-7895 [Full Text]

Maria N. Garnovskaya, Thomas W. Gettys, Tim van Biesen, Veronica Prpic, J. Kurt Chuprun, and John R. Raymond
5-HT1A Receptor Activates Na+/H+ Exchange in CHO-K1 Cells through GiAlpha2 and GiAlpha3
J. Biol. Chem. 272: 7770-7776, March 21, 1997. [Full Text]

Okuhara DY, Beck SG.
5-HT1A receptor linked to inward-rectifying potassium current in hippocampal CA3 pyramidal cells.
J Neurophysiol 1994 Jun;71(6):2161-7 [Abstract]

Singh JK, Yan Q, Dawson G, Banerjee P.
Cell-specific regulation of the stably expressed serotonin 5-HT1A receptor and altered ganglioside synthesis.
Biochim Biophys Acta 1996 Feb 2;1310(2):201-11 [Abstract]

Hendricks, Timothy, Francis, Nicole, Fyodorov, Dmitry, Deneris, Evan S.
The ETS Domain Factor Pet-1 Is an Early and Precise Marker of Central Serotonin Neurons and Interacts with a Conserved Element in Serotonergic Genes
J. Neurosci. 1999 19: 10348-10356 [Full Text]

Overstreet DH, Daws LC, Schiller GD, Orbach J, Janowsky DS.
Cholinergic/serotonergic interactions in hypothermia: implications for rat models of depression.
Pharmacol Biochem Behav 1998 Apr;59(4):777-85 [Abstract]

Claustre, Y, Benavides, J, Scatton, B
Potential mechanisms involved in the negative coupling between serotonin 5-HT1A receptors and carbachol-stimulated phosphoinositide turnover in the rat hippocampus.
J Neurochem 1991 56: 1276-1285 [Abstract]

Lembo, Paola M. C., Ghahremani, Mohammad H., Morris, Stephen J., Albert, Paul R.
A Conserved Threonine Residue in the Second Intracellular Loop of the 5-Hydroxytryptamine 1A Receptor Directs Signaling Specificity
Mol Pharmacol 1997 52: 164-171 [Full Text]

Talley, Edmund M., Sadr, Negar N., Bayliss, Douglas A.
Postnatal Development of Serotonergic Innervation, 5-HT1A Receptor Expression, and 5-HT Responses in Rat Motoneurons
J. Neurosci. 1997 17: 4473-4485 [Full Text]

Ya Fang Liu, Mohammad H. Ghahremani, Mark M. Rasenick, Karl H. Jakobs, and Paul R. Albert
Stimulation of cAMP Synthesis by Gi-coupled Receptors upon Ablation of Distinct G(Alpha)i Protein Expression. Gi SUBTYPE SPECIFICITY OF THE 5-HT1A RECEPTOR
J. Biol. Chem. 274: 16444-16450, June 4, 1999 [Full Text]

Garcia-Osta, Ana, Frechilla, Diana, Del Rio, Joaquin
Effect of p-Chloroamphetamine on 5-HT1A and 5-HT7 Serotonin Receptor Expression in Rat Brain
J Neurochem 2000 74: 1790-1797 [Abstract]

Singh, JK, Chromy, BA, Boyers, MJ, Dawson, G, Banerjee, P
Induction of the serotonin1A receptor in neuronal cells during prolonged stress and degeneration
J Neurochem 1996 66: 2361-2372 [Abstract]

Zhang, Yahong, D'Souza, Deborah, Raap, Dani K., Garcia, Francisca, Battaglia, George, Muma, Nancy A., Van de Kar, Louis D.
Characterization of the Functional Heterologous Desensitization of Hypothalamic 5-HT1A Receptors after 5-HT2A Receptor Activation
J. Neurosci. 2001 21: 7919-7927 [Abstract]

JR Raymond
Protein kinase C induces phosphorylation and desensitization of the human 5-HT1A receptor
J. Biol. Chem. 266: 14747-14753, Aug, 1991. [Abstract/Full Text]

Xiang Cai, Zhenglin Gu, Ping Zhong, Yong Ren, and Zhen Yan
Serotonin 5-HT1A receptors regulate AMPA receptor channels through inhibiting CaMKII in prefrontal cortical pyramidal neurons
JBC Papers in Press published on July 30, 2002 as 10.1074/jbc.M203752200
"We have studied the regulation of AMPA receptor channels by serotonin signaling in pyramidal neurons of prefrontal cortex (PFC). Application of serotonin reduced the amplitude of AMPA-evoked currents, an effect mimicked by 5-HT1A receptor agonists and blocked by 5-HT1A antagonists, indicating the mediation by 5-HT1A receptors. The serotonergic modulation of AMPA receptor currents was blocked by protein kinase A (PKA) activators, and occluded by PKA inhibitors. Inhibiting the catalytic activity of protein phosphatase 1 (PP1) also eliminated the effect of serotonin on AMPA currents. Furthermore, the serotonergic modulation of AMPA currents was occluded by application of the Ca2+/calmodulin-dependent kinase II (CaMKII) inhibitors, and blocked by intracellular injection of calmodulin or recombinant CaMKII. Application of serotonin or 5-HT1A agonists to PFC slices reduced CaMKII activity and the phosphorylation of AMPA receptor subunit GluR1 at the CaMKII site in a PP1-dependent manner. We concluded that serotonin, by activating 5-HT1A receptors, suppress glutamatergic signaling through the inhibition of CaMKII, which is achieved by the inhibition of PKA and ensuing activation of PP1. This modulation demonstrates the critical role of CaMKII in serotonergic regulation of PFC neuronal activity, which may explain the neuropsychiatric behavioral phenotypes seen in CaMKII knockout mice." [Abstract/Full Text]

Christopher L. Parks, Patricia S. Robinson, Etienne Sibille, Thomas Shenk, and Miklos Toth
Increased anxiety of mice lacking the serotonin1A receptor
PNAS 95: 10734-10739, September 1, 1998. [Full Text]
Parsons,, Loren H., Kerr, Tony M., Tecott, Laurence H.
5-HT1A receptor mutant mice exhibit enhanced tonic, stress-induced and fluoxetine-induced serotonergic neurotransmission
J Neurochem 2001 77: 607-617 [Abstract]

Sylvie Ramboz, Ronald Oosting, Djamel Aït Amara, Hank F. Kung, Pierre Blier, Monica Mendelsohn, J. John Mann, Dani Brunner, and René Hen
Serotonin receptor 1A knockout: An animal model of anxiety-related disorder
PNAS 95: 14476-14481, November 24, 1998. [Full Text]
Tsuji, Minoru, Takeda, Hiroshi, Matsumiya, Teruhiko
Protective effects of 5-HT1A receptor agonists against emotional changes produced by stress stimuli are related to their neuroendocrine effects
Br. J. Pharmacol. 2001 134: 585-595
"These results suggest that activation of the adrenocortical system via 5-HT1A receptors may facilitate some adaptive mechanism(s) involved in the recognition of and/or ability to cope with stressful situations." [Abstract]
Vicentic, A;Li, Q;Battaglia, G;Van de Kar, LD
WAY-100635 inhibits 8-OH-DPAT-stimulated oxytocin, ACTH and corticosterone, but not prolactin secretion
EUROPEAN JOURNAL OF PHARMACOLOGY 346: (2-3) 261-266 APR 10 1998
"This study investigated the effects of increasing doses of a selective 5-HT1A receptor antagonist, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide (WAY-100635) on neuroendocrine responses induced by the 5-HT1A receptor agonist 8-OH-DPAT in adult male rats." [Abstract]

Okuhara, Dayne Y., Beck, Sheryl G.
Corticosteroids Alter 5-Hydroxytryptamine1A Receptor-effector Pathway in Hippocampal Subfield CA3 Pyramidal Cells
J Pharmacol Exp Ther 1998 284: 1227-1233 [Full Text]

Sacha Wissink, Onno Meijer, David Pearce, Bart van der Burg, and Paul T. van der Saag
Regulation of the Rat Serotonin-1A Receptor Gene by Corticosteroids
J. Biol. Chem. 275: 1321-1326, January 14, 2000. [Full Text]
Y. J. G. Karten, S. M. Nair, L. van Essen, R. Sibug, and M. Joëls
Long-term exposure to high corticosterone levels attenuates serotonin responses in rat hippocampal CA1 neurons
PNAS 96: 13456-13461, November 9, 1999 [Full Text]
Ichikawa, Junji, Meltzer, Herbert Y.
R(+)-8-OH-DPAT, a Serotonin1A Receptor Agonist, Potentiated S(-)-Sulpiride-Induced Dopamine Release in Rat Medial Prefrontal Cortex and Nucleus Accumbens But Not Striatum
J Pharmacol Exp Ther 1999 291: 1227-1232 [Full Text]
Zoltán Sarnyai, Etienne L. Sibille, Constantine Pavlides, Robert J. Fenster, Bruce S. McEwen, and Miklós Tóth
Impaired hippocampal-dependent learning and functional abnormalities in the hippocampus in mice lacking serotonin1A receptors
PNAS 97: 14731-14736, December 19, 2000. [Full Text]
Newman-Tancredi, Adrian, Cussac, Didier, Marini, Laetitia, Millan, Mark J.
Antibody Capture Assay Reveals Bell-Shaped Concentration-Response Isotherms for h5-HT1A Receptor-Mediated Galpha i3 Activation: Conformational Selection by High-Efficacy Agonists, and Relationship to Trafficking of Receptor Signaling
Mol Pharmacol 2002 62: 590-601 [Abstract]
Evans, Kenda L. J., Cropper, Jodie D., Berg, Kelly A., Clarke, William P.
Mechanisms of Regulation of Agonist Efficacy at the 5-HT1A Receptor by Phospholipid-Derived Signaling Components
J Pharmacol Exp Ther 2001 297: 1025-1035 [Full Text]
Lin, Stanley L., Setya, Shilpy, Johnson-Farley, Nadine N., Cowen, Daniel S.
Differential coupling of 5-HT1 receptors to G proteins of the Gi family
Br. J. Pharmacol. 2002 136: 1072-1078 [Abstract]

Catherine A. Chen, and David R. Manning
Regulation of Gi Palmitoylation by Activation of the 5-Hydroxytryptamine-1A Receptor
J. Biol. Chem. 275: 23516-23522, August 4, 2000. [Full Text]
Paul R. Albert, Naghmeh Sajedi, Sylvie Lemonde, and Mohammad H. Ghahremani
Constitutive Gi2-dependent Activation of Adenylyl Cyclase Type II by the 5-HT1A Receptor. INHIBITION BY ANXIOLYTIC PARTIAL AGONISTS
J. Biol. Chem. 274: 35469-35474, December 10, 1999. [Full Text]

Sacha Wissink, Bart van der Burg, Benita S. Katzenellenbogen, and Paul T. van der Saag
Synergistic Activation of the Serotonin-1A Receptor by Nuclear Factor-kappa B and Estrogen
Mol. Endocrinol. 15: 543-552, 2001. [Full Text]
Darmon, M, Langlois, X, Suffisseau, L, Fattaccini, CM, Hamon, M
Differential membrane targeting and pharmacological characterization of chimeras of rat serotonin 5-HT1A and 5-HT1B receptors expressed in epithelial LLC-PK1 cells.
J Neurochem 1998 71: 2294-2303 [Abstract]

Evans, Kenda L. J., Cropper, Jodie D., Berg, Kelly A., Clarke, William P.
Mechanisms of Regulation of Agonist Efficacy at the 5-HT1A Receptor by Phospholipid-Derived Signaling Components
J Pharmacol Exp Ther 2001 297: 1025-1035 [Full Text]
Holmes, Megan C., French, Karen L., Seckl, Jonathan R.
Dysregulation of Diurnal Rhythms of Serotonin 5-HT2C and Corticosteroid Receptor Gene Expression in the Hippocampus with Food Restriction and Glucocorticoids
J. Neurosci. 1997 17: 4056-4065 [Full Text]
Alastair J. Barr, and David R. Manning
Agonist-independent Activation of Gz by the 5-Hydroxytryptamine1A Receptor Co-expressed in Spodoptera frugiperda Cells. DISTINGUISHING INVERSE AGONISTS FROM NEUTRAL ANTAGONISTS
J. Biol. Chem. 272: 32979-32987, December 26, 1997. [Full Text]

Lim WK, Myung CS, Garrison JC, Neubig RR.
Receptor-G protein gamma specificity: gamma11 shows unique potency for A(1) adenosine and 5-HT(1A) receptors.
Biochemistry 2001 Sep 4;40(35):10532-41 [Abstract]

Boutrel, Benjamin, Monaca, Christelle, Hen, Rene, Hamon, Michel, Adrien, Joelle
Involvement of 5-HT1A Receptors in Homeostatic and Stress-Induced Adaptive Regulations of Paradoxical Sleep: Studies in 5-HT1A Knock-Out Mice
J. Neurosci. 2002 22: 4686-4692 [Abstract]
Lin MT, Chuang JI.
Melatonin potentiates 5-HT1A receptor activation in rat hypothalamus and results in hypothermia.
J Pineal Res 2002 Aug;33(1):14-9 [Abstract]
Dupuis, DS, Palmier, C, Colpaert, FC, Pauwels, PJ
Autoradiography of serotonin 5-HT1A receptor-activated G proteins in guinea pig brain sections by agonist-stimulated [35S]GTPgammaS binding.
J Neurochem 1998 70: 1258-1268 [Abstract]

Riad, Mustapha, Watkins, Kenneth C., Doucet, Edith, Hamon, Michel, Descarries, Laurent
Agonist-Induced Internalization of Serotonin-1A Receptors in the Dorsal Raphe Nucleus (Autoreceptors) But Not Hippocampus (Heteroreceptors)
J. Neurosci. 2001 21: 8378-8386 [Abstract]
Zhong P, Ciaranello RD.
Transcriptional regulation of hippocampal 5-HT1a receptors by corticosteroid hormones.
Brain Res Mol Brain Res 1995 Mar;29(1):23-34 [Medline]
Froger, Nicolas, Gardier, Alain M., Moratalla, Rosario, Alberti, Israel, Lena, Isabelle, Boni, Claudette, De Felipe, Carmen, Rupniak, Nadia M. J., Hunt, Stephen P., Jacquot, Christian, Hamon, Michel, Lanfumey, Laurence
5-Hydroxytryptamine (5-HT)1A Autoreceptor Adaptive Changes in Substance P (Neurokinin 1) Receptor Knock-Out Mice Mimic Antidepressant-Induced Desensitization
J. Neurosci. 2001 21: 8188-8197 [Abstract].
Daniel S. Cowen, Rebecca S. Sowers, and David R. Manning
Activation of a Mitogen-activated Protein Kinase (ERK2) by the 5-Hydroxytryptamine1A Receptor Is Sensitive Not Only to Inhibitors of Phosphatidylinositol 3-Kinase, but to an Inhibitor of Phosphatidylcholine Hydrolysis
J. Biol. Chem. 271: 22297-22300, September 13, 1996. [Full Text]
Gregory J. Della Rocca, Yurii V. Mukhin, Maria N. Garnovskaya, Yehia Daaka, Geoffrey J. Clark, Louis M. Luttrell, Robert J. Lefkowitz, and John R. Raymond
Serotonin 5-HT1A Receptor-mediated Erk Activation Requires Calcium/Calmodulin-dependent Receptor Endocytosis
J. Biol. Chem. 274: 4749-4753, February 19, 1999.
"Many receptors that couple to heterotrimeric guanine nucleotide-binding (G) proteins mediate rapid activation of the mitogen-activated protein kinases, Erk1 and Erk2. The Gi-coupled serotonin (5-hydroxytryptamine (5-HT)) 5-HT1A receptor, heterologously expressed in Chinese hamster ovary or human embryonic kidney 293 cells, mediated rapid activation of Erk1/2 via a mechanism dependent upon both Ras activation and clathrin-mediated endocytosis. This activation was attenuated by chelation of intracellular Ca2+ and Ca2+/calmodulin (CAM) inhibitors or the CAM sequestrant protein calspermin. The CAM-dependent step in the Erk1/2 activation cascade is downstream of Ras activation, because inhibitors of CAM antagonize Erk1/2 activation induced by constitutively activated mutants of Ras and c-Src but not by constitutively activated mutants of Raf and MEK (mitogen and extracellular signal-regulated kinase). Inhibitors of the classical CAM effectors myosin light chain kinase, CAM-dependent protein kinases II and IV, PP2B, and CAM-sensitive phosphodiesterase had no effect upon 5-HT1A receptor-mediated Erk1/2 activation. Because clathrin-mediated endocytosis was required for 5-HT1A receptor-mediated Erk1/2 activation, we postulated a role for CAM in receptor endocytosis. Inhibition of receptor endocytosis by use of sequestration-defective mutants of -arrestin1 and dynamin attenuated 5-HT1A receptor-stimulated Erk1/2 activation. Inhibition of CAM prevented agonist-dependent endocytosis of epitope-tagged 5-HT1A receptors. We conclude that CAM-dependent activation of Erk1/2 through the 5-HT1A receptor reflects its role in endocytosis of the receptor, which is a required step in the activation of MEK and subsequently Erk1/2." [Full Text]
Levkovitz, Y., Segal, M.
Serotonin 5-HT1A Receptors Modulate Hippocampal Reactivity to Afferent Stimulation
J. Neurosci. 1997 17: 5591-5598 [Full Text]
Cowen, Daniel S., Molinoff, Perry B., Manning, David R.
5-Hydroxytryptamine1A Receptor-Mediated Increases in Receptor Expression and Activation of Nuclear Factor-kappa B in Transfected Chinese Hamster Ovary Cells
Mol Pharmacol 1997 52: 221-226 [Full Text]
Li, Qian, Wichems, Christine, Heils, Armin, Lesch, Klaus-Peter, Murphy, Dennis L.
Reduction in the Density and Expression, But Not G-Protein Coupling, of Serotonin Receptors (5-HT1A) in 5-HT Transporter Knock-Out Mice: Gender and Brain Region Differences
J. Neurosci. 2000 20: 7888-7895 [Full Text]
Bosker FJ, Klompmakers A, Westenberg HG
Postsynaptic 5-HT1A receptors mediate 5-hydroxytryptamine release in the amygdala through a feedback to the caudal linear raphe.
Eur J Pharmacol 1997 Aug 27;333(2-3):147-57 [Abstract]

Foehring RC.
Serotonin modulates N- and P-type calcium currents in neocortical pyramidal neurons via a membrane-delimited pathway.
J Neurophysiol 1996 Feb;75(2):648-59
"The 5HT modulation was mimicked by 5HT1A agonists and was reduced by 5HT1A antagonists. 5HT2 antagonists had no effect on the modulation. These data suggest that the 5HT effects were mediated by 5HT1A receptors." [Abstract]
Maura, Guido, Marcoli, Manuela, Pepicelli, Olimpia, Rosu, Christian, Viola, Concetta, Raiteri, Maurizio
Serotonin inhibition of the NMDA receptor/nitric oxide/cyclic GMP pathway in human neocortex slices: involvement of 5-HT2C and 5-HT1A receptors
Br. J. Pharmacol. 2000 130: 1853-1858 [Abstract]

Testa R, Guarneri L, Angelico P, Velasco C, Poggesi E, Cilia A, Leonardi A.
Effect of different 5-hydroxytryptamine receptor subtype antagonists on the micturition reflex in rats.
BJU Int 2001 Feb;87(3):256-64
"These findings confirm that only selective 5-HT1A receptor antagonists have favourable effects on the bladder, inducing an increase in bladder capacity with no derangement of bladder contractility." [Abstract]
Hery, F., Boulenguez, P., Semont, A., Hery, M., Pesce, G., Becquet, D., Faudon, M., Deprez, P., Fache, M.-P.
Identification and Role of Serotonin 5-HT1A and 5-HT1B Receptors in Primary Cultures of Rat Embryonic Rostral Raphe Nucleus Neurons
J Neurochem 1999 72: 1791-1801 [Abstract]

Li, Q., Muma, N. A., Battaglia, G., Van De Kar, L. D.
A Desensitization of Hypothalamic 5-HT1A Receptors by Repeated Injections of Paroxetine: Reduction in the Levels of Gi and Go Proteins and Neuroendocrine Responses, but Not in the Density of 5-HT1A Receptors
J Pharmacol Exp Ther 1997 282: 1581-1590 [Full Text]
Raap, D. K., Evans, S., Garcia, F., Li, Q., Muma, N. A., Wolf, W. A., Battaglia, G., Van De Kar, L. D.
Daily Injections of Fluoxetine Induce Dose-Dependent Desensitization of Hypothalamic 5-HT1A Receptors: Reductions in Neuroendocrine Responses to 8-OH-DPAT and in Levels of Gz and Gi Proteins
J Pharmacol Exp Ther 1999 288: 98-106 [Full Text]

Griebel G, Rodgers RJ, Perrault G, Sanger DJ.
Risk assessment behaviour: evaluation of utility in the study of 5-HT-related drugs in the rat elevated plus-maze test.
Pharmacol Biochem Behav 1997 Aug;57(4):817-27
"The present findings demonstrate that risk assessment responses are sensitive to the action of 5-HT1A receptor ligands, but their modulation by drugs targetting 5-HT2A, 5-HT2C, and 5-HT3 receptors was not convincingly established." [Abstract]

Browning, Kirsteen N., Travagli, R. Alberto
The peptide TRH uncovers the presence of presynaptic 5-HT1A receptors via activation of a second messenger pathway in the rat dorsal vagal complex
J Physiol (Lond) 2001 531: 425-435 [Full Text]

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Recent 5-HT1A Receptor Research
1) 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]

2) Gu B, Wu G, Si J, Xu Y, Andersson KE
Improving voiding efficiency in the diabetic rat by a 5-HT1A serotonin receptor agonist.
Neurourol Urodyn. 2011 Jul 20;
AIMS: Serotonin affects micturition in the normal rat through actions not only on ascending and descending spinal pathways and supraspinal centers but also on the lumbosacral spinal cord level. The selective 5-HT1A receptor agonist, 8-OH-DPAT((R)-(+)-8-hydroxy-2-(di-n-propylamino) tetralin), reversed detrusor-sphincter dyssynergia (DSD) in the spinal cord injury (SCI) rat. Rats with experimental diabetes mellitus (DM) have been shown to have both bladder and urethral dysfunction during reflex voiding. We therefore examined the effects of 8-OH-DPAT on micturition in DM rats. METHODS: Female Sprague-Dawley rats were used. DM was induced by an intraperitoneal injection of streptozotocin (STZ, 65?mg/kg) and a cystometric study was performed 8 weeks post-injection. External urethral sphincter electromyography (EUS-EMG) was also measured. The 5-HT1A antagonist WAY-100635(N-tert-butyl-3-(4-(2-methoxyphenyl)-piperazin-1-yl)-2-phenylpropanamide) was administered after each 8-OH-DPAT dose-response. RESULTS: Compared to controls, DM rats had a higher bladder capacity, residual volume, and a lower voiding efficiency. In DM rats, 8-OH-DPAT (3-1,000?�g/kg, i.v.) induced significant dose-dependent increases in micturition volume, and decreases in residual volume, resulting in increases in voiding efficiency. During the micturition, there was a dose-dependent increased phasic EUS activity correlated with the improved voiding efficiency. WAY-100635 (300?�g/kg, i.v.) reversed the 8-OH-DPAT-induced changes. CONCLUSIONS: Both the bladder voiding efficiency and the periodic EUS activity were decreased in DM rats. 5-HT1A receptor agonism promoted periodic EUS activity, thereby improving voiding efficiency. Whether or not these results may have implications for the future treatment of voiding dysfunction in DM patients remains to be studied. Neurourol. Urodynam. � 2011 Wiley-Liss, Inc. [PubMed Citation] [Order full text from Infotrieve]

3) Alvarez E, Perez V, Dragheim M, Loft H, Artigas F
A double-blind, randomized, placebo-controlled, active reference study of Lu AA21004 in patients with major depressive disorder.
Int J Neuropsychopharmacol. 2011 Jul 18;:1-12.
The efficacy, safety, and tolerability of Lu AA21004 vs. placebo using venlafaxine XR as active reference in patients with DSM-IV-TR major depressive disorder (MDD) were evaluated. Lu AA21004 is a novel antidepressant that is a 5-HT3 and 5-HT7 receptor antagonist, 5-HT1A receptor agonist, 5-HT1B receptor partial agonist and inhibitor of the 5-HT transporter in recombinant cell lines. In this 6-wk, multi-site study, 429 patients were randomly assigned (1:1:1:1) to 5 or 10 mg Lu AA21004, placebo or 225 mg venlafaxine XR. All patients had a baseline Montgomery-�sberg Depression Rating Scale (MADRS) total score ?30. The primary efficacy analysis was based on the MADRS total score adjusting for multiplicity using a hierarchical testing procedure starting with the highest dose vs. placebo. Lu AA21004 was statistically significantly superior to placebo (n=105) in mean change from baseline in MADRS total score at week 6 (p<0.0001, last observation carried forward), with a mean treatment difference vs. placebo of 5.9 (5 mg, n=108), and 5.7 (10 mg, n=100) points. Venlafaxine XR (n=112) was also significantly superior to placebo at week 6 (p<0.0001). In total, 30 patients withdrew due to adverse events (AEs) - placebo: four (4%); 5 mg Lu AA21004: three (3%); 10 mg Lu AA21004: seven (7%); and venlafaxine: 16 (14%). The most common AEs were nausea, headache, hyperhidrosis, and dry mouth. No clinically relevant changes over time were seen in the clinical laboratory results, vital signs, weight, or ECG parameters. In this study, treatment with 5 mg and 10 mg Lu AA21004 for 6 wk was efficacious and well tolerated in patients with MDD. [PubMed Citation] [Order full text from Infotrieve]

4) Bose SK, Mehta MA, Selvaraj S, Howes OD, Hinz R, Rabiner EA, Grasby PM, Turkheimer FE, Murthy V
Presynaptic 5-HT1A is Related to 5-HTT Receptor Density in the Human Brain.
Neuropsychopharmacology. 2011 Jul 13;
5-Hydroxytryptamine (5-HT or serotonin) is an important neurotransmitter for a number of brain functions and widely distributed throughout the brain. Physiological and pharmacological relationship between 5-HT1A receptors and serotonin transporter (5-HTT) in the regulation of 5-HT neurotransmission has now been documented. A relationship between 5-HT1A receptors and 5-HTT is also suggested by the pathophysiology of depression and the mechanism of action of antidepressants. We have scanned 42 healthy adults with both [11C] WAY-100635 and [11C] DASB to investigate the anatomical co-distribution of multiple serotonergic markers. We hypothesized that lower 5-HTT densities in the dorsal raphe nucleus (DRN) and limbic regions will be accompanied by lower 5-HT1A receptor density in the same regions, contributing to the 5-HT1A receptor desensitization. In addition, variations in DRN 5-HT1A receptor density can theoretically influence the density and/or function of other serotonin receptor subtypes and the 5-HTT consequent to changes in serotonergic tone. In a comparatively large sample of volunteers, we have shown that the relationship between 5-HT1A and 5-HTT PET indices was complex. We were unable to demonstrate robust, intra-regional relationships between 5-HT1A and 5-HTT densities. Inter-regionally, DRN 5-HT1A receptors were related to cortical (temporal and frontal regions) and paralimbic (insula), but not limbic 5-HTT. This latter finding may reflect differences in 5-HT tone between individuals, and highlights probable substrates sensitive to variations in DRN 5-HT function.Neuropsychopharmacology advance online publication, 13 July 2011; doi:10.1038/npp.2011.113. [PubMed Citation] [Order full text from Infotrieve]

5) Shishkina GT, Kalinina TS, Berezova IV, Dygalo NN
Stress-induced activation of the brainstem Bcl-xL gene expression in rats treated with fluoxetine: Correlations with serotonin metabolism and depressive-like behavior.
Neuropharmacology. 2011 Jun 29;
Mechanisms underlying stress-induced depression and antidepressant drug action were shown to involve alterations in serotonergic (5-HT) neurotransmission and expression of genes coding for proteins associated with neurotrophic signaling pathways and cell-survival in the hippocampus and cortex. Expression of these genes in the brainstem containing 5-HT neurons may also be related to vulnerability or resilience to stress-related psychopathology. Here we investigated 5-HT markers and expression of genes for Brain-Derived Neurotrophic Factor (BDNF) and apoptotic proteins in the brainstem in relation to swim stress-induced behavioral despair. We found that anti-apoptotic Bcl-xL gene is sensitive to stress during the course of fluoxetine administration. Responsiveness of this gene to stress appeared concomitantly with an antidepressant-like effect of fluoxetine in the forced swim test. Bcl-xL transcript levels showed negative correlations with duration of immobility in the test and 5-HT turnover in the brainstem. In contrast, BDNF and pro-apoptotic protein Bax mRNA levels were unchanged by either fluoxetine or stress, suggesting specificity of Bcl-xL gene responses to these treatments. We also found that the levels of mRNAs for tryptophan hydroxylase-2 (TPH2) and 5-HT transporter (5-HTT) were significantly down-regulated following prolonged treatment with fluoxetine, but were not affected by stress. Unlike TPH2 and 5-HTT, 5-HT1A receptor mRNA levels were not altered by fluoxetine but significantly increased in response to swim stress. These data show that long-term fluoxetine treatment leads to changes in 5-HT and Bcl-xL responses to stress associated with antidepressant-like effects of the drug. This article is part of a Special Issue entitled 'Anxiety and Depression'. [PubMed Citation] [Order full text from Infotrieve]

6) 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]

7) Luo FF, Han F, Shi YX
Changes in 5-HT1A receptor in the dorsal raphe nucleus in a rat model of post-traumatic stress disorder.
Mol Med Report. 2011 Sep-Oct;4(5):843-7.
Post-traumatic stress disorder (PTSD) is characterized mainly by symptoms of re-experiencing, avoidance and hyperarousal as a consequence of catastrophic and traumatic events that are distinguished from ordinary stressful life events. Single-prolonged stress (SPS) is an established animal model for post-traumatic stress disorder (PTSD). The dorsal raphe nucleus (DR)-serotonin (5-HT) system is markedly affected by swim stress and has been implicated in affective disorders. The 5-HT1A receptor (5-HT1AR) is critically involved in regulating mood and anxiety levels. In this study, we investigated changes in the expression of 5-HT1AR in the DR of rats after SPS that may reveal part of the pathogenesis of PTSD. 5-HT1AR expression in the DR was examined using immunohistochemistry, Western blotting and reverse transcription polymerase chain reaction. The expression of 5-HT1AR in the DR after SPS exposure was increased when compared to that in the control group (P<0.05). These findings indicate an increase in 5-HT1AR in the DR of SPS rats, which may play important roles in the pathogenesis of PTSD rats. [PubMed Citation] [Order full text from Infotrieve]

8) 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]

9) Sevak RJ, Vansickel AR, Stoops WW, Glaser PE, Hays LR, Rush CR
Discriminative-stimulus, subject-rated, and physiological effects of methamphetamine in humans pretreated with aripiprazole.
J Clin Psychopharmacol. 2011 Aug;31(4):470-80.
Methamphetamine is thought to produce its behavioral effects by facilitating release of dopamine, serotonin (5-HT) and norepinephrine. Results from animal studies support this notion, whereas results from human laboratory studies have not consistently demonstrated the importance of monoamine systems in the behavioral effects of methamphetamine. Human drug-discrimination procedures are well suited to assess neuropharmacological mechanisms of the training drug by studying pharmacological manipulation. In this human laboratory study, 6 participants with a history of recreational stimulant use learned to discriminate 10 mg oral methamphetamine. After acquiring the discrimination (ie, ?80% correct responding on 4 consecutive sessions), the effects of a range of doses of methamphetamine (0, 2.5, 5, 10, and 15 mg), alone and in combination with 0 and 20 mg aripiprazole (a partial agonist at D2 and 5-HT1A receptors), were assessed. Methamphetamine alone functioned as a discriminative stimulus, produced prototypical stimulant-like subject-rated drug effects (eg, increased ratings of Good Effects, Talkative-Friendly, and Willing to Pay For) and elevated cardiovascular indices. These effects were generally a function of dose. Aripiprazole alone did not occasion methamphetamine-appropriate responding or produce subject-rated effects but modestly impaired performance. Administration of aripiprazole significantly attenuated the discriminative-stimulus and cardiovascular effects of methamphetamine, as well as some of the subject-rated drug effects. These results indicate that monoamine systems likely play a role in the behavioral effects of methamphetamine in humans. Moreover, given the concordance between past results with d-amphetamine and the present findings, d-amphetamine can likely serve as a model for the pharmacological effects of methamphetamine. [PubMed Citation] [Order full text from Infotrieve]

10) Crisafulli C, Fabbri C, Porcelli S, Drago A, Spina E, De Ronchi D, Serretti A
Pharmacogenetics of antidepressants.
Front Pharmacol. 2011;2:6.
Up to 60% of depressed patients do not respond completely to antidepressants (ADs) and up to 30% do not respond at all. Genetic factors contribute for about 50% of the AD response. During the recent years the possible influence of a set of candidate genes as genetic predictors of AD response efficacy was investigated by us and others. They include the cytochrome P450 superfamily, the P-glycoprotein (ABCB1), the tryptophan hydroxylase, the catechol-O-methyltransferase, the monoamine oxidase A, the serotonin transporter (5-HTTLPR), the norepinephrine transporter, the dopamine transporter, variants in the 5-hydroxytryptamine receptors (5-HT1A, 5-HT2A, 5-HT3A, 5-HT3B, and 5-HT6), adrenoreceptor beta-1 and alpha-2, the dopamine receptors (D2), the G protein beta 3 subunit, the corticotropin releasing hormone receptors (CRHR1 and CRHR2), the glucocorticoid receptors, the c-AMP response-element binding, and the brain-derived neurotrophic factor. Marginal associations were reported for angiotensin I converting enzyme, circadian locomotor output cycles kaput protein, glutamatergic system, nitric oxide synthase, and interleukin 1-beta gene. In conclusion, gene variants seem to influence human behavior, liability to disorders and treatment response. Nonetheless, gene?�?environment interactions have been hypothesized to modulate several of these effects. [PubMed Citation] [Order full text from Infotrieve]

11) Hsieh JT, Liu SP, Chang HC, Tsai VF, Chien CT, Yu HJ, Ho CH
The Activation of Peripheral 5-HT1A Receptors Can Inhibit Seminal Vesicle Contraction: An In Vivo Animal Study.
Urology. 2011 Jun 13;
OBJECTIVES: To elucidate the differential effects of stimulating various peripheral 5-HT receptor subtypes on the contractile response of seminal vesicles (SVs) induced by electrical stimulation (ES). METHODS: Male Wistar rats (aged 12-14 weeks) were prepared as our previously established model, which allows an intraarterial injection of test agents to directly act on SV. Four selective 5-HT agonists-8-OH-DPAT (5-HT1A), 5-nonyloxytryptamine (5-HT1B), BW723C86 (5-HT2B), and MK-212 (5-HT2C)-were injected at various concentrations (from 10(-8) to 10(-4) mmol/kg). After an injection, the SV contractile response was recorded after ES of lesser splanchnic nerve was applied. Relationships between the concentration of an agonist and its effect on SV contraction were plotted and analyzed. RESULTS: The peripheral injection of 5-HT1A agonist had a dose-dependent inhibitory effect on SV contraction and could achieve an inhibition of >50%; the IC50 was 3.16x10(-6) mmol/kg. No significant effects were observed with the peripheral injection of 5-HT1B, 5-HT2B, or 5-HT2C agonist. CONCLUSIONS: Our in vivo animal study shows that the activation of peripheral 5-HT1A receptors can inhibit ES-induced SV contraction, whereas the activation of peripheral 5-HT1B, 5-HT2B, or 5-HT2C receptors has no significant effect. The results suggest that the peripheral 5-HT pathway is a potential therapeutic target of the treatment for premature ejaculation. [PubMed Citation] [Order full text from Infotrieve]

12) de Oliveira Sergio T, de Bortoli VC, Zangrossi H
Serotonin-2A receptor regulation of panic-like behavior in the rat dorsal periaqueductal gray matter: the role of GABA.
Psychopharmacology (Berl). 2011 Jun 10;
RATIONALE: Electrical stimulation of the dorsal periaqueductal gray (dPAG) evokes escape, a defensive response associated with panic attacks. Stimulation of 5-HT1A or 5-HT2A receptors in this midbrain area equally inhibits escape performance, even though at the molecular level these receptors cause opposite effects, i.e., activation of the former hyperpolarizes the cell membrane, while the latter excites it. A proposal has been made that 5-HT2A receptor agonists exert their inhibitory effect on escape by activating GABAergic interneurons located in the dPAG. OBJECTIVES: In the present study, we evaluated this hypothesis by investigating whether previous intra-dPAG administration of the GABAA receptor antagonist bicuculline blocks the anti-escape effect caused by the local injection of different 5-HT2A/2C receptor agonists. RESULTS: Intra-dPAG administration of 5-HT, the preferential 5-HT2A receptor agonist DOI, the nonselective 5-HT2C receptor agonist mCPP or the 5-HT2C receptor agonist RO 60-0175 significantly inhibited the escape reaction induced by electrical stimulation of the same brain area. In all cases, this panicolytic-like effect was blocked by previous microinjection of bicuculline. This GABAA antagonist, however, failed to antagonize the anti-escape effect caused by the 5-HT1A receptor agonist 8-OH-DPAT. The inhibitory effect caused by DOI, RO 60-0175, and mCPP was also blocked by previous intra-dPAG injection of the preferential 5-HT2A receptor antagonist ketanserin. Pre-administration of the 5-HT2C receptor antagonist SB-242084 in the dPAG did not block the anti-escape effect of RO 60-0175. CONCLUSIONS: Stimulation of 5-HT2A but not 5-HT2C receptors in the dPAG causes a panicolytic-like effect that is mediated by facilitation of GABAergic neurotransmission. [PubMed Citation] [Order full text from Infotrieve]

13) Lee TH, Kim KH, Lee SO, Lee KR, Son M, Jin M
Tetrahydroberberine, an Isoquinoline Alkaloid Isolated from Corydalis Tuber, Enhances Gastrointestinal Motor Function.
J Pharmacol Exp Ther. 2011 Jun 9;
As delayed gastric emptying and impaired gastric accommodation are regarded as the pathophysiological mechanisms underlying functional dyspepsia (FD), prokinetic and fundic relaxants have been suggested as a new treatment for FD. We isolated tetrahydroberberine (THB), an isoquinoline alkaloid, (5,8,13,13 a-Tetrahydro-9,10-dimethoxy-6H-benzo[g]-1,3-benzodioxolo[5,6-a]quinolizine) from Corydalis Tuber, and found that it has micromolar affinity for dopamine D2 (pKi 6.08) and 5-HT1A (pKi 5.38) receptors, but moderate to no affinity for other relevant serotonin receptors [i.e., 5-HT1B, 5-HT1D, 5-HT3, and 5-HT4: pKi < 5.00]. Oral administration of THB not only significantly accelerated gastric emptying of normal rats in a bell-shaped relationship with a maximal efficacy at the dose of 30 ?g/kg, but also restored the delayed gastric emptying caused by apomorphine, which might be mediated by an anti-dopaminergic effect. Data from electromyography indicated that THB enhanced gastro motor function of the upper GI tract by strengthening contractility and shortening the contraction interval. Furthermore, in rats stressed by repeated restraint, a significantly higher shift in pressure-volume curve by THB (10 ?g/kg, P<0.05), which was inhibited by WAY100635, a 5- HT1A antagonist and L-NAME, a NOS inhibitor, but not VIP antagonist, was observed. Oral administration of THB resulted in a drastic increase of gastric accommodation in Beagle dogs. Area under the volume versus time curve was significantly increased by THB (30 ?g/kg, p<0.01), comparable to that of sumatriptan (3 mg/kg), a potent fundic relaxant. Taken together, our data suggested that THB, with D2 antagonist and 5-HT1A agonist properties, has great potential as a therapeutic for treatment of FD. [PubMed Citation] [Order full text from Infotrieve]

14) Beste C, Domschke K, Radenz B, Falkenstein M, Konrad C
The functional 5-HT1A receptor polymorphism affects response inhibition processes in a context-dependent manner.
Neuropsychologia. 2011 Jul;49(9):2664-72.
Cognitive control processes may depend on contextual information, sometimes improving performance, but impairing performance if expectancies about forthcoming events induce pre-potent responses. The neurobiological bases of these effects are not understood. Here, we examine context-dependent variations of response control processes using the AX-CPT task with respect to the relevance of the functional serotonin 1A receptor polymorphism (5-HT1A C(-1019)G) in a sample of healthy subjects (N=90) by means of event-related potentials (ERPs). The results show that, when context information is helpful to drive behavioural performance, carriers of the -1019G allele reveal compromised cognitive control. Yet, they show enhanced task performance when strong context representations would lead to declines in behavioural control. These findings are paralleled by modulations of the (Nogo)-P3 ERP-component. These results show for the first time that, even though the -1019G allele enhances the risk to develop anxiety disorders, it also confers an advantage to its carriers in terms of better cognitive control processes in conditions where contextual information compromises cognitive control. Effects of the 5-HT1A C(-1019)G polymorphism were further modulated by anxiety sensitivity. As the functional effect of the 5-HT1A C(-1019)G polymorphism has previously been shown to be rather specific for serotonergic 1A autoreceptors in the dorsal raphe nucleus (DRN), the results suggest that contextual modulations in cognitive control may be exerted by the DRN. [PubMed Citation] [Order full text from Infotrieve]

15) Ostock CY, Dupre KB, Eskow Jaunarajs KL, Walters H, George J, Krolewski D, Walker PD, Bishop C
Role of the primary motor cortex in l-DOPA-induced dyskinesia and its modulation by 5-HT1A receptor stimulation.
Neuropharmacology. 2011 Sep;61(4):753-60.
While serotonin 5-HT1A receptor (5-HT1AR) agonists reduce l-DOPA-induced dyskinesias (LID) by normalizing activity in the basal ganglia neurocircuitry, recent evidence suggests putative 5-HT1AR within the primary motor cortex (M1) may also contribute. To better characterize this possible mechanism, c-fos immunohistochemistry was first used to determine the effects of systemic administration of the full 5-HT1AR agonist �8-OH-DPAT on l-DOPA-induced immediate early gene expression within M1 and the prefrontal cortex (PFC) of rats with unilateral medial forebrain bundle (MFB) dopamine (DA) lesions. Next, in order to determine if direct stimulation of 5-HT1AR within M1 attenuates the onset of LID, rats with MFB lesions were tested for l-DOPA-induced abnormal involuntary movements (AIMs) and rotations following M1 microinfusions of �8-OH-DPAT with or without coadministration of the 5-HT1AR antagonist WAY100635. Finally, �8-OH-DPAT was infused into M1 at peak dyskinesia to determine if 5-HT1AR stimulation attenuates established l-DOPA-induced AIMs and rotations. While no treatment effects were seen within the PFC, systemic �8-OH-DPAT suppressed l-DOPA-induced c-fos within M1. Intra-M1 5-HT1AR stimulation diminished the onset of AIMs and this effect was reversed by WAY100635 indicating receptor specific effects. Finally, continuous infusion of �8-OH-DPAT into M1 at peak dyskinesia alleviated l-DOPA-induced AIMs. Collectively, these findings support an integral role for M1 in LID and its modulation by local 5-HT1AR. [PubMed Citation] [Order full text from Infotrieve]

16) Kulikov AV, Tikhonova MA, Kulikova EA, Khomenko TM, Korchagina DV, Volcho KP, Salachutdinov HF, Popova NK
[Effect of new potential psychotropic drug, 8-(trifluoromethyl)-1,2,3,4,5-benzopentathiepin-6-amine hydrochloride, on the expression of serotonin-related genes in mouse brain].
Mol Biol (Mosk). 2011 Mar-Apr;45(2):282-8.
Study of molecular mechanisms of psychotropic drug action is the main aim of molecular psychopharmacology. New synthetic analog of variacin 8-(Trifluoromethyl)-1,2,3,4,5-benzopentathiepin-6-amine (TX-2153) was shown to produce anxiolytic and anticonvulsant effects on mice. Here the effect of chronic administration of TX-2153 on expression of some serotonin-related genes in mouse brain was investigated. The drug (10 mg/kg, per os, 16 days) was administered to adult males of ASC (Antidepressant Sensitive Catalepsy) mouse strain characterizing by alterations in behavior and brain serotonin system. The expression of genes encoding 1) the key enzyme of serotonin synthesis, tryptophan hydroxylase 2 (TPH2), 2) main enzyme of serotonin degradation, monoamine oxydase A (MAOA), 3) 5-HT transporter (SERT) and 4) 5-HT(1A) receptor was studied using quantitative RT-PCR. TX-2153 significantly reduced m-RNA level of 5-HT(1A) receptor and MAOA genes in the midbrain without any effect on expression of these genes in the frontal cortex and hippocampus. The drug failed to affect expression of TPH2 and SERT genes in the midbrain. The result indicates involvement of the brain 5-HT system in the molecular mechanism underlying the effect of TX-2153. [PubMed Citation] [Order full text from Infotrieve]

17) Gleason G, Zupan B, Toth M
Maternal genetic mutations as gestational and early life influences in producing psychiatric disease-like phenotypes in mice.
Front Psychiatry. 2011;2:25.
Risk factors for psychiatric disorders have traditionally been classified as genetic or environmental. Risk (candidate) genes, although typically possessing small effects, represent a clear starting point to elucidate downstream cellular/molecular pathways of disease. Environmental effects, especially during development, can also lead to altered behavior and increased risk for disease. An important environmental factor is the mother, demonstrated by the negative effects elicited by maternal gestational stress and altered maternal care. These maternal effects can also have a genetic basis (e.g., maternal genetic variability and mutations). The focus of this review is "maternal genotype effects" that influence the emotional development of the offspring resulting in life-long psychiatric disease-like phenotypes. We have recently found that genetic inactivation of the serotonin 1A receptor (5-HT1AR) and the fmr1 gene (encoding the fragile X mental retardation protein) in mouse dams results in psychiatric disease-like phenotypes in their genetically unaffected offspring. 5-HT1AR deficiency in dams results in anxiety and increased stress responsiveness in their offspring. Offspring of 5-HT1AR deficient dams display altered development of the hippocampus, which could be linked to their anxiety-like phenotype. Maternal inactivation of fmr1, like its inactivation in the offspring, results in a hyperactivity-like condition and is associated with receptor alterations in the striatum. These data indicate a high sensitivity of the offspring to maternal mutations and suggest that maternal genotype effects can increase the impact of genetic risk factors in a population by increasing the risk of the genetically normal offspring as well as by enhancing the effects of offspring mutations. [PubMed Citation] [Order full text from Infotrieve]

18) Albert PR, Le Fran�ois B, Millar AM
Transcriptional dysregulation of 5-HT1A autoreceptors in mental illness.
Mol Brain. 2011;4:21.
ABSTRACT: The serotonin-1A (5-HT1A) receptor is among the most abundant and widely distributed 5-HT receptors in the brain, but is also expressed on serotonin neurons as an autoreceptor where it plays a critical role in regulating the activity of the entire serotonin system. Over-expression of the 5-HT1A autoreceptor has been implicated in reducing serotonergic neurotransmission, and is associated with major depression and suicide. Extensive characterization of the transcriptional regulation of the 5-HT1A gene (HTR1A) using cell culture systems has revealed a GC-rich "housekeeping" promoter that non-selectively drives its expression; this is flanked by a series of upstream repressor elements for REST, Freud-1/CC2D1A and Freud-2/CC2D1B factors that not only restrict its expression to neurons, but may also regulate the level of expression of 5-HT1A receptors in various subsets of neurons, including serotonergic neurons. A separate set of allele-specific factors, including Deaf1, Hes1 and Hes5 repress at the HTR1A C(-1019)G (rs6295) polymorphism in serotonergic neurons in culture, as well as in vivo. Pet1, an obligatory enhancer for serotonergic differentiation, has been identified as a potent activator of 5-HT1A autoreceptor expression. Taken together, these results highlight an integrated regulation of 5-HT1A autoreceptors that differs in several aspects from regulation of post-synaptic 5-HT1A receptors, and could be selectively targeted to enhance serotonergic neurotransmission. [PubMed Citation] [Order full text from Infotrieve]

19) Avgustinovich DF, Vishnevetskaia GB
[Effects of chronic buspirone treatment on female mice exposed to the long-lasting psychoemotional influence].
Ross Fiziol Zh Im I M Sechenova. 2011 Feb;97(2):189-202.
The effects of chronic treatment (30 days) with the 5-HT1A receptor partial agonist buspirone (0.05, 1 and 10 mg/kg i.p.) on the behaviour of C57BL/6J female mice exposed to long-lasting psychoemotional influence were studied. The influence involved forced living of each female with an aggressive male separated with a perforated transparent partition in the same cage and daily female's presence during 10-min intermale confrontations behind a partition caused by introducing of another male to the aggressive male. Chronic buspirone injection (in all used doses) did not affect the behaviour of females estimated in the "partitions" and "open field" tests at the end of the drug treatment. The anxiolytic effect of buspirone only at the dose of 1 mg/kg on the female's plus-maze behaviour was revealed. In the Porsolt, test buspirone in the dose of 1 mg/kg caused a slight increase in the duration of immobility indicating a slight pro-depressive effect. Thus, chronic buspirone treatment of females exposed to the long-lasting psychoemotional impact has a different effect on their behaviour depending on the dose and test conditions. [PubMed Citation] [Order full text from Infotrieve]

20) Fedotova IuO
[Effects of 5-HT1 and 5-HT2 serotonin receptors on anxiety- and depression-like behavior in female rats].
Eksp Klin Farmakol. 2011;74(3):6-9.
The influence of the chronic (14-day) administration of 5-HT1A receptor agonist 8-OH-DPAT (0.05 mg/kg, s.c.) and 5-HT2B/2C receptor agonist m-CPP (0.5 mg/kg, i.p.) on the anxiety- and depression-like behavior has been studied in adult female rats during key phases of the ovarian cycle. The chronic administration of m-CPP at the estrous phase produced an anxiolytic effect, while at the proestrous phase, the same drug produced an anxiogenic effect. At the same time, both 8-OH-DPAT and m-CPP exhibited pronounced antidepressant effect irrespective of the ovarian cycle phase. [PubMed Citation] [Order full text from Infotrieve]