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) Nalivaiko E, Sgoifo A
Central 5-HT receptors in cardiovascular control during stress.
Neurosci Biobehav Rev. 2008 Jun 5;
Our aim is to consolidate recent data on relationship between central serotonergic neurotransmission and stress-elicited cardiovascular changes. Activation of central of 5-HT1A receptors attenuates tachycardic and pressor changes elicited by a wide range of stressors (airjet, restraint, open field, fear conditioning, social defeat), supporting the previous view of these receptors as "sympathoinhibitory". Their likely location is the medullary raphe. It is still unknown whether 5-TH1A receptors are sympathoinhibitory in physiological condition, as 5-HT1A antagonists do not affect basal or stress-altered cardiovascular parameters. In contrast to the established view that central 5-HT2A receptors are "sympathoexcitatory", experiments with new selective antagonists indicate that these receptors do not mediate stress-induced pressor and tachycardic responses, and are not involved in cardiovascular control at rest. The exception is control of cutaneous vascular bed, both at rest and during stress, likely at the spinal level. 5-HT3 receptors located in the nucleus tractus silitarius (NTS) contribute to stress-induced suppression of the baroreflex. 5-HT3 receptors located in sympathetic ganglia possibly contribute to the development of sustained hypertension in chronically stressed rats. [PubMed Citation] [Order full text from Infotrieve]

2) Szewczyk B, Albert PR, Burns AM, Czesak M, Overholser JC, Jurjus GJ, Meltzer HY, Konick LC, Dieter L, Herbst N, May W, Rajkowska G, Stockmeier CA, Austin MC
Gender-specific decrease in NUDR and 5-HT1A receptor proteins in the prefrontal cortex of subjects with major depressive disorder.
Int J Neuropsychopharmacol. 2008 Jun 19;:1-14.
A variety of studies have documented alterations in 5-HT1A receptor binding sites in the brain of subjects with major depressive disorder (MDD). The recently identified transcription factor, nuclear deformed epidermal autoregulatory factor (NUDR/Deaf-1) has been shown to function as a transcriptional modulator of the human 5-HT1A receptor gene. The present study was undertaken to document the regional and cellular localization of NUDR in the human prefrontal cortex and to examine the levels of NUDR and 5-HT1A receptor protein in prefrontal cortex of female and male depressed and control subjects. NUDR immunoreactivity was present in neurons and glia across cortical layers and was co-localized with 5-HT1A receptor immunoreactive neurons. NUDR immunoreactivity as measured by Western blot was significantly decreased in the prefrontal cortex of female depressed subjects (42%, p=0.02) and unchanged in male depressed subjects relative to gender-matched control subjects. Similarly, 5-HT1A receptor protein level was significantly reduced in the prefrontal cortex of female depressed subjects (46%, p=0.03) and unchanged in male depressed subjects compared to gender-matched control subjects. Reduced protein expression of NUDR in the prefrontal cortex of female subjects with MDD may reflect a functional alteration in this transcription factor, which may contribute to the decrease in 5-HT1A receptors observed in the same female subjects with MDD. In addition, the gender-specific alterations in cortical NUDR and 5-HT1A receptor proteins could represent an underlying biological mechanism associated with the higher incidence of depression in women. [PubMed Citation] [Order full text from Infotrieve]

3) Desbr�e A, Verdurand M, Godart J, Dubois A, Mastrippolito R, Pain F, Pinot L, Delzescaux T, Gurden H, Zimmer L, Lani�ce P
The Potential of a Radiosensitive Intracerebral Probe to Monitor 18F-MPPF Binding in Mouse Hippocampus In Vivo.
J Nucl Med. 2008 Jun 13;
As mouse imaging has become more challenging in preclinical research, efforts have been made to develop dedicated PET systems. Although these systems are currently used for the study of physiopathologic murine models, they present some drawbacks for brain studies, including a low temporal resolution that limits the pharmacokinetic study of radiotracers. The aim of this study was to demonstrate the ability of a radiosensitive intracerebral probe to measure the binding of a radiotracer in the mouse brain in vivo. METHODS: The potential of a probe 0.25 mm in diameter for pharmacokinetic studies was assessed. First, Monte Carlo simulations followed by experimental studies were used to evaluate the detection volume and sensitivity of the probe and its adequacy for the size of loci in the mouse brain. Second, ex vivo autoradiography of 5-hydroxytryptamine receptor 1A (5-HT1A) receptors in the mouse brain was performed with the PET radiotracer 2'-methoxyphenyl-(N-2'-pyridinyl)-p- (18)F-fluorobenzamidoethylpiperazine ((18)F-MPPF). Finally, the binding kinetics of (18)F-MPPF were measured in vivo in both the hippocampus and the cerebellum of mice. RESULTS: Both the simulations and the experimental studies demonstrated the feasibility of using small probes to measure radioactive concentrations in specific regions of the mouse brain. Ex vivo autoradiography showed a heterogeneous distribution of (18)F-MPPF consistent with the known distribution of 5-HT1A in the mouse brain. Finally, the time-activity curves obtained in vivo were reproducible and validated the capacity of the new probe to accurately measure (18)F-MPPF kinetics in the mouse hippocampus. CONCLUSION: Our results demonstrate the ability of the tested radiosensitive intracerebral probe to monitor binding of PET radiotracers in anesthetized mice in vivo, with high temporal resolution suited for compartmental modeling. [PubMed Citation] [Order full text from Infotrieve]

4) Rav-Acha M, Bergman H, Yarom Y
PRE AND POST SYNAPTIC SEROTONINERGIC EXCITATION OF GLOBUS PALLIDUS NEURONS.
J Neurophysiol. 2008 Jun 11;
The basal ganglia (BG) play a critical role in the pathogenesis and pathophysiology of Parkinson's disease (PD). Recent studies indicate that serotoninergic systems modulate BG activity, and may be implicated in the pathophysiology and treatment of PD. The globus pallidus (GP), the rodent homologue of the primate GPe, is the main central nucleus of the basal ganglia, affecting the striatum, the subthalamic nucleus (STN) and BG output structures. We therefore studied the effect of serotonin (5-HT) and specific 5-HT agonist and antagonist on GP neurons from rat brain slices. Using intra and extra-cellular recording of GP neurons we found that serotonin increases the firing rate of GP neurons. Analyzing the effects of specific 5-HT agonist and antagonist on the firing rate of GP neurons showed that the increase in firing rate is due to the activation of 5-HT1B and 5-HT1A receptors. Intracellular recordings in voltage and current clamp mode revealed that serotonin mediates its effect via pre and post synaptic mechanisms. The pre synaptic effect is mediated by attenuation of GABA release, probably through activation of 5-HT1B receptors. Post synaptically, serotonin activates the I-h current, probably via 5-HT1A receptors. Furthermore, serotonin decreases the fast synaptic depression characteristic of the striatal afferent input. The decreased serotonin concentrations in the BG nuclei in PD may contribute to depressed GP activity and enhance the emergence of BG pathological synchronous oscillations. We therefore suggest that future therapeutics of PD should be directed towards restoration of normal serotonin levels in BG nuclei. [PubMed Citation] [Order full text from Infotrieve]

5) Dupre KB, Eskow KL, Steiniger A, Klioueva A, Negron GE, Lormand L, Park JY, Bishop C
Effects of coincident 5-HT(1A) receptor stimulation and NMDA receptor antagonism on L: -DOPA-induced dyskinesia and rotational behaviors in the hemi-parkinsonian rat.
Psychopharmacology (Berl). 2008 Jun 11;
RATIONALE: Serotonin 1A receptor (5-HT1AR) agonists reduce L: -DOPA-induced dyskinesia and enhance motor function in experimental and clinical investigations of Parkinson's disease (PD). While the mechanism(s) by which these effects occur are unclear, recent research suggests that modulation of glutamate neurotransmission contributes. OBJECTIVE: To further delineate the relationship between 5-HT(1A) receptors and glutamate, the current study examined the effects of the 5-HT(1A)R agonist, +/-8-OH-DPAT and the N-methyl-D: -aspartic acid receptor (NMDAR) antagonist, MK-801, on L: -DOPA-induced motor behavior. MATERIALS AND METHODS: Unilateral 6-hydroxydopamine lesioned male Sprague-Dawley rats were rendered dyskinetic with 1 week of daily L: -DOPA (12 mg/kg, i.p.) + benserazide (15 mg/kg, i.p.). On test days, one group of rats received pretreatments of: +/-8-OH-DPAT (0, 0.03, 0.1, 0.3 mg/kg, i.p.) or MK-801 (0, 0.03, 0.1, 0.3 mg/kg, i.p.). A second group was administered combined +/-8-OH-DPAT (0, 0.03 or 0.1 mg/kg, i.p.) + MK-801 (0, 0.1 mg/kg, i.p.). Pretreatments were followed by L: -DOPA administration, after which, abnormal involuntary movements (AIMs) and rotations were monitored. To investigate effects on motor performance, subthreshold doses of +/-8-OH-DPAT (0.03 mg/kg, i.p.) + MK-801 (0.1 mg/kg, i.p.) were administered to L: -DOPA-na�ve hemiparkinsonian rats before the forepaw adjusting steps test. RESULTS: Individually, both +/-8-OH-DPAT and MK-801 dose-dependently decreased L: -DOPA-induced AIMs without affecting rotations. Combined subthreshold doses of +/-8-OH-DPAT+MK-801 reduced L: -DOPA-induced AIMs and potently enhanced contralateral rotations without altering L: -DOPA-induced motor improvements. CONCLUSIONS: The current results indicate a functional interaction between 5-HT(1A)R and NMDAR that may improve pharmacological treatment of PD patients. [PubMed Citation] [Order full text from Infotrieve]

6) Rusyniak DE, Ootsuka Y, Blessing WW
When administered to rats in a cold environment, 3,4-methylenedioxymethamphetamine reduces brown adipose tissue thermogenesis and increases tail blood flow: Effects of pretreatment with 5-HT(1A) and dopamine D(2) antagonists.
Neuroscience. 2008 May 2;
When given in a warm environment MDMA (3,4-methylenedioxymethamphetamine, ecstasy) causes hyperthermia by increasing interscapular brown adipose tissue (iBAT) heat production and decreasing heat loss via cutaneous vasoconstriction. When given in a cold environment, however, MDMA causes hypothermia by an unknown mechanism. This paper addresses these mechanisms and in addition examines whether antagonists at 5-HT(1A) and D(2) receptors reduce the hypothermic action of MDMA. Male Sprague-Dawley rats instrumented with a Doppler probe for measuring tail blood flow, and probes for measuring core and iBAT temperatures, were placed in a temperature-controlled chamber. The chamber temperature was reduced to 10 degrees C and vehicle (0.5 ml Ringer), the 5-HT(1A) antagonist WAY 100635 (0.5 mg/kg), the D(2) antagonist spiperone (20 mug/kg), or the combination of Way 100635 and spiperone were injected s.c. Thirty minutes later the antagonists were injected again along with MDMA (10 mg/kg) or vehicle. MDMA reduced core body temperature by preventing cold-elicited iBAT thermogenesis and by transiently reversing cold-elicited cutaneous vasoconstriction. Pretreatment with WAY 100635 prevented MDMA induced increases in tail blood flow, and briefly attenuated MDMA's effects on iBAT and core temperature. While spiperone alone failed to affect any of the parameters, the combination of spiperone and WAY 100635 decreased MDMA-mediated hypothermia by attenuating both the effects on tail blood flow and iBAT thermogenesis. MDMA's prevention of cold-induced iBAT thermogenesis appears to have a central origin as it rapidly reverses cold-induced increases in iBAT sympathetic nerve discharge in anesthetized rats. Our results demonstrate that MDMA in a cold environment reduces core body temperature by inhibiting iBAT thermogenesis and tail artery vasoconstriction and suggest that mechanisms by which this occurs include the activation of 5-HT1A and dopamine D2 receptors. [PubMed Citation] [Order full text from Infotrieve]

7) Ago Y, Nakamura S, Arikawa S, Yata M, Matsuda T
[Involvement of prefrontal serotonergic neurons in methamphetamine-induced behavioral sensitization]
Nihon Shinkei Seishin Yakurigaku Zasshi. 2008 Apr;28(2):85-91.
Repeated administration of psychostimulants in rodents can enhance the stimulating effect on locomotor activity, a phenomenon called behavioral sensitization. This has been widely used as animal models for schizophrenia as well as addiction and psychosis, because of the similarity to its process in acquisition and progression. However, there are no studies demonstrating whether the drugs improve the psychostimulant-induced behavioral sensitization when administered after establishment of the sensitization, while previous studies have mainly focused on the analyses of the development (induction) phase of the sensitization. We demonstrated that the activation of serotonin (5-HT) receptors or blockade of 5-HT2 receptors, given after establishment of the sensitization, attenuates the expression of methamphetamine-induced behavioral sensitization in mice. In addition, we also showed that repeated administration of methamphetamine induces the increased reactivity of prefrontal serotonergic neurons specifically. These observations suggest that the 5-HT system is a neurochemical basis for the behavioral sensitization, and imply that 5-HT1A and 5-HT2 receptors may have potential therapeutic values in the remission of methamphetamine abuse or psychosis. Here, we provide an overview of the roles of serotonergic neurons in the psychostimulant-induced behavioral sensitization. [PubMed Citation] [Order full text from Infotrieve]

8) Martinotti G, Di Nicola M, Di Giannantonio M, Janiri L
Aripiprazole in the treatment of patients with alcohol dependence: a double-blind, comparison trial vs. Naltrexone.
J Psychopharmacol. 2008 May 30;
Abstract Substantial evidence suggests that both partial dopamine agents and mixed 5-HT1A/2A receptor drugs independently show significant efficacy in reducing alcohol use in both animals and humans. Aripiprazole, which acts as a dopamine/5-HT system stabilizer, approaches the optimal characteristics sought in medication to be considered for testing in the treatment of alcohol dependence. In this randomised, double-blind, confrontation trial with naltrexone, we aimed to investigate the efficacy of aripiprazole on alcohol-drinking indices. Craving and psychiatric symptom improvements were the secondary end points. Seventy-five alcohol dependent subjects were detoxified and were subsequently randomised into two groups, receiving 50 mg of naltrexone and 5-15 mg of aripiprazole, respectively. Craving (Visual Analogue Scale; Obsessive and Compulsive Drinking Scale) and withdrawal (Clinical Institute Withdrawal Assessment) rating scales were applied; psychiatric symptoms were evaluated through the Symptom Check List 90-Revised. The number of subjects remained alcohol free for the entire study period (16 weeks) and the number of subjects relapsed were not significantly different in the two groups. The survival function showed that patients treated with aripiprazole remained abstinent from any alcohol amount for a longer time with respect to those treated with naltrexone. As for craving scores, patients treated with naltrexone showed a better outcome. Results from this study globally place aripiprazole at the same range of efficacy of naltrexone, one of the approved drugs used in alcohol relapse prevention. If it could be demonstrated in placebo-controlled trials that aripiprazole is efficacious in decreasing alcohol use, lessening craving, and attenuating psychopathological symptom severity, we will have gained a powerful agent for the treatment of alcohol-dependent subjects. [PubMed Citation] [Order full text from Infotrieve]

9) Dahan L, Husum H, Mnie-Filali O, Arnt J, Hertel P, Haddjeri N
Effects of bifeprunox and aripiprazole on rat serotonin and dopamine neuronal activity and anxiolytic behaviour.
J Psychopharmacol. 2008 May 30;
Abstract The atypical antipsychotic bifeprunox is a partial dopamine D2 and 5-HT1A receptor agonist. Using in-vivo electrophysiological and behavioural paradigms in the rat, the effects of bifeprunox and aripiprazole were assessed on ventral tegmental area (VTA) dopamine and dorsal raphe serotonin (5-HT) cell activity and on foot shock-induced ultrasonic vocalisation (USV). In VTA, bifeprunox and aripiprazole decreased (by 20-50%) firing of dopamine neurons. Interestingly, bursting activity was markedly reduced (by 70-100%), bursting being associated with a larger synaptic dopamine release than single spike firing. Both ligands reduced inhibition of firing rate induced by the full dopamine receptor agonist apomorphine, whereas the D2 receptor antagonist haloperidol prevented these inhibitory effects, confirming partial D2-like agonistic properties. On 5-HT neurons, bifeprunox was more potent than aripiprazole to suppress firing activity. The 5-HT1A receptor antagonist WAY-100,635 prevented their effects. In the USV test of anxiolytic-like activity, bifeprunox had higher potency than aripiprazole to reduce vocalisations. Both WAY-100,635 and haloperidol reversed the effects of both agonists. The present in-vivo study shows that bifeprunox is a potent partial D2-like and 5-HT1A receptor agonist reducing preferentially the phasic activity of dopamine neurons. Thus, bifeprunox would be expected to be an effective compound against positive and negative symptoms of schizophrenia. [PubMed Citation] [Order full text from Infotrieve]

10) Shields J, King JA
The role of 5-HT1A receptors in the behavioral responses associated with innate fear.
Behav Neurosci. 2008 Jun;122(3):611-7.
Fear is a response induced by threatening stimuli and represents an important adaptive system. The serotonin (5-HT) system has been shown to be involved in the modulation of fear responses and anxiety disorders. In preclinical studies, it has been demonstrated that R (+)-8-hydroxy-dipropylaminotetralin (8-OHDPAT), a 5-HT1A agonist, has anxiolytic properties. However, 8-OHDPATs potential role in unconditioned fear has yet to be elucidated. The current study was designed to investigate the effects of 8-OHDPAT on behavioral and HPA axis function in response to an innate fear-inducing stimulus. Pretreatment with 8-OHDPAT resulted in a significant decrease in freezing grooming, and climbing and caused a significant increase in approach after exposure to an extract from fox feces, 2,5-dihyrdo-2,4,5-trimethylthiazoline (TMT), an unconditioned fear-inducing stimulus. Furthermore, 8-OHDPAT pretreatment also resulted in a significant decrease in blood corticosterone levels, a marker of HPA activation. Taken together, these results suggest an additional anxyolitic-like effect of 8-OHDPAT in innate fear paradigms. [PubMed Citation] [Order full text from Infotrieve]

11) Lapointe NP, Ung RV, Rouleau P, Guertin PA
Tail pinching-induced hindlimb movements are suppressed by clonidine in spinal cord injured mice.
Behav Neurosci. 2008 Jun;122(3):576-88.
Experiments in completely spinal cord transected (Tx) cats have provided compelling evidence that clonidine combined with tail stimulation can promote locomotor function recovery. However, clonidine has generally failed to induce locomotor activity in other comparable animal models suggesting the existence of species- or condition-specific effects. This study aimed at investigating the effects of clonidine administered (0.25 or 5.0 mg/kg, i.p.) in mice during tail pinching in early (6-7 days post-Tx) or late (41-42 days post-Tx) paraplegic animals (Th9/10 level). Comparisons were made with the effects induced by 8-OH-DPAT (1.0 mg/kg, i.p.), a 5-HT1A/7 receptor agonist known to display prolocomotor effects. Clonidine with or without tail pinching failed to induce hind limb movements and even suppressed the frequency of spontaneously occurring nonlocomotor (NLM) and locomotor-like movements (LM) whereas tail pinching alone (prior to clonidine administration) increased the frequency of spontaneous movements specifically in late chronic animals. In turn, 8-OH-DPAT clearly induced hind limb movements that remained relatively unchanged during tail pinching. Altogether, the results suggest that the prolocomotor effects of clonidine reported elsewhere must depend upon stimuli or factors that remain to be identified. [PubMed Citation] [Order full text from Infotrieve]

12) Yamauchi M, Dostal J, Kimura H, Strohl KP
Effects of Buspirone on Post-hypoxic Ventilatory Behavior in the C57BL/6J and A/J Mouse Strains.
J Appl Physiol. 2008 May 29;
Buspirone, a partial agonist of the 5-HT1A receptor, improves breathing irregularities in humans with Rett syndrome or brainstem injury. The purpose was to examine whether buspirone alters post-hypoxic ventilatory behavior in C57BL/6J (B6) and A/J mouse strains. Measurements of ventilatory behavior were collected from unanaesthetized adult male mice (n = 6 for each strain) using the plethysmographic method. Mice were given intraperitoneal injections of vehicle or several doses of buspirone and exposed to 2-min of hypoxia (10% O2) followed by rapid reoxygenation (100% O2). Twenty-minutes later, mice were tested for hypercapnic response (8% CO2, 92% O2). On a separate day, mice were injected with the 5-HT1A receptor antagonist, p-MPPI, before the injection of buspirone, and measurements were repeated. In separate studies, arterial blood gas analysis was performed for each strain (n = 12 in B6 and 10 in A/J) with buspirone or vehicle. In both strains, buspirone stimulated ventilation at rest. In the B6 mice, the hypoxic response was unchanged, but the response to hypercapnia was reduced with buspirone (5 mg/kg; p<0.05). With reoxygenation, vehicle-treated B6 exhibited periodic breathing and greater variation in ventilation compared to A/J (p<0.01). In B6 animals, 3 mg/kg or more of buspirone reduced variation and prevented the occurrence of post-hypoxic periodic breathing. Both effects were reversed by p-MPPI. Treatment effect of buspirone was not explained by a difference in resting arterial blood gases. We conclude that buspirone improves post-hypoxic ventilatory irregularities in the B6 mouse through its agonist effects on the 5-HT1A receptor. Key words: ventilation, periodic breathing, 5-HT1A receptor , apnea. [PubMed Citation] [Order full text from Infotrieve]

13) Jacobsen KX, Vanderluit JL, Slack RS, Albert PR
HES1 regulates 5-HT1A receptor gene transcription at a functional polymorphism: Essential role in developmental expression.
Mol Cell Neurosci. 2008 Apr 1;
Mammalian HES1 and HES5 are abundant in developing CNS and inhibit neurogenesis, while HES6 promotes neurogenesis. An early serotonergic differentiation marker, the 5-HT1A receptor, is repressed by HES5 and DEAF1 which recognize the C(-1019), but not G(-1019) allele of a human 5-HT1A promoter polymorphism associated with mood disorders. We tested whether HES1 and HES6 regulate transcriptional activity at this element. HES1 strongly repressed 5-HT1A transcription in neuronal and non-neuronal cells, while HES6 reversed HES1- and HES5-mediated repression. Mutation of a putative HES consensus site blocked HES1 and HES5, but, unlike HES5, HES1 repressed at the G(-1019) allele. To address its role in vivo, the temporal expression of 5-HT1A receptor RNA and protein was examined in HES1-/- mice, and elevated levels in E12.5 hindbrain and midbrain were observed. Thus, HES1 and HES6 oppositely regulate 5-HT1A receptor transcription and HES1 is required for its correct developmental expression. [PubMed Citation] [Order full text from Infotrieve]

14) Ben-Daniel R, Deuther-Conrad W, Scheunemann M, Steinbach J, Brust P, Mishani E
Carbon-11 labeled indolylpropylamine analog as a new potential PET agent for imaging of the serotonin transporter.
Bioorg Med Chem. 2008 Jun 15;16(12):6364-70.
The synthesis and structure-activity relationship of a new class of indole derivatives with low-nanomolar affinity for the SERT and high selectivity versus the 5-HT1A receptor were recently reported. Based on their chemical structure, four new indolylpropylamine derivatives which contain atoms to afford future labeling with PET isotopes, were synthesized and evaluated as SERT ligands. The chemistry of these novel derivatives, their biological evaluation, the general method of preparing the precursor indole for labeling, and the C-11 labeling of the most promising indole derivative, are described herein. [PubMed Citation] [Order full text from Infotrieve]

15) Kato M, Fukuda T, Wakeno M, Okugawa G, Takekita Y, Watanabe S, Yamashita M, Hosoi Y, Azuma J, Kinoshita T, Serretti A
Effect of 5-HT1A gene polymorphisms on antidepressant response in major depressive disorder.
Am J Med Genet B Neuropsychiatr Genet. 2008 May 15;
Variability in antidepressant response is due to genetic and environmental factors. Among genetic factors, the ones controlling for availability of the drug at the target site are interesting candidates. Rs6295C/G SNP in the 5-HT1A gene (HTR1A) has been found to affect the expression and function of HTR1A. In fact rs6295C/G is in strong linkage disequilibrium with other polymorphisms of HTR1A suggesting that those functional effects could be associated with polymorphisms other than or together with the synonymous rs6295C/G. In the present study we examined the possible association of a panel of markers in strong linkage disequilibrium of the HTR1A with SSRI/SNRI response in 137 Japanese major depression subjects followed for 6 weeks. We observed a significant association of better response to antidepressant in rs10042486C/C (P < 0.0001), rs6295G/G (P < 0.0001) and rs1364043T/T (P = 0.018) genotype carriers (minor allele homozygotes), independently from clinical variables. Furthermore minor allele homozygous carriers in all these three SNPs were associated with treatment response by various assessment such as HAM-D score change over time (P = 0.001), week 2 (P < 0.0001), 4 (P = 0.007), and 6 (P = 0.048) as well as response rate (P = 0.0005) and remission rate (P = 0.004). We also pointed out the genotyping mis-definition of rs6295C/G in the previous four articles. In conclusion, this is the first study that reports a significant association of antidepressant response with rs10042486C/T and rs1364043T/G variants of HTR1A and also with rs10042486-rs6295-rs1364043 combination. This finding adds an important information for the pathway of detecting the genetics of antidepressant response even if results must be verified on larger samples. (c) 2008 Wiley-Liss, Inc. [PubMed Citation] [Order full text from Infotrieve]

16) Dias BG, Crews D
Regulation of Pseudosexual Behavior in the Parthenogenetic Whiptail Lizard, Cnemidophorus uniparens.
Endocrinology. 2008 May 15;
Neuroendocrine mechanisms underlying complementary behaviors like male-typical mounting and female-typical receptivity are most often studied independently in males and females, respectively. Cnemidophorus uniparens is a unisexual lizard species consisting only of females that alternately express male- and female-like pseudosexual behavior across the ovarian cycle. Intact, postovulatory (PostOv) and ovariectomized, androgen-implanted animals (OVX+T) exhibit male-like mounting but not receptivity, while intact, preovulatory (PreOv) and ovariectomized lizards injected with estradiol (OVX+E) express receptivity, but not mounting. We tested whether the serotonergic system in the preoptic area (POA) and ventromedial nucleus of the hypothalamus (VMN) gates the reciprocal inhibition characterizing this alternating expression of mounting and receptivity. Serotonergic signaling at the POA appears to be key to gating male-like behavior: PostOv and OVX+T animals have lower intracellular serotonin (5-HT) levels, and greater abundance of inhibitory 5-HT1A receptor mRNA in the POA compared to both PreOv and OVX+E lizards. Moreover, injecting serotonin into the POA of OVX+T animals suppresses mounting, while injection into VMN of OVX+E lizards suppresses receptivity. Although 5-HT levels in the VMN do not differ across the ovarian cycle or between hormonally-manipulated animals, PreOv and OVX+E lizards have lower abundance of 5-HT2A mRNA in the VMN. Stimulating 5-HT1A receptors using systemic drug administration inhibits mounting, while activating 5-HT2A receptors facilitates receptivity. This study illuminates how male- and female-typical sexual behaviors share common neural circuits, and that serotonin regulates these naturally complementary, and mutually exclusive, behaviors. [Free Full Text] [PubMed Citation] [Order full text from Infotrieve]

17) Lapointe NP, Guertin PA
Synergistic effects of D1/5 and 5-HT1A/7 receptor agonists on locomotor movement induction in complete spinal cord-transected mice.
J Neurophysiol. 2008 May 28;
Monoamines are well known to modulate locomotion in several vertebrate species. Co-application of DA and 5-HT has also been shown to potently induce fictive locomotor rhythms in isolated spinal cord preparations. However, a synergistic contribution of these monoamines to locomotor rhythmogenesis in vivo has never been examined. Here, we characterized the effects induced by selective DA and 5-HT receptor agonists on hindlimb movement induction in completely spinal cord-transected (adult) mice. Administration of the lowest effective doses of SKF-81297 (D1/5 agonist, 1-2 mg/kg, i.p.) or 8-OH-DPAT (5-HT1A/7 agonist, 0.5 mg/kg, i.p.) acutely elicited some locomotor-like movements (5.85 +/- 1.22 and 3.67 +/- 1.44 LM per min, respectively). Co-administration of the same doses of SKF-81297 and 8-OH-DPAT led to a significant increase (seven- to ten-fold) of LM (37.70 +/- 5.01 LM/min). Weight-bearing and plantar foot placement capabilities were also found with the combination treatment only (i.e., with no assistance or other forms of stimulation). These results clearly show that D1/5 and 5-HT1A/7 receptor agonists can synergistically activate spinal locomotor networks and, hence, generate powerful basic stepping movements in complete paraplegic animals. While previous work from this laboratory has reported the partial rhythmogenic potential of monoamines in vivo, the present study shows that drug combinations such as SKF-81297 and 8-OH-DPAT can elicit weight-bearing stepping. [PubMed Citation] [Order full text from Infotrieve]

18) Munn RG, McNaughton N
Effects of fluoxetine on hippocampal rhythmic slow activity and behavioural inhibition.
Behav Pharmacol. 2008 May;19(3):257-64.
Anxiolytics that act as GABAA agonists and those that act as 5-HT1A receptor agonists all reduce the frequency of hippocampal rhythmic slow activity (RSA). Changes in RSA have been linked to changes in behavioural inhibition and therefore anxiety - but this has not been tested with specific serotonin reuptake inhibitors, which are antidepressant and anxiolytic; therefore we tested the effects of fluoxetine on RSA and behavioural inhibition. Fluoxetine (FLU; 10 and 20 mg/kg, intraperitoneally) produced a dose-related reduction in the frequency of reticular-elicited RSA. Groups of rats received, intraperitoneally, either (i) saline, or 5 mg/kg fluoxetine, or 10 mg/kg fluoxetine; or (ii) saline, or 20 mg/kg fluoxetine, or 6.6 mg/kg of the 5-HT1A agonist buspirone (BUS) and were tested on a fixed interval 60-s schedule and a differential reinforcement of low rates 15-s schedule. FLU at 5 mg/kg produced effects similar to low doses of BUS and other anxiolytics. FLU (10 and 20 mg/kg) produced effects more like those reported earlier for higher doses of BUS. These results continue to link anxiolysis, RSA and behavioural inhibition, and suggest that serotonergic anxiolytics share some of the central actions of GABAergic anxiolytics, but at higher doses, administered acutely, have distinct side effects that can obscure their anxiolytic action in behavioural tasks. [PubMed Citation] [Order full text from Infotrieve]

19) Farrell MS, Gilmore K, Raffa RB, Walker EA
Behavioral characterization of serotonergic activation in the flatworm Planaria.
Behav Pharmacol. 2008 May;19(3):177-82.
Serotonin (5-hydroxytryptamine, 5-HT) receptors have been identified in Planaria, a model used for studying the pharmacology of behavioral phenomena. This study characterized the behavioral and locomotor effects of 5-HT, a 5-HT1A agonist, a 5-HT1B/2C agonist, and a 5-HT1A antagonist to examine the role of 5-HT receptor activation in this species. Planarians were video recorded individually in a clear plastic cube containing drug solution or vehicle. To quantify locomotor velocity (pLMV), planarians were placed individually into a dish containing drug solution or vehicle and the rate of gridline crossings was recorded. For the antagonist experiments, four conditions were studied: water alone, agonist alone, antagonist alone, and agonist plus antagonist. The decrease in pLMV induced by the5-HT1A agonist (8-OH-DPAT), and the 5-HT1B/2C agonist (mCPP), was antagonized by pretreatment with the 5-HT1A antagonist (WAY-100635) at a dose that had no effect of its own on pLMV. At a higher concentration of WAY-100635, further decreases in pLMV induced by 8-OH-DPAT were observed. Each agonist produced increased occurrences of 'C-like position' and 'screw-like hyperkinesia', 5-HT and mCPP produced 'writhing', and only mCPP produced a significant increase in duration of 'headswing' behavior. The results demonstrate that the 5-HT1A receptor identified in Planaria mediates behavioral responses to 5-HT receptor ligands, supporting the notion that planarians possess functional 5-HT receptors and might serve as a simple model for their study. [PubMed Citation] [Order full text from Infotrieve]

20) Zhou JS, Li LJ, Cao X, Zhang XH, Li WH, Li ZX
[Effect of 5-HT and postsynaptic 5-HT1A on the mood and recogniztion of the repeated restraint stress in rats.]
Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2008 Apr;33(4):305-11.
Objective To explore the role of 5-HT and postsynaptic 5-HT1A receptors in the stress adaptation.Methods p-PCA was used to deplete the 5-HT in rats. The 5-HT1A agonist 8-OH-DPAT and antagonist WAY100635 were used to determine the effect of postsynaptic 5-HT1A receptors on the ratso behaviors in the Elevated Plus-Maze test, the Forced Swimming test, and the Morris Water Maze test. Results Compared with the intact rats, the 5-HT depleted rats showed more seriously anxious behaviors in the Elevated Plus-Maze test and more obvious learned helplessness in the Forced Swimming test. After having been stressed the 5-HT depleted rats showed significantly impaired learning and memory compared with the intact rats according to Morris Water Maze test. Activation of postsynaptic 5-HT1A receptors by 8-OH-DPAT in the 5-HT depleted rats or the 5-HT depleted stress rats significantly decreased the symptoms of anxiety and learned helplessness behaviors which were prevented by the treatment of WAY100635. The 8-OH-DPAT and WAY100635 had no obvious effect on the 5-HT depletion or 5-HT depleted stress rats in the Morris Water Maze test. Conclusion Deficiency of 5-HT in rats may suppress its ability to stress adaptation. Activation of post-synaptic 5-HT1A receptors can attenuate the anxiety and depressive behavior symptoms, and facilitate rats to adapt stress. [PubMed Citation] [Order full text from Infotrieve]