serotonin 5-HT1A receptors


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(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."

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, 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]

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]

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]

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
"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) Khan P, Maloney PR, Hedrick M, Gosalia P, Milewski M, Li L, Roth GP, Sergienko E, Suyama E, Sugarman E, Nguyen K, Mehta A, Vasile S, Su Y, Shi S, Stonich D, Nguyen H, Zeng FY, Novo AM, Vicchiarelli M, Diwan J, Chung TDY, Pinkerton AB, Smith LH, da Silva Lopes L, Marques RB, Fernandes HB, da Silva Pereira S, Ayres MC, Chaves MH, Almeida FR
Mechanisms of the antinociceptive action of (-) Epicatechin obtained from the hydroalcoholic fraction of Combretum leprosum Mart & Eic in rodents.
J Biomed Sci. 2010;19(1):68.
The recently discovered apelin receptor (APJ, AGTRL-1, APLNR) system has emerged as a critical mediator of cardiovascular homeostasis involved in the pathogenesis of hypertension, heart failure, atherosclerosis and other cardiovascular diseases. Herein is presented the discovery and characterization the first non-peptide based potent (3.7 ?M) small molecule APJ functional agonist in cell-based assays, that is >21 fold selective over the closely related angiotensin 1 (AT1) receptor, derived from a high throughput screen (HTS) of the ~330,600 compound Molecular Libraries Small Molecule Repository (MLSMR) collection. This agonist showed some binding activity against 4 out of 37 other GPCRs and transporters, including the 5-HT1A, ?2C adrenergic, and benzylpiperazine receptors (55%I, 51%I and 65%I at 10 ?M, respectively) and the norepinephrine transporter (57%I at 10 ?M). The synthetic methodology, development of structure-activity relationships (SAR), and initial in vitro pharmacologic characterization are also presented. This probe molecule provides a useful tool compound for investigators interested in understanding apelin receptor pharmacology and function. [PubMed Citation] [Order full text from Infotrieve]

2) Bergman J, Roof RA, Furman CA, Conroy JL, Mello NK, Sibley DR, Skolnick P
Modification of cocaine self-administration by buspirone (buspar®): potential involvement of D3 and D4 dopamine receptors.
Int J Neuropsychopharmacol. 2012 Jul 25;:1-14.
Converging lines of evidence indicate that elevations in synaptic dopamine levels play a pivotal role in the reinforcing effects of cocaine, which are associated with its abuse liability. This evidence has led to the exploration of dopamine receptor blockers as pharmacotherapy for cocaine addiction. While neither D1 nor D2 receptor antagonists have proven effective, medications acting at two other potential targets, D3 and D4 receptors, have yet to be explored for this indication in the clinic. Buspirone, a 5-HT1A partial agonist approved for the treatment of anxiety, has been reported to also bind with high affinity to D3 and D4 receptors. In view of this biochemical profile, the present research was conducted to examine both the functional effects of buspirone on these receptors and, in non-human primates, its ability to modify the reinforcing effects of i.v. cocaine in a behaviourally selective manner. Radioligand binding studies confirmed that buspirone binds with high affinity to recombinant human D3 and D4 receptors (~98 and ~29 nm respectively). Live cell functional assays also revealed that buspirone, and its metabolites, function as antagonists at both D3 and D4 receptors. In behavioural studies, doses of buspirone that had inconsistent effects on food-maintained responding (0.1 or 0.3 mg/kg i.m.) produced a marked downward shift in the dose-effect function for cocaine-maintained behaviour, reflecting substantial decreases in self-administration of one or more unit doses of i.v. cocaine in each subject. These results support the further evaluation of buspirone as a candidate medication for the management of cocaine addiction. [PubMed Citation] [Order full text from Infotrieve]

3) Descarries L, Riad M
Effects of the antidepressant fluoxetine on the subcellular localization of 5-HT1A receptors and SERT.
Philos Trans R Soc Lond B Biol Sci. 2012 Jul 25;367(1601):2416-25.
Serotonin (5-HT) 5-HT(1A) autoreceptors (5-HT(1A)autoR) and the plasmalemmal 5-HT transporter (SERT) are key elements in the regulation of central 5-HT function and its responsiveness to antidepressant drugs. Previous immuno-electron microscopic studies in rats have demonstrated an internalization of 5-HT(1A)autoR upon acute administration of the selective agonist 8-OH-DPAT or the selective serotonin reuptake inhibitor antidepressant fluoxetine. Interestingly, it was subsequently shown in cats as well as in humans that this internalization is detectable by positron emission tomography (PET) imaging with the 5-HT(1A) radioligand [(18)F]MPPF. Further immunocytochemical studies also revealed that, after chronic fluoxetine treatment, the 5-HT(1A)autoR, although present in normal density on the plasma membrane of 5-HT cell bodies and dendrites, do not internalize when challenged with 8-OH-DPAT. Resensitization requires several weeks after discontinuation of the chronic fluoxetine treatment. In contrast, the SERT internalizes in both the cell bodies and axon terminals of 5-HT neurons after chronic but not acute fluoxetine treatment. Moreover, the total amount of SERT immunoreactivity is then reduced, suggesting that SERT is not only internalized, but also degraded in the course of the treatment. Ongoing and future investigations prompted by these finding are briefly outlined by way of conclusion. [PubMed Citation] [Order full text from Infotrieve]

4) Albert PR
Transcriptional regulation of the 5-HT1A receptor: implications for mental illness.
Philos Trans R Soc Lond B Biol Sci. 2012 Sep 5;367(1601):2402-15.
The serotonin-1A (5-HT(1A)) receptor is an abundant post-synaptic 5-HT receptor (heteroreceptor) implicated in regulation of mood, emotion and stress responses and is the major somatodendritic autoreceptor that negatively regulates 5-HT neuronal activity. Based on animal models, an integrated model for opposing roles of pre- and post-synaptic 5-HT(1A) receptors in anxiety and depression phenotypes and response to antidepressants is proposed. Understanding differential transcriptional regulation of pre- versus post-synaptic 5-HT(1A) receptors could provide better tools for their selective regulation. This review examines the transcription factors that regulate brain region-specific basal and stress-induced expression of the 5-HT(1A) receptor gene (Htr1a). A functional polymorphism, rs6295 in the Htr1a promoter region, blocks the function of specific repressors Hes1, Hes5 and Deaf1, resulting in increased 5-HT(1A) autoreceptor expression in animal models and humans. Its association with altered 5-HT(1A) expression, depression, anxiety and antidepressant response are related to genotype frequency in different populations, sample homogeneity, disease outcome measures and severity. Preliminary evidence from gene × environment studies suggests the potential for synergistic interaction of stress-mediated repression of 5-HT(1A) heteroreceptors, and rs6295-induced upregulation of 5-HT(1A) autoreceptors. Targeted therapeutics to inhibit 5-HT(1A) autoreceptor expression and induce 5-HT(1A) heteroreceptor expression may ameliorate treatment of anxiety and major depression. [PubMed Citation] [Order full text from Infotrieve]

5) Costa L, Spatuzza M, D'Antoni S, Bonaccorso CM, Trovato C, Musumeci SA, Leopoldo M, Lacivita E, Catania MV, Ciranna L
Activation of 5-HT7 Serotonin Receptors Reverses Metabotropic Glutamate Receptor-Mediated Synaptic Plasticity in Wild-Type and Fmr1 Knockout Mice, a Model of Fragile X Syndrome.
Biol Psychiatry. 2012 Sep 5;
BACKGROUND: Fragile X syndrome (FXS) is a genetic cause of intellectual disability and autism. Fmr1 knockout (Fmr1 KO) mice, an animal model of FXS, exhibit spatial memory impairment and synapse malfunctioning in the hippocampus, with abnormal enhancement of long-term depression mediated by metabotropic glutamate receptors (mGluR-LTD). The neurotransmitter serotonin (5-HT) modulates hippocampal-dependent learning through serotonin 1A (5-HT1A) and serotonin 7 (5-HT7) receptors; the underlying mechanisms are unknown. METHODS: We used electrophysiology to test the effects of 5-HT on mGluR-LTD in wild-type and Fmr1 KO mice and immunocytochemistry and biotinylation assay to study related changes of 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)propanoic acid (AMPA) glutamate receptor surface expression. RESULTS: Application of 5-HT or 8-OH-DPAT (a mixed 5-HT1A/5-HT7 agonist) reversed mGluR-LTD in hippocampal slices. Reversal of mGluR-LTD by 8-OH-DPAT persisted in the presence of the 5-HT1A receptor antagonist WAY-100635, was abolished by SB-269970 (5-HT7 receptor antagonist), and was mimicked by LP-211, a novel selective 5-HT7 receptor agonist. Consistently, 8-OH-DPAT decreased mGluR-mediated reduction of AMPA glutamate receptor 2 (GluR2) subunit surface expression in hippocampal slices and cultured hippocampal neurons, an effect mimicked by LP-211 and blocked by SB-269970. In Fmr1 KO mice, mGluR-LTD was abnormally enhanced; similarly to wild-type, 8-OH-DPAT reversed mGluR-LTD and decreased mGluR-induced reduction of surface AMPA receptors, an effect antagonized by SB-269970. CONCLUSIONS: Serotonin 7 receptor activation reverses metabotropic glutamate receptor-induced AMPA receptor internalization and LTD both in wild-type and in Fmr1 KO mice, correcting excessive mGluR-LTD. Therefore, selective activation of 5-HT7 receptors may represent a novel strategy in the therapy of FXS. [PubMed Citation] [Order full text from Infotrieve]

6) Tack J, Janssen P, Masaoka T, Farré R, Van Oudenhove L
Efficacy Of Buspirone, A Fundus-Relaxing Drug, In Patients With Functional Dyspepsia.
Clin Gastroenterol Hepatol. 2012 Jul 17;
BACKGROUND & AIMS: Impaired accommodation and hypersensitivity to gastric distention are believed to be involved in the development of functional dyspepsia (FD). Buspirone, a 5-HT1A receptor agonist, relaxes the proximal stomach in healthy individuals. We studied the effects of buspirone on symptoms and mechanisms of FD. METHODS: We performed a randomized, double-blind, placebo-controlled, crossover study of 17 patients (13 women, mean age 38.5±2.4 years). The study included 2 treatment periods of 4 weeks each, separated by a 2-week wash-out period. In the first period, 7 participants were given buspirone (10 mg, 3 times daily for 4 weeks) and 10 were given placebo, 15 minutes before meals; patients switched groups for the second period. We assessed meal-related symptoms and severity, along with gastric sensitivity, accommodation, and emptying (using barostat and breath tests) before and after 4 weeks of treatment. RESULTS: Buspirone significantly reduced the overall severity of symptoms of dyspepsia (7.5±1.3 vs 11.5±1.2 for placebo, P<.005) and individual symptoms of postprandial fullness, early satiation, and upper abdominal bloating, whereas placebo had no significant effect (all P<.05). Buspirone did not alter the rate of gastric emptying of solids or sensitivity to gastric distention, but significantly increased gastric accommodation, compared with placebo (229±28 vs 141±32 ml, respectively; P<.05) and delayed gastric emptying of liquids (t1/2= 64±5 vs 119±24 min, respectively). Adverse events were similar when patients were given buspirone or placebo. CONCLUSION: In patients with FD, 4 weeks administration of buspirone significantly improved symptoms and gastric accommodation, compared with placebo, whereas gastric emptying of liquids was delayed. [PubMed Citation] [Order full text from Infotrieve]

7) Uchiumi O, Kasahara Y, Fukui A, Hall FS, Uhl GR, Sora I
Serotonergic involvement in the amelioration of behavioral abnormalities in dopamine transporter knockout mice by nicotine.
Neuropharmacology. 2012 Jul 16;
Dopamine transporter knockout (DAT KO) mice exhibit elevated extracellular dopamine levels in brain regions that include the striatum and the nucleus accumbens, but not the prefrontal cortex. DAT KO mice model some aspects of psychiatric disorders, including schizophrenia. Smoking is more common in patients with schizophrenia, suggesting that nicotine might ameliorate aspects of the behavioral abnormalities and/or treatment side effects seen in these individuals. We report nicotine-induced normalization of effects on locomotion and prepulse inhibition of acoustic startle (PPI) in DAT KO mice that require intact serotonin 5-HT1A systems. First, we observed that the marked hyperactivity displayed by DAT KO mice was reduced by administration of nicotine. This nicotine effect was blocked by pretreatment with the non-specific nicotinic acetylcholine (nACh) receptor antagonist mecamylamine, or the 5-HT1A antagonist WAY100635. Secondly, we examined the effects of nicotine on PPI in DAT KO mice. Treatment with nicotine significantly ameliorated the PPI deficits observed in DAT KO mice. The ameliorating action of nicotine on PPI deficits in DAT KO mice was blocked by mecamylamine, the ?(7) nACh receptor antagonist methyllycaconitine or WAY100635, while the ?(4)?(2) nACh receptor antagonist dihydro-?-erythroidinehydrobromide (DH?E) produced only a non-significant trend toward attenuation of nicotine effects. Finally, we observed that administration of the 5-HT1A receptor agonist 8-OH-DPAT also ameliorated the deficit in PPI observed in DAT KO mice. This amelioration was antagonized by pretreatment with WAY100635. These data support the idea that nicotine might ameliorate some of the cognitive dysfunctions found in schizophrenia in a 5-HT1A-dependent fashion. This article is part of a Special Issue entitled 'Cognitive Enhancers'. [PubMed Citation] [Order full text from Infotrieve]

8) Lacivita E, Di Pilato P, De Giorgio P, Colabufo NA, Berardi F, Perrone R, Leopoldo M
The therapeutic potential of 5-HT1A receptors: a patent review.
Expert Opin Ther Pat. 2012 Jul 15;22(8):887-902.
Introduction: The 5-HT(1A) receptors are implicated in mood disorders (anxiety, depression), in cognition, and in modulation of pain. Nearly 30 years of research in this field, there is still interest in developing new chemical entities capable of 5-HT(1A) receptor activation or blockade. Areas covered: This review article will highlight and review the research advances published in the patent literature between January 2007 and December 2011, giving emphasis to the medicinal chemist's standpoint. Literature search methodology included search in Scifinder and PubMed Databases and browsing website. Expert opinion: Almost no new therapeutic applications have been proposed for molecules targeting the 5-HT(1A) receptor, during the years covered by the present review. The discovery that stimulation of 5-HT(1A) receptor can promote neurogenesis will likely renew the interest for selective 5-HT(1A) receptor agonists as therapeutics to replace neural populations damaged by disease or injury. [PubMed Citation] [Order full text from Infotrieve]

9) Sankar R, Mazarati A, Manta S, El Mansari M, Debonnel G, Blier P
Electrophysiological and neurochemical effects of long-term vagus nerve stimulation on the rat monoaminergic systems.
Int J Neuropsychopharmacol. 2012 Aug;:1-12.
Depression represents one of the most disabling comorbidities of epilepsy and impacts profoundly negatively on the quality of life of patients with epilepsy. Some of the clinical features of depression in patients with epilepsy suggest a neurobiological connection, although it is difficult to eliminate psychosocial and iatrogenic factors in human studies. Basic research in animal models has involved the study of depression in a model of absence epilepsy as well as models of limbic epilepsy. In this chapter we focus on studies on animal models with emphasis on discernible mechanistic connections between epilepsy and depression. Depression-like behaviors of despair (immobility in the forced swim test) and anhedonia (loss of preference for sweetened water) have been described in the generalized spike-wave epilepsy model involving the WAG/Rij strain of rats as well as models of limbic epilepsy. The rapid-kindling model of epileptogenesis is not accompanied by discernible injury to the hippocampus or other structures. The lithium-pilocarpine model of status epilepticus (SE)-induced temporal lobe epilepsy displays hippocampal and extra-hippocampal injury and plasticity associated with human temporal lobe epilepsy. Both models produced despair, anhedonia, and alterations in the raphe-hippocampal serotonergic pathways. Pharmacologic studies on the post-SE animals revealed enhanced interleukin-1? signaling in the hippocampus and augmentation of ?gain? in the hypothalamus-pituitary-adrenal axis. Chronic infusion of recombinant interleukin receptor antagonist into the hippocampus, as well as infusion of a selective glucocorticoid receptor antagonist or selective 5-HT1A blocker into the raphe restored evoked serotonin release and behavior. These studies furnish a model system to serve as a screening platform for developing therapies to manage the comorbidity between epilepsy and depression. [PubMed Citation] [Order full text from Infotrieve]

10) Ikram H, Choudhry AM, Haleem DJ
Regional neurochemical profile following development of apomorphine-induced reinforcement.
Pak J Pharm Sci. 2012;25(3):513-9.
Dopamine is primary neurotransmitter which mediates the reinforcing effects of abused drugs, serotonin (5-Hydroxytryptamine; 5-HT) also has a crucial role in the pathophysiology of addiction. The binding sites of various drugs of abuse are different from each other, their final rewarding effects are mediated by an increase in the dopamine level in the Nucleus Accumbens. The present study used conditioned place preference (CPP) test to monitor apomorphine's reinforcing effects. Associated alterations in 5-HT and dopamine metabolism were also monitored in various brain regions by HPLC-EC. Withdrawal from apomorphine administration (at a dose of 1.0 mg/kg on six alternate days) induced reinforcement as monitored in the conditioned place preference (CPP) paradigm. Serotonin and dopamine metabolism was also changed particularly in the ventral and dorsal striatum. Results therefore suggest desensitization of dopamine receptors in the presynaptic site is involved in apomorphine-induced reinforcement. Desensitization of somatodendritic 5-HT(1A) receptors resulting in increased availability of 5-HT at 5-HT(2C) receptors could attenuate apomorphine-induced reinforcement. Therefore, further investigations in this area should focus on attempts to attenuate apomorphine-induced reinforcement by desensitizing somatodendritic 5-HT(1A) receptors. [PubMed Citation] [Order full text from Infotrieve]

11) Neufeld-Cohen A, Kelly PA, Paul ED, Carter RN, Skinner E, Olverman HJ, Vaughan JM, Issler O, Kuperman Y, Lowry CA, Vale WW, Seckl JR, Chen A, Jamieson PM
Chronic Activation of Corticotropin-Releasing Factor Type 2 Receptors Reveals a Key Role for 5-HT1A Receptor Responsiveness in Mediating Behavioral and Serotonergic Responses to Stressful Challenge.
Biol Psychiatry. 2012 Apr 17;
BACKGROUND: The corticotropin-releasing factor type 2 receptor (CRFR2) is suggested to play an important role in aiding recovery from acute stress, but any chronic effects of CRFR2 activation are unknown. CRFR2 in the midbrain raphé nuclei modulate serotonergic activity of this key source of serotonin (5-HT) forebrain innervation. METHODS: Transgenic mice overexpressing the highly specific CRFR2 ligand urocortin 3 (UCN3OE) were analyzed for stress-related behaviors and hypothalamic-pituitary-adrenal axis responses. Responses to 5-HT receptor agonist challenge were assessed by local cerebral glucose utilization, while 5-HT and 5-hydroxyindoleacetic acid content were quantified in limbic brain regions. RESULTS: Mice overexpressing urocortin 3 exhibited increased stress-related behaviors under basal conditions and impaired retention of spatial memory compared with control mice. Following acute stress, unlike control mice, they exhibited no further increase in these stress-related behaviors and showed an attenuated adrenocorticotropic hormone response. 5-HT and 5-hydroxyindoleacetic acid content of limbic nuclei were differentially regulated by stress in UCN3OE mice as compared with control mice. Responses to 5-HT type 1A receptor challenge were significantly and specifically reduced in UCN3OE mice. The distribution pattern of local cerebral glucose utilization and 5-HT type 1A receptor messenger RNA expression levels suggested this effect was mediated in the raphé nuclei. CONCLUSIONS: Chronic activation of CRFR2 promotes an anxiety-like state, yet with attenuated behavioral and hypothalamic-pituitary-adrenal axis responses to stress. This is reminiscent of stress-related atypical psychiatric syndromes such as posttraumatic stress disorder, chronic fatigue, and chronic pain states. This new understanding indicates CRFR2 antagonism as a potential novel therapeutic target for such disorders. [PubMed Citation] [Order full text from Infotrieve]

12) Al'perina EL, Zhukova EN, Iur'ev DV, Idova GV
[Effect of activation of serotonin 5-HT1A-receptors on the immune response in mice of the ASC strain with depressive-like behavior].
Zh Vyssh Nerv Deiat Im I P Pavlova. 2012 Jul;62(2):243-9.
Selective activation of serotonin 5-HT(1A)-receptors produced different effects on immunological reactivity in mice of ASC strain with genetic predisposition to depressive-like behavior, and parental CBA and AKR strains displaying no depressive reactions. Administration of 5-HT(1A)-receptors agonist 8-OH-DPAT at low dose (0.1 mg/kg) affecting upon presynaptic receptors resulted in immunostimulation in CBA mice and did not change the immune response level in mice of ASC strain. Activation of postsynaptic 5-HT(1A)-receptors with higher dose of 8-OH-DPAT (1.0 mg/kg) caused immunosuppression in CBA and AKR strains while under the same conditions the immune response of ASC mice was increased. Decrease the immune reactions in ASC mice was observed only after application of 8-OHDPAT at dose of 5 mg/kg. The changes of functional activity of pre- and postsynaptic 5-HT(1A)-receptors under a high predisposition to depressive-like behavior providing different effects of this receptor activation on immune function are discussed. [PubMed Citation] [Order full text from Infotrieve]

13) Gorinski N, Kowalsman N, Renner U, Wirth A, Reinartz MT, Seifert R, Zeug A, Ponimaskin E, Niv M
Computational and Experimental Analysis of the TM4/TM5 Dimerization Interface of the Serotonin 5-HT1A Receptor.
Mol Pharmacol. 2012 Jun 13;
Experimental evidence suggests that most members of class A G-protein coupled receptors (GPCRs) can form homomers and heteromers, in addition to functioning as single monomers. In particular, serotonin receptors were shown to homodimerize and heterodimerize with other GPCRs, although the physiological role of the oligomerization has not yet been fully elucidated. Here we used computational modeling of the 5-HT(1A) receptor monomer and dimer to predict residues important for dimerization. Based on these results we carried out rationally designed site-directed mutagenesis. The ability of the mutants to dimerize was evaluated using different FRET-based approaches. The reduced levels of acceptor photobleaching-FRET, and the lower number of monomers participating in oligomers, as assessed by lux-FRET, confirmed the decreased ability of the mutants to dimerize and the involvement of the predicted contacts (namely, W175(4.64), Y198(5.41), R151(4.40) and R152(4.41)) at the interface. This information was reintroduced as constraints for computational protein-protein docking, to obtain a high-quality dimer model. Analysis of the refined model as well as molecular dynamics simulations of wild-type (WT) and mutant dimers revealed compensating interactions in dimer composed of WT and W175A mutant. This provides an explanation for the requirement of mutations of W175(4.64) in both homomers for disrupting dimerization. Our iterative computational-experimental study demonstrates that transmembrane domains TM4/TM5 can form an interaction interface in 5-HT(1A) receptor dimers and indicates that specific amino acid interactions maintain this interface. The mutants and the optimized model of the dimer structure may be used in functional studies of serotonin dimers. [PubMed Citation] [Order full text from Infotrieve]

14) Obniska J, Chlebek I, Kamiński K, Bojarski AJ, Satała G
Synthesis, anticonvulsant activity and 5-HT1A/5-HT7 receptors affinity of 1-[(4-arylpiperazin-1-yl)-propyl]-succinimides.
Pharmacol Rep. 2012 Mar-Apr;64(2):326-35.
[PubMed Citation] [Order full text from Infotrieve]

15) Nonogaki K
Serotonin conflict in sleep-feeding.
Vitam Horm. 2012 Jun 5;89:223-39.
Short sleep duration has been suggested to be a risk factor for weight gain and adiposity. Serotonin (5-HT) substantially contributes to the regulation of sleep and feeding behavior. Although 5-HT predominately promotes waking and satiety, the effects of 5-HT depend on 5-HT receptor function. The 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2C, 5-HT6, and 5-HT7 receptors reportedly contribute to sleep-waking regulation, whereas the 5-HT1B and 5-HT2C receptors contribute to the regulation of satiety. The 5-HT1B and 2C receptors may therefore be involved in the regulation of sleep-feeding. In genetic studies, 5-HT1B receptor mutant mice display greater amounts of rapid eye movement sleep (REMS) than wild-type mice, while displaying no effects on waking or slow wave sleep (SWS). On the other hand, 5-HT2C receptor mutant mice exhibit increased wakefulness and decreased SWS, without any effect on REMS. Moreover, the 5-HT2C receptor mutants display leptin-independent hyperphagia, leading to a middle-aged onset of obesity, whereas 5-HT1B receptor mutants do not display any effect on food intake. Thus, the genetic deletion of 5-HT2C receptors results in sleep loss-associated hyperphagia, leading to the late onset of obesity. This is a quite different pattern of sleep-feeding behavior than is observed in disturbed leptin signaling, which displays an increase in sleep-associated hyperphagia. In pharmacologic studies, 5-HT1B and 5-HT2C receptors upregulate wakefulness and downregulate SWS, REMS, and food intake. These findings suggest that 5-HT1B/2C receptor stimulation induces sleep loss-associated anorexia. Thus, the central 5-HT regulation of sleep-feeding can be dissociated. Functional hypothalamic proopiomelanocortin and orexin activities may contribute to the dissociated 5-HT regulation. [PubMed Citation] [Order full text from Infotrieve]

16) Peleg-Raibstein D, Luca E, Wolfrum C
Maternal high-fat diet in mice programs emotional behavior in adulthood.
Behav Brain Res. 2012;233(2):398-404.
The maternal environment has a significant role in the normal development of the fetus and may have long-term impact on brain development including critical central pathways such as the gamma-aminobutyric acid (GABA), serotonergic and the neurotrophin systems. For example, maternal malnutrition plays an important role in programming many aspects of physiology and behavior including predisposition to mental-health related disorders such as anxiety. Here we investigated the effects of maternal high-fat diet or control diet for nine weeks (prior to gestation, gestation and lactation) on the adult offspring with respect to anxiety related behaviors as well as exploration and conditioned fear response. We found that offspring born to high-fat diet mothers showed increased anxiety-like behaviors, but intact conditioned fear response and exploratory behavior. In addition, brain-derived neurotrophic factor (BDNF) was significantly increased in the dorsal hippocampus, while GABA(A) alpha2 receptor subunit and 5-hydroxytryptamine 1A (5-HT1A) receptor showed increased levels in the ventral hippocampus. In summary, these findings suggest that maternal high-fat diet consumption during critical periods in the development of the fetus, might increase the risk of abnormal behaviors in adulthood related to anxiety. [PubMed Citation] [Order full text from Infotrieve]

17) Zhang Y, Zhang RX, Zhang M, Shen XY, Li A, Xin J, Ren K, Berman BM, Tan M, Lao L
Electroacupuncture inhibition of hyperalgesia in an inflammatory pain rat model: involvement of distinct spinal serotonin and norepinephrine receptor subtypes.
Br J Anaesth. 2012;109(2):245-52.
[PubMed Citation] [Order full text from Infotrieve]

18) Bortolozzi A, Castañé A, Semakova J, Santana N, Alvarado G, Cortés R, Ferrés-Coy A, Fernández G, Carmona MC, Toth M, Perales JC, Montefeltro A, Artigas F
New antidepressant strategy based on acute siRNA silencing of 5-HT1A autoreceptors.
Mol Psychiatry. 2012 Aug 1;17(6):567.
[PubMed Citation] [Order full text from Infotrieve]