serotonin 5-HT1B / 5-HT1D receptors


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(Updated 3rd or 4th quarter 2002)

Clark MS, Neumaier JF.
The 5-HT1B receptor: behavioral implications.
Psychopharmacol Bull 2001 Autumn;35(4):170-85
"5-HT1B receptors are expressed throughout the mammalian central nervous system. These receptors are located in the axon terminals of both serotonergic and nonserotonergic neurons, where they act as inhibitory autoreceptos or heteroreceptors, respectively. 5-HT1B receptors inhibit the release of a range of neurotransmitters, including serotonin, GABA, acetylcholine, and glutamate. These receptors have been difficult to study because of the diversity of their cellular localization and the absence of highly selective agonists and antagonists. There has been accumulating evidence, however, that 5-HT1B receptors modulate drug reinforcement, stress sensitivity, mood, anxiety, and aggression. The general results of a number of studies suggest that reduced 5-HT1B heteroreceptor activity may increase impulsive behaviors, whereas reduced 5-HT1B autoreceptor activity may have an antidepressant-like effect. This review focuses on the evidence from animal studies and human genetics that suggest that 5-HT1B receptors may be involved in the mechanism of action of antidepressants and may become important targets of drug therapy in the future." [Abstract]

Ferrari MD, Goadsby PJ, Roon KI, Lipton RB.
Triptans (serotonin, 5-HT1B/1D agonists) in migraine: detailed results and methods of a meta-analysis of 53 trials.
Cephalalgia 2002 Oct;22(8):633-58
"The triptans, selective serotonin 5-HT1B/1D agonists, are very effective acute migraine drugs. Soon, seven different triptans will be clinically available at 13 different oral doses, making evidence-based selection guidelines necessary. Triptan trials have similar designs, facilitating meta-analysis. We wished to provide an evidence-based foundation for using triptans in clinical practice, and to review the methodological issues surrounding triptan trials. We asked pharmaceutical companies and the principal investigators of company-independent trials for the 'raw patient data' of all double-blind, randomized, controlled, clinical trials with oral triptans in migraine. All data were cross-checked with published or presented data. We calculated summary estimates across studies for important efficacy and tolerability parameters, and compared these with those from direct, head-to-head, comparator trials. Out of 76 eligible clinical trials, 53 (12 not yet published) involving 24089 patients met the criteria for inclusion. Mean results (and 95% confidence intervals) for sumatriptan 100 mg, the first available and most widely prescribed oral triptan, are 59% (57-60) for 2 h headache response (improvement from moderate or severe to mild or no pain); 29% (27-30) for 2 h pain free (improvement to no pain); 20% (18-21) for sustained pain free (pain free by 2 h and no headache recurrence or use of rescue medication 2-24 h post-dose), and 67% (63-70) for consistency (response in at least two out of three treated attacks); placebo-subtracted proportions for patients with at least one adverse event (AE) are 13% (8-18), for at least one central nervous system AE 6% (3-9), and for at least one chest AE 1.9% (1.0-2.7). Compared with these data: rizatriptan 10 mg shows better efficacy and consistency, and similar tolerability; eletriptan 80 mg shows better efficacy, similar consistency, but lower tolerability; almotriptan 12.5 mg shows similar efficacy at 2 h but better sustained pain-free response, consistency, and tolerability; sumatriptan 25 mg, naratriptan 2.5 mg and eletriptan 20 mg show lower efficacy and better tolerability; zolmitriptan 2.5 mg and 5 mg, eletriptan 40 mg, and rizatriptan 5 mg show very similar results. The results of the 22 trials that directly compared triptans show the same overall pattern. We received no data on frovatriptan, but publicly available data suggest substantially lower efficacy. The major methodological issues involve the choice of the primary endpoint, consistency over multiple attacks, how to evaluate headache recurrence, use of placebo-subtracted proportions to control for across-study differences, and the difference between tolerability and safety. In addition, there are a number of methodological issues specific for direct comparator trials, including encapsulation and patient selection. At marketed doses, all oral triptans are effective and well tolerated. Differences among them are in general relatively small, but clinically relevant for individual patients. Rizatriptan 10 mg, eletriptan 80 mg and almotriptan 12.5 mg provide the highest likelihood of consistent success. Sumatriptan features the longest clinical experience and the widest range of formulations. All triptans are contra-indicated in the presence of cardiovascular disease." [Abstract]

Tepper SJ, Rapoport AM, Sheftell FD.
Mechanisms of action of the 5-HT1B/1D receptor agonists.
Arch Neurol 2002 Jul;59(7):1084-8
"Recent studies of the pathophysiology of migraine provide evidence that the headache phase is associated with multiple physiologic actions. These actions include the release of vasoactive neuropeptides by the trigeminovascular system, vasodilation of intracranial extracerebral vessels, and increased nociceptive neurotransmission within the central trigeminocervical complex. The 5-HT(1B/1D) receptor agonists, collectively known as triptans, are a major advance in the treatment of migraine. The beneficial effects of the triptans in patients with migraine are related to their multiple mechanisms of action at sites implicated in the pathophysiology of migraine. These mechanisms are mediated by 5-HT(1B/1D) receptors and include vasoconstriction of painfully dilated cerebral blood vessels, inhibition of the release of vasoactive neuropeptides by trigeminal nerves, and inhibition of nociceptive neurotransmission. The high affinity of the triptans for 5-HT(1B/1D) receptors and their favorable pharmacologic properties contribute to the beneficial effects of these drugs, including rapid onset of action, effective relief of headache and associated symptoms, and low incidence of adverse effects." [Abstract]

de Almeida RM, Miczek KA.
Aggression escalated by social instigation or by discontinuation of reinforcement ("frustration") in mice: inhibition by anpirtoline: a 5-HT1B receptor agonist.
Neuropsychopharmacology 2002 Aug;27(2):171-81
"Experiments with social instigation or the omission of scheduled reinforcement show that serotonergic mechanisms may be involved in escalated aggression in animals. 5-HT1B receptor agonists have anti-aggressive effects in individuals who show moderate as well as high levels of aggression. The present study compared the effects of the 5-HT1B agonist anpirtoline (0.125-1.5 mg/kg) on (1) species-typical aggressive behavior in male mice, (2) aggression "instigated" or primed by prior exposure to the opponent, and (3) aggression heightened by "frustration" caused by omission of scheduled reinforcement. The effects of anpirtoline on species-typical behavior were also assessed after pretreatment with the 5-HT1B/1D receptor antagonist GR127935 (10 mg/kg). Anpirtoline, like other 5-HT1B agonists (CP-94,253, zolmitriptan), decreased both instigated and frustration-heightened aggression, while motor behavior was unaffected. The aggression-inhibiting effects of anpirtoline were blocked by pretreatment with GR127935. The current results indicate that the 5-HT(1B) receptor is critically involved in the modulation of escalated aggression." [Abstract]

Gardier AM, Trillat AC, Malagie I, David D, Hascoet M, Colombel MC, Jolliet P, Jacquot C, Hen R, Bourin M.
[5-HT1B serotonin receptors and antidepressant effects of selective serotonin reuptake inhibitors ]
C R Acad Sci III 2001 May;324(5):433-41
"Furthermore, we demonstrate that SSRIs decrease immobility in the forced swimming test; this effect is absent in 5-HT1B knockout mice and blocked by GR 127935 in wild-type suggesting therefore that activation of 5-HT1B receptors mediate the antidepressant-like effects of SSRIs. Taken together these data demonstrate that 5-HT1B autoreceptors appear to limit the effects of SSRI on dialysate 5-HT levels particularly in the hippocampus while presynaptic 5-HT1B heteroreceptors are likely to be required for the antidepressant activity of SSRIs." [Abstract]

Mendez, Jorge, Kadia, Tapan M., Somayazula, Ravi K., El-Badawi, Khaled I., Cowen, Daniel S.
Differential Coupling of Serotonin 5-HT1A and 5-HT1B Receptors to Activation of ERK2 and Inhibition of Adenylyl Cyclase in Transfected CHO Cells.
J Neurochem 1999 73: 162-168
"In summary, there are accumulating data demonstrating that Gi-coupled receptors are not identical but exhibit functional differences." [Abstract]

Carr, David B., Cooper, Donald C., Ulrich, Sasha L., Spruston, Nelson, Surmeier, D. James
Serotonin Receptor Activation Inhibits Sodium Current and Dendritic Excitability in Prefrontal Cortex via a Protein Kinase C-Dependent Mechanism
J. Neurosci. 2002 22: 6846-6855
"Although 5-HT2a,c receptor activation did not affect somatic action potentials of layer V pyramidal neurons in PFC slices, it did reduce the amplitude of action potentials backpropagating into the apical dendrite. These findings show that 5-HT2a,c receptor activation reduces dendritic excitability and may negatively modulate activity-dependent dendritic synaptic plasticity."

Laurent, Alban, Goaillard, Jean-Marc, Cases, Olivier, Lebrand, Cecile, Gaspar, Patricia, Ropert, Nicole
Activity-Dependent Presynaptic Effect of Serotonin 1B Receptors on the Somatosensory Thalamocortical Transmission in Neonatal Mice
J. Neurosci. 2002 22: 886-900 [Abstract]

Berg, KA, Maayani, S, Clarke, WP
5-hydroxytryptamine2C receptor activation inhibits 5- hydroxytryptamine1B-like receptor function via arachidonic acid metabolism
Mol Pharmacol 1996 50: 1017-1023
"Activation of 5-HT2C receptors with 5-HT or (+/-)-1-(2,5-dimethoxy-4- iodophenyl)-2-aminopropane increased release of arachidonic acid via a phospholipase A2 (PLA2)-dependent mechanism."

Hsu, Eugenia H., Lochan, Anthony C., Cowen, Daniel S.
Activation of Akt1 by Human 5-Hydroxytryptamine (Serotonin)1B Receptors Is Sensitive to Inhibitors of MEK
J Pharmacol Exp Ther 2001 298: 825-832 [Full Text]

Hain, Heather S., Belknap, John K., Mogil, Jeffrey S.
Pharmacogenetic Evidence for the Involvement of 5-Hydroxytryptamine (Serotonin)-1B Receptors in the Mediation of Morphine Antinociceptive Sensitivity
J Pharmacol Exp Ther 1999 291: 444-449 [Full text]

Jeffrey S. Mogil
The genetic mediation of individual differences in sensitivity to pain and its inhibition
PNAS 96: 7744-7751, July 6, 1999. [Full Text]

Crabbe, John C., Manzoni, Olivier J., Morikawa, Hitoshi, Williams, John T.
Regulation of central synaptic transmission by 5-HT1B auto- and heteroreceptors.
MOLECULAR PHARMACOLOGY , 58(6):1271-1278 2000
"In the ventral midbrain, 5-HT1B receptor-dependent inhibition of gamma-aminobutyric acidB IPSPs in dopamine neurons was present in wild-type animals and absent in knockout animals. Similar results were obtained in the nucleus accumbens measuring glutamate-mediated excitatory postsynaptic currents in medium spiny neurons." [Full Text]

Muramatsu M, Lapiz MD, Tanaka E, Grenhoff J.

Serotonin inhibits synaptic glutamate currents in rat nucleus accumbens neurons via presynaptic 5-HT1B receptors.
Eur J Neurosci 1998 Jul;10(7):2371-9 [Abstract]

Jolimay, Nicolas, Franck, Louis, Langlois, Xavier, Hamon, Michel, Darmon, Michele
Dominant Role of the Cytosolic C-Terminal Domain of the Rat 5-HT1B Receptor in Axonal-Apical Targeting
J. Neurosci. 2000 20: 9111-9118
"Therefore, the short tail of the 5-HT1BR presents an apical targeting signal that can also act as an axonal targeting signal. In addition, a domain within the third intracytoplasmic loop of the 5-HT1BR, responsible for its Golgi sequestration in LLC-PK1 cells, appeared to act as another axonal targeting signal in hippocampal neurons."
[Full Text]

Garabette, M. L., Martin, K. F., Redfern, P. H.
Circadian variation in the activity of the 5-HT1B autoreceptor in the region of the suprachiasmatic nucleus, measured by microdialysis in the conscious freely-moving rat
Br. J. Pharmacol. 2000 131: 1569-1576 [Abstract]

Pickard, Gary E., Smith, Bret N., Belenky, Michael, Rea, Michael A., Dudek, F. Edward, Sollars, Patricia J.
5-HT1B Receptor-Mediated Presynaptic Inhibition of Retinal Input to the Suprachiasmatic Nucleus
J. Neurosci. 1999 19: 4034-4045 [Full Text]

Pickard, Gary E., Weber, E. Todd, Scott, Paul A., Riberdy, Anne F., Rea, Michael A.
5HT1B Receptor Agonists Inhibit Light-Induced Phase Shifts of Behavioral Circadian Rhythms and Expression of the Immediate-Early Gene c-fos in the Suprachiasmatic Nucleus
J. Neurosci. 1996 16: 8208-8220 [Full Text]

Rea, M. A.
Photic Entrainment of Circadian Rhythms in Rodents
"In addition, serotonin appears to regulate the response of the SCN circadian clock to light through postsynaptic 5-HT1A or 5-ht7 receptors, as well as presynaptic 5-HT1B heteroreceptors on RHT [retinohypothalamic tract] terminals."

Knobelman, Deborah A., Hen, Rene, Lucki, Irwin
Genetic Regulation of Extracellular Serotonin by 5-Hydroxytryptamine1A and 5-Hydroxytryptamine1B Autoreceptors in Different Brain Regions of the Mouse
J Pharmacol Exp Ther 2001 298: 1083-1091 [Full Text]

Knobelman, Deborah A., Hen, Rene, Blendy, Julie A., Lucki, Irwin
Regional Patterns of Compensation following Genetic Deletion of Either 5-Hydroxytryptamine1A or 5-Hydroxytryptamine1B Receptor in the Mouse
J Pharmacol Exp Ther 2001 298: 1092-1100
"Based on their altered response to microdialysis studies, we propose that striatal 5-HT1B receptors increase their sensitivity in 5-HT1A receptor knockout mice and MR [median raphe nucleus] 5-HT1A receptors are desensitized in 5-HT1B receptor knockout mice."
[Full Text]

R Jackisch, A Haaf, H Jeltsch, C Lazarus, C Kelche, J C Cassel
Modulation of 5-hydroxytryptamine release in hippocampal slices of rats: effects of fimbria-fornix lesions on 5-HT1B-autoreceptor and alpha2-heteroreceptor function
Brain Res Bull. 1999 Jan 1;48(1):49-59. [Abstract]

Daws, Lynette C., Gould, Georgianna G., Teicher, Susan D., Gerhardt, Greg A., Frazer, Alan
5-HT1B Receptor-Mediated Regulation of Serotonin Clearance in Rat Hippocampus In Vivo
J Neurochem 2000 75: 2113-2122
"Using high-speed chronoamperometry, we have demonstrated that local application of 5-HT1B antagonists into the CA3 region of the hippocampus prolongs the clearance of 5-HT from extracellular fluid (ECF). In the present study, we demonstrate that the 5-HT1B antagonist cyanopindolol does not produce this effect by increasing release of endogenous 5-HT or by directly binding to the 5-HTT. Dose-response studies showed that the potency of cyanopindolol to inhibit clearance of 5-HT was equivalent to that of the selective 5-HT reuptake inhibitor fluvoxamine. Local application of the 5-HT1A antagonist WAY 100635 did not alter 5-HT clearance, suggesting that the effect of cyanopindolol to prolong clearance is not via a mechanism involving 5-HT1A receptors. Finally, the effect of low doses of cyanopindolol and fluvoxamine to inhibit clearance of 5-HT from ECF was additive. These data are consistent with the hypothesis that activation of terminal 5-HT1B autoreceptors increases 5-HTT activity." [Abstract]

Daws LC, Gerhardt GA, Frazer A.
5-HT1B antagonists modulate clearance of extracellular serotonin in rat hippocampus.
Neurosci Lett. 1999 May 14;266(3):165-8.
"In vivo chronoamperometry was used to determine the effects of locally applied antagonists of the serotonin-1B (5-HT1B) receptor (cyanopindolol, 5-HT-moduline and methiothepin) on the clearance of 5-HT in the CA3 region of the dorsal hippocampus and the corpus callosum (a brain region devoid of serotonin transporters and 5-HT1B receptors) of the rat. When 5-HT was pressure ejected into these regions, reproducible signals were detected. In the CA3 region, local application of 5-HT1B antagonists decreased the rate of clearance of the serotonin signal comparably to the selective 5-HT uptake inhibitor (SSRI), fluvoxamine. By contrast, in the corpus callosum, none of the drugs altered the 5-HT signal. One interpretation of these data is that 5-HT1B receptors can modulate the activity of the 5-HT transporter." [Abstract]

Sayer, Tamsin J.O., Hannon, Serina D., Redfern, Peter H., Martin, Keith F.
Diurnal variation in 5-HT1B autoreceptor function in the anterior hypothalamus in vivo: effect of chronic antidepressant drug treatment
Br. J. Pharmacol. 1999 126: 1777-1784
"Following treatment with either paroxetine hydrochloride (10 mg kg-1 i.p.) or desipramine hydrochloride (10 mg kg-1 i.p.) for 21 days the function of the terminal 5-HT1B autoreceptor was more markedly attenuated at end-light." [Abstract]

Yan QS , Yan SE
Serotonin-1B receptor-mediated inhibition of [(3)H]GABA release from rat ventral tegmental area slices.
J Neurochem, 79(4): 914-22 2001 [Abstract]

Mayorga, Arthur J., Dalvi, Ashutosh, Page, Michelle E., Zimov-Levinson, Sarah, Hen, Rene, Lucki, Irwin
Antidepressant-Like Behavioral Effects in 5-Hydroxytryptamine1A and 5-Hydroxytryptamine1B Receptor Mutant Mice
J Pharmacol Exp Ther 2001 298: 1101-1107 [Full Text]

Trillat, AC, Malagie, I, Scearce, K, Pons, D, Anmella, MC, Jacquot, C, Hen, R, Gardier, AM
Regulation of serotonin release in the frontal cortex and ventral hippocampus of homozygous mice lacking 5-HT1B receptors: in vivo microdialysis studies.
J Neurochem 1997 69: 2019-2025
"These data provide in vivo evidence that, in mice, 5-HT1B, but not 5-HT1D, autoreceptors inhibit 5-HT release at nerve terminals located in the frontal cortex and ventral hippocampus."

Hermann H, Marsicano G, Lutz B.
Coexpression of the cannabinoid receptor type 1 with dopamine and serotonin receptors in distinct neuronal subpopulations of the adult mouse forebrain.
Neuroscience 2002;109(3):451-60
"The cannabinoid receptor type 1 (CB1) displays unusual properties, including the dual capacity to inhibit or stimulate adenylate cyclase and a brain density considerably higher than the majority of G protein-coupled receptors. Together with overlapping expression patterns of dopamine and serotonin receptors this suggests a potential of CB1 to modulate the function of the dopamine and serotonin system. Indeed, pharmacological studies provide evidence for cross-talks between CB1 and receptors of these neurotransmitter systems. In trying to obtain further insights into possible functional and/or structural interactions between CB1 and the dopamine receptors and the serotonin receptors, we performed double-label in situ hybridization at the cellular level on mouse forebrain sections by combining a digoxigenin-labelled riboprobe for CB1 with 35S-labelled riboprobes for dopamine receptors D1 and D2, and for serotonin receptors 5-HT1B and 5-HT3, respectively. As a general rule, we found that CB1 colocalizes with D1, D2 and 5-HT1B only in low-CB1-expressing cells which are principal projecting neurons, whereas CB1 coexpression with 5-HT3 was also observed in high-CB1-expressing cells which are considered to be mostly GABAergic. In striatum and olfactory tubercle, CB1 is coexpressed to a high extent with D1, D2 and 5-HT1B. Throughout the hippocampal formation, CB1 is coexpressed with D2, 5-HT1B and 5-HT3. In the neocortex, coexpression was detected only with 5-HT1B and 5-HT3. In summary a distinct pattern is emerging for the cannabinoid system with regard to its colocalization with dopamine and serotonin receptors and, therefore, it is likely that different mechanisms underlie its cross-talk with these neurotransmitter systems." [Abstract]

Massot, O, Rousselle, JC, Fillion, MP, Grimaldi, B, Cloez-Tayarani, I, Fugelli, A, Prudhomme, N, Seguin, L, Rousseau, B, Plantefol, M, Hen, R, Fillion, G
5-hydroxytryptamine-moduline, a new endogenous cerebral peptide, controls the serotonergic activity via its specific interaction with 5- hydroxytryptamine1B/1D receptors
Mol Pharmacol 1996 50: 752-762
"The interaction of 5-HT-moduline with the 5-HT1B/1D receptor corresponds to a decrease in the functional activity of the receptor (i.e., a decrease in the inhibitory effect of a 5-HT1B agonist on the evoked release of [3H]5-HT from synaptosomal preparation). It was also shown that 5-HT- moduline possess an in vivo effect in the social interaction test in mouse. Finally, it was demonstrated that 5-HT-moduline was released from brain synaptosomal preparation by a K+/Ca(2+)-dependent mechanism. In conclusion, 5-HT-moduline is a novel endogenous peptide regulating the serotonergic activity via a direct action at presynaptic 5-HT receptor. It may play an important role in the physiological mechanisms involving the serotonergic system, particularly in mechanisms corresponding to the elaboration of an appropriate response of the central nervous system to a given stimulus." [Abstract]

Grimaldi B , Fillion G
5-HT-moduline controls serotonergic activity: implication in neuroimmune reciprocal regulation mechanisms
Prog Neurobiol, 60(1): 1-12 2000
"In particular, the receptors located on immunocompetent cells control their activity and are themselves regulated by 5-HT-moduline likely originating from adrenal medulla and released after acute stress. The serotonergic system appears to play a major role in the reciprocal signalling existing between the neuronal and the immune system. The participation of 5-HT-moduline is likely in physiological functions as well as in pathological disorders affecting central and peripheral activities." [Abstract]

Maes M, Kenis G, Bosmans E.
Cytokine 2002 Nov;19(6):308-311
"BACKGROUND: Serotonin (5-HT) has negative immunoregulatory effects by reducing the interferon-gamma (IFNgamma)/interleukin-10 (IL-10) production ratio by stimulated immune cells. Leukocytes have functional 5-HT1B receptors. 5-HT moduline, an endogenous 5-HT1B receptor antagonist, may antagonize the 5-HT1B agonist-induced proliferation of immune cells. AIMS: To examine the effects of 5-HT moduline on the stimulated production of IFNgamma, tumor necrosis factor alpha (TNFalpha) and IL-10. RESULTS: 5-HT moduline, 10(-6) M and 10(-5)M, significantly reduced the production of IFNgamma and the IFNgamma/IL-10 ratio. 5-HT moduline 10(-5)M significantly reduced the production of TNFalpha. The combination of 5-HT, 15&mgr;g/mL, with 5-HT moduline, 10(-6)M and 10(-5)M, further decreases the IFNgamma/IL-10 production ratio. INTERPRETATION: 5-HT moduline has negative immunoregulatory effects." [Abstract]

Isabelle Cloëz-Tayarani, Ana Cardona, Jean-Claude Rousselle, Olivier Massot, Lena Edelman, and Gilles Fillion
Autoradiographic characterization of [3H]-5-HT-moduline binding sites in rodent brain and their relationship to 5-HT1B receptors
PNAS 94: 9899-9904.
"The highest binding densities were found in septum, olfactory system, frontoparietal, and cingulate cortices. In septum, the strongest signals were observed in lateral septal nuclei, horizontal limb diagonal band, whereas in olfactory system, the primary olfactory cortex and the anterior olfactory nucleus were the predominant labeled structures. Other areas with significant [3H]-5-HT-moduline binding sites included the amygdala, hypothalamus, frontal, entorhinal and cingulate cortices, accumbens nucleus, ventral pallidum, dentate gyrus of hippocampus, superficial gray layer of the superior colliculus." [Full Text]

Rousselle JC, Plantefol M, Fillion MP, Massot O, Pauwels PJ, Fillion G.
Specific interaction of 5-HT-moduline with human 5-HT1b as well as 5-HT1d receptors expressed in transfected cultured cells.
Naunyn Schmiedebergs Arch Pharmacol. 1998 Sep;358(3):279-86. [Abstract]

Hedo, G., Lopez-Garcia, J.A.
5-HT1B but not 5-HT6 or 5-HT7 receptors mediate depression of spinal nociceptive reflexes in vitro
Br. J. Pharmacol. 2002 135: 935-942
"The data suggest an important contribution of 5-HT1B receptors to the inhibition of spinal C-fibre mediated nociceptive reflexes but no experimental support was found for the intervention of 5-HT2, 5-HT6 or 5-HT7 receptors in this in vitro model." [Abstract]

Plantefol, Mathieu, Rousselle, Jean Claude, Massot, Olivier, Bernardi, Elizabeth, Schoofs, Alain Rene, Pourrias, Bernard, Ollivier, Roland, Fillion, Gilles
Structural Requirements of 5-Hydroxytryptamine-Moduline Analogues to Interact with the 5-Hydroxytryptamine1B Receptor
J Neurochem 1999 73: 2617-2620
"This work focuses on the ability of 5-hydroxytryptamine-moduline analogues to recognize the high- and low-affinity sites for 5-hydroxytryptamine-moduline. The results obtained show that the two conformers of the 5-hydroxytryptamine1B receptor have similar but not identical binding pockets for 5-hydroxytryptamine-moduline." [Abstract]

Sibella-Arguelles C
The proliferation of human T lymphoblastic cells induced by 5-HT1B receptors activation is regulated by 5-HT-moduline.
C R Acad Sci III, 324(4): 365-72 2001
"The purpose of the herein reported experiments was to investigate whether serotonin could regulate the proliferation of a human T lymphoblastic leukemia cell line (CCRF-CEM cells) and to characterize the 5-HT receptor(s) involved in this phenomenon using a pharmacological approach. The herein presented results show that serotonin alone stimulated the proliferation of CCRF-CEM cells and that this effect could be mimicked by two 5-HT1B/1D receptor agonists (L-694,247 and GR 46611)." [Abstract]

Plantefol_M, Rousselle_J_C, Bernardi_E, Schoofs_A_R, Pourrias_B, Fillion_G
Endoproteolytic activity in mammalian brain membranes cleaves 5-hydroxytryptamine-moduline into dipeptides
European journal of pharmacology , 376(1-2):109-117 1999 [Abstract]

Bentue-Ferrer D, Reymann JM, Rousselle JC, Massot O, Bourin M, Allain H, Fillion G.
5-HT-moduline, a 5-HT(1B/1D) receptor endogenous modulator, interacts with dopamine release measured in vivo by microdialysis.
Eur J Pharmacol. 1998 Oct 2;358(2):129-37. [Abstract]

Decreased sensitivity of 5-HT1D receptors in melancholic depression
Br J Psychiatry 2001 178: 454-457 [Full Text]

BolanosJimenez, F;deCastro, RM;Seguin, L;CloezTayarani, I;Monneret, V;Drieu, K;Fillion, G
Effects of stress on the functional properties of pre- and postsynaptic 5-HT1B receptors in the rat brain
"Similarly, the responsiveness of 5-HT1B receptors inhibiting the release of [H-3]acetylcholine (presynaptic 5-HT1B heteroreceptors), was reduced by restraint. These effects were observed in the hippocampus, but using the inhibitory effect of CP-93,129 on forskolin-stimulated adenylyl cyclase activity as an index of 5-HT1B receptor function, it could be shown that the 5-HT1B receptors located in the substantia nigra are also desensitized by stress." [Abstract]

Bolanos-Jimenez F, Manhaes de Castro R, Fillion G
Effect of chronic antidepressant treatment on 5-HT1B presynaptic heteroreceptors inhibiting acetylcholine release.
Neuropharmacology, 33(1): 77-81 1994
"These data suggest that chronic antidepressant treatment desensitizes 5-HT1B presynaptic heteroreceptors through a mechanism which seems to be independent of the synaptic availability of 5-HT." [Abstract]

Ase, Ariel R., Reader, Tomas A., Hen, Rene, Riad, Mustapha, Descarries, Laurent
Regional changes in density of serotonin transporter in the brain of 5-HT1A and 5-HT1B knockout mice, and of serotonin innervation in the 5-HT1B knockout.
J Neurochem 2001 78: 619-630 [Abstract]

Hsu, Eugenia H., Lochan, Anthony C., Cowen, Daniel S.
Activation of Akt1 by Human 5-Hydroxytryptamine (Serotonin)1B Receptors Is Sensitive to Inhibitors of MEK
J Pharmacol Exp Ther 2001 298: 825-832 [Full Text]

Lione, Angelique M., Errico, Monica, Lin, Stanley L., Cowen, Daniel S.
Activation of Extracellular Signal-Regulated Kinase (ERK) and Akt by Human Serotonin 5-HT1B Receptors in Transfected BE(2)-C Neuroblastoma Cells Is Inhibited by RGS4.
J Neurochem 2000 75: 934-938 [Abstract]

Newman-Tancredi, Adrian, Audinot, Valerie, Moreira, Celia, Verriele, Laurence, Millan, Mark J.
Inverse Agonism and Constitutive Activity as Functional Correlates of Serotonin h5-HT1B Receptor/G-Protein Stoichiometry
Mol Pharmacol 2000 58: 1042-1049
"The key findings of the present study are that an augmentation of h5-HT1B R:G [receptor/G-protein] stoichiometry is associated with changes in ligand-binding affinities, increased relative efficacies of partial agonists, and, notably, increased constitutive G-protein activation and negative efficacy of inverse agonists at h5-HT1B receptors." [Full Text]

Ase, Ariel R., Reader, Tomas A., Hen, Rene, Riad, Mustapha, Descarries, Laurent
Altered Serotonin and Dopamine Metabolism in the CNS of Serotonin 5-HT1A or 5-HT1B Receptor Knockout Mice.
J Neurochem 2000 75: 2415-2426 [Abstract]

Rodriguez-Manzo, Gabriela, Lopez-Rubalcava, Carolina, Hen, Rene, Fernandez-Guasti, Alonso
Participation of 5-HT1B receptors in the inhibitory actions of serotonin on masculine sexual behaviour of mice: pharmacological analysis in 5-HT1B receptor knockout mice
Br. J. Pharmacol. 2002 136: 1127-1134 [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]

Salichon, Nathalie, Gaspar, Patricia, Upton, A. Louise, Picaud, Sandrine, Hanoun, Naima, Hamon, Michel, De Maeyer, Edward, Murphy, Dennis L., Mossner, Rainald, Lesch, Klaus Peter, Hen, Rene, Seif, Isabelle
Excessive Activation of Serotonin (5-HT) 1B Receptors Disrupts the Formation of Sensory Maps in Monoamine Oxidase A and 5-HT Transporter Knock-Out Mice
J. Neurosci. 2001 21: 884-896
"This demonstrates that the 5-HT1B receptor is a key factor in abnormal segregation of sensory projections and suggests that serotonergic drugs represent a risk for the development of these projections. We also found that the 5-HT1B receptor has an adverse developmental impact on beam-walking behavior in MAOA knock-outs. Finally, because the 5-HT1B receptor inhibits glutamate release, our results suggest that visual and somatosensory projections must release glutamate for proper segregation." [Full Text]

Parsons, Loren H., Weiss, Friedbert, Koob, George F.
Serotonin1B Receptor Stimulation Enhances Cocaine Reinforcement
J. Neurosci. 1998 18: 10078-10089 [Full Text]

Lucas, Jose J., Segu, Louis, Hen, Rene
5-Hydroxytryptamine1B Receptors Modulate the Effect of Cocaine on c-fos Expression: Converging Evidence Using 5-Hydroxytryptamine1B Knockout Mice and the 5-Hydroxytryptamine1B/1D Antagonist GR127935
Mol Pharmacol 1997 51: 755-763 [Full Text]

Hjorth S, Bengtsson HJ, Kullberg A, Carlzon D, Peilot H, Auerbach SB.
Serotonin autoreceptor function and antidepressant drug action.
J Psychopharmacol 2000 Jun;14(2):177-85
"In particular, emerging data suggest that somatodendritic 5-HT1A autoreceptor- and nerve terminal 5-HT1B autoreceptor-mediated feedback may be relatively more important in the control of 5-HT output in dorsal raphe-frontal cortex and median raphe-dorsal hippocampus systems, respectively." [Abstract]

Trillat AC, Malagie I, Bourin M, Jacquot C, Hen R, Gardier AM.
[Homozygote mice deficient in serotonin 5-HT1B receptor and antidepressant effect of selective serotonin reuptake inhibitors]
C R Seances Soc Biol Fil 1998;192(6):1139-47
"Using microdialysis in awake 129/Sv mice, we show that the absence of the 5-HT1B receptor in mutant mice (KO 1B -/-) potentiated the effect of paroxetine on extracellular 5-HT levels in the ventral hippocampus, but not in the frontal cortex compared to wild-type mice (WT). Furthermore, using the forced swimming test, we demonstrate that SSRIs decreased immobility of WT mice, and this effect is absent in KO 1B -/- mice showing therefore that activation of 5-HT1B receptors mediate the antidepressant-like effects of SSRIs. Taken together these findings suggest that 5-HT1B autoreceptors limit the effects of SSRI particularly in the hippocampus while postsynaptic 5-HT1B receptors are required for the antidepressant activity of SSRIs." [Abstract]

Evrard A, Laporte AM, Chastanet M, Hen R, Hamon M, Adrien J.
5-HT1A and 5-HT1B receptors control the firing of serotoninergic neurons in the dorsal raphe nucleus of the mouse: studies in 5-HT1B knock-out mice.
Eur J Neurosci 1999 Nov;11(11):3823-31 [Abstract]

Davidson, C, Ho, M, Price, GW, Jones, BJ, Stamford, JA
(+)-WAY 100135, a partial agonist, at native and recombinant 5-HT1B/1D receptors
Br. J. Pharmacol. 1997 121: 737-742 [Abstract]

Gobert A, Rivet JM, Cistarelli L, Millan MJ.
Potentiation of the fluoxetine-induced increase in dialysate levels of serotonin (5-HT) in the frontal cortex of freely moving rats by combined blockade of 5-HT1A and 5-HT1B receptors with WAY 100,635 and GR 127,935.
J Neurochem 1997 Mar;68(3):1159-63 [Abstract]

Stenfors C, Magnusson T, Larsson LG, Yu H, Hallbus M, Magnusson O, Ross SB.
Synergism between 5-HT1B/1D and 5-HT1A receptor antagonists on turnover and release of 5-HT in guinea-pig brain in vivo.
Naunyn Schmiedebergs Arch Pharmacol 1999 Feb;359(2):110-6 [Abstract]

Molderings GJ, Frolich D, Likungu J, Gothert M.
Inhibition of noradrenaline release via presynaptic 5-HT1D alpha receptors in human atrium.
Naunyn Schmiedebergs Arch Pharmacol 1996 Feb;353(3):272-80 [Abstract]

Malagie, Isabelle, Trillat, Anne-Cecile, Bourin, Michel, Jacquot, Christian, Hen, Rene, Gardier, Alain M.
5-HT1B Autoreceptors limit the effects of selective serotonin re-uptake inhibitors in mouse hippocampus and frontal cortex
J Neurochem 2001 76: 865-871 [Abstract]

Enhanced aggressive behavior in mice lacking 5-HT1B receptor.
SCIENCE 265: (5180) 1875-1878 SEP 23 1994
"Moreover, when confronted with an intruder, mutant mice attacked the intruder faster and more intensely than did wild-type mice, suggesting the participation of 5-HT1B receptors in aggressive behavior." [Abstract]

Sarhan, Hala, Fillion, Gilles
Differential sensitivity of 5-HT1B auto and heteroreceptors

Scearce-Levie K, Viswanathan SS, Hen R.
Locomotor response to MDMA is attenuated in knockout mice lacking the 5-HT1B receptor.
Psychopharmacology (Berl) 1999 Jan;141(2):154-61 [Abstract]

Ferris, Craig F., Melloni Jr, Richard H., Koppel, Gary, Perry, Kenneth W., Fuller, Ray W., Delville, Yvon
Vasopressin/Serotonin Interactions in the Anterior Hypothalamus Control Aggressive Behavior in Golden Hamsters
J. Neurosci. 1997 17: 4331-4340
"Because postsynaptic 5-HT1B receptors seem to be fundamental in the modulation of offensive aggression, it is reasonable to postulate that 5-HT activates these receptors, making a neuron co-innervated by AVP unresponsive to the excitatory effects of the neuropeptide." [Full Text]

Callahan PM, Cunningham KA.
Modulation of the discriminative stimulus properties of cocaine: comparison of the effects of fluoxetine with 5-HT1A and 5-HT1B receptor agonists.
Neuropharmacology 1997 Mar;36(3):373-81 [Abstract]

el Mansari M, Blier P.
Functional characterization of 5-HT1D autoreceptors on the modulation of 5-HT release in guinea-pig mesencephalic raphe, hippocampus and frontal cortex.
Br J Pharmacol 1996 Jun;118(3):681-9 [Abstract]

Manrique C, Francois-Bellan AM, Segu L, Becquet D, Hery M, Faudon M, Hery F.
Impairment of serotoninergic transmission is followed by adaptive changes in 5HT1B binding sites in the rat suprachiasmatic nucleus.
Brain Res 1994 Nov 7;663(1):93-100 [Abstract]

Fernandez-Guasti A, Rodriguez-Manzo G.
Further evidence showing that the inhibitory action of serotonin on rat masculine sexual behavior is mediated after the stimulation of 5-HT1B receptors.
Pharmacol Biochem Behav 1992 Jul;42(3):529-33 [Abstract]

Bourin M, Hascoet M.
Drug mechanisms in anxiety.
Curr Opin Investig Drugs 2001 Feb;2(2):259-65 [Abstract]

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Recent 5-HT1B and 5-HT1D Receptor Research

1) Cologno D, Mazzeo A, Lecce B, Mundi C, Petretta V, Casucci G, d'Onofrio F
Triptans: over the migraine.
Neurol Sci. 2012 May;33 Suppl 1:S193-8.
Migraine is a chronic, recurrent, disabling condition that affects millions of people worldwide. Proper acute care treatment for migraineurs is based on triptans, a class of specific medications approved over 20 years ago. Triptans are serotonin (5-HT1B/1D) receptor agonists that are generally effective, well tolerated and safe. Seven triptans are available worldwide, although not all are available in every country, with multiple routes of administration, giving to doctors and patients a wide choice. Despite the similarities of the available triptans, pharmacological heterogeneity offers slightly different efficacy profiles. Triptans are not pain medications, they are abortive migraine medications which cannot prevent migraines. In addition to migraine attacks, triptans are also helpful for cluster headaches. If they are useful in other primary headaches rather than migraine and cluster headache it is yet to be addressed. In the literature there are only limited controlled clinical data to support a migraine-selective activity for triptans. Reports are available about efficacy of triptans to stop attacks of other types of primary headache, such as tension type headache, hypnic headache and other rare forms of primary headaches. On the other hand, sumatriptan failed to treat the indomethacin-responsive primary headache disorders like chronic paroxysmal hemicrania and hemicrania continua, nor was it effective in the myofascial temporal muscle pain or in atypical facial pain. Why triptans are effective in so different types of primary headaches remain unclear. Up to date, it is not clear whether the antimigrainous activity of the triptans involves an action only in the periphery or in the CNS as well. Probably we should consider triptans as "pain killers" and not only as "migraine killers". We clearly need additional studies on triptans as putative analgesics in well-accepted animal and clinical models of acute and chronic somatic pain. [PubMed Citation] [Order full text from Infotrieve]

2) Nonogaki K
Serotonin conflict in sleep-feeding.
Vitam Horm. 2012;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]

3) Davis RP, Pattison J, Thompson JM, Tiniakov R, Scrogin KE, Watts SW
5-hydroxytryptamine (5-HT) reduces total peripheral resistance during chronic infusion: direct arterial mesenteric relaxation is not involved.
BMC Pharmacol. 2012 May 6;12(1):4.
ABSTRACT: Serotonin (5-hydroxytryptamine; 5-HT) delivered over 1 week results in a sustained fall in blood pressure in the sham and deoxycorticosterone acetate (DOCA)-salt rat. We hypothesized 5-HT lowers blood pressure through direct receptor-mediated vascular relaxation. In vivo, 5-HT reduced mean arterial pressure (MAP), increased heart rate, stroke volume, cardiac index, and reduced total peripheral resistance during a 1 week infusion of 5-HT (25 micrograms/kg/min) in the normotensive Sprague Dawley rat. The mesenteric vasculature was chosen as an ideal candidate for the site of 5-HT receptor mediated vascular relaxation given the high percentage of cardiac output the site receives. Real-time RT-PCR demonstrated that mRNA transcripts for the 5-HT2B, 5-HT1B, and 5-HT7 receptors are present in sham and DOCA-salt superior mesenteric arteries. Immunohistochemistry and Western blot validated the presence of the 5-HT2B, 5-HT1B and 5-HT7 receptor protein in sham and DOCA-salt superior mesenteric artery. Isometric contractile force was measured in endothelium-intact superior mesenteric artery and mesenteric resistance arteries in which the contractile 5-HT2A receptor was antagonized. Maximum concentrations of BW-723C86 (5-HT2B agonist), CP 93129 (5-HT1B agonist) or LP-44 (5-HT7 agonist) did not relax the superior mesenteric artery from DOCA-salt rats vs. vehicle. Additionally, 5-HT (1 nM to 10 uM) did not cause relaxation in either contracted mesenteric resistance arteries or superior mesenteric arteries from normotensive Sprague-Dawley rats. Thus, although 5-HT receptors known to mediate vascular relaxation are present in the superior mesenteric artery, they are not functional, and are therefore not likely involved in a 5-HT-induced fall in total peripheral resistance and MAP. [PubMed Citation] [Order full text from Infotrieve]

4) Yohe LR, Suzuki H, Lucas LR
Aggression is suppressed by acute stress but induced by chronic stress: Immobilization effects on aggression, hormones, and cortical 5-HT(1B)/ striatal dopamine D (2) receptor density.
Cogn Affect Behav Neurosci. 2012 Sep;12(3):446-59.
Although it has been established by a number of investigators that a variety of stressors are associated with the induction of aggressive behavior, two specific issues remain unanswered. First, it is unclear whether the contexts surrounding stressors (e.g., stressor length and chance of winning over opponents) change outcomes regarding aggressive behavior. Second, if a relationship exists between stress and aggressive behavior, altered levels of stress-related hormone (e.g., corticosterone [CORT]), as well as aggression-related biomarkers (e.g., testosterone [T], density of prefronto-cortical 5-HT(1B) receptor and striatal dopamine D(2) receptor [D2r]) may contribute to changes in aggressive behavior. Thus, we examined how immobilization (with a 1-, 5-, or 10-day exposure) would impact (1) a longitudinal course of aggression toward different-sized opponents, (2) levels of CORT and T, and (3) densities of 5-HT(1B) receptor (5-HT1Br) in the prefrontal cortex (PFC) and D2r in the striatum. It was found that, regardless of small or large opponents, a single 2-h exposure to immobilization reduced aggressive behavior (stress-suppressed aggression) over time, whereas repeated (10-day) exposure to immobilization escalated aggressive behavior (stress-induced aggression). These stress effects persisted up to 1 week of recovery from immobilization stress. Moreover, immobilized rats demonstrated elevated levels of T, but not CORT, as compared with controls. Finally, acute immobilization altered D2r densities in the shell of the nucleus accumbens, and chronic immobilization changed 5-HT1Br in the PFC, including the downregulation of 5-HT1Br densities in the right prelimbic and orbitolateral cortices. The potential relationships among stress, aggression, and 5-HT1Br/D2r roles are discussed. [PubMed Citation] [Order full text from Infotrieve]

5) Chopra A, Wang TY, Lee SY, Chen SL, Chang YH, Chen SH, Chu CH, Huang SY, Tzeng NS, Wang CL, Lee IH, Yeh TL, Yang YK, Lu RB
Interaction between Serotonin Transporter and Serotonin Receptor 1 B genes polymorphisms may be associated with antisocial alcoholism.
Behav Brain Funct. 2004;8:18.
Serotonin (5-hydroxytryptamine; 5-HT), a derivative of the tryptophan amino acid, is a low molecular weight neurotransmitter that plays an important role in the functioning of different physiological, cognitive, and emotional processes. Impairment of the serotonergic system is associated with psychiatric disorders, such as anxiety and depression, and neurological afflictions, such as Parkinson?s disease, Alzheimer?s disease, and epilepsy (1). The 5-HT mediates its biological activity through a group of seven receptors (5-HT1-7R) that are further classified into 14 distinct subtypes on the basis of their structure and pharmacological activity. Except for the 5-HT3R, which is a ligand-gated ion channel, all other 5-HTRs belong to the family of G-protein?coupled seven-transmembrane receptors (2). Radiolabeled tracers have been developed for use with positron emission tomography (PET) to study the different 5-HTR subtypes, and much information is available regarding only the 5-HT1AR, 5-HT1BR, 5-HT2AR, and 5-HT4R subtypes (3). Compared to the discovery of the other 5-HTR subtypes, the identification of 5-HT6R is fairly recent, and this receptor is located mostly in the limbic and cortical regions of the mammalian central nervous system (4). Although the exact mechanism of action of the 5-HT6R is not clear, there are indications that antagonists of this receptor reverse amnesia and improve cognitive and memory functions in individuals suffering from schizophrenia, Parkinson's disease, or Alzheimer?s disease (5). Therefore, it was imperative to develop a ligand that could be used to study the biological characteristics of this receptor. Radioiodinated SB-258585 ([125I]-SB258585), a selective antagonist of the 5-HT6R, has been shown to have a high affinity for this receptor in membranes derived from rat or pig striatum and human caudate putamen (6). Autoradiography of rat brain sections exposed to [125I]-SB258585 revealed that the 5-HT6R was located primarily in the striatum, followed by the cerebral cortex; accumulation was lowest in the cerebellum of these animals. From this observation, the investigators concluded that the receptor was probably involved in cognition, memory, and locomotor control functions in the animals (7). In another study, [N-methyl]3-[(3-fluorophenyl)sulfonyl]-8-(4-methyl-1-piperazinyl)quinoline (GSK215083) was reported to have a 5-fold and >55-fold higher subnanomolar concentration affinity for the 5-HT6R compared to the concentrations required for the 5-HT2AR and the other 5-HTRs, respectively (3). In addition, the lipophilicity of GSK215083 was determined to be suitable for crossing the blood?brain barrier and penetration into the brain. On the basis of these observations, [11C]-GSK215083 was evaluated in vivo as a 5-HT6R ligand in pigs, non-human primates, and humans (3). [PubMed Citation] [Order full text from Infotrieve]

6) Henriksen R, Dizeyi N, Abrahamsson PA
Expression of serotonin receptors 5-HT1A, 5-HT1B, 5-HT2B and 5-HT4 in ovary and in ovarian tumours.
Anticancer Res. 2012;32(4):1361-6.
[PubMed Citation] [Order full text from Infotrieve]

7) Barbanti P, Fofi L, Dall'armi V, Aurilia C, Egeo G, Vanacore N, Bonassi S
Rizatriptan in migraineurs with unilateral cranial autonomic symptoms: a double-blind trial.
J Headache Pain. 2012 Apr;13(5):407-14.
The objective and background is to confirm in a double-blind, placebo-controlled study the high triptan response rates we had previously reported in an open study in migraine patients with unilateral cranial autonomic symptoms. In this randomized, double-blind, placebo-controlled study 80 migraineurs with unilateral cranial autonomic symptoms were assigned to receive rizatriptan 10 mg wafer or placebo (ratio 1:1) and treated for a single moderate or severe migraine attack. The primary endpoints were pain freedom at 2 h and total migraine freedom at 2 h. Secondary endpoints included pain relief, no associated symptoms and sustained pain freedom or relief. Significantly more patients reported pain freedom at 2 h after taking rizatriptan (54 %) than after placebo (8 %) (therapeutic gain 46 % [28 %; 64 %]; P < 0.001). Similarly, significantly more patients reported total migraine freedom at 2 h after rizatriptan (51 %) than after placebo (8 %) (therapeutic gain 43 % [26 %; 61 %]; P < 0.001). Rizatriptan was also more effective than placebo on most secondary endpoints. We confirm in a placebo-controlled study our previous data suggesting that the presence of unilateral cranial autonomic symptoms in migraineurs predicts a positive response to triptans, probably owing to intense trigeminal peripheral afferent activation which strongly recruits peripheral neurovascular 5-HT1B/1D receptors. Acute and preventive pharmacological trials in migraine should focus also on this subset of migraine patients. [PubMed Citation] [Order full text from Infotrieve]

8) Pašalić D, Pauković P, Cvijetić S, Pizent A, Jurasović J, Milković-Kraus S, Dodig S, Mück-Šeler D, Mustapić M, Pivac N, Lana-Feher-Turković M, Pavlović
Prostate Cancer in Elderly Croatian Men: 5-HT Genetic Polymorphisms and the Influence of Androgen Deprivation Therapy on Osteopenia-A Pilot Study.
Genet Test Mol Biomarkers. 2012 Jul;16(6):598-604.
Background: The aim of this study was to determine the relationship between body mass index, biochemical parameters, and 5-hydroxytryptamine (5-HT) genetic polymorphisms and prostate dysfunction in an elderly general male population. Results: One hundred and seventeen elderly male subjects [60 men without symptoms of prostate hyperplasia, 42 men with untreated benign prostatic hyperplasia (BPH), and 15 men with prostate cancer (PCa)] treated with finasteride or flutamide were included. Multiple comparisons showed significant difference in age, T-score, concentration of phosphorus, calcium, C-reactive protein, and prostate-specific antigen (PSA) between the groups. T-score was the lowest and phosphorus concentration was the highest in the PCa group. Highest PSA, proteins, calcium, and Hekal's formula score were found in the BPH group. Patients with PCa were more frequent GG+GA carriers of 5-HT1B 1997A/G gene polymorphism (p=0.035). Univariate regression analysis showed association of PCa-treated subjects with age (p=0.010) and 5-HT1B genetic polymorphism (p=0.018). Antiandrogen therapy affects T-score (p=0.017), serum phosphorus (p=0.008), glucose (p=0.036), and total proteins (p=0.050). Multivariate-stepwise logistic regression analysis showed the significant association of treated PCa with age (p=0.028) and inorganic phosphorus (p=0.005), and a marginal association with ultrasonographic T-score (p=0.052). Conclusions: Antiandrogen therapy might induce bone mineral loss in elderly PCa patients. Preliminary data imply that the genetic variants of the 5-HT1B receptor might be associated with PCa. [PubMed Citation] [Order full text from Infotrieve]

9) Dennis RL, Cheng HW
Effects of selective serotonin antagonism on central neurotransmission.
Poult Sci. 2012 Jun;91(4):817-22.
Aggression and cannibalism in laying hens can differ in intensity and degree due to many factors, including genetics. Previous behavioral analysis of 2 strains of White Leghorns, DeKalb XL (DXL) and HGPS (a group-selected line for high group productivity and survivability), revealed high and low aggressive phenotypes, respectively. However, the exact genetic mechanisms mediating aggressiveness are currently unknown. Analysis of serotonin (5-HT) mediation of aggression in subordinate hens of these strains revealed increases in aggression in DXL hens following antagonism of the 5-HT1A receptor and in HGPS hens following antagonism of the 5-HT1B receptor. Here, we investigate the different neurotransmitter response in the hypothalamus and raphe nucleus mediating these aggressive responses to receptor antagonism. Elevated aggressive response to 5-HT1B antagonism by HGPS hens was also accompanied by a decrease in raphe nucleus dopamine (DA) and an increase in DA turnover. Increased aggressiveness in DXL hens did not coincide with a reduction in raphe nucleus 5-HT or turnover (as indicated by 5-hydroxyindoleacetic acid levels) following 5-HT1A antagonism. A reduction in 5-hydroxyindoleacetic acid (but not 5-HT) was seen in HGPS hens treated with 5-HT1A antagonist; however, these hens exhibited no change in aggressive behaviors. Our data show evidence of different heritable mechanisms of neurotransmitter regulation of aggressive response, specifically heritable differences in the interaction between 5-HT and catecholamines in regulating aggression. [PubMed Citation] [Order full text from Infotrieve]

10) Fujii H, Takatori S, Zamami Y, Hashikawa-Hobara N, Miyake N, Tangsucharit P, Mio M, Kawasaki H
Adrenergic stimulation-released 5-HT stored in adrenergic nerves inhibits CGRPergic nerve-mediated vasodilatation in rat mesenteric resistance arteries.
Br J Pharmacol. 2012 Apr;166(7):2084-94.
[PubMed Citation] [Order full text from Infotrieve]

11) Kahsai L, Carlsson MA, Winther AM, Nässel DR
Distribution of metabotropic receptors of serotonin, dopamine, GABA, glutamate, and short neuropeptide F in the central complex of Drosophila.
Neuroscience. 2012 Aug;208:11-26.
The central complex is a prominent set of midline neuropils in the insect brain, known to be a higher locomotor control center that integrates visual inputs and modulates motor outputs. It is composed of four major neuropil structures, the ellipsoid body (EB), fan-shaped body (FB), noduli (NO), and protocerebral bridge (PB). In Drosophila different types of central complex neurons have been shown to express multiple neuropeptides and neurotransmitters; however, the distribution of corresponding receptors is not known. Here, we have mapped metabotropic, G-protein-coupled receptors (GPCRs) of several neurotransmitters to neurons of the central complex. By combining immunocytochemistry with GAL4 driven green fluorescent protein, we examined the distribution patterns of six different GPCRs: two serotonin receptor subtypes (5-HT(1B) and 5-HT(7)), a dopamine receptor (DopR), the metabotropic GABA(B) receptor (GABA(B)R), the metabotropic glutamate receptor (DmGluR(A)) and a short neuropeptide F receptor (sNPFR1). Five of the six GPCRs were mapped to different neurons in the EB (sNPFR1 was not seen). Different layers of the FB express DopR, GABA(B)R, DmGluR(A,) and sNPFR1, whereas only GABA(B)R and DmGluR(A) were localized to the PB. Finally, strong expression of DopR and DmGluR(A) was detected in the NO. In most cases the distribution patterns of the GPCRs matched the expression of markers for their respective ligands. In some nonmatching regions it is likely that other types of dopamine and serotonin receptors or ionotropic GABA and glutamate receptors are expressed. Our data suggest that chemical signaling and signal modulation are diverse and highly complex in the different compartments and circuits of the Drosophila central complex. The information provided here, on receptor distribution, will be very useful for future analysis of functional circuits in the central complex, based on targeted interference with receptor expression. [PubMed Citation] [Order full text from Infotrieve]

12) McCrory DC, Gray RN
WITHDRAWN: Oral sumatriptan for acute migraine.
Cochrane Database Syst Rev. 2012 Apr 19;2:CD002915.
[PubMed Citation] [Order full text from Infotrieve]

13) Silva SA, Ribeiro CA
Tachyphylaxis to the sumatriptan-induced contractile effect in the human uterine artery but not in human cerebral blood vessels: pharmacological demonstration of the 5-HT(1B) receptor functionality loss.
Pharmacology. 2012;89(1-2):29-36.
The in vitro contractile response of the human uterine artery to sumatriptan was compared to that of human cerebral blood vessels. Artery rings were prepared for isometric contraction. Tachyphylaxis to the triptan-induced vascular contraction was observed in the uterine artery, but not in basilar and middle cerebral arteries. To evaluate 5-HT(1) receptor subtypes functionality, concentration-response curves to sumatriptan were performed at 0 and 24 h after uterine artery isolation. Both 10 ?mol/l cyanopindolol and 63 nmol/l SB 224,289 (5-HT(1B) receptor antagonists) significantly antagonized the contractile response induced by sumatriptan at 0 h but not after 24 h of uterine artery isolation. The 5-HT(1B/1D) receptor antagonist BRL 15,572 at 10 ?mol/l significantly antagonized the sumatriptan contractile response at both experimental conditions. We conclude that the tachyphylaxis to sumatriptan observed in the non-cerebral blood vessels, and not in the cerebral ones, may be due to loss of functionality of the 5-HT(1B) receptor subtype, increasing the safety of triptans. [PubMed Citation] [Order full text from Infotrieve]

14) Enjin A, Leão KE, Mikulovic S, Le Merre P, Tourtellotte WG, Kullander K
Sensorimotor function is modulated by the serotonin receptor 1d, a novel marker for gamma motor neurons.
Mol Cell Neurosci. 2012;49(3):322-32.
Gamma motor neurons (MNs), the efferent component of the fusimotor system, regulate muscle spindle sensitivity. Muscle spindle sensory feedback is required for proprioception that includes sensing the relative position of neighboring body parts and appropriately adjust the employed strength in a movement. The lack of a single and specific genetic marker has long hampered functional and developmental studies of gamma MNs. Here we show that the serotonin receptor 1d (5-ht1d) is specifically expressed by gamma MNs and proprioceptive sensory neurons. Using mice expressing GFP driven by the 5-ht1d promotor, we performed whole-cell patch-clamp recordings of 5-ht1d::GFP? and 5-ht1d::GFP? motor neurons from young mice. Hierarchal clustering analysis revealed that gamma MNs have distinct electrophysiological properties intermediate to fast-like and slow-like alpha MNs. Moreover, mice lacking 5-ht1d displayed lower monosynaptic reflex amplitudes suggesting a reduced response to sensory stimulation in motor neurons. Interestingly, adult 5-ht1d knockout mice also displayed improved coordination skills on a beam-walking task, implying that reduced activation of MNs by Ia afferents during provoked movement tasks could reduce undesired exaggerated muscle output. In summary, we show that 5-ht1d is a novel marker for gamma MNs and that the 5-ht1d receptor is important for the ability of proprioceptive circuits to receive and relay accurate sensory information in developing and mature spinal cord motor circuits. [PubMed Citation] [Order full text from Infotrieve]

15) Jern P, Westberg L, Johansson A, Gunst A, Eriksson E, Sandnabba K, Santtila P
A study of possible associations between single nucleotide polymorphisms in the serotonin receptor 1A, 1B, and 2C genes and self-reported ejaculation latency time.
J Sex Med. 2012 Mar;9(3):866-72.
[PubMed Citation] [Order full text from Infotrieve]

16) Miszkiel J, Adamczyk P, Filip M, Przegaliński E
The effect of serotonin 5HT1B receptor ligands on amphetamine self-administration in rats.
Eur J Pharmacol. 2012 Mar;677(1-3):111-5.
A number of data indicate that serotonin (5-HT) 5-HT(1B) receptor ligands affect the behavioral effects of psychostimulants. In the present study we examined effects of the selective 5-HT(1B) receptor antagonist N-[3-[3-(dimethylamino)ethoxy]-4-methoxyphenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide hydrochloride (SB 216641) and the agonist 5-propoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-pyrrolo[3,2-b]pyridine hydrochloride (CP 94253) on amphetamine self-administration in rats. SB 216641 administered in doses of 2.5-7.5 mg/kg did not affect the self-administration of amphetamine injected in unit doses of 0.06 or 0.12 mg/kg/infusion. On the other hand, CP 94253 administered in doses of 2.5 or 5 mg/kg attenuated amphetamine self-administration, yet the effect of 2.5 mg/kg of the agonist was fairly weak and significant only in case of a higher unit dose of the psychostimulant. The inhibitory effect of CP 94253 administered in a dose of 5mg/kg on the self-administration of amphetamine injected in a unit dose of 0.06 mg/kg/infusion was significantly reduced by SB 216641 administrated in a dose of 7.5 mg/kg. These results indicate that tonic activation of 5-HT(1B) receptors is not involved in the self-administration of amphetamine, while pharmacological stimulation of these receptors attenuates this behavioral phenomenon. [PubMed Citation] [Order full text from Infotrieve]

17) Iwabayashi M, Taniyama Y, Sanada F, Azuma J, Iekushi K, Kusunoki H, Chatterjee A, Okayama K, Rakugi H, Morishita R
Role of serotonin in angiogenesis: induction of angiogenesis by sarpogrelate via endothelial 5-HT1B/Akt/eNOS pathway in diabetic mice.
Atherosclerosis. 2012 Feb 29;220(2):337-42.
Serotonin (5-hydroxytryptamine, 5-HT) plays a crucial role in peripheral artery disease (PAD) and diabetes mellitus (DM). In these conditions, the balance between the 5-HT2A receptor in smooth muscle cells and the 5-HT1B receptor in endothelial cells (ECs) regulates vascular tonus. In the present study, we focused on the role of 5-HT in endothelial dysfunction using a selective 5-HT2A receptor blocker, sarpogrelate. In human EC, 5-HT markedly stimulated eNOS expression and the phosphorylation of eNOS, Akt and ERK1/2. In addition, a dose-dependent increase in tubule-formation on Matrigel was observed after 5-HT treatment. In contrast, high glucose significantly inhibited tubule formation and eNOS expression through inactivation of Akt, while 5-HT significantly attenuated these actions of high glucose (P<0.01). These results indicate that 5-HT stimulated angiogenesis through activation of Akt in ECs. However, in clinical situations, 5-HT seems to act as the "devil". To examine the role of 5-HT in diabetic PAD, a hindlimb ischemia model was created in diabetic mice. The blood flow ratio of the ischemic to non-ischemic limb was significantly lower in DM mice than in normal mice, while sarpogrelate significantly attenuated the decrease in the blood flow ratio compared to control (P<0.01). Consistently, the decrease in eNOS expression and Akt activity in DM mice was significantly attenuated by sarpogrelate. Overall, the present study demonstrated that selective inhibition of 5-HT2A by sarpogrelate significantly restored ischemic limb blood perfusion in a severe diabetic mouse model through stimulation of the eNOS/Akt pathway via the endothelial 5-HT1B receptor. Enhancement of vasodilation and angiogenesis by sarpogrelate might provide a unique treatment for PAD and DM patients. [PubMed Citation] [Order full text from Infotrieve]

18) Mørk A, Pehrson A, Brennum LT, Nielsen SM, Zhong H, Lassen AB, Miller S, Westrich L, Boyle NJ, Sánchez C, Fischer CW, Liebenberg N, Wegener G, Bundgaard C, Hogg S, Bang-Andersen B, Stensbøl TB
Pharmacological effects of Lu AA21004: a novel multimodal compound for the treatment of major depressive disorder.
J Pharmacol Exp Ther. 2012 Feb;340(3):666-75.
1-[2-(2,4-Dimethylphenyl-sulfanyl)-phenyl]-piperazine (Lu AA21004) is a human (h) serotonin (5-HT)(3A) receptor antagonist (K(i) = 3.7 nM), h5-HT(7) receptor antagonist (K(i) = 19 nM), h5-HT(1B) receptor partial agonist (K(i) = 33 nM), h5-HT(1A) receptor agonist (K(i) = 15 nM), and a human 5-HT transporter (SERT) inhibitor (K(i) = 1.6 nM) (J Med Chem 54:3206-3221, 2011). Here, we confirm that Lu AA21004 is a partial h5-HT(1B) receptor agonist [EC(50) = 460 nM, intrinsic activity = 22%] using a whole-cell cAMP-based assay and demonstrate that Lu AA21004 is a rat (r) 5-HT(7) receptor antagonist (K(i) = 200 nM and IC(50) = 2080 nM). In vivo, Lu AA21004 occupies the r5-HT(1B) receptor and rSERT (ED(50) = 3.2 and 0.4 mg/kg, respectively) after subcutaneous administration and is a 5-HT(3) receptor antagonist in the Bezold-Jarisch reflex assay (ED(50) = 0.11 mg/kg s.c.). In rat microdialysis experiments, Lu AA21004 (2.5-10.0 mg/kg s.c.) increased extracellular 5-HT, dopamine, and noradrenaline in the medial prefrontal cortex and ventral hippocampus. Lu AA21004 (5 mg/kg per day for 3 days; minipump subcutaneously), corresponding to 41% rSERT occupancy, significantly increased extracellular 5-HT in the ventral hippocampus. Furthermore, the 5-HT(3) receptor antagonist, ondansetron, potentiated the increase in extracellular levels of 5-HT induced by citalopram. Lu AA21004 has antidepressant- and anxiolytic-like effects in the rat forced swim (Flinders Sensitive Line) and social interaction and conditioned fear tests (minimal effective doses: 7.8, 2.0, and 3.9 mg/kg). In conclusion, Lu AA21004 mediates its pharmacological effects via two pharmacological modalities: SERT inhibition and 5-HT receptor modulation. In vivo, this results in enhanced release of several neurotransmitters and antidepressant- and anxiolytic-like profiles at doses for which targets in addition to the SERT are occupied. The multimodal activity profile of Lu AA21004 is distinct from that of current antidepressants. [PubMed Citation] [Order full text from Infotrieve]

19) Finnema SJ, Varrone A, Hwang TJ, Halldin C, Farde L
Confirmation of fenfluramine effect on 5-HT(1B) receptor binding of [(11)C]AZ10419369 using an equilibrium approach.
J Cereb Blood Flow Metab. 2012 Mar;32(4):685-95.
Assessment of serotonin release in the living brain with positron emission tomography (PET) may have been hampered by the lack of suitable radioligands. We previously reported that fenfluramine caused a dose-dependent reduction in specific binding in monkeys using a classical displacement paradigm with bolus administration of [(11)C]AZ10419369. The aim of this study was to confirm our previous findings using an equilibrium approach in monkey. A total of 24 PET measurements were conducted using a bolus infusion protocol of [(11)C]AZ10419369 in three cynomolgus monkeys. Initial PET measurements were performed to assess suitable K(bol) values. The fenfluramine effect on [(11)C]AZ10419369 binding was evaluated in a displacement and pretreatment paradigm. The effect of fenfluramine on [(11)C]AZ10419369 binding potential (BP(ND)) was dose-dependent in the displacement paradigm and confirmed in the pretreatment paradigm. After pretreatment administration of fenfluramine (5.0 mg/kg), the mean BP(ND) of the occipital cortex decreased by 39%, from 1.38±0.04 to 0.84±0.09. This study confirms that the new 5-HT(1B) receptor radioligand [(11)C]AZ10419369 is sensitive to fenfluramine-induced changes in endogenous serotonin levels in vivo. The more advanced methodology is suitable for exploring the sensitivity limit to serotonin release as measured using [(11)C]AZ10419369 and PET. [PubMed Citation] [Order full text from Infotrieve]