Antagonism of the 5-HT6 receptor – Preclinical rationale for the treatment of Alzheimer's disease

Neuropharmacology

Volumn 125, Issue , 2017, Pages 50-63

  de Jong, Inge E M ^a   Mørk, Arne ^a  

^a H LUNDBECK A S   (Denmark)

Author keywords

5 HT6 receptor; Alzheimer's disease; Cholinesterase inhibitors; Cognition; Donepezil; Idalopirdine

Indexed keywords

4 AMINOBUTYRIC ACID; 5 CHLORO N [4 METHOXY 3 (1 PIPERAZINYL)PHENYL] 3 METHYL 2 BENZOTHIOPHENESULFONAMIDE; AVN 101; AVN 322; CHOLINESTERASE INHIBITOR; DONEPEZIL; GLUTAMIC ACID; IDALOPIRDINE; INTEPIRDINE; N (3,5 DICHLORO 2 METHOXYPHENYL) 4 METHOXY 3 (1 PIPERAZINYL)BENZENESULFONAMIDE; NEUROTRANSMITTER; NICOTINIC RECEPTOR; RO 046790; RO 4368554; SB 258585; SB 357134; SEROTONIN 6 ANTAGONIST; SEROTONIN 6 RECEPTOR; SEROTONIN ANTAGONIST; SUVN 502; UNCLASSIFIED DRUG; WAY 181187; PSYCHOTROPIC AGENT; SEROTONIN RECEPTOR;

ALZHEIMER DISEASE; BRAIN REGION; CHOLINESTERASE INHIBITION; COGNITION; DRUG POTENTIATION; DRUG RECEPTOR BINDING; DRUG TARGETING; FACILITATION; GABAERGIC SYSTEM; GLUTAMATERGIC SYNAPSE; HUMAN; MONOTHERAPY; NERVE CELL INHIBITION; NERVE CELL NETWORK; NERVE CELL STIMULATION; NEUROTRANSMISSION; NONHUMAN; PHASE 2 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN LOCALIZATION; REVIEW; ANIMAL; BRAIN; DRUG EFFECT; METABOLISM; PHYSIOLOGY;

ALZHEIMER DISEASE; ANIMALS; BRAIN; COGNITION; HUMANS; PSYCHOTROPIC DRUGS; RECEPTORS, SEROTONIN; SEROTONIN ANTAGONISTS;

EID: 85024408939     PISSN: 00283908     EISSN: 18737064     Source Type: Journal    
DOI: 10.1016/j.neuropharm.2017.07.010     Document Type: Review

References (172)

1. Ahnaou, A., Huysmans, H., Jacobs, T., Drinkenburg, W.H., Cortical EEG oscillations and network connectivity as efficacy indices for assessing drugs with cognition enhancing potential. Neuropharmacology 86 (2014), 362–377.
2. Arai, H., Kosaka, K., Iizuka, R., Changes of biogenic amines and their metabolites in postmortem brains from patients with Alzheimer-type dementia. J. Neurochem. 43 (1984), 388–393.
3. Arnt, J., Bang-Andersen, B., Grayson, B., Bymaster, F.P., Cohen, M.P., DeLapp, N.W., Giethlen, B., Kreilgaard, M., McKinzie, D.L., Neill, J.C., Nelson, D.L., Nielsen, S.M., Poulsen, M.N., Schaus, J.M., Witten, L.M., Lu AE58054, a 5-HT6 antagonist, reverses cognitive impairment induced by subchronic phencyclidine in a novel object recognition test in rats. Int. J. Neuropsychopharmacol. 13 (2010), 1021–1033.
4. Arroyo, S., Bennett, C., Aziz, D., Brown, S.P., Hestrin, S., Prolonged disynaptic inhibition in the cortex mediated by slow, non-alpha7 nicotinic excitation of a specific subset of cortical interneurons. J. Neurosci. 32 (2012), 3859–3864.
5. Asaoka, N., Nagayasu, K., Nishitani, N., Yamashiro, M., Shirakawa, H., Nakagawa, T., Kaneko, S., Olanzapine augments the effect of selective serotonin reuptake inhibitors by suppressing GABAergic inhibition via antagonism of 5-HT(6) receptors in the dorsal raphe nucleus. Neuropharmacology 95 (2015), 261–268.
6. Babiloni, C., Del, P.C., Bordet, R., Bourriez, J.L., Bentivoglio, M., Payoux, P., Derambure, P., Dix, S., Infarinato, F., Lizio, R., Triggiani, A.I., Richardson, J.C., Rossini, P.M., Effects of acetylcholinesterase inhibitors and memantine on resting-state electroencephalographic rhythms in Alzheimer's disease patients. Clin. Neurophysiol. 124 (2013), 837–850.
7. Baker, G.B., Reynolds, G.P., Biogenic amines and their metabolites in Alzheimer's disease: noradrenaline, 5-hydroxytryptamine and 5-hydroxyindole-3-acetic acid depleted in hippocampus but not in substantia innominata. Neurosci. Lett. 100 (1989), 335–339.
8. Basar, E., Basar-Eroglu, C., Guntekin, B., Yener, G.G., Brain's alpha, beta, gamma, delta, and theta oscillations in neuropsychiatric diseases: proposal for biomarker strategies. Suppl. Clin.Neurophysiol 62 (2013), 19–54.
9. Benhamu, B., Martin-Fontecha, M., Vazquez-Villa, H., Pardo, L., Lopez-Rodriguez, M.L., Serotonin 5-HT6 receptor antagonists for the treatment of cognitive deficiency in Alzheimer's disease. J. Med. Chem. 57 (2014), 7160–7181.
10. Birks, J., Harvey, R.J., Donepezil for dementia due to Alzheimer's disease. Cochrane. Database. Syst. Rev., 2006, CD001190.
11. Bland, B.H., The physiology and pharmacology of hippocampal formation theta rhythms. Prog. Neurobiol. 26 (1986), 1–54.
12. Blatow, M., Rozov, A., Katona, I., Hormuzdi, S.G., Meyer, A.H., Whittington, M.A., Caputi, A., Monyer, H., A novel network of multipolar bursting interneurons generates theta frequency oscillations in neocortex. Neuron 38 (2003), 805–817.
13. Bonsi, P., Cuomo, D., Ding, J., Sciamanna, G., Ulrich, S., Tscherter, A., Bernardi, G., Surmeier, D.J., Pisani, A., Endogenous serotonin excites striatal cholinergic interneurons via the activation of 5-HT 2C, 5-HT6, and 5-HT7 serotonin receptors: implications for extrapyramidal side effects of serotonin reuptake inhibitors. Neuropsychopharmacology 32 (2007), 1840–1854.
14. Borsini, F., Bordi, F., Poggi, A., Di, M. V, Effects of ST1936, a selective serotonin-6 agonist, on electrical activity of putative mesencephalic dopaminergic neurons in the rat brain. J. Psychopharmacol. 29 (2015), 802–811.
15. Bos, M., Sleight, A.J., Godel, T., Martin, J.R., Riemer, C., Stadler, H., 5-HT(6) receptor antagonists: lead optimisation and biological evaluation of N-aryl and N-heteroaryl 4-amino-benzene sulfonamides. Eur. J. Med. Chem. 36 (2001), 165–178.
16. Bourson, A., Borroni, E., Austin, R.H., Monsma, F.J. Jr., Sleight, A.J., Determination of the role of the 5-ht6 receptor in the rat brain: a study using antisense oligonucleotides. J. Pharmacol. Exp. Ther. 274 (1995), 173–180.
17. Bowen, D.M., Allen, S.J., Benton, J.S., Goodhardt, M.J., Haan, E.A., Palmer, A.M., Sims, N.R., Smith, C.C., Spillane, J.A., Esiri, M.M., Neary, D., Snowdon, J.S., Wilcock, G.K., Davison, A.N., Biochemical assessment of serotonergic and cholinergic dysfunction and cerebral atrophy in Alzheimer's disease. J. Neurochem. 41 (1983), 266–272.
18. Brouard, J.T., Schweimer, J.V., Houlton, R., Burnham, K.E., Queree, P., Sharp, T., Pharmacological evidence for 5-HT6 receptor modulation of 5-HT neuron firing in vivo. ACS Chem.Neurosci 6 (2015), 1241–1247.
19. Brouard, J.T., Herrik, K.F., De Jong, I.E., Sharp, T., In vivo pharmacological analysis of the effects of 5-HT6 receptor ligands on cortico-raphe connectivity. Accepted abstract at the Federation of European Neurosciences Societies meeting in Copenhagen, 2-6 July 2016.
20. Buhl, E.H., Tamas, G., Fisahn, A., Cholinergic activation and tonic excitation induce persistent gamma oscillations in mouse somatosensory cortex in vitro. J. Physiol. 513:Pt 1 (1998), 117–126.
21. Burnham, K.E., Baxter, M.G., Bainton, J.R., Southam, E., Dawson, L.A., Bannerman, D.M., Sharp, T., Activation of 5-HT(6) receptors facilitates attentional set shifting. Psychopharmacol. Berl. 208 (2010), 13–21.
22. Caputi, A., Rozov, A., Blatow, M., Monyer, H., Two calretinin-positive GABAergic cell types in layer 2/3 of the mouse neocortex provide different forms of inhibition. Cereb. Cortex 19 (2009), 1345–1359.
23. Cardin, J.A., Carlen, M., Meletis, K., Knoblich, U., Zhang, F., Deisseroth, K., Tsai, L.H., Moore, C.I., Driving fast-spiking cells induces gamma rhythm and controls sensory responses. Nature 459 (2009), 663–667.
24. Cho, K.K., Hoch, R., Lee, A.T., Patel, T., Rubenstein, J.L., Sohal, V.S., Gamma rhythms link prefrontal interneuron dysfunction with cognitive inflexibility in Dlx5/6(+/-) mice. Neuron 85 (2015), 1332–1343.
25. Chuang, A.T.T., Foley, A., Pugh, P.L., Sunter, D., Tong, X., Regan, C., Dawson, L.A., Medhurst, A.D., Upton, N., 5-HT6 receptor antagonist SB-742457 as a novel cognitive enhancing agent for Alzheimer's disease. Alzhheimers Dement. 2 (2006), 631–632.
26. Colgin, L.L., Denninger, T., Fyhn, M., Hafting, T., Bonnevie, T., Jensen, O., Moser, M.B., Moser, E.I., Frequency of gamma oscillations routes flow of information in the hippocampus. Nature 462 (2009), 353–357.
27. Cross, A.J., Crow, T.J., Johnson, J.A., Joseph, M.H., Perry, E.K., Perry, R.H., Blessed, G., Tomlinson, B.E., Monoamine metabolism in senile dementia of Alzheimer type. J. Neurol. Sci. 60 (1983), 383–392.
28. Cruikshank, S.J., Ahmed, O.J., Stevens, T.R., Patrick, S.L., Gonzalez, A.N., Elmaleh, M., Connors, B.W., Thalamic control of layer 1 circuits in prefrontal cortex. J. Neurosci. 32 (2012), 17813–17823.
29. Davies, P., Maloney, A.J., Selective loss of central cholinergic neurons in Alzheimer's disease. Lancet, 2, 1976, 1403.
30. Dawson, L.A., The central role of 5-HT6 receptors in modulating brain neurochemistry. Int. Rev. Neurobiol. 96 (2011), 1–26.
31. Dawson, L.A., Nguyen, H.Q., Li, P., In vivo effects of the 5-HT(6) antagonist SB-271046 on striatal and frontal cortex extracellular concentrations of noradrenaline, dopamine, 5-HT, glutamate and aspartate. Br. J. Pharmacol. 130 (2000), 23–26.
32. Dawson, L.A., Nguyen, H.Q., Li, P., The 5-HT(6) receptor antagonist SB-271046 selectively enhances excitatory neurotransmission in the rat frontal cortex and hippocampus. Neuropsychopharmacology 25 (2001), 662–668.
33. de Bruin, N.M., Prickaerts, J., van, L.A., Venhorst, J., de, G.L., Houba, P., Reneerkens, O., Akkerman, S., Kruse, C.G., Two novel 5-HT6 receptor antagonists ameliorate scopolamine-induced memory deficits in the object recognition and object location tasks in Wistar rats. Neurobiol. Learn. Mem. 96 (2011), 392–402.
34. de Bruin, N.M., van, L.A., Wicke, K.M., de, H.M., Venhorst, J., Lange, J.H., de, G.L., van der Neut, M.A., Prickaerts, J., Andriambeloson, E., Foley, A.G., van, D.M., van der Wetering, M., Kruse, C.G., The selective 5-HT6 receptor antagonist SLV has putative cognitive- and social interaction enhancing properties in rodent models of cognitive impairment. Neurobiol. Learn. Mem. 133 (2016), 100–117.
35. DeFelipe, J., Types of neurons, synaptic connections and chemical characteristics of cells immunoreactive for calbindin-D28K, parvalbumin and calretinin in the neocortex. J. Chem. Neuroanat. 14 (1997), 1–19.
36. del Rio, M.R., DeFelipe, J., Synaptic connections of calretinin-immunoreactive neurons in the human neocortex. J. Neurosci. 17 (1997), 5143–5154.
37. Draguhn, A., Keller, M., Reichinnek, S., Coordinated network activity in the hippocampus. Front. Neurol.Neurosci 34 (2014), 26–35.
38. Dringenberg, H.C., Alzheimer's disease: more than a ‘cholinergic disorder’ - evidence that cholinergic-monoaminergic interactions contribute to EEG slowing and dementia. Behav. Brain Res. 115 (2000), 235–249.
39. Dringenberg, H.C., Diavolitsis, P., Noseworthy, P.A., Effect of tacrine on EEG slowing in the rat: enhancement by concurrent monoamine therapy. Neurobiol. Aging 21 (2000), 135–143.
40. Duhr, F., Deleris, P., Raynaud, F., Seveno, M., Morisset-Lopez, S., C.C. Mannoury la, M.J. Millan, J. Bockaert, P. Marin, S. Chaumont-Dubel, Cdk5 induces constitutive activation of 5-HT6 receptors to promote neurite growth. Nat. Chem. Biol. 10 (2014), 590–597.
41. East, S.Z., Burnet, P.W., Leslie, R.A., Roberts, J.C., Harrison, P.J., 5-HT6 receptor binding sites in schizophrenia and following antipsychotic drug administration: autoradiographic studies with [125I]SB-258585. Synapse 45 (2002), 191–199.
42. Fellous, J.M., Sejnowski, T.J., Cholinergic induction of oscillations in the hippocampal slice in the slow (0.5-2 Hz), theta (5-12 Hz), and gamma (35-70 Hz) bands. Hippocampus 10 (2000), 187–197.
43. Ferrero, H., Solas, M., Francis, P.T., Ramirez, M.J., Serotonin 5-HT6 receptor antagonists in Alzheimer's disease: therapeutic rationale and current development status. CNS.Drugs 31 (2017), 19–32.
44. Ferris, C.F., Kulkarni, P., Nedelman, M., De Jong, I.E., The serotonin receptor 6 antagonist idalopirdine and acetylcholinesterase inhibitor donepezil have synergystic effects on brain activity - a functional MRI stduy in the awake rat. Front. Pharmacol., 8, 2017, 279 doi: http://dx.doi.org/10.3389/fphar.2017.00279.
45. Foley, A.G., Murphy, K.J., Hirst, W.D., Gallagher, H.C., Hagan, J.J., Upton, N., Walsh, F.S., Regan, C.M., The 5-HT(6) receptor antagonist SB-271046 reverses scopolamine-disrupted consolidation of a passive avoidance task and ameliorates spatial task deficits in aged rats. Neuropsychopharmacology 29 (2004), 93–100.
46. Fone, K.C., An update on the role of the 5-hydroxytryptamine6 receptor in cognitive function. Neuropharmacology 55 (2008), 1015–1022.
47. Foraster, M.A., Leiser, S.C., Herrik, K.F., Richard, N., Agerskov, C., Bundgaard, C., Bastlund, J.F., De Jong, I.E., The 5-HT6 receptor antagonist idalopirdine potentiates the effects of donepezil on gamma oscillations in the frontal cortex of anesthetized and awake rats without affecting sleep-wake architecture. Neuropharmacology 113 (2016), 45–59.
48. Francis, P.T., Glutamatergic systems in Alzheimer's disease. Int.J.Geriatr. Psychiatry 18 (2003), S15–S21.
49. Geldenhuys, W.J., Van der Schyf, C.J., Role of serotonin in Alzheimer's disease: a new therapeutic target?. CNS.Drugs 25 (2011), 765–781.
50. Gerard, C., el, M.S., Lebrand, C., Adrien, J., Ruat, M., Traiffort, E., Hamon, M., Martres, M.P., Quantitative RT-PCR distribution of serotonin 5-HT6 receptor mRNA in the central nervous system of control or 5,7-dihydroxytryptamine-treated rats. Synapse 23 (1996), 164–173.
51. Giacobini, E., Zhu, X.D., Williams, E., Sherman, K.A., The effect of the selective reversible acetylcholinesterase inhibitor E2020 on extracellular acetylcholine and biogenic amine levels in rat cortex. Neuropharmacology 35 (1996), 205–211.
52. Gonchar, Y., Burkhalter, A., Connectivity of GABAergic calretinin-immunoreactive neurons in rat primary visual cortex. Cereb. Cortex 9 (1999), 683–696.
53. Gonzalez-Vera, J.A., Medina, R.A., Martin-Fontecha, M., Gonzalez, A., de la Fuente, T., Vazquez-Villa, H., Garcia-Carceles, J., Botta, J., McCormick, P.J., Benhamu, B., Pardo, L., Lopez-Rodriguez, M.L., A new serotonin 5-HT6 receptor antagonist with procognitive activity - importance of a halogen bond interaction to stabilize the binding. Sci. Rep., 7, 2017, 41293.
54. Goutagny, R., Krantic, S., Hippocampal oscillatory activity in Alzheimer's disease: toward the identification of early biomarkers?. Aging Dis. 4 (2013), 134–140.
55. Gravius, A., Laszy, J., Pietraszek, M., Saghy, K., Nagel, J., Chambon, C., Wegener, N., Valastro, B., Danysz, W., Gyertyan, I., Effects of 5-HT6 antagonists, Ro-4368554 and SB-258585, in tests used for the detection of cognitive enhancement and antipsychotic-like activity. Behav. Pharmacol. 22 (2011), 122–135.
56. Grychowska, K., Satala, G., Kos, T., Partyka, A., Colacino, E., Chaumont-Dubel, S., Bantreil, X., Wesolowska, A., Pawlowski, M., Martinez, J., Marin, P., Subra, G., Bojarski, A.J., Lamaty, F., Popik, P., Zajdel, P., Novel 1H-Pyrrolo[3,2-c]quinoline based 5-HT6 receptor antagonists with potential application for the treatment of cognitive disorders associated with Alzheimer's disease. ACS Chem.Neurosci 7 (2016), 972–983.
57. Guadagna, S., Bundgaard, C., Hovelso, N., Volbracht, C., Francis, P.T., Egebjerg, J., Sotty, F., Memantine potentiates hippocampal theta oscillations at a therapeutic dose in anesthetized mice: a mechanistic link to its cognitive-enhancing properties. Neuropharmacology 62 (2012), 2208–2218.
58. Gulyas, A.I., Freund, T.F., Pyramidal cell dendrites are the primary targets of calbindin D28k-immunoreactive interneurons in the hippocampus. Hippocampus 6 (1996), 525–534.
59. Gulyas, A.I., Hajos, N., Freund, T.F., Interneurons containing calretinin are specialized to control other interneurons in the rat hippocampus. J. Neurosci. 16 (1996), 3397–3411.
60. Gulyas, A.I., Szabo, G.G., Ulbert, I., Holderith, N., Monyer, H., Erdelyi, F., Szabo, G., Freund, T.F., Hajos, N., Parvalbumin-containing fast-spiking basket cells generate the field potential oscillations induced by cholinergic receptor activation in the hippocampus. J. Neurosci. 30 (2010), 15134–15145.
61. Hatcher, P.D., Brown, V.J., Tait, D.S., Bate, S., Overend, P., Hagan, J.J., Jones, D.N., 5-HT6 receptor antagonists improve performance in an attentional set shifting task in rats. Psychopharmacol. Berl. 181 (2005), 253–259.
62. Heal, D., Gosden, J., Smith, S., The 5-HT6 receptor as a target for developing novel antiobesity drugs. Int. Rev. Neurobiol. 96 (2011), 73–109.
63. Helboe, L., Egebjerg, J., De Jong, I.E., Distribution of serotonin receptor 5-HT6 mRNA in rat neuronal subpopulations: a double in situ hybridization study. Neuroscience 310 (2015), 442–454.
64. Herrik, K.F., De Jong, I.E., Pedersen, J.T., Helboe, L., Arnt, J., Mørk, A., The 5-HT6 antagonist Lu AE58054 potentiates the effects of the acetylcholinesterase inhibitor donepezil on hippocampal extracellular acetylcholine efflux and oscillatory activity. Alzhheimers Dement., 9, 2013, P503.
65. Herrik, K.F., Mork, A., Richard, N., Bundgaard, C., Bastlund, J.F., De Jong, I.E., The 5-HT6 receptor antagonist idalopirdine potentiates the effects of acetylcholinesterase inhibition on neuronal network oscillations and extracellular acetylcholine levels in the rat dorsal hippocampus. Neuropharmacology 107 (2016), 351–363.
66. Hirst, W.D., Abrahamsen, B., Blaney, F.E., Calver, A.R., Aloj, L., Price, G.W., Medhurst, A.D., Differences in the central nervous system distribution and pharmacology of the mouse 5-hydroxytryptamine-6 receptor compared with rat and human receptors investigated by radioligand binding, site-directed mutagenesis, and molecular modeling. Mol. Pharmacol. 64 (2003), 1295–1308.
67. Hirst, W.D., Stean, T.O., Rogers, D.C., Sunter, D., Pugh, P., Moss, S.F., Bromidge, S.M., Riley, G., Smith, D.R., Bartlett, S., Heidbreder, C.A., Atkins, A.R., Lacroix, L.P., Dawson, L.A., Foley, A.G., Regan, C.M., Upton, N., SB-399885 is a potent, selective 5-HT6 receptor antagonist with cognitive enhancing properties in aged rat water maze and novel object recognition models. Eur. J. Pharmacol. 553 (2006), 109–119.
68. http://files.shareholder.com/downloads/AMDA-GGC00/3874732780x0x926925/C05FC4E6-75BB-4467-881D-53786BFBE2DD/LUNDBECK_ANNUAL_REPORT_2016.pdf.
69. Huang, Y., Yoon, K., Ko, H., Jiao, S., Ito, W., Wu, J.Y., Yung, W.H., Lu, B., Morozov, A., 5-HT3a Receptors modulate hippocampal gamma oscillations by regulating synchrony of parvalbumin-positive interneurons. Cereb. Cortex 26 (2014), 576–585.
70. Ichimiya, Y., Arai, H., Kosaka, K., Iizuka, R., Morphological and biochemical changes in the cholinergic and monoaminergic systems in Alzheimer-type dementia. Acta Neuropathol. 70 (1986), 112–116.
71. Ivachtchenko, A.V., Ivanenkov, Y.A., Veselov, M.S., Okun, I.M., AVN-322 is a safe orally bio-available potent and highly selective antagonist of 5-HT6R with demonstrated ability to improve impaired memory in animal models. Curr. Alzheimer Res. 14 (2017), 268–294.
72. Jackisch, R., Forster, S., Kammerer, M., Rothmaier, A.K., Ehret, A., Zentner, J., Feuerstein, T.J., Inhibitory potency of choline esterase inhibitors on acetylcholine release and choline esterase activity in fresh specimens of human and rat neocortex. J. Alzheimers. Dis. 16 (2009), 635–647.
73. Joosen, M.J., van Helden, H.P., Correlations between acetylcholinesterase inhibition, acetylcholine levels and EEG changes during perfusion with neostigmine and N6-cyclopentyladenosine in rat brain. Eur. J. Pharmacol. 555 (2007), 122–128.
74. Jutras, M.J., Fries, P., Buffalo, E.A., Gamma-band synchronization in the macaque hippocampus and memory formation. J. Neurosci. 29 (2009), 12521–12531.
75. Kendall, I., Slotten, H.A., Codony, X., Burgueno, J., Pauwels, P.J., Vela, J.M., Fone, K.C., E-6801, a 5-HT6 receptor agonist, improves recognition memory by combined modulation of cholinergic and glutamatergic neurotransmission in the rat. Psychopharmacol. Berl. 213 (2011), 413–430.
76. Kim, H., Ahrlund-Richter, S., Wang, X., Deisseroth, K., Carlen, M., Prefrontal parvalbumin neurons in control of attention. Cell 164 (2016), 208–218.
77. King, M.V., Sleight, A.J., Woolley, M.L., Topham, I.A., Marsden, C.A., Fone, K.C., 5-HT6 receptor antagonists reverse delay-dependent deficits in novel object discrimination by enhancing consolidation–an effect sensitive to NMDA receptor antagonism. Neuropharmacology 47 (2004), 195–204.
78. Kinney, G.G., Patino, P., Mermet-Bouvier, Y., Starrett, J.E. Jr., Gribkoff, V.K., Cognition-enhancing drugs increase stimulated hippocampal theta rhythm amplitude in the urethane-anesthetized rat. J. Pharmacol. Exp. Ther. 291 (1999), 99–106.
79. Lacroix, L.P., Dawson, L.A., Hagan, J.J., Heidbreder, C.A., 5-HT6 receptor antagonist SB-271046 enhances extracellular levels of monoamines in the rat medial prefrontal cortex. Synapse 51 (2004), 158–164.
80. Lai, M.K., Tsang, S.W., Francis, P.T., Keene, J., Hope, T., Esiri, M.M., Spence, I., Chen, C.P., Postmortem serotoninergic correlates of cognitive decline in Alzheimer's disease. Neuroreport 13 (2002), 1175–1178.
81. Lee, S.H., Lee, K.J., Lee, H.J., Ham, B.J., Ryu, S.H., Lee, M.S., Association between the 5-HT6 receptor C267T polymorphism and response to antidepressant treatment in major depressive disorder. Psychiatry Clin. Neurosci. 59 (2005), 140–145.
82. Lee, S., Hjerling-Leffler, J., Zagha, E., Fishell, G., Rudy, B., The largest group of superficial neocortical GABAergic interneurons expresses ionotropic serotonin receptors. J. Neurosci. 30 (2010), 16796–16808.
83. Leiser, S.C., Li, Y., Pehrson, A.L., Dale, E., Smagin, G., Sanchez, C., Serotonergic Regulation of prefrontal cortical circuitries involved in cognitive processing: a review of individual 5-HT Receptor mechanisms and concerted effects of 5-HT Receptors exemplified by the multimodal antidepressant vortioxetine. ACS Chem.Neurosci 6 (2015), 970–986.
84. Li, Z., Huang, M., Prus, A.J., Dai, J., Meltzer, H.Y., 5-HT6 receptor antagonist SB-399885 potentiates haloperidol and risperidone-induced dopamine efflux in the medial prefrontal cortex or hippocampus. Brain Res. 1134 (2007), 70–78.
85. Lieben, C.K., Blokland, A., Sik, A., Sung, E., van, N.P., Schreiber, R., The selective 5-HT6 receptor antagonist Ro4368554 restores memory performance in cholinergic and serotonergic models of memory deficiency in the rat. Neuropsychopharmacology 30 (2005), 2169–2179.
86. Lindner, M.D., Hodges, D.B. Jr., Hogan, J.B., Orie, A.F., Corsa, J.A., Barten, D.M., Polson, C., Robertson, B.J., Guss, V.L., Gillman, K.W., Starrett, J.E. Jr., Gribkoff, V.K., An assessment of the effects of serotonin 6 (5-HT6) receptor antagonists in rodent models of learning. J. Pharmacol. Exp. Ther. 307 (2003), 682–691.
87. Ly, S., Pishdari, B., Lok, L.L., Hajos, M., Kocsis, B., Activation of 5-HT6 receptors modulates sleep-wake activity and hippocampal theta oscillation. ACS Chem.Neurosci 4 (2013), 191–199.
88. Maher-Edwards, G., Zvartau-Hind, M., Hunter, A.J., Gold, M., Hopton, G., Jacobs, G., Davy, M., Williams, P., Double-blind, controlled phase II study of a 5-HT6 receptor antagonist, SB-742457, in Alzheimer's disease. Curr. Alzheimer Res. 7 (2010), 374–385.
89. Maher-Edwards, G., Dixon, R., Hunter, J., Gold, M., Hopton, G., Jacobs, G., Hunter, J., Williams, P., SB-742457 and donepezil in Alzheimer disease: a randomized, placebo-controlled study. Int.J.Geriatr. Psychiatry 26 (2011), 536–544.
90. Maher-Edwards, G., Watson, C., Ascher, J., Barnett, C., Boswell, D., Davies, J., Fernandez, M., Kurz, A., Zanetti, O., Safirstein, B., Schronen, J., Zvartau-Hind, M., Gold, M., Two randomized controlled trials of SB742457 in mild-to-moderate Alzheimer's disease. Alzheimer's Dementia Transl. Res. Clin. Interventions 1 (2015), 23–36.
91. Maragos, W.F., Greenamyre, J.T., Penney, J.B., Young, A.B., Glutamate dysfunction in Alzheimer's disease: an hypothesis. Trends Neurosci. 10 (1987), 65–68.
92. Marcos, B., Gil-Bea, F.J., Hirst, W.D., Garcia-Alloza, M., Ramirez, M.J., Lack of localization of 5-HT6 receptors on cholinergic neurons: implication of multiple neurotransmitter systems in 5-HT6 receptor-mediated acetylcholine release. Eur. J. Neurosci. 24 (2006), 1299–1306.
93. Marcos, B., Chuang, T.T., Gil-Bea, F.J., Ramirez, M.J., Effects of 5-HT6 receptor antagonism and cholinesterase inhibition in models of cognitive impairment in the rat. Br. J. Pharmacol. 155 (2008), 434–440.
94. McNaughton, N., Kocsis, B., Hajos, M., Elicited hippocampal theta rhythm: a screen for anxiolytic and procognitive drugs through changes in hippocampal function?. Behav. Pharmacol. 18 (2007), 329–346.
95. Meffre, J., Chaumont-Dubel, S., Mannoury la, C.C., Loiseau, F., Watson, D.J., Dekeyne, A., Seveno, M., Rivet, J.M., Gaven, F., Deleris, P., Herve, D., Fone, K.C., Bockaert, J., Millan, M.J., Marin, P., 5-HT(6) receptor recruitment of mTOR as a mechanism for perturbed cognition in schizophrenia. EMBO Mol.Med 4 (2012), 1043–1056.
96. Meneses, A., Effects of the 5-HT(6) receptor antagonist Ro 04-6790 on learning consolidation. Behav. Brain Res. 118 (2001), 107–110.
97. Meneses, A., 5-HT systems: emergent targets for memory formation and memory alterations. Rev. Neurosci. 24 (2013), 629–664.
98. Meneses, A., Liy-Salmeron, G., Serotonin and emotion, learning and memory. Rev. Neurosci. 23 (2012), 543–553.
99. Meneses, A., Perez-Garcia, G., Ponce-Lopez, T., Castillo, C., 5-HT6 receptor memory and amnesia: behavioral pharmacology–learning and memory processes. Int. Rev. Neurobiol. 96 (2011), 27–47.
100. Messina, D., Annesi, G., Serra, P., Nicoletti, G., Pasqua, A., Annesi, F., Tomaino, C., Ciro-Candiano, I.C., Carrideo, S., Caracciolo, M., Spadafora, P., Zappia, M., Savettieri, G., Quattrone, A., Association of the 5-HT6 receptor gene polymorphism C267T with Parkinson's disease. Neurology 58 (2002), 828–829.
101. Mitchell, E.S., Neumaier, J.F., 5-HT6 receptors: a novel target for cognitive enhancement. Pharmacol. Ther. 108 (2005), 320–333.
102. Mitchell, E.S., Neumaier, J.F., 5-HT6 receptor antagonist reversal of emotional learning and prepulse inhibition deficits induced by apomorphine or scopolamine. Pharmacol. Biochem. Behav. 88 (2008), 291–298.
103. Mohler, E.G., Baker, P.M., Gannon, K.S., Jones, S.S., Shacham, S., Sweeney, J.A., Ragozzino, M.E., The effects of PRX-07034, a novel 5-HT6 antagonist, on cognitive flexibility and working memory in rats. Psychopharmacol. Berl. 220 (2012), 687–696.
104. Monsma, F.J. Jr., Shen, Y., Ward, R.P., Hamblin, M.W., Sibley, D.R., Cloning and expression of a novel serotonin receptor with high affinity for tricyclic psychotropic drugs. Mol. Pharmacol. 43 (1993), 320–327.
105. Monti, J.M., Jantos, H., Schechter, L.E., The effects of systemic and local microinjection into the central nervous system of the selective serotonin 5-HT6 receptor agonist WAY-208466 on sleep and wakefulness in the rat. Behav. Brain Res. 249 (2013), 65–74.
106. Morales, M., Hein, K., Vogel, Z., Hippocampal interneurons co-express transcripts encoding the alpha7 nicotinic receptor subunit and the cannabinoid receptor 1. Neuroscience 152 (2008), 70–81.
107. Mork, A., Russell, R.V., De Jong, I.E., Smagin, G., Effects of the 5-HT6 receptor antagonist idalopirdine on extracellular levels of monoamines, glutamate and acetylcholine in the rat medial prefrontal cortex. Eur. J. Pharmacol. 799 (2017), 1–6.
108. Nazarali, A.J., Reynolds, G.P., Monoamine neurotransmitters and their metabolites in brain regions in Alzheimer's disease: a postmortem study. Cell Mol. Neurobiol. 12 (1992), 581–587.
109. Nikiforuk, A., Fijal, K., Potasiewicz, A., Popik, P., Kos, T., The 5-hydroxytryptamine (serotonin) receptor 6 agonist EMD 386088 ameliorates ketamine-induced deficits in attentional set shifting and novel object recognition, but not in the prepulse inhibition in rats. J. Psychopharmacol. 27 (2013), 469–476.
110. Nirogi, R.V., Kambhampati, R., Kothmirkar, P., Konda, J., Bandyala, T.R., Gudla, P., Arepalli, S., Gangadasari, N.P., Shinde, A.K., Deshpande, A.D., Dwarampudi, A., Chindhe, A.K., Dubey, P.K., Synthesis and structure-activity relationship of novel conformationally restricted analogues of serotonin as 5-HT6 receptor ligands. J.Enzyme Inhib.Med.Chem. 27 (2012), 443–450.
111. Nirogi, R.V., Bandyala, T.R., Gangadasari, P.R., Khagga, M., Synthesis and biological evaluation of novel N1-phenylsulphonyl indole derivatives as potent and selective 5-HT6R ligands for the treatment of cognitive disorders. J.Enzyme Inhib.Med.Chem. 31 (2016), 1–15.
112. Nirogi, R., Shinde, A., Kambhampati, R.S., Mohammed, A.R., Saraf, S.K., Badange, R.K., Bandyala, T.R., Bhatta, V., Bojja, K., Reballi, V., Subramanian, R., Benade, V., Palacharla, R.C., Bhyrapuneni, G., Jayarajan, P., Goyal, V., Jasti, V., Discovery and Development of 1-[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indol e Dimesylate Monohydrate (SUVN-502): a Novel, Potent, Selective and Orally Active Serotonin 6 (5-HT6) Receptor Antagonist for Potential Treatment of Alzheimer's Disease. J. Med. Chem. 60 (2017), 1843–1859.
113. Nyhus, E., Curran, T., Functional role of gamma and theta oscillations in episodic memory. Neurosci. Biobehav. Rev. 34 (2010), 1023–1035.
114. Olah, S., Fule, M., Komlosi, G., Varga, C., Baldi, R., Barzo, P., Tamas, G., Regulation of cortical microcircuits by unitary GABA-mediated volume transmission. Nature 461 (2009), 1278–1281.
115. Palmer, L.M., Schulz, J.M., Murphy, S.C., Ledergerber, D., Murayama, M., Larkum, M.E., The cellular basis of GABA(B)-mediated interhemispheric inhibition. Science 335 (2012), 989–993.
116. Palop, J.J., Chin, J., Mucke, L., A network dysfunction perspective on neurodegenerative diseases. Nature 443 (2006), 768–773.
117. Palop, J.J., Chin, J., Roberson, E.D., Wang, J., Thwin, M.T., Bien-Ly, N., Yoo, J., Ho, K.O., Yu, G.Q., Kreitzer, A., Finkbeiner, S., Noebels, J.L., Mucke, L., Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer's disease. Neuron 55 (2007), 697–711.
118. Parker, C.A., Gunn, R.N., Rabiner, E.A., Slifstein, M., Comley, R., Salinas, C., Johnson, C.N., Jakobsen, S., Houle, S., Laruelle, M., Cunningham, V.J., Martarello, L., Radiosynthesis and characterization of 11C-GSK215083 as a PET radioligand for the 5-HT6 receptor. J. Nucl. Med. 53 (2012), 295–303.
119. Pereira, M., Martynhak, B.J., Andreatini, R., Svenningsson, P., 5-HT6 receptor agonism facilitates emotional learning. Front. Pharmacol. 6 (2015), 1–9.
120. Perez-Garcia, G., Meneses, A., Oral administration of the 5-HT6 receptor antagonists SB-357134 and SB-399885 improves memory formation in an autoshaping learning task. Pharmacol. Biochem. Behav. 81 (2005), 673–682.
121. Phillips, J.M., Ehrlichman, R.S., Siegel, S.J., Mecamylamine blocks nicotine-induced enhancement of the P20 auditory event-related potential and evoked gamma. Neuroscience 144 (2007), 1314–1323.
122. Puig, M.V., Santana, N., Celada, P., Mengod, G., Artigas, F., In vivo excitation of GABA interneurons in the medial prefrontal cortex through 5-HT3 receptors. Cereb. Cortex 14 (2004), 1365–1375.
123. Raina, P., Santaguida, P., Ismaila, A., Patterson, C., Cowan, D., Levine, M., Booker, L., Oremus, M., Effectiveness of cholinesterase inhibitors and memantine for treating dementia: evidence review for a clinical practice guideline. Ann. Intern. Med. 148 (2008), 379–397.
124. Ramirez, M.J., 5-HT6 receptors and Alzheimer's disease. Alzheimers. Res. Ther. 5 (2013), 2–15.
125. Reznic, J., Staubli, U., Effects of 5-HT3 receptor antagonism on hippocampal cellular activity in the freely moving rat. J. Neurophysiol. 77 (1997), 517–521.
126. Riccioni, T., Bordi, F., Minetti, P., Spadoni, G., Yun, H.M., Im, B.H., Tarzia, G., Rhim, H., Borsini, F., ST1936 stimulates cAMP, Ca2+, ERK1/2 and Fyn kinase through a full activation of cloned human 5-HT6 receptors. Eur. J. Pharmacol. 661 (2011), 8–14.
127. Riemer, C., Borroni, E., Levet-Trafit, B., Martin, J.R., Poli, S., Porter, R.H., Bos, M., Influence of the 5-HT6 receptor on acetylcholine release in the cortex: pharmacological characterization of 4-(2-bromo-6-pyrrolidin-1-ylpyridine-4-sulfonyl)phenylamine, a potent and selective 5-HT6 receptor antagonist. J. Med. Chem. 46 (2003), 1273–1276.
128. Riga, M.S., Sanchez, C., Celada, P., Artigas, F., Involvement of 5-HT receptors in the action of vortioxetine in rat brain: focus on glutamatergic and GABAergic neurotransmission. Neuropharmacology 108 (2016), 73–81.
129. Roberts, J.C., Reavill, C., East, S.Z., Harrison, P.J., Patel, S., Routledge, C., Leslie, R.A., The distribution of 5-HT(6) receptors in rat brain: an autoradiographic binding study using the radiolabelled 5-HT(6) receptor antagonist [(125)I]SB-258585. Brain Res. 934 (2002), 49–57.
130. Rodefer, J.S., Nguyen, T.N., Karlsson, J.J., Arnt, J., Reversal of subchronic PCP-induced deficits in attentional set shifting in rats by sertindole and a 5-HT6 receptor antagonist: comparison among antipsychotics. Neuropsychopharmacology 33 (2008), 2657–2666.
131. Rogers, D.C., Hagan, J.J., 5-HT6 receptor antagonists enhance retention of a water maze task in the rat. Psychopharmacol. Berl. 158 (2001), 114–119.
132. Romero, G., Pujol, M., Perez, P., Buschmann, H., Pauwels, P.J., Whole spectrum analysis of ligand efficacy at constitutively active human wild-type and S267K 5-HT6 receptors in HEK-293F cells. J.Pharmacol.Toxicol. Methods 55 (2007), 144–150.
133. Rossor, M., Iversen, L.L., Non-cholinergic neurotransmitter abnormalities in Alzheimer's disease. Br. Med. Bull. 42 (1986), 70–74.
134. Ruat, M., Traiffort, E., Arrang, J.M., Tardivel-Lacombe, J., Diaz, J., Leurs, R., Schwartz, J.C., A novel rat serotonin (5-HT6) receptor: molecular cloning, localization and stimulation of cAMP accumulation. Biochem. Biophys. Res. Commun. 193 (1993), 268–276.
135. Rudy, B., Fishell, G., Lee, S., Hjerling-Leffler, J., Three groups of interneurons account for nearly 100% of neocortical GABAergic neurons. Dev. Neurobiol. 71 (2011), 45–61.
136. Schechter, L.E., Lin, Q., Smith, D.L., Zhang, G., Shan, Q., Platt, B., Brandt, M.R., Dawson, L.A., Cole, D., Bernotas, R., Robichaud, A., Rosenzweig-Lipson, S., Beyer, C.E., Neuropharmacological profile of novel and selective 5-HT6 receptor agonists: WAY-181187 and WAY-208466. Neuropsychopharmacology 33 (2008), 1323–1335.
137. Schmitt, J.A., Wingen, M., Ramaekers, J.G., Evers, E.A., Riedel, W.J., Serotonin and human cognitive performance. Curr. Pharm. Des. 12 (2006), 2473–2486.
138. Schreiber, R., Vivian, J., Hedley, L., Szczepanski, K., Secchi, R.L., Zuzow, M., van, L.S., Moreau, J.L., Martin, J.R., Sik, A., Blokland, A., Effects of the novel 5-HT(6) receptor antagonist RO4368554 in rat models for cognition and sensorimotor gating. Eur. Neuropsychopharmacol. 17 (2007), 277–288.
139. Shearman, E., Rossi, S., Szasz, B., Juranyi, Z., Fallon, S., Pomara, N., Sershen, H., Lajtha, A., Changes in cerebral neurotransmitters and metabolites induced by acute donepezil and memantine administrations: a microdialysis study. Brain Res. Bull. 69 (2006), 204–213.
140. Shirazi-Southall, S., Rodriguez, D.E., Nomikos, G.G., Effects of typical and atypical antipsychotics and receptor selective compounds on acetylcholine efflux in the hippocampus of the rat. Neuropsychopharmacology 26 (2002), 583–594.
141. Shukla, R., Watakabe, A., Yamamori, T., mRNA expression profile of serotonin receptor subtypes and distribution of serotonergic terminations in marmoset brain. Front. Neural Circuits 8 (2014), 1–22.
142. Singer, J.M., Wilson, M.W., Johnson, P.D., Graham, S.R., Cooke, L.W., Roof, R.L., Boxer, P.A., Gold, L.H., Meltzer, L.T., Janssen, A., Roush, N., Campbell, J.E., Su, T.Z., Hurst, S.I., Stoner, C.L., Schwarz, J.B., Synthesis and SAR of tolylamine 5-HT6 antagonists. Bioorg. Med. Chem. Lett. 19 (2009), 2409–2412.
143. Sleight, A.J., Monsma, F.J. Jr., Borroni, E., Austin, R.H., Bourson, A., Effects of altered 5-ht6 expression in the rat: functional studies using antisense oligonucleotides. Behav. Brain Res. 73 (1996), 245–248.
144. Spencer, J.P., Middleton, L.J., Davies, C.H., Investigation into the efficacy of the acetylcholinesterase inhibitor, donepezil, and novel procognitive agents to induce gamma oscillations in rat hippocampal slices. Neuropharmacology 59 (2010), 437–443.
145. Staubli, U., Xu, F.B., Effects of 5-HT3 receptor antagonism on hippocampal theta rhythm, memory, and LTP induction in the freely moving rat. J. Neurosci. 15 (1995), 2445–2452.
146. Stean, T.O., Hirst, W.D., Thomas, D.R., Price, G.W., Rogers, D., Riley, G., Bromidge, S.M., Serafinowska, H.T., Smith, D.R., Bartlett, S., Deeks, N., Duxon, M., Upton, N., Pharmacological profile of SB-357134: a potent, selective, brain penetrant, and orally active 5-HT(6) receptor antagonist. Pharmacol. Biochem. Behav. 71 (2002), 645–654.
147. Steriade, M., Brainstem activation of thalamocortical systems. Brain Res. Bull. 50 (1999), 391–392.
148. Talpos, J.C., Wilkinson, L.S., Robbins, T.W., A comparison of multiple 5-HT receptors in two tasks measuring impulsivity. J. Psychopharmacol. 20 (2006), 47–58.
149. Tamas, G., Lorincz, A., Simon, A., Szabadics, J., Identified sources and targets of slow inhibition in the neocortex. Science 299 (2003), 1902–1905.
150. Tan, C.C., Yu, J.T., Wang, H.F., Tan, M.S., Meng, X.F., Wang, C., Jiang, T., Zhu, X.C., Tan, L., Efficacy and safety of donepezil, galantamine, rivastigmine, and memantine for the treatment of Alzheimer's disease: a systematic review and meta-analysis. J. Alzheimers. Dis. 41 (2014), 615–631.
151. Tassone, A., Madeo, G., Schirinzi, T., Vita, D., Puglisi, F., Ponterio, G., Borsini, F., Pisani, A., Bonsi, P., Activation of 5-HT6 receptors inhibits corticostriatal glutamatergic transmission. Neuropharmacology 61 (2011), 632–637.
152. Thur, K.E., Nelson, A.J., Cassaday, H.J., Ro 04-6790-induced cognitive enhancement: no effect in trace conditioning and novel object recognition procedures in adult male Wistar rats. Pharmacol. Biochem. Behav. 127 (2014), 42–48.
153. Traub, R.D., Jefferys, J.G., Whittington, M.A., Functionally relevant and functionally disruptive (epileptic) synchronized oscillations in brain slices. Adv. Neurol. 79 (1999), 709–724.
154. Traub, R.D., Bibbig, A., Fisahn, A., LeBeau, F.E., Whittington, M.A., Buhl, E.H., A model of gamma-frequency network oscillations induced in the rat CA3 region by carbachol in vitro. Eur. J. Neurosci. 12 (2000), 4093–4106.
155. Tsai, S.J., Chiu, H.J., Wang, Y.C., Hong, C.J., Association study of serotonin-6 receptor variant (C267T) with schizophrenia and aggressive behavior. Neurosci. Lett. 271 (1999), 135–137.
156. Tsai, S.J., Liu, H.C., Liu, T.Y., Wang, Y.C., Hong, C.J., Association analysis of the 5-HT6 receptor polymorphism C267T in Alzheimer's disease. Neurosci. Lett. 276 (1999), 138–139.
157. Upton, N., Chuang, T.T., Hunter, A.J., Virley, D.J., 5-HT6 receptor antagonists as novel cognitive enhancing agents for Alzheimer's disease. Neurotherapeutics 5 (2008), 458–469.
158. Valentini, V., Frau, R., Bordi, F., Borsini, F., Di, C.G., A microdialysis study of ST1936, a novel 5-HT6 receptor agonist. Neuropharmacology 60 (2011), 602–608.
159. Vandecasteele, M., Varga, V., Berenyi, A., Papp, E., Bartho, P., Venance, L., Freund, T.F., Buzsaki, G., Optogenetic activation of septal cholinergic neurons suppresses sharp wave ripples and enhances theta oscillations in the hippocampus. Proc. Natl. Acad. Sci. U.S.A 111 (2014), 13535–13540.
160. Wang, H.Y., Lu, C.W., Lin, T.Y., Kuo, J.R., Wang, S.J., WAY208466 inhibits glutamate release at hippocampal nerve terminals. Eur. J. Pharmacol. 781 (2016), 117–127.
161. Wesolowska, A., Jastrzebska-Wiesek, M., Behavioral pharmacology: potential antidepressant and anxiolytic properties. Int. Rev. Neurobiol. 96 (2011), 49–71.
162. West, P.J., Marcy, V.R., Marino, M.J., Schaffhauser, H., Activation of the 5-HT(6) receptor attenuates long-term potentiation and facilitates GABAergic neurotransmission in rat hippocampus. Neuroscience 164 (2009), 692–701.
163. Whitehouse, P.J., Price, D.L., Struble, R.G., Clark, A.W., Coyle, J.T., Delon, M.R., Alzheimer's disease and senile dementia: loss of neurons in the basal forebrain. Science 215 (1982), 1237–1239.
164. Whittington, M.A., Traub, R.D., Jefferys, J.G., Synchronized oscillations in interneuron networks driven by metabotropic glutamate receptor activation. Nature 373 (1995), 612–615.
165. Wilkinson, D., Windfeld, K., Colding-Jorgensen, E., Safety and efficacy of idalopirdine, a 5-HT6 receptor antagonist, in patients with moderate Alzheimer's disease (LADDER): a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Neurol. 13 (2014), 1092–1099.
166. Woolley, M.L., Bentley, J.C., Sleight, A.J., Marsden, C.A., Fone, K.C., A role for 5-ht6 receptors in retention of spatial learning in the Morris water maze. Neuropharmacology 41 (2001), 210–219.
167. Woolley, M.L., Marsden, C.A., Sleight, A.J., Fone, K.C., Reversal of a cholinergic-induced deficit in a rodent model of recognition memory by the selective 5-HT6 receptor antagonist, Ro 04-6790. Psychopharmacol. Berl. 170 (2003), 358–367.
168. Woolley, M.L., Marsden, C.A., Fone, K.C., 5-ht6 receptors. Curr. Drug Targets.CNS.Neurol.Disord 3 (2004), 59–79.
169. Yu, Y.W., Tsai, S.J., Lin, C.H., Hsu, C.P., Yang, K.H., Hong, C.J., Serotonin-6 receptor variant (C267T) and clinical response to clozapine. Neuroreport 10 (1999), 1231–1233.
170. Yun, H.M., Kim, S., Kim, H.J., Kostenis, E., Kim, J.I., Seong, J.Y., Baik, J.H., Rhim, H., The novel cellular mechanism of human 5-HT6 receptor through an interaction with Fyn. J. Biol. Chem. 282 (2007), 5496–5505.
171. Zhang, J.Y., Nawoschik, S., Kowal, D., Smith, D., Spangler, T., Ochalski, R., Schechter, L., Dunlop, J., Characterization of the 5-HT6 receptor coupled to Ca2+ signaling using an enabling chimeric G-protein. Eur. J. Pharmacol. 472 (2003), 33–38.
172. Zhu, X.D., Cuadra, G., Brufani, M., Maggi, T., Pagella, P.G., Williams, E., Giacobini, E., Effects of MF-268, a new cholinesterase inhibitor, on acetylcholine and biogenic amines in rat cortex. J. Neurosci. Res. 43 (1996), 120–126.