Can small molecules provide truly effective enhancement of cognition? Current achievements and future directions

Expert Opinion on Investigational Drugs

Volumn 20, Issue 6, 2011, Pages 795-811

  Plath, Niels ^a   Lerdrup, Linda ^a   Larsen, Peter Hjørringgaard ^a   Redrobe, John Paul ^a  

^a H LUNDBECK A S   (Denmark)

Author keywords

animal models; cognition; cognitive remediation training; functional outcome; translational medicine

Indexed keywords

2 CHLORO N [ALPHA (2 PIPERIDINYL)BENZYL] 3 TRIFLUOROMETHYLBENZAMIDE; 3 (2,4 DIMETHOXYBENZYLIDENE)ANABASEINE; 3 PHENYLSULFONYL 8 (1 PIPERAZINYL)QUINOLINE; ABIXA; CARIM; DAVUNETIDE; DIMEBON; EVP 6124; HISTAMINE H3 RECEPTOR ANTAGONIST; ISPRONICLINE; MEM 3454; MEMANTINE; MEMOX; METABOTROPIC RECEPTOR 2; METABOTROPIC RECEPTOR 3; METABOTROPIC RECEPTOR AGONIST; METHYLPHENIDATE; MK 0249; MODAFINIL; MODAFINILO; MODALERT; NICOTINIC RECEPTOR; NOOTROPIC AGENT; POMAGLUMETAD METHIONIL; POZANICLINE; RG 1678; RO 5313534; SAM 531; SARCOSINE; SEROTONIN 6 RECEPTOR; SSR 103800; SUVN 502; TC 5619; THIOPERAMIDE; UNCLASSIFIED DRUG; UNINDEXED DRUG; VIGIA;

COGNITIVE DEFECT; DRUG ACTIVITY; DRUG EFFICACY; DRUG INDICATION; DRUG MECHANISM; DRUG RESEARCH; DRUG TARGETING; HUMAN; NONHUMAN; REVIEW;

AGE FACTORS; ANIMALS; BIOLOGICAL MARKERS; CENTRAL NERVOUS SYSTEM DISEASES; COGNITION; COGNITION DISORDERS; DRUG DESIGN; ELECTROENCEPHALOGRAPHY; HUMANS; MENTAL DISORDERS; QUALITY OF LIFE; TRANSLATIONAL RESEARCH;

EID: 79955824983     PISSN: 13543784     EISSN: None     Source Type: Journal    
DOI: 10.1517/13543784.2011.574612     Document Type: Review

References (143)

1. Neisser U. Cognitive psychology. Prentice Hall; 1967
2. Raina P, Santaguida P, Ismaila A, et al. Effectiveness of cholinesterase inhibitors and memantine for treating dementia: evidence review for a clinical practice guideline. Ann Intern.Med 2008;148:379-97 (Pubitemid 351665469)
3. Parsons CG, Stoffler A, Danysz W. Memantine: a NMDA receptor antagonist that improves memory by restoration of homeostasis in the glutamatergic system-too little activation is bad, too much is even worse. Neuropharmacology 2007;53:699-723 (Pubitemid 47532143)
4. Birks J. Cholinesterase inhibitors for Alzheimer's disease. Cochrane Database Syst Rev 2006:CD005593
5. Lopez OL, Becker JT, Wahed AS, et al. Long-term effects of the concomitant use of memantine with cholinesterase inhibition in Alzheimer disease. J Neurol Neurosurg Psychiatry 2009;80:600-7
6. Ribeiz SR, Bassitt DP, Arrais JA, et al. Cholinesterase inhibitors as adjunctive therapy in patients with schizophrenia and schizoaffective disorder: a review and meta-analysis of the literature. CNS Drugs 2010;24:303-17
7. Kavirajan H, Schneider LS. Efficacy and adverse effects of cholinesterase inhibitors and memantine in vascular dementia: a meta-analysis of randomised controlled trials. Lancet Neurol 2007;6:782-92 (Pubitemid 47243710)
8. Samuel W, Caligiuri M, Galasko D, et al. Better cognitive and psychopathologic response to donepezil in patients prospectively diagnosed as dementia with Lewy bodies: a preliminary study. Int J Geriatr Psychiatry 2000;15:794-802
9. Ravina B, Putt M, Siderowf A, et al. Donepezil for dementia in Parkinson's disease: a randomised, double blind, placebo controlled, crossover study. J Neurol Neurosurg Psychiatry 2005;76:934-9 (Pubitemid 40909549)
10. Leroi I, Brandt J, Reich SG, et al. Randomized placebo-controlled trial of donepezil in cognitive impairment in Parkinson's disease. Int J Geriatr Psychiatry 2004;19:1-8 (Pubitemid 38180686)
11. Christodoulou C, Melville P, Scherl WF, et al. Effects of donepezil on memory and cognition in multiple sclerosis. J Neurol Sci 2006;245:127-36 (Pubitemid 43775935)
12. Kesler SR, Lightbody AA, Reiss AL. Cholinergic dysfunction in fragile X syndrome and potential intervention: a preliminary 1H MRS study. Am.J Med Genet A 2009;149A:403-7
13. Lindner MD, McArthur RA, Deadwyler SA, et al. Development, Optimization and Use of Preclinical Behavioral Models to Maximize the Productivity of Drug Discovery for Alzheimer's Disease. In: McArthur RA, Borsini F, editors, In Animal and Translational Models for CNS Drug Discovery. Academic Press, Elsevier; 2008. p. 93-157
14. Lindner MD, Hogan JB, Hodges DB Jr, et al. Donepezil primarily attenuates scopolamine-induced deficits in psychomotor function, with moderate effects on simple conditioning and attention, and small effects on working memory and spatial mapping. Psychopharmacology 2006;188:629-40 (Pubitemid 46758973)
15. Martinez-Coria H, Green KN, Billings LM, et al. Memantine improves cognition and reduces Alzheimer's-like neuropathology in transgenic mice. Am J Pathol 2010;176:870-80
16. DecisionBase. Cognitive Impairment Associated with Schizophrenia: Emerging Consensus Expected to Define a New Indication as Physicians Await the Launch of the First Approved Drug. 2009. Decision Resources
17. Kumar R. Approved and investigational uses of modafinil: an evidence-based review. Drugs 2008;68:1803-39
18. Lee YS, Silva AJ. The molecular and cellular biology of enhanced cognition. Nat Rev Neurosci 2009;10:126-40
19. Buccafusco JJ. Emerging cognitive enhancing drugs. Expert Opin Emerg Drugs 2009;14:577-89
20. Hunter J. Animal and translational models of neurological disorders. In: McArthur RA, Borsini F, editors, In Animal and translational models for CNS drug discovery. Animal and translational models for CNS drug discovery. Elsevier; 2010
21. Carpenter WT, Koenig JI. The evolution of drug development in schizophrenia: past issues and future opportunities. Neuropsychopharmacology 2008;33:2061-79 (Pubitemid 351992095)
22. Korczyn AD, Aharonson V. Computerized methods in the assessment and prediction of dementia. Curr Alzheimer Res 2007;4:364-9 (Pubitemid 47416629)
23. Newman LA, Darling J, McGaughy J. Atomoxetine reverses attentional deficits produced by noradrenergic deafferentation of medial prefrontal cortex. Psychopharmacology 2008;200:39-50
24. Kukull WA, Higdon R, Bowen JD, et al. Dementia and Alzheimer disease incidence: a prospective cohort study. Arch Neurol 2002;59:1737-46 (Pubitemid 35340484)
25. Kawas C, Gray S, Brookmeyer R, et al. Age-specific incidence rates of Alzheimer's disease: the Baltimore Longitudinal Study of Aging. Neurology 2000;54:2072-7 (Pubitemid 30397204)
26. Gallagher M, Rapp PR. The use of animal models to study the effects of aging on cognition. Annu Rev Psychol 1997;48:339-70 (Pubitemid 127485180)
27. Hilborn JV, Strauss E, Hultsch DF, Hunter MA. Intraindividual variability across cognitive domains: investigation of dispersion levels and performance profiles in older adults. J Clin Exp Neuropsychol 2009;31:412-24
28. Stark SM, Yassa MA, Stark CE: Individual differences in spatial pattern separation performance associated with healthy aging in humans. Learn.Mem. 2010;17:284-8
29. Toner CK, Pirogovsky E, Kirwan CB, Gilbert PE. Visual object pattern separation deficits in nondemented older adults. Learn Mem 2009;16:338-42
30. Bakker A, Kirwan CB, Miller M, Stark CE. Pattern separation in the human hippocampal CA3 and dentate gyrus. Science 2008;319:1640-2 (Pubitemid 351432495)
31. Yassa MA, Stark SM, Bakker A, et al. High-resolution structural and functional MRI of hippocampal CA3 and dentate gyrus in patients with amnestic Mild Cognitive Impairment. Neuroimage 2010;51:1242-52
32. Miller SL, Celone K, DePeau K, et al. Age-related memory impairment associated with loss of parietal deactivation but preserved hippocampal activation. Proc Natl Acad Sci USA 2008;105:2181-6 (Pubitemid 351439485)
33. Wilson IA, Gallagher M, Eichenbaum H, Tanila H. Neurocognitive aging: prior memories hinder new hippocampal encoding. Trends Neurosci 2006;29:662-70 (Pubitemid 44779851)
34. Wilson IA, Ikonen S, McMahan RW, et al. Place cell rigidity correlates with impaired spatial learning in aged rats. Neurobiol Aging 2003;24:297-305 (Pubitemid 36007811)
35. Wilson IA, Ikonen S, Gallagher M, et al. Age-associated alterations of hippocampal place cells are subregion specific. J Neurosci 2005;25:6877-86 (Pubitemid 41023155)
36. Koh MT, Haberman RP, Foti S, et al. Treatment strategies targeting excess hippocampal activity benefit aged rats with cognitive impairment. Neuropsychopharmacology 2010;35:1016-25
37. Hunter MD, Ganesan V, Wilkinson ID, Spence SA. Impact of modafinil on prefrontal executive function in schizophrenia. Am J Psychiatry 2006;163:2184-6 (Pubitemid 46114242)
38. Birrell JM, Brown VJ. Medial frontal cortex mediates perceptual attentional set shifting in the rat. J Neurosci 2000;20:4320-4 (Pubitemid 30365702)
39. Turner DC, Clark L, Pomarol-Clotet E, et al. Modafinil improves cognition and attentional set shifting in patients with chronic schizophrenia. Neuropsychopharmacology 2004;29:1363-73 (Pubitemid 38780659)
40. Goetghebeur P, Dias R. Comparison of haloperidol, risperidone, sertindole, and modafinil to reverse an attentional set-shifting impairment following subchronic PCP administration in the rat-a back translational study. Psychopharmacology 2009;202:287-93
41. Antonova E, Parslow D, Brammer M, et al. Scopolamine disrupts hippocampal activity during allocentric spatial memory in humans: an fMRI study using a virtual reality analogue of the Morris Water Maze. J Psychopharmacol 2010 [Epub ahead of print]
42. Kahana MJ, Sekuler R, Caplan JB, et al. Human theta oscillations exhibit task dependence during virtual maze navigation. Nature 1999;399:781-4 (Pubitemid 29293173)
43. Cornwell BR, Johnson LL, Holroyd T, et al. Human hippocampal and parahippocampal theta during goal-directed spatial navigation predicts performance on a virtual Morris water maze. J Neurosci 2008;28:5983-90
44. Day M, Balci F, Wan HI, et al. Cognitive endpoints as disease biomarkers: optimizing the congruency of preclinical models to the clinic. Curr Opin Investig Drugs 2008;9:696-706 (Pubitemid 351950866)
45. Harvey PD, Green MF, Keefe RS, Velligan DI. Cognitive functioning in schizophrenia: a consensus statement on its role in the definition and evaluation of effective treatments for the illness. J Clin Psychiatry 2004;65:361-72
46. Green MF, Kern RS, Braff DL, Mintz J. Neurocognitive deficits and functional outcome in schizophrenia: are we measuring the "right stuff"? Schizophr Bull 2000;26:119-36 (Pubitemid 30317696)
47. Addington J, Addington D. Neurocognitive and social functioning in schizophrenia: a 2.5 year follow-up study. Schizophr Res 2000;44:47-56 (Pubitemid 30365206)
48. Kurtz MM, Moberg PJ, Ragland JD, et al. Symptoms versus neurocognitive test performance as predictors of psychosocial status in schizophrenia: a 1-and 4-year prospective study. Schizophr Bull 2005;31:167-74 (Pubitemid 41214365)
49. Prouteau A, Verdoux H, Briand C, et al. Cognitive predictors of psychosocial functioning outcome in schizophrenia: a follow-up study of subjects participating in a rehabilitation program. Schizophr Res 2005;77:343-53 (Pubitemid 41112227)
50. Hofer A, Baumgartner S, Bodner T, et al. Patient outcomes in schizophrenia II: the impact of cognition. Eur Psychiatry 2005;20:395-402 (Pubitemid 41318005)
51. Koren D, Seidman LJ, Goldsmith M, Harvey PD. Real-world cognitive-and metacognitive-dysfunction in schizophrenia: a new approach for measuring (and remediating) more "right stuff". Schizophr Bull 2006;32:310-26
52. Fujii DE, Wylie AM, Nathan JH. Neurocognition and long-term prediction of quality of life in outpatients with severe and persistent mental illness. Schizophr Res 2004;69:67-73 (Pubitemid 38625760)
53. Brekke JS, Kohrt B, Green MF. Neuropsychological functioning as a moderator of the relationship between psychosocial functioning and the subjective experience of self and life in schizophrenia. Schizophr Bull 2001;27:697-708 (Pubitemid 34093255)
54. Green MF, Kern RS, Heaton RK. Longitudinal studies of cognition and functional outcome in schizophrenia: implications for MATRICS. Schizophr Res 2004;72:41-51 (Pubitemid 39452904)
55. Startup M, Jackson MC, Bendix S. The concurrent validity of the Global Assessment of Functioning (GAF). Br J Clin Psychol 2002;41:417-22 (Pubitemid 35439333)
56. Soderberg P, Tungstrom S, Armelius BA. Reliability of global assessment of functioning ratings made by clinical psychiatric staff. Psychiatr Serv 2005;56:434-8 (Pubitemid 40471585)
57. Bowie CR, Harvey PD. Cognition in schizophrenia: impairments, determinants, and functional importance. Psychiatr Clin North Am 2005;28:613-33, 626 (Pubitemid 41191137)
58. Fleischhacker WW, Rabinowitz J, Kemmler G, et al. Perceived functioning, well-being and psychiatric symptoms in patients with stable schizophrenia treated with long-acting risperidone for 1 year. Br J Psychiatry 2005;187:131-6 (Pubitemid 41139684)
59. McKibbin CL, Brekke JS, Sires D, et al. Direct assessment of functional abilities: relevance to persons with schizophrenia. Schizophr Res 2004;72:53-67 (Pubitemid 39452905)
60. Patterson TL, Goldman S, McKibbin CL, et al. UCSD Performance-Based Skills Assessment: development of a new measure of everyday functioning for severely mentally ill adults. Schizophr Bull 2001;27:235-45 (Pubitemid 33644299)
61. Eisler RM, Hersen M, Miller PM, Blanchard EB. Situational determinants of assertive behaviors. J Consult Clin Psychol 1975;43:330-40
62. Cohen AS, Forbes CB, Mann MC, Blanchard JJ. Specific cognitive deficits and differential domains of social functioning impairment in schizophrenia. Schizophr Res 2006;81:227-38 (Pubitemid 43107697)
63. Addae JI, Youssef FF, Stone TW. Neuroprotective role of learning in dementia: a biological explanation. J Alzheimers Dis 2003;5:91-104 (Pubitemid 36582769)
64. Laurin D, Verreault R, Lindsay J, et al. Physical activity and risk of cognitive impairment and dementia in elderly persons. Arch Neurol 2001;58:498-504 (Pubitemid 32217469)
65. Lazarov O, Robinson J, Tang YP, et al. Environmental enrichment reduces Abeta levels and amyloid deposition in transgenic mice. Cell 2005;120:701-13 (Pubitemid 40343081)
66. van Praag H, Kempermann G, Gage FH. Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nat Neurosci 1999;2:266-70 (Pubitemid 30491298)
67. Kempermann G, Kuhn HG, Gage FH. More hippocampal neurons in adult mice living in an enriched environment. Nature 1997;386:493-5 (Pubitemid 27164074)
68. Medalia A, Choi J. Cognitive remediation in schizophrenia. Neuropsychol Rev 2009;19:353-64
69. Barnes DE, Yaffe K, Belfor N, et al. Computer-based cognitive training for mild cognitive impairment: results from a pilot randomized, controlled trial. Alzheimer Dis Assoc Disord 2009;23:205-10
70. Belleville S. Cognitive training for persons with mild cognitive impairment. Int Psychogeriatr 2008;20:57-66 (Pubitemid 350256068)
71. Cicerone KD, Dahlberg C, Malec JF, et al. Evidence-based cognitive rehabilitation: updated review of the literature from 1998 through 2002. Arch Phys Med Rehabil 2005;86:1681-92 (Pubitemid 41115836)
72. Edwards BG, Barch DM, Braver TS. Improving prefrontal cortex function in schizophrenia through focused training of cognitive control. Front Hum Neurosci 2010;4:32
73. McGurk SR, Twamley EW, Sitzer DI, et al. A meta-analysis of cognitive remediation in schizophrenia. Am J Psychiatry 2007;164:1791-802 (Pubitemid 351739231)
74. Wykes T, Huddy V. Cognitive remediation for schizophrenia: it is even more complicated. Curr Opin Psychiatry 2009;22:161-7
75. Alzforum webpage. Available from: http://www.alzforum.org/new/detail.asp? id=2277, http://www.alzforum.org/new/ detail.asp?id=2277. 2010
76. Heresco-Levy U, Javitt DC, Ermilov M, et al. Double-blind, placebo-controlled, crossover trial of glycine adjuvant therapy for treatment-resistant schizophrenia. Br J Psychiatry 1996;169:610-17
77. Tsai GE, Yang P, Chang YC, Chong MY. D-alanine added to antipsychotics for the treatment of schizophrenia. Biol Psychiatry 2006;59:230-4 (Pubitemid 43208969)
78. Tsai G, Yang P, Chung LC, et al. D-serine added to antipsychotics for the treatment of schizophrenia. Biol Psychiatry 1998;44:1081-9 (Pubitemid 28547143)
79. Kitagawa H, Takenouchi T, Azuma R, et al. Safety, pharmacokinetics, and effects on cognitive function of multiple doses of GTS-21 in healthy, male volunteers. Neuropsychopharmacology 2003;28:542-51
80. Olincy A, Harris JG, Johnson LL, et al. Proof-of-concept trial of an alpha7 nicotinic agonist in schizophrenia. Arch Gen Psychiatry 2006;63:630-8 (Pubitemid 43848294)
81. Freedman R, Olincy A, Buchanan RW, et al. Initial phase 2 trial of a nicotinic agonist in schizophrenia. Am J Psychiatry 2008;165:1040-7
82. ICAD meeting 2009, Vienna, Austria, 2010
83. Schmitt JA, Wingen M, Ramaekers JG, et al. Serotonin and human cognitive performance. Curr Pharm Des 2006;12:2473-86 (Pubitemid 44026030)
84. Roth BL, Craigo SC, Choudhary MS, et al. Binding of typical and atypical antipsychotic agents to 5-hydroxytryptamine-6 and 5-hydroxytryptamine-7 receptors. J Pharmacol Exp Ther 1994;268:1403-10 (Pubitemid 24100360)
85. Rosse G, Schaffhauser H. 5-HT6 receptor antagonists as potential therapeutics for cognitive impairment. Curr Top Med Chem 2010;10:207-21
86. Upton N, Chuang TT, Hunter AJ, Virley DJ. 5-HT6 receptor antagonists as novel cognitive enhancing agents for Alzheimer's disease. Neurotherapeutics 2008;5:458-69 (Pubitemid 351952494)
87. Gsk webpage. Available from: http:// www.gsk.com/investors/presentations/ 2007/neurosciences-seminar-dec07/jackie-hunter.pdf. http://www.gsk.com/ investors/presentations/2007/ neurosciences-seminar-dec07/ jackie-hunter.pdf. 2010
88. Heresco-Levy U, Javitt DC, Ebstein R, et al. D-serine efficacy as add-on pharmacotherapy to risperidone and olanzapine for treatment-refractory schizophrenia. Biol Psychiatry 2005;57:577-85 (Pubitemid 40409697)
89. Goff DC, Henderson DC, Evins AE, Amico E. A placebo-controlled crossover trial of D-cycloserine added to clozapine in patients with schizophrenia. Biol Psychiatry 1999;45:512-14 (Pubitemid 29130454)
90. Tsai G, Lane HY, Yang P, et al. Glycine transporter I inhibitor, N-methylglycine (sarcosine), added to antipsychotics for the treatment of schizophrenia. Biol Psychiatry 2004;55:452-6
91. Liem-Moolenaar M, Zoethout RW, de BP, et al. The effects of the glycine reuptake inhibitor R213129 on the central nervous system and on scopolamine-induced impairments in psychomotor and cognitive function in healthy subjects. J Psychopharmacol 2010;24(11):1671-9
92. Liem-Moolenaar M, Zoethout R, de BP, et al. The effects of a glycine reuptake inhibitor R231857 on the central nervous system and on scopolamine-induced impairments in cognitive and psychomotor function in healthy subjects. J Psychopharmacol 2009;24(11):1681-7
93. Ayala JE, Chen Y, Banko JL, et al. mGluR5 positive allosteric modulators facilitate both hippocampal LTP and LTD and enhance spatial learning. Neuropsychopharmacology 2009;34:2057-71
94. Uslaner JM, Parmentier-Batteur S, Flick RB, et al. Dose-dependent effect of CDPPB, the mGluR5 positive allosteric modulator, on recognition memory is associated with GluR1 and CREB phosphorylation in the prefrontal cortex and hippocampus. Neuropharmacology 2009;57:531-8
95. Balschun D, Zuschratter W, Wetzel W. Allosteric enhancement of metabotropic glutamate receptor 5 function promotes spatial memory. Neuroscience 2006;142:691-702 (Pubitemid 44485913)
96. Spinelli S, Ballard T, Gatti-McArthur S, et al. Effects of the mGluR2/3 agonist LY354740 on computerized tasks of attention and working memory in marmoset monkeys. Psychopharmacology 2005;179:292-302 (Pubitemid 40576717)
97. Higgins GA, Ballard TM, Kew JN, et al. Pharmacological manipulation of mGlu2 receptors influences cognitive performance in the rodent. Neuropharmacology 2004;46:907-17 (Pubitemid 38471944)
98. Schreiber R, Lowe D, Voerste A, de VJ. LY354740 affects startle responding but not sensorimotor gating or discriminative effects of phencyclidine. Eur J Pharmacol 2000;388:R3-4 (Pubitemid 30077509)
99. Krystal JH, bi-Saab W, Perry E, et al. Preliminary evidence of attenuation of the disruptive effects of the NMDA glutamate receptor antagonist, ketamine, on working memory by pretreatment with the group II metabotropic glutamate receptor agonist, LY354740, in healthy human subjects. Psychopharmacology 2005;179:303-9 (Pubitemid 40576718)
100. Patil ST, Zhang L, Martenyi F, et al. Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase II clinical trial. Nat Med 2007;13:1102-7
101. Raddatz R, Tao M, Hudkins RL. Histamine H3 antagonists for treatment of cognitive deficits in CNS diseases. Curr Top Med Chem 2010;10:153-69
102. Esbenshade TA, Browman KE, Bitner RS, et al. The histamine H3 receptor: an attractive target for the treatment of cognitive disorders. Br J Pharmacol 2008;154:1166-81 (Pubitemid 351992052)
103. Rizk A, Curley J, Robertson J, Raber J. Anxiety and cognition in histamine H3 receptor-/-mice. Eur J Neurosci 2004;19:1992-6
104. Southam E, Cilia J, Gartlon JE, et al. Preclinical investigations into the antipsychotic potential of the novel histamine H3 receptor antagonist GSK207040. Psychopharmacology 2009;201:483-94
105. Ligneau X, Perrin D, Landais L, et al. BF2.649 [1-{3-[3-(4-Chlorophenyl) propoxy]propyl}piperidine, hydrochloride], a nonimidazole inverse agonist/antagonist at the human histamine H3 receptor: preclinical pharmacology. J Pharmacol Exp Ther 2007;320:365-75 (Pubitemid 46025751)
106. Medhurst AD, Atkins AR, Beresford IJ, et al. GSK189254, a novel H3 receptor antagonist that binds to histamine H3 receptors in Alzheimer's disease brain and improves cognitive performance in preclinical models. J Pharmacol Exp Ther 2007;321:1032-45 (Pubitemid 46762709)
107. Fox GB, Esbenshade TA, Pan JB, et al. Pharmacological properties of ABT-239 [4-(2-{2-[(2R)-2-Methylpyrrolidinyl] ethyl}-benzofuran-5-yl) benzonitrile]: II. Neurophysiological characterization and broad preclinical efficacy in cognition and schizophrenia of a potent and selective histamine H3 receptor antagonist. J Pharmacol Exp Ther 2005;313:176-90 (Pubitemid 40411341)
108. Munzar P, Tanda G, Justinova Z, Goldberg SR. Histamine h3 receptor antagonists potentiate methamphetamine self-administration and methamphetamine-induced accumbal dopamine release. Neuropsychopharmacology 2004;29:705-17 (Pubitemid 38402478)
109. Schmidt CJ. Phosphodiesterase inhibitors as potential cognition enhancing agents. Curr Top Med Chem 2010;10:222-30
110. Reneerkens OA, Rutten K, Steinbusch HW, et al. Selective phosphodiesterase inhibitors: a promising target for cognition enhancement. Psychopharmacology 2009;202:419-43
111. van der Staay FJ, Rutten K, Barfacker L, et al. The novel selective PDE9 inhibitor BAY 73-6691 improves learning and memory in rodents. Neuropharmacology 2008;55:908-18
112. Rutten K, Vente JD, Sik A, et al. The selective PDE5 inhibitor, sildenafil, improves object memory in Swiss mice and increases cGMP levels in hippocampal slices. Behav Brain Res 2005;164:11-16 (Pubitemid 41253727)
113. Boess FG, Hendrix M, van der Staay FJ, et al. Inhibition of phosphodiesterase 2 increases neuronal cGMP, synaptic plasticity and memory performance. Neuropharmacology 2004;47:1081-92 (Pubitemid 39535847)
114. Goff DC, Cather C, Freudenreich O, et al. A placebo-controlled study of sildenafil effects on cognition in schizophrenia. Psychopharmacology 2009;202:411-17
115. Bachurin S, Bukatina E, Lermontova N, et al. Antihistamine agent Dimebon as a novel neuroprotector and a cognition enhancer. Ann NY Acad Sci 2001;939:425-35 (Pubitemid 32620096)
116. Lermontova NN, Redkozubov AE, Shevtsova EF, et al. Dimebon and tacrine inhibit neurotoxic action of beta-amyloid in culture and block L-type Ca(2+) channels. Bull Exp Biol Med 2001;132:1079-83 (Pubitemid 34295938)
117. Wu J, Li Q, Bezprozvanny I. Evaluation of Dimebon in cellular model of Huntington's disease. Mol Neurodegener 2008;3:15
118. Grigorev VV, Dranyi OA, Bachurin SO. Comparative study of action mechanisms of dimebon and memantine on AMPA-and NMDA-subtypes glutamate receptors in rat cerebral neurons. Bull Exp Biol Med 2003;136:474-7 (Pubitemid 39137308)
119. Doody RS, Gavrilova SI, Sano M, et al. Effect of dimebon on cognition, activities of daily living, behaviour, and global function in patients with mild-to-moderate Alzheimer's disease: a randomised, double-blind, placebo-controlled study. Lancet 2008;372:207-15 (Pubitemid 351978110)
120. Gozes I, Stewart A, Morimoto B, et al. Addressing Alzheimer's disease tangles: from NAP to AL-108. Curr Alzheimer Res 2009;6:455-60
121. Decker MW, Bannon AW, Curzon P, et al. ABT-089 [2-methyl-3-(2-(S)- pyrrolidinylmethoxy)pyridine dihydrochloride]: II. A novel cholinergic channel modulator with effects on cognitive performance in rats and monkeys. J Pharmacol Exp Ther 1997;283:247-58 (Pubitemid 27438968)
122. Lippiello P, Gatto GJ, Bencherif M, et al. RJR-1734: a potent selective nicotinic ligand that improves cognition acutely and chronically [abstract 39.25.]. Society for Neuroscience; 1998
123. Gatto GJ, Bohme GA, Caldwell WS, et al. TC-1734: an orally active neuronal nicotinic acetylcholine receptor modulator with antidepressant, neuroprotective and long-lasting cognitive effects. CNS Drug Rev 2004;10:147-66 (Pubitemid 38879108)
124. Meyer EM, King MA, Meyers C. Neuroprotective effects of 2,4-dimethoxybenzylidene anabasine (DMXB) and tetrahydroaminoacridine (THA) in neocortices of nucleus basalis lesioned rats. Brain Res 1998;768:49-56
125. Arendash GW, Sengstock GJ, Sanberg PR, Kem WR. Improved learning and memory in aged rats with chronic administration of the nicotinic receptor agonist GTS-21. Brain Res 1995;674:252-9
126. Briggs CA, Anderson DJ, Brioni JD, et al. Functional characterization of the novel neuronal nicotinic acetylcholine receptor ligand GTS-21 in vitro and in vivo. Pharmacol Biochem Behav 1997;57:231-41 (Pubitemid 27261416)
127. Wallace-Boone WL, Chiu G, Dao H. R3487/MEM3454, a novel nicotinic alpha7 receptor partial agonist, improves attention and working memory in cynomolgus macaques [abstract 887.5/ FF135]. Society for Neuroscience; 2010
128. Callahan PM, Rowe WB, Xie W, et al. MEM3454, a novel nicotinic alpha7 receptor partial agonist. II. Effects in models predictive of cognitive restoration in Alzheimer's disease [abstract 163.5/Z11]. Society for Neuroscience; 2006
129. Huang M, Prus AJ, Li Z, et al. The nicotinic alpha7 receptor partial agonist MEM3454 increases dopamine and acetylcholine in rat medial prefrontal cortex and hippocampus [abstract 163.1/Z7]. Society for Neuroscience 2006
130. Wang S, Michael T, Dragan S, et al. MEM3454, a novel nicotinic alpha7 partial agonist. I. In vitro pharmacological profiling [abstract 163.2/Z8]. Society for Neuroscience; 2006
131. Koenig G, Palfreyman MG, Chesworth R. EVP-6124, a novel and potent alpha7 acetylcholine receptor agonist, improves memory acquisition, retention and retrieval and reverses scopolamine-induced memory deficits [abstract 887.6/FF136]. Society for Neuroscience; 2009
132. Rowe WB, Callahan PM, Hsu C. Characterisation of the 5-HT6 receptor agonist, WAY-181187, and antagonist, SB-742457: Effects on spatial reference and spatial working memory function in aged Fischer 344 rats [abstract 883.2/ FF46]. Society for Neuroscience; 2009
133. Callahan PM, Rowe WB, Hsu C. Characterisation of the 5-HT6 agonist, WAY-181187, and antagonist, SB-742457: Effects on recognition, associative and spatial reference memory function in young animals [abstract 883.3/FF47]. Society for Neuroscience 2009
134. Ray AM, Hirst WD, Ahmed M, et al. Effects of the novel 5-HT6 SB-742457 antagonist and the cholinesterase inhibitor donepezil in models of cognition. Alzheimers Dement 2008;4:T768
135. Robichaud AJ. Identification of SAM-531 (WAY-262531), a selective 5-HT6 antagonist for the treatment of cognitive dysfunction associated with schizophrenia and Alzheimer's disease [Medi-34]. American Chemical Society National Meeting and Exposition; 2010
136. Jayarajan P, Vishwakarma SL, Abraham R, et al. Effect of SUVN-502, cholinesterase inhibitors in scopolamine-induced memory deficit: a comparative study [abstract 162.13/ Z4]. Society for Neuroscience 2006
137. Hashimoto K, Fujita Y, Ishima T, et al. Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of the glycine transporter-1 inhibitor NFPS and D-serine. Eur Neuropsychopharmacol 2008;18:414-21 (Pubitemid 351608551)
138. Manahan-Vaughan D, Wildforster V, Thomsen C. Rescue of hippocampal LTP and learning deficits in a rat model of psychosis by inhibition of glycine transporter-1 (GlyT1). Eur J Neurosci 2008;28:1342-50
139. Boulay D, Pichat P, Dargazanli G, et al. Characterization of SSR103800, a selective inhibitor of the glycine transporter-1 in models predictive of therapeutic activity in schizophrenia. Pharmacol Biochem Behav 2008;91:47-58
140. Black MD, Varty GB, Arad M, et al. Procognitive and antipsychotic efficacy of glycine transport 1 inhibitors (GlyT1) in acute and neurodevelopmental models of schizophrenia: latent inhibition studies in the rat. Psychopharmacology 2009;202:385-96
141. Singer P, Feldon J, Yee BK. The glycine transporter 1 inhibitor SSR504734 enhances working memory performance in a continuous delayed alternation task in C57BL/6 mice. Psychopharmacology 2009;202:371-84
142. Sabbagh MN, Shill HA. Latrepirdine, a potential novel treatment for Alzheimer's disease and Huntington's chorea. Curr Opin Investig Drugs 2010;11:80-91
143. Geerts H. AL-108 and AL-208, formulations of the neuroprotective NAP fragment of activity-dependent neuroprotective protein, for cognitive disorders. Curr Opin Investig Drugs 2008;9:800-11 (Pubitemid 351950875)