Selective activation of M4 muscarinic acetylcholine receptors reverses MK-801-induced behavioral impairments and enhances associative learning in rodents

ACS Chemical Neuroscience

Volumn 5, Issue 10, 2014, Pages 920-942

  Bubser, Michael ^a   Bridges, Thomas M ^a,b   Dencker, Ditte ^d   Gould, Robert W ^a   Grannan, Michael ^a   Noetzel, Meredith J ^a,b   Lamsal, Atin ^a,b   Niswender, Colleen M ^a,b   Daniels, J Scott ^a,b   Poslusney, Michael S ^a,b   Melancon, Bruce J ^a,b   Tarr, James C ^a,b   Byers, Frank W ^a,b   Wess, Jürgen ^e   Duggan, Mark E ^f   Dunlop, John ^f   Wood, Michael W ^f   Brandon, Nicholas J ^f   Wood, Michael R ^a,b,c   Lindsley, Craig W ^a,b,c   Conn, P Jeffrey ^a,b   Jones, Carrie K ^a,b   more..

^a VANDERBILT UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b VANDERBILT UNIVERSITY MEDICAL CENTER   (United States)

^c VANDERBILT UNIVERSITY   (United States)

^d Mental Health Services CPH   (Denmark)

^e NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES   (United States)

^f ASTRAZENECA   (United Kingdom)

Author keywords

Allosteric modulator; antipsychotic; cognitive enhancement; M4 muscarinic; MK 801; VU0467154

Indexed keywords

5 AMINO 3,4 DIMETHYL N (4 ((TRIFLUOROMETHYL)SULFONYL)BENZYL)THIENO[2,3 C]PYRIDAZINE 6 CARBOXAMIDE; AMPHETAMINE; DIZOCILPINE; MUSCARINIC M4 RECEPTOR; NEUROLEPTIC AGENT; UNCLASSIFIED DRUG; VU 0152100; 5-AMINO-3,4-DIMETHYL-N-(4-((TRIFLUOROMETHYL)SULFONYL)BENZYL)THIENO(2,3-C)PYRIDAZINE-6-CARBOXAMIDE; AMINO ACID RECEPTOR BLOCKING AGENT; AMPHETAMINE DERIVATIVE; CENTRAL STIMULANT AGENT; CHOLINERGIC RECEPTOR STIMULATING AGENT; DIZOCILPINE MALEATE; PSYCHOTROPIC AGENT; PYRIDAZINE DERIVATIVE; THIOPHENE DERIVATIVE;

ANIMAL EXPERIMENT; ANIMAL TISSUE; ARTICLE; BEHAVIOR DISORDER; CENTRAL NERVOUS SYSTEM; CHOLINERGIC ACTIVITY; COGNITION; CONTEXTUAL FEAR CONDITIONING; CONTROLLED STUDY; DRUG POTENCY; DRUG SELECTIVITY; FEAR; HUMAN; IN VITRO STUDY; LOCOMOTION; MALE; MEMORY; MOUSE; NEUROCHEMISTRY; NONHUMAN; RAT; RECEPTOR UPREGULATION; RODENT; SCHIZOPHRENIA; SIGNAL TRANSDUCTION; STATE DEPENDENT LEARNING; VISUAL DISCRIMINATION; ANIMAL; BRAIN; C57BL MOUSE; CELL LINE; CRICETULUS; DOG; DOSE RESPONSE; DRUG EFFECTS; KNOCKOUT MOUSE; LEARNING; MACACA FASCICULARIS; METABOLISM; MOTOR ACTIVITY; PHYSIOLOGY; SPRAGUE DAWLEY RAT; SYNTHESIS;

RODENTIA;

AMPHETAMINES; ANIMALS; ASSOCIATION LEARNING; BRAIN; CELL LINE; CENTRAL NERVOUS SYSTEM STIMULANTS; CHOLINERGIC AGENTS; CRICETULUS; DIZOCILPINE MALEATE; DOGS; DOSE-RESPONSE RELATIONSHIP, DRUG; EXCITATORY AMINO ACID ANTAGONISTS; HUMANS; MACACA FASCICULARIS; MALE; MICE, INBRED C57BL; MICE, KNOCKOUT; MOTOR ACTIVITY; PSYCHOTROPIC DRUGS; PYRIDAZINES; RATS; RATS, SPRAGUE-DAWLEY; RECEPTOR, MUSCARINIC M4; THIOPHENES;

EID: 84907456436     PISSN: None     EISSN: 19487193     Source Type: Journal    
DOI: 10.1021/cn500128b     Document Type: Article

References (71)

1. Poels, E. M., Kegeles, L. S., Kantrowitz, J. T., Slifstein, M., Javitt, D. C., Lieberman, J. A., Abi-Dargham, A., and Girgis, R. R. (2014) Imaging glutamate in schizophrenia: Review of findings and implications for drug discovery. Mol. Psychiatry 19, 20-29.
2. Kantrowitz, J. T., and Javitt, D. C. (2010) N-methyl-d-aspartate (NMDA) receptor dysfunction or dysregulation: The final common pathway on the road to schizophrenia? Brain Res. Bull. 83, 108-121.
3. Coyle, J. T., and Tsai, G. (2004) NMDA receptor function, neuroplasticity, and the pathophysiology of schizophrenia. Int. Rev. Neurobiol. 59, 491-515.
4. Rezvani, A. H. (2006) Involvement of the NMDA System in Learning and Memory, In Animal Models of Cognitive Impairment (Levin, E. D., and Buccafusco, J. J., Eds.), pp 37-48, CRC Press, Boca Raton, Florida, U.S.A.
5. Bubser, M., Byun, N., Wood, M. R., and Jones, C. K. (2012) Muscarinic receptor pharmacology and circuitry for the modulation of cognition. Handb. Exp. Pharmacol., 121-166.
6. Jones, C. K., Byun, N., and Bubser, M. (2012) Muscarinic and nicotinic acetylcholine receptor agonists and allosteric modulators for the treatment of schizophrenia. Neuropsychopharmacology 37, 16-42.
7. Bonner, T. I., Buckley, N. J., Young, A. C., and Brann, M. R. (1987) Identification of a family of muscarinic acetylcholine receptor genes. Science 237, 527-532.
8. Bonner, T. I., Young, A. C., Brann, M. R., and Buckley, N. J. (1988) Cloning and expression of the human and rat m5 muscarinic acetylcholine receptor genes. Neuron 1, 403-410.
9. Jones, C. K., Brady, A. E., Davis, A. A., Xiang, Z., Bubser, M., Tantawy, M. N., Kane, A. S., Bridges, T. M., Kennedy, J. P., Bradley, S. R., Peterson, T. E., Ansari, M. S., Baldwin, R. M., Kessler, R. M., Deutch, A. Y., Lah, J. J., Levey, A. I., Lindsley, C. W., and Conn, P. J. (2008) Novel selective allosteric activator of the M1 muscarinic acetylcholine receptor regulates amyloid processing and produces antipsychotic-like activity in rats. J. Neurosci. 28, 10422-10433.
10. Shirey, J. K., Brady, A. E., Jones, P. J., Davis, A. A., Bridges, T. M., Kennedy, J. P., Jadhav, S. B., Menon, U. N., Xiang, Z., Watson, M. L., Christian, E. P., Doherty, J. J., Quirk, M. C., Snyder, D. H., Lah, J. J., Levey, A. I., Nicolle, M. M., Lindsley, C. W., and Conn, P. J. (2009) A selective allosteric potentiator of the M1 muscarinic acetylcholine receptor increases activity of medial prefrontal cortical neurons and restores impairments in reversal learning. J. Neurosci. 29, 14271-14286.
11. Marino, M. J., and Conn, P. J. (2002) Direct and indirect modulation of the N-methyl D-aspartate receptor. Curr. Drug Targets: CNS Neurol. Disord. 1, 1-16.
12. Marino, M. J., Rouse, S. T., Levey, A. I., Potter, L. T., and Conn, P. J. (1998) Activation of the genetically defined M1 muscarinic receptor potentiates N-methyl-D-asparate (NMDA) receptor currents in hippocampal pyramidal cells. Proc. Natl. Acad. Sci. U. S. A. 95, 11465-11470.
13. Sur, C., Mallogora, P. J., Wittmann, M., al, e., Jacobson, M. A., Pascarella, D., Williams, J. B., Brandish, P. E., Pettibone, D. J., Scolnick, E. M., and Conn, P. J. (2003) N-Desmethylclozapine, an allosteric agonist at muscarinic 1 receptor, potentiate N-methyl-D-aspartate receptor activity. Proc. Natl. Acad. Sci. U. S. A. 100, 13674-13679.
14. Digby, G. J., Noetzel, M. J., Bubser, M., Utley, T. J., Walker, A. G., Byun, N. E., Lebois, E. P., Xiang, Z., Sheffler, D. J., Cho, H. P., Davis, A. A., Nemirovsky, N. E., Mennenga, S. E., Camp, B. W., Bimonte-Nelson, H. A., Bode, J., Italiano, K., Morrison, R., Daniels, J. S., Niswender, C. M., Olive, M. F., Lindsley, C. W., Jones, C. K., and Conn, P. J. (2012) Novel allosteric agonists of M1 muscarinic acetylcholine receptors induce brain region-specific responses that correspond with behavioral effects in animal models. J. Neurosci. 32, 8532-8544.
15. Anagnostaras, S. G., Murphy, G. G., Hamilton, S. E., Mitchell, S. L., Rahnama, N. P., Nathanson, N. M., and Silva, A. J. (2003) Selective cognitive dysfunction in acetylcholine M1 muscarinic receptor mutant mice. Nat. Neurosci. 6, 51-58.
16. Brady, A. E., Jones, C. K., Bridges, T. M., Kennedy, J. P., Thompson, A. D., Heiman, J. U., Breininger, M. L., Gentry, P. R., Yin, H., Jadhav, S. B., Shirey, J. K., Conn, P. J., and Lindsley, C. W. (2008) Centrally active allosteric potentiators of the M4 muscarinic acetylcholine receptor reverse amphetamine-induced hyperlocomotor activity in rats. J. Pharmacol. Exp. Ther. 327, 941-953.
17. Shirey, J. K., Xiang, Z., Orton, D., Brady, A. E., Johnson, K. A., Williams, R., Ayala, J. E., Rodriguez, A. L., Wess, J., Weaver, D., Niswender, C. M., and Conn, P. J. (2008) An allosteric potentiator of M4 mAChR modulates hippocampal synaptic transmission. Nat. Chem. Biol. 4, 42-50.
18. Byun, N. E., Grannan, M., Bubser, M., Barry, R. L., Thompson, A., Rosanelli, J., Gowrishankar, R., Kelm, N. D., Damon, S., Bridges, T. M., Melancon, B. J., Tarr, J. C., Brogan, J. T., Avison, M. J., Deutch, A. Y., Wess, J., Wood, M. R., Lindsley, C. W., Gore, J. C., Conn, P. J., and Jones, C. K. (2014) Antipsychotic drug-like effects of the selective M4 muscarinic acetylcholine receptor positive allosteric modulator VU0152100. Neuropsychopharmacology 39, 1578-1593.
19. Chan, W. Y., McKinzie, D. L., Bose, S., Mitchell, S. N., Witkin, J. M., Thompson, R. C., Christopoulos, A., Lazareno, S., Birdsall, N. J., Bymaster, F. P., and Felder, C. C. (2008) Allosteric modulation of the muscarinic M4 receptor as an approach to treating schizophrenia. Proc. Natl. Acad. Sci. U. S. A. 105, 10978-10983.
20. Leach, K., Loiacono, R. E., Felder, C. C., McKinzie, D. L., Mogg, A., Shaw, D. B., Sexton, P. M., and Christopoulos, A. (2010) Molecular mechanisms of action and in vivo validation of an M4 muscarinic acetylcholine receptor allosteric modulator with potential antipsychotic properties. Neuropsychopharmacology 35, 855-869.
21. Leach, K., Sexton, P. M., and Christopoulos, A. (2007) Allosteric GPCR modulators: Taking advantage of permissive receptor pharmacology. Trends Pharmacol. Sci. 28, 382-389.
22. Leysen, J. E., Janssen, P. M., Schotte, A., Luyten, W. H., and Megens, A. A. (1993) Interaction of antipsychotic drugs with neurotransmitter receptor sites in vitro and in vivo in relation to pharmacological and clinical effects: Role of 5HT2 receptors. Psychopharmacology 112, S40-54.
23. Schotte, A., Janssen, P. F., Megens, A. A., and Leysen, J. E. (1993) Occupancy of central neurotransmitter receptors by risperidone, clozapine and haloperidol, measured ex vivo by quantitative autoradiography. Brain Res. 631, 191-202.
24. Stanhope, K. J., Mirza, N. R., Bickerdike, M. J., Bright, J. L., Harrington, N. R., Hesselink, M. B., Kennett, G. A., Lightowler, S., Sheardown, M. J., Syed, R., Upton, R. L., Wadsworth, G., Weiss, S. M., and Wyatt, A. (2001) The muscarinic receptor agonist xanomeline has an antipsychotic-like profile in the rat. J. Pharmacol. Exp. Ther. 299, 782-792.
25. Coyle, J. T., Basu, A., Benneyworth, M., Balu, D., and Konopaske, G. (2012) Glutamatergic synaptic dysregulation in schizophrenia: therapeutic implications. Handb. Exp. Pharmacol., 267-295.
26. Mathe, J. M., Nomikos, G. G., Blakeman, K. H., and Svensson, T. H. (1999) Differential actions of dizocilpine (MK-801) on the mesolimbic and mesocortical dopamine systems: Role of neuronal activity. Neuropharmacology 38, 121-128.
27. Moghaddam, B., Adams, B., Verma, A., and Daly, D. (1997) Activation of glutamatergic neurotransmission by ketamine: A novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex. J. Neurosci. 17, 2921-2927.
28. Adams, B., and Moghaddam, B. (1998) Corticolimbic dopamine neurotransmission is temporally dissociated from the cognitive and locomotor effects of phencyclidine. J. Neurosci. 18, 5545-5554.
29. Jackson, M. E., Homayoun, H., and Moghaddam, B. (2004) NMDA receptor hypofunction produces concomitant firing rate potentiation and burst activity reduction in the prefrontal cortex. Proc. Natl. Acad. Sci. U. S. A. 101, 8467-8472.
30. Kelly, P. H., Seviour, P. W., and Iversen, S. D. (1975) Amphetamine and apomorphine responses in the rat following 6- OHDA lesions of the nucleus accumbens septi and corpus striatum. Brain Res. 94, 507-522.
31. Joyce, E. M., Stinus, L., and Iversen, S. D. (1983) Effect of injections of 6-OHDA into either nucleus accumbens septi or frontal cortex on spontaneous and drug-induced activity. Neuropharmacology 22, 1141-1145.
32. Sharp, T., Zetterstrom, T., Ljungberg, T., and Ungerstedt, U. (1987) A direct comparison of amphetamine-induced behaviours and regional brain dopamine release in the rat using intracerebral dialysis. Brain Res. 401, 322-330.
33. Ljungberg, T., and Ungerstedt, U. (1985) A rapid and simple behavioural screening method for simultaneous assessment of limbic and striatal blocking effects of neuroleptic drugs. Pharmacol., Biochem. Behav. 23, 479-485.
34. Bubser, M., Keseberg, U., Notz, P. K., and Schmidt, W. J. (1992) Differential behavioural and neurochemical effects of competitive and non-competitive NMDA receptor antagonists in rats. Eur. J. Pharmacol. 229, 75-82.
35. Svensson, A., Pileblad, E., and Carlsson, M. (1991) A comparison between the non-competitive NMDA antagonist dizocilpine (MK-801) and the competitive NMDA antagonist D-CPPene with regard to dopamine turnover and locomotor-stimulatory properties in mice. J. Neural Transm.: Gen. Sect. 85, 117-129.
36. Liljequist, S., Ossowska, K., Grabowska-Anden, M., and Anden, N. E. (1991) Effect of the NMDA receptor antagonist, MK-801, on locomotor activity and on the metabolism of dopamine in various brain areas of mice. Eur. J. Pharmacol. 195, 55-61.
37. Bartko, S. J., Romberg, C., White, B., Wess, J., Bussey, T. J., and Saksida, L. M. (2011) Intact attentional processing but abnormal responding in M1 muscarinic receptor-deficient mice using an automated touchscreen method. Neuropharmacology 61, 1366-1378.
38. Brigman, J. L., Feyder, M., Saksida, L. M., Bussey, T. J., Mishina, M., and Holmes, A. (2008) Impaired discrimination learning in mice lacking the NMDA receptor NR2A subunit. Learn. Mem. 15, 50-54.
39. Bussey, T. J., Padain, T. L., Skillings, E. A., Winters, B. D., Morton, A. J., and Saksida, L. M. (2008) The touchscreen cognitive testing method for rodents: How to get the best out of your rat. Learn. Mem. 15, 516-523.
40. Horner, A. E., Heath, C. J., Hvoslef-Eide, M., Kent, B. A., Kim, C. H., Nilsson, S. R., Alsio, J., Oomen, C. A., Holmes, A., Saksida, L. M., and Bussey, T. J. (2013) The touchscreen operant platform for testing learning and memory in rats and mice. Nat. Protoc. 8, 1961-1984.
41. Schmidt, L. S., Thomsen, M., Weikop, P., Dencker, D., Wess, J., Woldbye, D. P., Wortwein, G., and Fink-Jensen, A. (2011) Increased cocaine self-administration in M4 muscarinic acetylcholine receptor knockout mice. Psychopharmacology 216, 367-378.
42. Zhang, W. N., Bast, T., and Feldon, J. (2001) The ventral hippocampus and fear conditioning in rats: Different anterograde amnesias of fear after infusion of N-methyl-D-aspartate or its noncompetitive antagonist MK-801 into the ventral hippocampus. Behav. Brain Res. 126, 159-174.
43. Gould, T. J., McCarthy, M. M., and Keith, R. A. (2002) MK-801 disrupts acquisition of contextual fear conditioning but enhances memory consolidation of cued fear conditioning. Behav. Pharmacol. 13, 287-294.
44. Bodick, N. C., Offen, W. W., Levey, A. I., Cutler, N. R., Gauthier, S. G., Satlin, A., Shannon, H. E., Tollefson, G. D., Rasmussen, K., Bymaster, F. P., Hurley, D. J., Potter, W. Z., and Paul, S. M. (1997) Effects of xanomeline, a selective muscarinic receptor agonist, on cognitive function and behavioral symptoms in Alzheimer disease. Arch. Neurol. 54, 465-473.
45. Felder, C. C., Porter, A. C., Skillman, T. L., Zhang, L., Bymaster, F. P., Nathanson, N. M., Hamilton, S. E., Gomeza, J., Wess, J., and McKinzie, D. L. (2001) Elucidating the role of muscarinic receptors in psychosis. Life Sci. 68, 2605-2613.
46. Irwin, S. (1968) Comprehensive observational assessment: Ia. A systematic, quantitative procedure for assessing the behavioral and physiologic state of the mouse. Psychopharmacologia 13, 222-257.
47. Konieczny, J., Ossowska, K., Schulze, G., Coper, H., and Wolfarth, S. (1999) L-701,324, a selective antagonist at the glycine site of the NMDA receptor, counteracts haloperidol-induced muscle rigidity in rats. Psychopharmacology 143, 235-243.
48. Kirschbaum, K. M., Hiemke, C., and Schmitt, U. (2009) Rotarod impairment: Catalepsy-like screening test for antipsychotic side effects. Int. J. Neurosci. 119, 1509-1522.
49. Perry, K. W., Nisenbaum, L. K., George, C. A., Shannon, H. E., Felder, C. C., and Bymaster, F. P. (2001) The muscarinic agonist xanomeline increases monoamine release and immediate early gene expression in the rat prefrontal cortex. Biol. Psychiatry 49, 716-725.
50. Shannon, H. E., Hart, J. C., Bymaster, F. P., Calligaro, D. O., DeLapp, N. W., Mitch, C. H., Ward, J. S., Fink-Jensen, A., Sauerberg, P., Jeppesen, L., Sheardown, M. J., and Swedberg, M. D. (1999) Muscarinic receptor agonists, like dopamine receptor antagonist antipsychotics, inhibit conditioned avoidance response in rats. J. Pharmacol. Exp. Ther. 290, 901-907.
51. Shannon, H. E., Rasmussen, K., Bymaster, F. P., Hart, J. C., Peters, S. C., Swedberg, M. D., Jeppesen, L., Sheardown, M. J., Sauerberg, P., and Fink-Jensen, A. (2000) Xanomeline, an M(1)/M(4) preferring muscarinic cholinergic receptor agonist, produces antipsychotic-like activity in rats and mice. Schizophr. Res. 42, 249-259.
52. French, E. D., and Ceci, A. (1990) Non-competitive N-methyl-D-aspartate antagonists are potent activators of ventral tegmental A10 dopamine neurons. Neurosci. Lett. 119, 159-162.
53. Ouagazzal, A., Nieoullon, A., and Amalric, M. (1994) Locomotor activation induced by MK-801 in the rat: postsynaptic interactions with dopamine receptors in the ventral striatum. Eur. J. Pharmacol. 251, 229-236.
54. Lapin, I. P., and Rogawski, M. A. (1995) Effects of D1 and D2 dopamine receptor antagonists and catecholamine depleting agents on the locomotor stimulation induced by dizocilpine in mice. Behav. Brain Res. 70, 145-151.
55. Jeon, J., Dencker, D., Wortwein, G., Woldbye, D. P., Cui, Y., Davis, A. A., Levey, A. I., Schutz, G., Sager, T. N., Mork, A., Li, C., Deng, C. X., Fink-Jensen, A., and Wess, J. (2010) A subpopulation of neuronal M4 muscarinic acetylcholine receptors plays a critical role in modulating dopamine-dependent behaviors. J. Neurosci. 30, 2396-2405.
56. Dencker, D., Wortwein, G., Weikop, P., Jeon, J., Thomsen, M., Sager, T. N., Mork, A., Woldbye, D. P., Wess, J., and Fink-Jensen, A. (2011) Involvement of a subpopulation of neuronal M4 muscarinic acetylcholine receptors in the antipsychotic-like effects of the M1/M4 preferring muscarinic receptor agonist xanomeline. J. Neurosci. 31, 5905-5908.
57. Pancani, T., Bolarinwa, C., Smith, Y., Lindsley, C. W., Conn, P. J., and Xiang, Z. (2014) M4 mAChR-Mediated Modulation of Glutamatergic Transmission at Corticostriatal Synapses. ACS Chem. Neurosci. 5, 318-324.
58. Johansen, J. P., Cain, C. K., Ostroff, L. E., and LeDoux, J. E. (2011) Molecular mechanisms of fear learning and memory. Cell 147, 509-524.
59. Rampon, C., Tang, Y. P., Goodhouse, J., Shimizu, E., Kyin, M., and Tsien, J. Z. (2000) Enrichment induces structural changes and recovery from nonspatial memory deficits in CA1 NMDAR1-knockout mice. Nat. Neurosci. 3, 238-244.
60. Shimizu, E., Tang, Y. P., Rampon, C., and Tsien, J. Z. (2000) NMDA receptor-dependent synaptic reinforcement as a crucial process for memory consolidation. Science 290, 1170-1174.
61. Hillman, B. G., Gupta, S. C., Stairs, D. J., Buonanno, A., and Dravid, S. M. (2011) Behavioral analysis of NR2C knockout mouse reveals deficit in acquisition of conditioned fear and working memory. Neurobiol. Learn. Mem. 95, 404-414.
62. Koshimizu, H., Leiter, L. M., and Miyakawa, T. (2012) M4 muscarinic receptor knockout mice display abnormal social behavior and decreased prepulse inhibition. Mol. Brain 5, 10.
63. Sacchetti, B., Baldi, E., Lorenzini, C. A., and Bucherelli, C. (2002) Differential contribution of some cortical sites to the formation of memory traces supporting fear conditioning. Exp. Brain Res. 146, 223-232.
64. Galloway, C. R., Lebois, E. P., Shagarabi, S. L., Hernandez, N. A., and Manns, J. R. (2014) Effects of selective activation of m1 and m4 muscarinic receptors on object recognition memory performance in rats. Pharmacology 93, 57-64.
65. Keefe, R. S., Sweeney, J. A., Gu, H., Hamer, R. M., Perkins, D. O., McEvoy, J. P., and Lieberman, J. A. (2007) Effects of olanzapine, quetiapine, and risperidone on neurocognitive function in early psychosis: a randomized, double-blind 52-week comparison. Am. J. Psychiatry 164, 1061-1071.
66. Swartz, M. S., Stroup, T. S., McEvoy, J. P., Davis, S. M., Rosenheck, R. A., Keefe, R. S., Hsiao, J. K., and Lieberman, J. A. (2008) What CATIE found: Results from the schizophrenia trial. Psychiatr. Serv. 59, 500-506.
67. Rubio, A., Hilliard, D. W. (2006) Thienopyridines as allosteric potentiators of the m4 muscarinic receptor. Int. Patent WO 2006047124 A1.
68. Wenthur, C. J., Morrison, R., Felts, A. S., Smith, K. A., Engers, J. L., Byers, F. W., Daniels, J. S., Emmitte, K. A., Conn, P. J., and Lindsley, C. W. (2013) Discovery of (R)-(2-fluoro-4-((-4-methoxyphenyl)-ethynyl)phenyl) (3-hydroxypiperidin-1-yl)methanone (ML337), an mGlu3 selective and CNS penetrant negative allosteric modulator (NAM). J. Med. Chem. 56, 5208-5212.
69. Hackler, E. A., Airey, D. C., Shannon, C. C., Sodhi, M. S., and Sanders-Bush, E. (2006) 5-HT(2C) receptor RNA editing in the amygdala of C57BL/6J, DBA/2J, and BALB/cJ mice. Neurosci. Res 55, 96-104.
70. Lebois, E. P., Bridges, T. M., Lewis, L. M., Dawson, E. S., Kane, A. S., Xiang, Z., Jadhav, S. B., Yin, H., Kennedy, J. P., Meiler, J., Niswender, C. M., Jones, C. K., Conn, P. J., Weaver, C. D., and Lindsley, C. W. (2010) Discovery and characterization of novel subtype-selective allosteric agonists for the investigation of M1 receptor function in the central nervous system. ACS Chem. Neurosci. 1, 104-121.
71. van der Staay, F. J., Rutten, K., Erb, C., and Blokland, A. (2011) Effects of the cognition impairer MK-801 on learning and memory in mice and rats. Behav. Brain Res. 220, 215-229.