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Modulation of prepulse inhibition through both M1 and M4 muscarinic receptors in mice

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Abstract

Rationale

Muscarinic cholinergic M1 and M4 receptors may participate in schizophrenia’s etiology and have been proposed as targets for antipsychotic medications.

Objective

Here, we investigated the involvement of these receptors in behavioral measures pertinent to schizophrenia using knockout mice lacking M1 receptors (M1−/−), M4 receptors (M4−/−), or both (M1−/−M4−/−).

Methods

We measured prepulse inhibition (PPI) of startle without drugs and after treatment with scopolamine (0.32–1.8 mg/kg), xanomeline (3.2 mg/kg), oxotremorine (0.032–0.1 mg/kg), clozapine (1.0–5.6 mg/kg), or haloperidol (0.32–3.2 mg/kg).

Results

In female (but not male) mice, combined deletion of both M1 and M4 receptors decreased PPI relative to wild-type mice, while knockout of either receptor alone had no significant effect. Scopolamine disrupted PPI in wild-type and M4−/− mice, but not in female M1−/−M4−/− or female M1−/− mice. When administered before scopolamine, xanomeline restored PPI in wild-type mice and M1−/− mice, but not in M4−/− mice. In contrast, pretreatment with oxotremorine increased PPI regardless of genotype. Effects of clozapine and haloperidol on PPI were not hindered by either mutation.

Conclusions

Deletion of both M1 and M4 receptors can disrupt PPI, suggesting that (at least partially redundant) M1 and M4 receptor-dependent functions are involved in sensorimotor gating mechanisms. PPI-disrupting effects of muscarinic antagonists appeared dependent upon M1 receptor blockade. Our data also suggest that xanomeline exerts antipsychotic-like effects mainly through M4 receptor stimulation, while stimulation of non-M1/M4 subtypes may also have antipsychotic potential. Finally, our results do not support a role of M1/M4 receptors in mediating antipsychotic-like effects of clozapine.

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References

  • Anagnostaras SG, Murphy GG, Hamilton SE, Mitchell SL, Rahnama NP, Nathanson NM, Silva AJ (2003) Selective cognitive dysfunction in acetylcholine M1 muscarinic receptor mutant mice. Nat Neurosci 6:51–58

    Article  PubMed  CAS  Google Scholar 

  • Andersen MB, Fink-Jensen A, Peacock L, Gerlach J, Bymaster F, Lundbaek JA, Werge T (2003) The muscarinic M1/M4 receptor agonist xanomeline exhibits antipsychotic-like activity in Cebus apella monkeys. Neuropsychopharmacology 28:1168–1175

    PubMed  CAS  Google Scholar 

  • Bartus RT (1979) Physostigmine and recent memory: effects in young and aged nonhuman primates. Science 206:1087–1089

    Article  PubMed  CAS  Google Scholar 

  • Bodick NC, Offen WW, Levey AI, Cutler NR, Gauthier SG, Satlin A, Shannon HE, Tollefson GD, Rasmussen K, Bymaster FP, Hurley DJ, Potter WZ, Paul SM (1997) Effects of xanomeline, a selective muscarinic receptor agonist, on cognitive function and behavioral symptoms in Alzheimer disease. Arch Neurol 54:465–473

    PubMed  CAS  Google Scholar 

  • Bonsi P, Martella G, Cuomo D, Platania P, Sciamanna G, Bernardi G, Wess J, Pisani A (2008) Loss of muscarinic autoreceptor function impairs long-term depression but not long-term potentiation in the striatum. J Neurosci 28:6258–6263

    Article  PubMed  CAS  Google Scholar 

  • Borda T, Perez Rivera R, Joensen L, Gomez RM, Sterin-Borda L (2002) Antibodies against cerebral M1 cholinergic muscarinic receptor from schizophrenic patients: molecular interaction. J Immunol 168:3667–3674

    PubMed  CAS  Google Scholar 

  • Brady AE, Jones CK, Bridges TM, Kennedy JP, Thompson AD, Heiman JU, Breininger ML, Gentry PR, Yin H, Jadhav SB, Shirey JK, Conn PJ, Lindsley CW (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

    Article  PubMed  CAS  Google Scholar 

  • Braff DL, Geyer MA, Swerdlow NR (2001) Human studies of prepulse inhibition of startle: normal subjects, patient groups, and pharmacological studies. Psychopharmacology (Berl) 156:234–258

    Article  CAS  Google Scholar 

  • Buchanan RW, Freedman R, Javitt DC, Abi-Dargham A, Lieberman JA (2007) Recent advances in the development of novel pharmacological agents for the treatment of cognitive impairments in schizophrenia. Schizophr Bull 33:1120–1130

    Article  PubMed  Google Scholar 

  • Bymaster FP, Shannon HE, Rasmussen K, Delapp NW, Mitch CH, Ward JS, Calligaro DO, Ludvigsen TS, Sheardown MJ, Olesen PH, Swedberg MD, Sauerberg P, Fink-Jensen A (1998) Unexpected antipsychotic-like activity with the muscarinic receptor ligand (5R, 6R)6-(3-propylthio-1, 2, 5-thiadiazol-4-yl)-1-azabicyclo[3.2.1]octane. Eur J Pharmacol 356:109–119

    Article  PubMed  CAS  Google Scholar 

  • Bymaster FP, Felder C, Ahmed S, McKinzie D (2002) Muscarinic receptors as a target for drugs treating schizophrenia. Curr Drug Targets CNS Neurol Disord 1:163–181

    Article  PubMed  CAS  Google Scholar 

  • Bymaster FP, Felder CC, Tzavara E, Nomikos GG, Calligaro DO, McKinzie DL (2003) Muscarinic mechanisms of antipsychotic atypicality. Prog Neuropsychopharmacol Biol Psychiatry 27:1125–1143

    Article  PubMed  CAS  Google Scholar 

  • Chan WY, McKinzie DL, Bose S, Mitchell SN, Witkin JM, Thompson RC, Christopoulos A, Lazareno S, Birdsall NJ, Bymaster FP, Felder CC (2008) Allosteric modulation of the muscarinic M4 receptor as an approach to treating schizophrenia. Proc Natl Acad Sci USA 105:10978–10983

    Article  PubMed  Google Scholar 

  • Chapman CA, Yeomans JS, Blaha CD, Blackburn JR (1997) Increased striatal dopamine efflux follows scopolamine administered systemically or to the tegmental pedunculopontine nucleus. Neuroscience 76:177–186

    Article  PubMed  CAS  Google Scholar 

  • Conn PJ, Jones CK, Lindsley CW (2009) Subtype-selective allosteric modulators of muscarinic receptors for the treatment of CNS disorders. Trends Pharmacol Sci 30:148–155

    Article  PubMed  CAS  Google Scholar 

  • Crook JM, Dean B, Pavey G, Copolov D (1999) The binding of [3H]AF-DX 384 is reduced in the caudate–putamen of subjects with schizophrenia. Life Sci 64:1761–1771

    Article  PubMed  CAS  Google Scholar 

  • Davies MA, Compton-Toth BA, Hufeisen SJ, Meltzer HY, Roth BL (2005) The highly efficacious actions of N-desmethylclozapine at muscarinic receptors are unique and not a common property of either typical or atypical antipsychotic drugs: is M1 agonism a pre-requisite for mimicking clozapine's actions? Psychopharmacology (Berl) 178:451–460

    Article  CAS  Google Scholar 

  • Davis KL, Mohs RC, Tinklenberg JR, Pfefferbaum A, Hollister LE, Kopell BS (1978) Physostigmine: improvement of long-term memory processes in normal humans. Science 201:272–274

    Article  PubMed  CAS  Google Scholar 

  • Dean B, McLeod M, Keriakous D, McKenzie J, Scarr E (2002) Decreased muscarinic1 receptors in the dorsolateral prefrontal cortex of subjects with schizophrenia. Mol Psychiatry 7:1083–1091

    Article  PubMed  CAS  Google Scholar 

  • Deng C, Huang XF (2005) Decreased density of muscarinic receptors in the superior temporal gyrusin schizophrenia. J Neurosci Res 81:883–890

    Article  PubMed  CAS  Google Scholar 

  • Dewey SL, Smith GS, Logan J, Brodie JD, Simkowitz P, MacGregor RR, Fowler JS, Volkow ND, Wolf AP (1993) Effects of central cholinergic blockade on striatal dopamine release measured with positron emission tomography in normal human subjects. Proc Natl Acad Sci USA 90:11816–11820

    Article  PubMed  CAS  Google Scholar 

  • Di Chiara G, Morelli M, Consolo S (1994) Modulatory functions of neurotransmitters in the striatum: ACh/dopamine/NMDA interactions. Trends Neurosci 17:228–233

    Article  PubMed  Google Scholar 

  • Ellis JR, Ellis KA, Bartholomeusz CF, Harrison BJ, Wesnes KA, Erskine FF, Vitetta L, Nathan PJ (2006) Muscarinic and nicotinic receptors synergistically modulate working memory and attention in humans. Int J Neuropsychopharmacol 9:175–189

    Article  PubMed  CAS  Google Scholar 

  • Felder CC, Porter AC, Skillman TL, Zhang L, Bymaster FP, Nathanson NM, Hamilton SE, Gomeza J, Wess J, McKinzie DL (2001) Elucidating the role of muscarinic receptors in psychosis. Life Sci 68:2605–2613

    Article  PubMed  CAS  Google Scholar 

  • Fink-Jensen A, Kristensen P, Shannon HE, Calligaro DO, Delapp NW, Whitesitt C, Ward JS, Thomsen C, Rasmusseen T, Sheardown MJ, Jeppesen L, Sauerberg P, Bymaster FP (1998) Muscarinic agonists exhibit functional dopamine antagonism in unilaterally 6-OHDA lesioned rats. Neuroreport 9:3481–3486

    Article  PubMed  CAS  Google Scholar 

  • Fragkouli A, Stamatakis A, Zographos E, Pachnis V, Stylianopoulou F (2006) Sexually dimorphic effects of the Lhx7 null mutation on forebrain cholinergic function. Neuroscience 137:1153–1164

    Article  PubMed  CAS  Google Scholar 

  • Friedman JI (2004) Cholinergic targets for cognitive enhancement in schizophrenia: focus on cholinesterase inhibitors and muscarinic agonists. Psychopharmacology (Berl) 174:45–53

    Article  CAS  Google Scholar 

  • Gerber DJ, Sotnikova TD, Gainetdinov RR, Huang SY, Caron MG, Tonegawa S (2001) Hyperactivity, elevated dopaminergic transmission, and response to amphetamine in M1 muscarinic acetylcholine receptor-deficient mice. Proc Natl Acad Sci USA 98:15312–15317

    Article  PubMed  CAS  Google Scholar 

  • Geyer MA, Krebs-Thomson K, Braff DL, Swerdlow NR (2001) Pharmacological studies of prepulse inhibition models of sensorimotor gating deficits in schizophrenia: a decade in review. Psychopharmacology (Berl) 156:117–154

    Article  CAS  Google Scholar 

  • Geyer MA, McIlwain KL, Paylor R (2002) Mouse genetic models for prepulse inhibition: an early review. Mol Psychiatry 7:1039–1053

    Article  PubMed  CAS  Google Scholar 

  • Gomeza J, Zhang L, Kostenis E, Felder C, Bymaster F, Brodkin J, Shannon H, Xia B, Deng C, Wess J (1999) Enhancement of D1 dopamine receptor-mediated locomotor stimulation in M(4) muscarinic acetylcholine receptor knockout mice. Proc Natl Acad Sci USA 96:10483–10488

    Article  PubMed  CAS  Google Scholar 

  • Halpern JH (2004) Hallucinogens and dissociative agents naturally growing in the United States. Pharmacol Ther 102:131–138

    Article  PubMed  CAS  Google Scholar 

  • Harries MH, Samson NA, Cilia J, Hunter AJ (1998) The profile of sabcomeline (SB-202026), a functionally selective M1 receptor partial agonist, in the marmoset. Br J Pharmacol 124:409–415

    Article  PubMed  CAS  Google Scholar 

  • Hasselmo ME (2006) The role of acetylcholine in learning and memory. Curr Opin Neurobiol 16:710–715

    Article  PubMed  CAS  Google Scholar 

  • Hodges H, Peters S, Gray JA, Hunter AJ (1999) Counteractive effects of a partial (sabcomeline) and a full (RS86) muscarinic receptor agonist on deficits in radial maze performance induced by S-AMPA lesions of the basal forebrain and medial septal area. Behav Brain Res 99:81–92

    Article  PubMed  CAS  Google Scholar 

  • Johnstone EC, Crow TJ, Ferrier IN, Frith CD, Owens DG, Bourne RC, Gamble SJ (1983) Adverse effects of anticholinergic medication on positive schizophrenic symptoms. Psychol Med 13:513–527

    Article  PubMed  CAS  Google Scholar 

  • Jones CK, Shannon HE (2000) Muscarinic cholinergic modulation of prepulse inhibition of the acoustic startle reflex. J Pharmacol Exp Ther 294:1017–1023

    PubMed  CAS  Google Scholar 

  • Jones CK, Eberle EL, Shaw DB, McKinzie DL, Shannon HE (2005) Pharmacologic interactions between the muscarinic cholinergic and dopaminergic systems in the modulation of prepulse inhibition in rats. J Pharmacol Exp Ther 312:1055–1063

    Article  PubMed  CAS  Google Scholar 

  • Jones CK, Brady AE, Davis AA, Xiang Z, Bubser M, Tantawy MN, Kane AS, Bridges TM, Kennedy JP, Bradley SR, Peterson TE, Ansari MS, Baldwin RM, Kessler RM, Deutch AY, Lah JJ, Levey AI, Lindsley CW, Conn PJ (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

    Article  PubMed  CAS  Google Scholar 

  • Kane BE, Grant MK, El-Fakahany EE, Ferguson DM (2008) Synthesis and evaluation of xanomeline analogs-probing the wash-resistant phenomenon at the M1 muscarinic acetylcholine receptor. Bioorg Med Chem 16:1376–1392

    Article  PubMed  CAS  Google Scholar 

  • Kitamura N, Araya R, Kudoh M, Kishida H, Kimura T, Murayama M, Takashima A, Sakamaki Y, Hashikawa T, Ito S, Ohtsuki S, Terasaki T, Wess J, Yamada M (2009) Beneficial effects of estrogen in a mouse model of cerebrovascular insufficiency. PLoS One 4:e5159

    Article  PubMed  CAS  Google Scholar 

  • Kumari V, Zachariah E, Galea A, Mehrotra R, Taylor D, Sharma T (2001) Effects of procyclidine on prepulse inhibition of the acoustic startle response in healthy human volunteers. Psychopharmacology (Berl) 154:221–229

    Article  CAS  Google Scholar 

  • Langmead CJ, Austin NE, Branch CL, Brown JT, Buchanan KA, Davies CH, Forbes IT, Fry VA, Hagan JJ, Herdon HJ, Jones GA, Jeggo R, Kew JN, Mazzali A, Melarange R, Patel N, Pardoe J, Randall AD, Roberts C, Roopun A, Starr KR, Teriakidis A, Wood MD, Whittington M, Wu Z, Watson J (2008a) Characterization of a CNS penetrant, selective M1 muscarinic receptor agonist, 77-LH-28-1. Br J Pharmacol 154:1104–1115

    Article  PubMed  CAS  Google Scholar 

  • Langmead CJ, Watson J, Reavill C (2008b) Muscarinic acetylcholine receptors as CNS drug targets. Pharmacol Ther 117:232–243

    Article  PubMed  CAS  Google Scholar 

  • Levey AI, Kitt CA, Simonds WF, Price DL, Brann MR (1991) Identification and localization of muscarinic acetylcholine receptor proteins in brain with subtype-specific antibodies. J Neurosci 11:3218–3226

    PubMed  CAS  Google Scholar 

  • Maehara S, Hikichi H, Satow A, Okuda S, Ohta H (2008) Antipsychotic property of a muscarinic receptor agonist in animal models for schizophrenia. Pharmacol Biochem Behav 91:140–149

    Article  PubMed  CAS  Google Scholar 

  • Mancama D, Arranz MJ, Landau S, Kerwin R (2003) Reduced expression of the muscarinic 1 receptor cortical subtype in schizophrenia. Am J Med Genet B Neuropsychiatr Genet 119B:2–6

    Article  PubMed  CAS  Google Scholar 

  • McGinty JF (1999) Regulation of neurotransmitter interactions in the ventral striatum. Ann N Y Acad Sci 877:129–139

    Article  PubMed  CAS  Google Scholar 

  • Minzenberg MJ, Poole JH, Benton C, Vinogradov S (2004) Association of anticholinergic load with impairment of complex attention and memory in schizophrenia. Am J Psychiatry 161:116–124

    Article  PubMed  Google Scholar 

  • Miyakawa T, Yamada M, Duttaroy A, Wess J (2001) Hyperactivity and intact hippocampus-dependent learning in mice lacking the M1 muscarinic acetylcholine receptor. J Neurosci 21:5239–5250

    PubMed  CAS  Google Scholar 

  • Newell KA, Zavitsanou K, Jew SK, Huang XF (2007) Alterations of muscarinic and GABA receptor binding in the posterior cingulate cortex in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 31:225–233

    Article  PubMed  CAS  Google Scholar 

  • Norbury R, Travis MJ, Erlandsson K, Waddington W, Ell PJ, Murphy DG (2007) Estrogen therapy and brain muscarinic receptor density in healthy females: a SPET study. Horm Behav 51:249–257

    Article  PubMed  CAS  Google Scholar 

  • Olianas MC, Maullu C, Onali P (1999) Mixed agonist–antagonist properties of clozapine at different human cloned muscarinic receptor subtypes expressed in Chinese hamster ovary cells. Neuropsychopharmacology 20:263–270

    Article  PubMed  CAS  Google Scholar 

  • Onali P, Olianas MC (2002) Muscarinic M4 receptor inhibition of dopamine D1-like receptor signalling in rat nucleus accumbens. Eur J Pharmacol 448:105–111

    Article  PubMed  CAS  Google Scholar 

  • Ouagazzal AM, Jenck F, Moreau JL (2001) Drug-induced potentiation of prepulse inhibition of acoustic startle reflex in mice: a model for detecting antipsychotic activity? Psychopharmacology (Berl) 156:273–283

    Article  CAS  Google Scholar 

  • Perry EK, Perry RH (1995) Acetylcholine and hallucinations: disease-related compared to drug-induced alterations in human consciousness. Brain Cogn 28:240–258

    Article  PubMed  CAS  Google Scholar 

  • Power AE, Vazdarjanova A, McGaugh JL (2003) Muscarinic cholinergic influences in memory consolidation. Neurobiol Learn Mem 80:178–193

    Article  PubMed  CAS  Google Scholar 

  • Prus AJ, Baker LE, Meltzer HY (2004) Discriminative stimulus properties of 1.25 and 5.0 mg/kg doses of clozapine in rats: examination of the role of dopamine, serotonin, and muscarinic receptor mechanisms. Pharmacol Biochem Behav 77:199–208

    Article  PubMed  CAS  Google Scholar 

  • Raedler TJ, Knable MB, Jones DW, Urbina RA, Gorey JG, Lee KS, Egan MF, Coppola R, Weinberger DR (2003) In vivo determination of muscarinic acetylcholine receptor availability in schizophrenia. Am J Psychiatry 160:118–127

    Article  PubMed  Google Scholar 

  • Raedler TJ, Bymaster FP, Tandon R, Copolov D, Dean B (2007) Towards a muscarinic hypothesis of schizophrenia. Mol Psychiatry 12:232–246

    PubMed  CAS  Google Scholar 

  • Rhodes ME, Billings TE, Czambel RK, Rubin RT (2005) Pituitary–adrenal responses to cholinergic stimulation and acute mild stress are differentially elevated in male and female M(2) muscarinic receptor knockout mice. J Neuroendocrinol 17:817–826

    PubMed  CAS  Google Scholar 

  • Rhodes ME, Rubin RT, McKlveen JM, Karwoski TE, Fulton BA, Czambel RK (2008) Pituitary–adrenal responses to oxotremorine and acute stress in male and female M1 muscarinic receptor knockout mice: comparisons to M2 muscarinic receptor knockout mice. J Neuroendocrinol 20:617–625

    Article  PubMed  CAS  Google Scholar 

  • Sarter M, Nelson CL, Bruno JP (2005) Cortical cholinergic transmission and cortical information processing in schizophrenia. Schizophr Bull 31:117–138

    Article  PubMed  Google Scholar 

  • Sauerberg P, Olesen PH, Nielsen S, Treppendahl S, Sheardown MJ, Honore T, Mitch CH, Ward JS, Pike AJ, Bymaster FP et al (1992) Novel functional M1 selective muscarinic agonists. Synthesis and structure–activity relationships of 3-(1, 2, 5-thiadiazolyl)-1, 2, 5, 6-tetrahydro-1-methylpyridines. J Med Chem 35:2274–2283

    Article  PubMed  CAS  Google Scholar 

  • Scarr E, Sundram S, Keriakous D, Dean B (2007) Altered hippocampal muscarinic M4, but not M1, receptor expression from subjects with schizophrenia. Biol Psychiatry 61:1161–1170

    Article  PubMed  CAS  Google Scholar 

  • Seeger T, Fedorova I, Zheng F, Miyakawa T, Koustova E, Gomeza J, Basile AS, Alzheimer C, Wess J (2004) M2 muscarinic acetylcholine receptor knock-out mice show deficits in behavioral flexibility, working memory, and hippocampal plasticity. J Neurosci 24:10117–10127

    Article  PubMed  CAS  Google Scholar 

  • Shannon HE, Bymaster FP, Calligaro DO, Greenwood B, Mitch CH, Sawyer BD, Ward JS, Wong DT, Olesen PH, Sheardown MJ et al (1994) Xanomeline: a novel muscarinic receptor agonist with functional selectivity for M1 receptors. J Pharmacol Exp Ther 269:271–281

    PubMed  CAS  Google Scholar 

  • Shannon HE, Hart JC, Bymaster FP, Calligaro DO, DeLapp NW, Mitch CH, Ward JS, Fink-Jensen A, Sauerberg P, Jeppesen L, Sheardown MJ, Swedberg MD (1999) Muscarinic receptor agonists, like dopamine receptor antagonist antipsychotics, inhibit conditioned avoidance response in rats. J Pharmacol Exp Ther 290:901–907

    PubMed  CAS  Google Scholar 

  • Shannon HE, Rasmussen K, Bymaster FP, Hart JC, Peters SC, Swedberg MD, Jeppesen L, Sheardown MJ, Sauerberg P, 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

    Article  PubMed  CAS  Google Scholar 

  • Shekhar A, Potter WZ, Lightfoot J, Lienemann J, Dube S, Mallinckrodt C, Bymaster FP, McKinzie DL, Felder CC (2008) Selective muscarinic receptor agonist xanomeline as a novel treatment approach for schizophrenia. Am J Psychiatry 165:1033–1039

    Article  PubMed  Google Scholar 

  • Shirey JK, Xiang Z, Orton D, Brady AE, Johnson KA, Williams R, Ayala JE, Rodriguez AL, Wess J, Weaver D, Niswender CM, Conn PJ (2008) An allosteric potentiator of M4 mAChR modulates hippocampal synaptic transmission. Nat Chem Biol 4:42–50

    Article  PubMed  CAS  Google Scholar 

  • Sipos ML, Burchnell V, Galbicka G (2001) Effects of selected anticholinergics on acoustic startle response in rats. J Appl Toxicol 21(Suppl 1):S95–S101

    Article  PubMed  CAS  Google Scholar 

  • Sitaram N, Weingartner H, Gillin JC (1978) Human serial learning: enhancement with arecholine and choline impairment with scopolamine. Science 201:274–276

    Article  PubMed  CAS  Google Scholar 

  • Stanhope KJ, Mirza NR, Bickerdike MJ, Bright JL, Harrington NR, Hesselink MB, Kennett GA, Lightowler S, Sheardown MJ, Syed R, Upton RL, Wadsworth G, Weiss SM, Wyatt A (2001) The muscarinic receptor agonist xanomeline has an antipsychotic-like profile in the rat. J Pharmacol Exp Ther 299:782–792

    PubMed  CAS  Google Scholar 

  • Stefansson H, Ophoff RA, Steinberg S, Andreassen OA, Cichon S, Rujescu D, Werge T, Pietilainen OP, Mors O, Mortensen PB, Sigurdsson E, Gustafsson O, Nyegaard M, Tuulio-Henriksson A, Ingason A, Hansen T, Suvisaari J, Lonnqvist J, Paunio T, Borglum AD, Hartmann A, Fink-Jensen A, Nordentoft M, Hougaard D, Norgaard-Pedersen B, Bottcher Y, Olesen J, Breuer R, Moller HJ, Giegling I, Rasmussen HB, Timm S, Mattheisen M, Bitter I, Rethelyi JM, Magnusdottir BB, Sigmundsson T, Olason P, Masson G, Gulcher JR, Haraldsson M, Fossdal R, Thorgeirsson TE, Thorsteinsdottir U, Ruggeri M, Tosato S, Franke B, Strengman E, Kiemeney LA, Melle I, Djurovic S, Abramova L, Kaleda V, Sanjuan J, de Frutos R, Bramon E, Vassos E, Fraser G, Ettinger U, Picchioni M, Walker N, Toulopoulou T, Need AC, Ge D, Yoon JL, Shianna KV, Freimer NB, Cantor RM, Murray R, Kong A, Golimbet V, Carracedo A, Arango C, Costas J, Jonsson EG, Terenius L, Agartz I, Petursson H, Nothen MM, Rietschel M, Matthews PM, Muglia P, Peltonen L, St Clair D, Goldstein DB, Stefansson K, Collier DA (2009) Common variants conferring risk of schizophrenia. Nature 460:744–747

    PubMed  CAS  Google Scholar 

  • Sur C, Mallorga PJ, Wittmann M, Jacobson MA, Pascarella D, Williams JB, Brandish PE, Pettibone DJ, Scolnick EM, Conn PJ (2003) N-Desmethylclozapine, an allosteric agonist at muscarinic 1 receptor, potentiates N-methyl-D-aspartate receptor activity. Proc Natl Acad Sci USA 100:13674–13679

    Article  PubMed  CAS  Google Scholar 

  • Swerdlow NR, Weber M, Qu Y, Light GA, Braff DL (2008) Realistic expectations of prepulse inhibition in translational models for schizophrenia research. Psychopharmacology (Berl) 199:331–388

    Article  CAS  Google Scholar 

  • Tandon R, Shipley JE, Greden JF, Mann NA, Eisner WH, Goodson JA (1991) Muscarinic cholinergic hyperactivity in schizophrenia. Relationship to positive and negative symptoms. Schizophr Res 4:23–30

    Article  PubMed  CAS  Google Scholar 

  • Thomsen M, Wortwein G, Fink-Jensen A, Woldbye DP, Wess J, Caine SB (2007) Decreased prepulse inhibition and increased sensitivity to muscarinic, but not dopaminergic drugs in M5 muscarinic acetylcholine receptor knockout mice. Psychopharmacology (Berl) 192:97–110

    Article  CAS  Google Scholar 

  • Tzavara ET, Bymaster FP, Felder CC, Wade M, Gomeza J, Wess J, McKinzie DL, Nomikos GG (2003) Dysregulated hippocampal acetylcholine neurotransmission and impaired cognition in M2, M4 and M2/M4 muscarinic receptor knockout mice. Mol Psychiatry 8:673–679

    Article  PubMed  CAS  Google Scholar 

  • Tzavara ET, Bymaster FP, Davis RJ, Wade MR, Perry KW, Wess J, McKinzie DL, Felder C, Nomikos GG (2004) M4 muscarinic receptors regulate the dynamics of cholinergic and dopaminergic neurotransmission: relevance to the pathophysiology and treatment of related CNS pathologies. Faseb J 18:1410–1412

    PubMed  CAS  Google Scholar 

  • Ukai M, Okuda A, Mamiya T (2004) Effects of anticholinergic drugs selective for muscarinic receptor subtypes on prepulse inhibition in mice. Eur J Pharmacol 492:183–187

    Article  PubMed  CAS  Google Scholar 

  • Vakalopoulos C (2006) Neuropharmacology of cognition and memory: a unifying theory of neuromodulator imbalance in psychiatry and amnesia. Med Hypotheses 66: 394–431

    Article  PubMed  CAS  Google Scholar 

  • Watson J, Brough S, Coldwell MC, Gager T, Ho M, Hunter AJ, Jerman J, Middlemiss DN, Riley GJ, Brown AM (1998) Functional effects of the muscarinic receptor agonist, xanomeline, at 5-HT1 and 5-HT2 receptors. Br J Pharmacol 125:1413–1420

    Article  PubMed  CAS  Google Scholar 

  • Weiner DM, Meltzer HY, Veinbergs I, Donohue EM, Spalding TA, Smith TT, Mohell N, Harvey SC, Lameh J, Nash N, Vanover KE, Olsson R, Jayathilake K, Lee M, Levey AI, Hacksell U, Burstein ES, Davis RE, Brann MR (2004) The role of M1 muscarinic receptor agonism of N-desmethylclozapine in the unique clinical effects of clozapine. Psychopharmacology (Berl) 177:207–216

    Article  CAS  Google Scholar 

  • Wess J (2004) Muscarinic acetylcholine receptor knockout mice: novel phenotypes and clinical implications. Annu Rev Pharmacol Toxicol 44:423–450

    Article  PubMed  CAS  Google Scholar 

  • Woolley ML, Carter HJ, Gartlon JE, Watson JM, Dawson LA (2009) Attenuation of amphetamine-induced activity by the non-selective muscarinic receptor agonist, xanomeline, is absent in muscarinic M4 receptor knockout mice and attenuated in muscarinic M1 receptor knockout mice. Eur J Pharmacol 603:147–149

    Article  PubMed  CAS  Google Scholar 

  • Wu MF, Jenden DJ, Fairchild MD, Siegel JM (1993) Cholinergic mechanisms in startle and prepulse inhibition: effects of the false cholinergic precursor N-aminodeanol. Behav Neurosci 107:306–316

    Article  PubMed  CAS  Google Scholar 

  • Zavitsanou K, Katsifis A, Mattner F, Huang XF (2004) Investigation of m1/m4 muscarinic receptors in the anterior cingulate cortex in schizophrenia, bipolar disorder, and major depression disorder. Neuropsychopharmacology 29:619–625

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This research was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Disorders (J.W). M.T. was supported in part by a NARSAD Young Investigator Award and an Eleanor and Miles Shore/Harvard Medical School Fellowship during this work. All procedures were carried out in accordance with the Guidelines for the Care and Use of Mammals in Neuroscience and Behavioral Research (National Research Council 2003). We thank Joon Y. Boon and Kate Woodard for technical assistance.

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Author notes

  1. Brian S. Fulton

    Present address: Center for Drug Discovery, Northeastern University, 360 Huntington Avenue, Boston, MA, 02115, USA

Authors and Affiliations

  1. Alcohol and Drug Abuse Research Center, McLean Hospital/Harvard Medical School, 115 Mill Street, Belmont, MA, 02478, USA

    Morgane Thomsen, Brian S. Fulton & S. Barak Caine

  2. Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892, USA

    Jürgen Wess

  3. Laboratory of Neuropsychiatry, Rigshospitalet University Hospital, 9 Blegdamsvej, 2100, Copenhagen, Denmark

    Anders Fink-Jensen

  4. Department of Pharmacology, University of Copenhagen, 9 Blegdamsvej, 2100, Copenhagen, Denmark

    Anders Fink-Jensen

Authors
  1. Morgane Thomsen
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  2. Jürgen Wess
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  3. Brian S. Fulton
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  4. Anders Fink-Jensen
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  5. S. Barak Caine
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Correspondence to Morgane Thomsen.

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Thomsen, M., Wess, J., Fulton, B.S. et al. Modulation of prepulse inhibition through both M1 and M4 muscarinic receptors in mice. Psychopharmacology 208, 401–416 (2010). https://doi.org/10.1007/s00213-009-1740-z

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  • DOI: https://doi.org/10.1007/s00213-009-1740-z

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