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Acute and chronic effects of the M1/M4-preferring muscarinic agonist xanomeline on cocaine vs. food choice in rats

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Abstract

Rationale

We previously showed that the M1/M4-preferring muscarinic agonist xanomeline can acutely attenuate or eliminate cocaine self-administration in mice.

Objective

Medications used to treat addictions will arguably be administered in (sub)chronic or repeated regimens. Tests of acute effects often fail to predict chronic effects, highlighting the need for chronic testing of candidate medications.

Methods

Rats were trained to lever press under a concurrent FR5 FR5 schedule of intravenous cocaine and food reinforcement. Once baseline behavior stabilized, the effects of 7 days once-daily injections of xanomeline were evaluated.

Results

Xanomeline pretreatment dose-dependently (1.8–10 mg/kg/day) shifted the dose-effect curve for cocaine rightward (up to 5.6-fold increase in A 50), with reallocation of behavior to the food-reinforced lever. There was no indication of tolerance, rather effects grew over days. The suppression of cocaine choice appeared surmountable at high cocaine doses, and xanomeline treatment did not significantly decrease total-session cocaine or food intake.

Conclusions

In terms of xanomeline's potential for promoting abstinence from cocaine in humans, the findings were mixed. Xanomeline did produce reallocation of behavior from cocaine to food with a robust increase in food reinforcers earned at some cocaine/xanomeline dose combinations. However, effects appeared surmountable, and food-maintained behavior was also decreased at some xanomeline/cocaine dose combinations, suggesting clinical usefulness may be limited. These data nevertheless support the notion that chronic muscarinic receptor stimulation can reduce cocaine self-administration. Future studies should show whether ligands with higher selectivity for M1 or M1/M4 subtypes would be less limited by undesired effects and can achieve higher efficacy.

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References

  • Ahmed SH (2010) Validation crisis in animal models of drug addiction: beyond non-disordered drug use toward drug addiction. Neurosci Biobehav Rev 35:172–184

    Article  CAS  PubMed  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

    CAS  PubMed  Google Scholar 

  • Andersen MB, Werge T, Fink-Jensen A (2007) The acetylcholinesterase inhibitor galantamine inhibits d-amphetamine-induced psychotic-like behavior in Cebus monkeys. J Pharmacol Exp Ther 321:1179–1182

    Article  CAS  PubMed  Google Scholar 

  • Bergman J, Kamien JB, Spealman RD (1990) Antagonism of cocaine self-administration by selective dopamine D1 and D2 antagonists. Behav Pharmacol 1:355–363

    PubMed  Google Scholar 

  • Bernard V, Normand E, Bloch B (1992) Phenotypical characterization of the rat striatal neurons expressing muscarinic receptor genes. J Neurosci 12:3591–3600

    CAS  PubMed  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

    Article  CAS  PubMed  Google Scholar 

  • Bymaster FP, Wong DT, Mitch CH, Ward JS, Calligaro DO, Schoepp DD, Shannon HE, Sheardown MJ, Olesen PH, Suzdak PD, Swedberg MDB, Sauerberg P (1994) Neurochemical effects of the M1 muscarinic agonist zanomeline (LY246708/NNC11-0232). J Pharmacol Exp Ther 269:282–289

    CAS  PubMed  Google Scholar 

  • Bymaster FP, Whitesitt CA, Shannon HE, DeLapp N, Ward JS, Calligaro DO, Shipley LA, Buelke-Sam JL, Bodick NC, Farde L, Sheardown MJ, Olesen PH, Hansen KT, Suzdak PD, Swedberg MDB, Sauerberg P, Mitch CH (1997) Xanomeline: a selective muscarinic agonist for the treatment of Alzheimer's disease. Drug Dev Res 40:158–170

    Article  CAS  Google Scholar 

  • De La Garza R 2nd, Mahoney JJ 3rd, Culbertson C, Shoptaw S, Newton TF (2008a) The acetylcholinesterase inhibitor rivastigmine does not alter total choices for methamphetamine, but may reduce positive subjective effects, in a laboratory model of intravenous self-administration in human volunteers. Pharmacol Biochem Behav 89:200–208

    Article  Google Scholar 

  • De La Garza R, Shoptaw S, Newton TF (2008b) Evaluation of the cardiovascular and subjective effects of rivastigmine in combination with methamphetamine in methamphetamine-dependent human volunteers. Int J Neuropsychopharmacol 11:729–741

    Google Scholar 

  • De La Garza R 2nd, Newton TF, Haile CN, Yoon JH, Nerumalla CS, Mahoney JJ 3rd, Aziziyeh A (2011) Rivastigmine reduces "Likely to use methamphetamine" in methamphetamine-dependent volunteers. Prog Neuropsychopharmacol Biol Psychiatry 37:141–146

    Article  Google Scholar 

  • De Lorme KC, Grant MKO, Noetzel MJ, Polson SB, El-Fakahany EE (2007) Long-term changes in the muscarinic M1 receptor induced by instantaneous formation of wash-resistant xanomeline-receptor complex. J Pharmacol Exp Ther 323:868–876

    Article  PubMed  Google Scholar 

  • Dencker D, Wortwein G, Weikop P, Jeon J, Thomsen M, Sager TN, Mork A, Woldbye DP, Wess J, Fink-Jensen (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

    Article  CAS  PubMed  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 

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

    Article  CAS  Google Scholar 

  • Grabowski J, Rhoades H, Schmitz J, Stotts A, Daruzska LA, Creson D, Moeller FG (2001) Dextroamphetamine for cocaine-dependence treatment: a double-blind randomized clinical trial. J Clin Psychopharmacol 21:522–526

    Article  CAS  PubMed  Google Scholar 

  • Grasing K, He S, Yang Y (2008) Dose-related effects of the acetylcholinesterase inhibitor tacrine on cocaine and food self-administration in rats. Psychopharmacol (Berl) 196:133–142

    Article  CAS  Google Scholar 

  • Grasing K, He S, Yang Y (2009) Long-lasting decreases in cocaine-reinforced behavior following treatment with the cholinesterase inhibitor tacrine in rats selectively bred for drug self-administration. Pharmacol Biochem Behav 94:169–178

    Article  CAS  PubMed  Google Scholar 

  • Grasing K, Mathur D, Newton TF, DeSouza C (2010) Donepezil treatment and the subjective effects of intravenous cocaine in dependent individuals. Drug Alcohol Depend 107:69–75

    Article  CAS  PubMed  Google Scholar 

  • Greenwald MK, Lundahl LH, Steinmiller CL (2010) Sustained release d-amphetamine reduces cocaine but not 'speedball'-seeking in buprenorphine-maintained volunteers: a test of dual-agonist pharmacotherapy for cocaine/heroin polydrug abusers. Neuropsychopharmacology 35:2624–2637

    Article  CAS  PubMed  Google Scholar 

  • Haney M, Spealman R (2008) Controversies in translational research: drug self-administration. Psychopharmacol (Berl) 199:403–419

    Article  CAS  Google Scholar 

  • Haney M, Ward AS, Foltin RW, Fischman MW (2001) Effects of ecopipam, a selective dopamine d1 antagonist, on smoked cocaine self-administration by humans. Psychopharmacol (Berl) 155:330–337

    Article  CAS  Google Scholar 

  • Haney M, Rubin E, Foltin RW (2010) Aripiprazole maintenance increases smoked cocaine self-administration in humans. Psychopharmacol (Berl) 216:379–387

    Article  Google Scholar 

  • Heinrich JN, Butera JA, Carrick T, Kramer A, Kowal D, Lock T, Marquis KL, Pausch MH, Popiolek M, Sun SC, Tseng E, Uveges AJ, Mayer SC (2009) Pharmacological comparison of muscarinic ligands: historical versus more recent muscarinic M1-preferring receptor agonists. Eur J Pharmacol 605:53–56

    Article  CAS  PubMed  Google Scholar 

  • Hersch SM, Gutekunst CA, Rees HD, Heilman CJ, Levey AI (1994) Distribution of M1–M4 muscarinic receptor proteins in the rat striatum: light and electron microscopic immunocytochemistry using subtype-specific antibodies. J Neurosci 14:3351–3363

    CAS  PubMed  Google Scholar 

  • Hikida T, Kaneko S, Isobe T, Kitabatake Y, Watanabe D, Pastan I, Nakanishi S (2001) Increased sensitivity to cocaine by cholinergic cell ablation in nucleus accumbens. Proc Natl Acad Sci U S A 98:13351–13354

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Hikida T, Kitabatake Y, Pastan I, Nakanishi S (2003) Acetylcholine enhancement in the nucleus accumbens prevents addictive behaviors of cocaine and morphine. Proc Natl Acad Sci U S A 100:6169–6173

    Article  CAS  PubMed Central  PubMed  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  CAS  PubMed  Google Scholar 

  • Karila L, Gorelick D, Weinstein A, Noble F, Benyamina A, Coscas S, Blecha L, Lowenstein W, Martinot JL, Reynaud M, Lepine JP (2008) New treatments for cocaine dependence: a focused review. Int J Neuropsychopharmacol 11:425–438

    Article  CAS  PubMed  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 (2008) Characterization of a CNS penetrant, selective M1 muscarinic receptor agonist, 77-LH-28-1. Br J Pharmacol 154:1104–1115

    Article  CAS  PubMed  Google Scholar 

  • Machova E, Jakubik J, El-Fakahany EE, Dolezal V (2007) Wash-resistantly bound xanomeline inhibits acetylcholine release by persistent activation of presynaptic M2 and M4 muscarinic receptors in rat brain. J Pharmacol Exp Ther 322:316–323

    Article  CAS  PubMed  Google Scholar 

  • Mark GP, Kinney AE, Grubb MC, Zhu X, Finn DA, Mader SL, Berger SP, Bechtholt AJ (2006) Injection of oxotremorine in nucleus accumbens shell reduces cocaine but not food self-administration in rats. Brain Res 1123:51–59

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Mirza NR, Peters D, Sparks RG (2003) Xanomeline and the antipsychotic potential of muscarinic receptor subtype selective agonists. CNS Drug Reviews 9:159–186

    Article  CAS  PubMed  Google Scholar 

  • Negus SS (2003) Rapid assessment of choice between cocaine and food in rhesus monkeys: effects of environmental manipulations and treatment with d-amphetamine and flupenthixol. Neuropsychopharmacology 28:919–931

    PubMed  Google Scholar 

  • Negus SS, Banks ML (2011) Making the right choice: lessons from drug discrimination for research on drug reinforcement and drug self-administration. In: Glennon RA, Young R (eds) Drug discrimination: applications to medicinal chemistry and drug studies. John Wiley and Sons, Hoboken, pp 361–388

    Chapter  Google Scholar 

  • Negus SS, Mello NK (2003) Effects of chronic d-amphetamine treatment on cocaine- and food-maintained responding under a progressive-ratio schedule in rhesus monkeys. Psychopharmacol (Berl) 167:324–332

    CAS  Google Scholar 

  • Newman JL, Negus SS, Lozama A, Prisinzano TE, Mello NK (2010) Behavioral evaluation of modafinil and the abuse-related effects of cocaine in rhesus monkeys. Exp Clin Psychopharmacol 18:395–408

    Article  CAS  PubMed Central  PubMed  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  CAS  PubMed  Google Scholar 

  • Rush CR, Stoops WW, Hays LR (2009) Cocaine effects during d-amphetamine maintenance: a human laboratory analysis of safety, tolerability and efficacy. Drug Alcohol Depend 99:261–271

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Samaha AN, Reckless GE, Seeman P, Diwan M, Nobrega JN, Kapur S (2008) Less is more: antipsychotic drug effects are greater with transient rather than continuous delivery. Biol Psychiatry 64:145–152

    Article  CAS  PubMed  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

    CAS  PubMed  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  CAS  PubMed  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 

  • Shoaib M, Swanner LS, Beyer CE, Goldberg SR, Schindler CW (1998) The GABAB agonist baclofen modifies cocaine self-administration in rats. Behav Pharmacol 9:195–206

    CAS  PubMed  Google Scholar 

  • Smiley JF, Levey AI, Mesulam MM (1999) m2 muscarinic receptor immunolocalization in cholinergic cells of the monkey basal forebrain and striatum. Neuroscience 90:803–814

    Article  CAS  PubMed  Google Scholar 

  • Smith JE, Co C, Yin X, Sizemore GM, Liguori A, Johnson WE 3rd, Martin TJ (2004) Involvement of cholinergic neuronal systems in intravenous cocaine self-administration. Neurosci Biobehav Rev 27:841–850

    Article  CAS  PubMed  Google Scholar 

  • Sofuoglu M (2010) Cognitive enhancement as a pharmacotherapy target for stimulant addiction. Addiction 105:38–48

    Article  PubMed Central  PubMed  Google Scholar 

  • Sofuoglu M, Mooney M (2009) Cholinergic functioning in stimulant addiction: implications for medications development. CNS Drugs 23:939–952

    Article  CAS  PubMed Central  PubMed  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

    CAS  PubMed  Google Scholar 

  • Takamatsu Y, Yamanishi Y, Hagino Y, Yamamoto H, Ikeda K (2006) Differential effects of donepezil on methamphetamine and cocaine dependencies. Ann N Y Acad Sci 1074:418–426

    Article  CAS  PubMed  Google Scholar 

  • The National Research Council (US) Committee for the Update of the Guide for the Care and Use of Laboratory Animals (2011). Guide for the care and use of laboratory animals, 8th edn. National Academies Press (US), Washington (DC)

  • Thomsen M, Caine SB (2005) Chronic intravenous drug self-administration in rats and mice. Curr Protoc Neurosci Chapter 9: Unit 9 20

  • Thomsen M, Fink-Jensen A, Woldbye PD, Wortwein G, Sager TN, Holm R, Pepe LM, Caine SB (2008) Effects of acute and chronic aripiprazole treatment on choice between cocaine self-administration and food under a concurrent schedule of reinforcement in rats. Psychopharmacol (Berl) 201:43–53

    Article  CAS  Google Scholar 

  • Thomsen M, Conn PJ, Lindsley C, Wess J, Boon JY, Fulton BS, Fink-Jensen A, Caine SB (2010a) Attenuation of cocaine's reinforcing and discriminative stimulus effects via muscarinic M1 acetylcholine receptor stimulation. J Pharmacol Exp Ther 332:959–969

    Article  CAS  PubMed  Google Scholar 

  • Thomsen M, Wess J, Fulton B, Fink-Jensen A, Caine SB (2010b) Modulation of prepulse inhibition through both M1 and M4 muscarinic receptors in mice. Psychopharmacology 208:401–416

    Article  CAS  PubMed  Google Scholar 

  • Thomsen M, Lindsley CW, Conn PJ, Wessell JE, Fulton BS, Wess J, Caine SB (2012) Contribution of both M1 and M4 receptors to muscarinic agonist-mediated attenuation of the cocaine discriminative stimulus in mice. Psychopharmacol (Berl) 220:673–685

    Article  CAS  Google Scholar 

  • Thomsen M, Barrett AC, Negus SS, Caine SB (2013) Cocaine versus food choice procedure in rats: environmental manipulations and effects of amphetamine. J Exp Anal Behav 99:211–233

    Article  PubMed  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  CAS  PubMed  Google Scholar 

  • Weiner DM, Levey AI, Brann MR (1990) Expression of muscarinic acetylcholine and dopamine receptor mRNAs in rat basal ganglia. Proc Natl Acad Sci U S A 87:7050–7054

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Wess J, Eglen RM, Gautam D (2007) Muscarinic acetylcholine receptors: mutant mice provide new insights for drug development. Nat Rev Drug Discov 6:721–733

    Article  CAS  PubMed  Google Scholar 

  • Williams MJ, Adinoff B (2008) The role of acetylcholine in cocaine addiction. Neuropsychopharmacology 33:1779–1797

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Winhusen TM, Somoza EC, Harrer JM, Mezinskis JP, Montgomery MA, Goldsmith RJ, Coleman FS, Bloch DA, Leiderman DB, Singal BM, Berger P, Elkashef A (2005) A placebo-controlled screening trial of tiagabine, sertraline and donepezil as cocaine dependence treatments. Addiction 100(Suppl 1):68–77

    Article  PubMed  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  CAS  PubMed  Google Scholar 

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Acknowledgments

This research was supported by a grant from the National Institutes on Drug Abuse (DA027825, M.T.). 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 2011) and US laws. We thank Christopher Adam and Dana Angood for technical assistance.

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

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

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  1. Morgane Thomsen
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  2. Brian S. Fulton
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  3. S. Barak Caine
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Correspondence to Morgane Thomsen.

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Thomsen, M., Fulton, B.S. & Caine, S.B. Acute and chronic effects of the M1/M4-preferring muscarinic agonist xanomeline on cocaine vs. food choice in rats. Psychopharmacology 231, 469–479 (2014). https://doi.org/10.1007/s00213-013-3256-9

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