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Attenuation in rats of impairments of memory by scopolamine, a muscarinic receptor antagonist, by mecamylamine, a nicotinic receptor antagonist

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Abstract

Rationale

Scopolamine, a muscarinic antagonist, impairs learning and memory for many tasks, supporting an important role for the cholinergic system in these cognitive functions. The findings are most often interpreted to indicate that a decrease in postsynaptic muscarinic receptor activation mediates the memory impairments. However, scopolamine also results in increased release of acetylcholine in the brain as a result of blocking presynaptic muscarinic receptors.

Objectives

The present experiments assess whether scopolamine-induced increases in acetylcholine release may impair memory by overstimulating postsynaptic cholinergic nicotinic receptors, i.e., by reaching the high end of a nicotinic receptor activation inverted-U dose-response function.

Results

Rats tested in a spontaneous alternation task showed dose-dependent working memory deficits with systemic injections of mecamylamine and scopolamine. When an amnestic dose of scopolamine (0.15 mg/kg) was co-administered with a subamnestic dose of mecamylamine (0.25 mg/kg), this dose of mecamylamine significantly attenuated the scopolamine-induced memory impairments. We next assessed the levels of acetylcholine release in the hippocampus in the presence of scopolamine and mecamylamine. Mecamylamine injections resulted in decreased release of acetylcholine, while scopolamine administration caused a large increase in acetylcholine release.

Conclusions

These findings indicate that a nicotinic antagonist can attenuate impairments in memory produced by a muscarinic antagonist. The nicotinic antagonist may block excessive activation of nicotinic receptors postsynaptically or attenuate increases in acetylcholine release presynaptically. Either effect of a nicotinic antagonist—to decrease scopolamine-induced increases in acetylcholine output or to decrease postsynaptic acetylcholine receptor activation—may mediate the negative effects on memory of muscarinic antagonists.

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References

  • Araujo JA, Nobrega JN, Raymond R, Milgram NW (2011) Aged dogs demonstrate both increased sensitivity to scopolamine impairment and decreased muscarinic receptor density. Pharmacol Biochem Behav 98:203–209

    Article  CAS  PubMed  Google Scholar 

  • Baldi E, Bucherelli C (2005) The inverted “U-shaped” dose-effect relationships in learning and memory: modulation of arousal and consolidation. Nonlinearity in Biology, Toxicology, Medicine 3: nonlin-003.

  • Banuelos C, LaSarge CL, McQuail JA, Hartman JJ, Gilbert RJ, Ormerod BK, Bizon JL (2013) Age-related changes in rostral basal forebrain cholinergic and GABAergic projection neurons: relationship with spatial impairment. Neurobiol Aging 34:845–862

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Bartus RT, Dean RL, Beer B, Lippa AS (1982) The cholinergic hypothesis of geriatric memory dysfunction. Science 217:408–414

    Article  CAS  PubMed  Google Scholar 

  • Bejar C, Wang R-H, Weinstock M (1999) Effect of rivastigmine on scopolamine-induced memory impairment in rats. Eur J Pharmacol 383:231–240

    Article  CAS  PubMed  Google Scholar 

  • Bohdanecký Z, Jarvik ME (1967) Impairment of one-trial passive avoidance learning in mice by scopolamine, scopolamine methylbromide, and physostigmine. Int J Neuropharmacol 6:217–222

    Article  PubMed  Google Scholar 

  • Braida D, Paladini E, Griffini P, Lamperti M, Maggi A, Sala M (1996) An inverted U-shaped curve for heptylphysostigmine on radial maze performance in rats: comparison with other cholinesterase inhibitors. Eur J Pharmacol 302:13–20

    Article  CAS  PubMed  Google Scholar 

  • Bruno JP, Gash C, Martin B, Zmarowski A, Pomerleau F, Burmeister J, Huettl P, Gerhardt GA (2006) Second-by-second measurement of acetylcholine release in prefrontal cortex. Eur J Neurosci 24:2749–2757

    Article  PubMed  Google Scholar 

  • Calabrese EJ (2008) Converging concepts: adaptive response, preconditioning, and the Yerkes-Dodson Law are manifestations of hormesis. Ageing Res Rev 7:8–20

    Article  CAS  PubMed  Google Scholar 

  • Chambon C, Jatzke C, Wegener N, Gravius A, Danysz W (2012) Using cholinergic M1 receptor positive allosteric modulators to improve memory via enhancement of brain cholinergic communication. Eur J Pharmacol 697:73–80

    Article  CAS  PubMed  Google Scholar 

  • Chang Q, Savage LM, Gold PE (2006) Microdialysis measures of functional increases in ACh release in the hippocampus with and without inclusion of acetylcholinesterase inhibitors in the perfusate. J Neurochem 97:697–706

    Article  CAS  PubMed  Google Scholar 

  • Coyle JT, Price DL, DeLong MR (1983) Alzheimer's disease: a disorder of cortical cholinergic innervation. Science 219:1184–1190

    Article  CAS  PubMed  Google Scholar 

  • Decossas M, Doudnikoff E, Bloch B, Bernard V (2005) Aging and subcellular localization of m2 muscarinic autoreceptor in basalocortical neurons in vivo. Neurobiol Aging 26:1061–1072

    Article  CAS  PubMed  Google Scholar 

  • Deutsch JA (1971) The cholinergic synapse and the site of memory. Science 174:788–794

    Article  CAS  PubMed  Google Scholar 

  • Drachman DA (1977) Memory and cognitive function in man: does the cholinergic system have a specific role? Neurology 27:783–790

    Article  CAS  PubMed  Google Scholar 

  • Flood JF, Smith GE, Cherkin A (1983) Memory retention: potentiation of cholinergic drug combinations in mice. Neurobiol Aging 4:37–43

    Article  CAS  PubMed  Google Scholar 

  • Givens B, Olton DS (1995) Bidirectional modulation of scopolamine-induced working memory impairments by muscarinic activation of the medial septal area. Neurobiol Learn Mem 63:269–276

    Article  CAS  PubMed  Google Scholar 

  • Gold PE (2006) The many faces of amnesia. Learn Mem 13:506–514

    Article  PubMed  Google Scholar 

  • Gold PE, Korol DL (2012) Making memories matter. special issue: the impact of emotion on cognition – dissociating between enhancing and impairing effects. F. Dolcos, L. Wang, and M. Mather, hosts. Front Integr Neurosci 6:116. doi:10.3389/fnint.2012.00116.Epub

    Article  PubMed Central  PubMed  Google Scholar 

  • Gold PE, Newman LA, Scavuzzo CJ, Korol DL (2013) Modulation of multiple memory systems: from neurotransmitters to metabolic substrates. Hippocampus 23:1053–1065

    Article  CAS  PubMed  Google Scholar 

  • Grilly DM, Simon BB, Levin ED (2000) Nicotine enhances stimulus detection performance of middle- and old-aged rats: a longitudinal study. Pharmacol Biochem Behav 65:665–670

    Article  CAS  PubMed  Google Scholar 

  • Grothe M, Heinsen H, Teipel SJ (2012) Atrophy of the cholinergic basal forebrain over the adult age range and in early stages of Alzheimer's disease. Biol Psychiatry 71:805–813

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hamburg MD (1967) Retrograde amnesia produced by intraperitoneal injection of physostigmine. Science 156:973–974

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hasselmo ME, McGaughy J (2004) High acetylcholine levels set circuit dynamics for attention and encoding and low acetylcholine levels set dynamics for consolidation. Prog Brain Res 145:207–231

    Article  CAS  PubMed  Google Scholar 

  • Hasselmo ME, Sarter M (2011) Modes and models of forebrain cholinergic neuromodulation of cognition. Neuropsychopharmacology 36:52–73

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Higgins GA, Enderlin M, Fimbel R, Haman M, Grottick AJ, Soriano M, Richards JG, Kemp JA, Gill R (2002) Donepezil reverses a mnemonic deficit produced by scopolamine but not by perforant path lesion or transient cerebral ischaemia. Eur J Neurosci 15:1827–1840

    Article  CAS  PubMed  Google Scholar 

  • Himmelheber AM, Fadel J, Sarter M, Bruno JP (1998) Effects of local cholinesterase inhibition on acetylcholine release assessed simultaneously in prefrontal and frontoparietal cortex. Neuroscience 86:949–957

    Article  CAS  PubMed  Google Scholar 

  • Hoss W, Messer WS Jr, Monsma FJ Jr, Miller MD, Ellerbrock BR, Scranton T, Ghodsi-Hovsepian S, Price MA, Balan S, Mazloum Z, Bohnett M (1990) Biochemical and behavioral evidence for muscarinic autoreceptors in the CNS. Brain Res 517:195–201

    Article  CAS  PubMed  Google Scholar 

  • Huff FJ, Mickel SF, Corkin S, Growdon JH (1988) Cognitive functions affected by scopolamine in Alzheimer's disease and normal aging. Drug Dev Res 12:271–278

    Article  CAS  Google Scholar 

  • Kato G (1972) Acetylcholinesterase. II. A study by nuclear magnetic resonance of the acceleration of acetylcholinesterase by atropine and inhibition by eserine. Mol Pharmacol 8:582–588

    CAS  PubMed  Google Scholar 

  • Koob GF (1991) Arousal, stress and inverted-U shaped curves: implications for cognitive function. In: Lister RG, Weingartner HJ (eds) Perspectives on Cognitive Neuroscience. Oxford University Press, London, pp 300–313

    Google Scholar 

  • Kutlu MG, Gould TJ (2015) Nicotinic receptors, memory, and hippocampus. In The Neurobiology and Genetics of Nicotine and Tobacco (pp. 137-163). Springer International Publishing.

  • Levin ED, Caldwell DP (2006) Low-dose mecamylamine improves learning of rats in the radial-arm maze repeated acquisition procedure. Neurobiol Learn Mem 86:117–122

    Article  CAS  PubMed  Google Scholar 

  • Liu JK, Kato T (1994) Effect of physostigmine on relative acetylcholine output induced by systemic treatment with scopolamine in in vivo microdialysis of rat frontal cortex. Neurochem Int 24:589–596

    Article  CAS  PubMed  Google Scholar 

  • MacLeod JE, Potter AS, Simoni MK, Bucci DJ (2006) Nicotine administration enhances conditioned inhibition in rats. Eur J Pharmacol 551:76–79

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Mash DC, Flynn DD, Potter LT (1985) Loss of M2 muscarine receptors in the cerebral cortex in alzheimer's disease and experimental cholinergic denervation. Science 228:1115–1117

    Article  CAS  PubMed  Google Scholar 

  • Mattson MP (2008) Hormesis defined. Ageing Res Rev 7:1–7

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Mesulam MM (2013) Cholinergic circuitry of the human nucleus basalis and its fate in Alzheimer's disease. J Comp Neurol 521:4124–4144

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Mishima K, Iwasaki K, Tsukikawa H, Matsumoto Y, Egashira N, Abe K, Egawa T, Fujiwara M (2000) The scopolamine-induced impairment of spatial cognition parallels the acetylcholine release in the ventral hippocampus in rats. Jpn J Pharmacol 84:163–173

    Article  CAS  PubMed  Google Scholar 

  • Moor E, Deboer P, Auth F, Westerink BHC (1995) Characterisation of muscarinic autoreceptors in the septo-hippocampal system of the rat: a microdialysis study. Eur J Pharmacol 294:155–161

    Article  CAS  PubMed  Google Scholar 

  • Moore H, Stuckman S, Sarter M, Bruno JP (1996) Potassium, but not atropine-stimulated cortical acetylcholine efflux, is reduced in aged rats. Neurobiol Aging 17:565–571

    Article  CAS  PubMed  Google Scholar 

  • Morris KA, Li S, Bui DD, Gold PE (2013) Glucose attenuates impairments in memory and CREB activation produced by an α4β2 but not an α7 nicotinic receptor antagonist. Neuropharmacology 67:233–242

    Article  CAS  PubMed  Google Scholar 

  • Nakahara N, Fujise N, Kawanishi G, Mizobe F (1990) Central muscarinic activities of an M1-selective agonist: preferential effect on reversal of amnesia. Brain Res 507:172–175

    Article  CAS  PubMed  Google Scholar 

  • Newman LA, Korol DL, Gold PE (2011) Lactate produced by glycogenolysis in astrocytes regulates memory. PLoS One 6:e28427

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Noori HR, Fliegel S, Brand I, Spanagel R (2012) The impact of acetylcholinesterase inhibitors on the extracellular acetylcholine concentrations in the adult rat brain: a meta-analysis. Synapse 66:893–901

    Article  CAS  PubMed  Google Scholar 

  • Nordstrom Ö, Bartfai T (1980) Muscarinic autoreceptor regulates acetylcholine release in rat hippocampus: in vitro evidence. Acta Physiol Scand 108:347–353

    Article  CAS  PubMed  Google Scholar 

  • Pan SY, Han YF, Yu ZL, Yang R, Dong H, Ko KM (2006) Evaluation of acute tacrine treatment on passive-avoidance response, open-field behavior, and toxicity in 17-and 30-day-old mice. Pharmacol Biochem Behav 85:50–56

    Article  CAS  PubMed  Google Scholar 

  • Pepeu G, Giovannini MG (2010) Cholinesterase inhibitors and memory. Chem Biol Interact 187:403–408

    Article  CAS  PubMed  Google Scholar 

  • Quirion R, Richard J, Wilson A (1994) Muscarinic and nicotinic modulation of cortical acetylcholine release monitored by in vivo microdialysis in freely moving adult rats. Synapse 17:92–100

    Article  CAS  PubMed  Google Scholar 

  • Ragozzino ME, Arankowsky-Sandoval G, Gold PE (1994) Glucose attenuates the effect of combined muscarinic-nicotinic receptor blockade on spontaneous alternation. Eur J Pharmacol 256:31–36

    Article  CAS  PubMed  Google Scholar 

  • Ragozzino ME, Unick KE, Gold PE (1996) Hippocampal acetylcholine release during memory testing in rats: augmentation by glucose. Proc Natl Acad Sci U S A 93:4693–4698

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Ragozzino ME, Pal SN, Unick K, Stefani MR, Gold PE (1998) Modulation of hippocampal acetylcholine release and spontaneous alternation scores by intrahippocampal glucose injections. J Neurosci 18:1595–1601

    CAS  PubMed  Google Scholar 

  • Robbins TW, McAlonan G, Muir JL, Everitt BJ (1997) Cognitive enhancers in theory and practice: studies of the cholinergic hypothesis of cognitive deficits in Alzheimer's disease. Behav Brain Res 83:15–23

    Article  CAS  PubMed  Google Scholar 

  • Sakai K, El Mansari M, Jouvet M (1990) Inhibition of carbachol microinjections of presumptive cholinergic PGO-on neurons in freely moving cats. Brain Res 527:213–223

    Article  CAS  PubMed  Google Scholar 

  • Snyder PJ, Bednar MM, Cromer JR, Maruff P (2005) Reversal of scopolamine-induced deficits with a single dose of donepezil, an acetylcholinesterase inhibitor. Alzheimers Dement 1:126–135

    Article  CAS  PubMed  Google Scholar 

  • Stillman MJ, Shukitt-Hale B, Galli RL, Levy A, Lieberman HR (1996) Effects of M2 antagonists on in vivo hippocampal acetylcholine levels. Brain Res Bull 41:221–226

    Article  CAS  PubMed  Google Scholar 

  • Stone WS, Croul CE, Gold PE (1988) Attenuation of scopolamine-induced amnesia in mice. Psychopharmacology 96:417–420

    Article  CAS  PubMed  Google Scholar 

  • Stone WS, Walser B, Gold SD, Gold PE (1991) Scopolamine- and morphine-induced impairments of spontaneous alternation performance in mice: reversal with glucose and with cholinergic and adrenergic agonists. Behav Neurosci 105:264–271

    Article  CAS  PubMed  Google Scholar 

  • Stratton LO, Petrinovich L (1963) Post-trial injections of an anti-cholinesterase drug and maze learning in two strains of rats. Psychopharmacologia 5:47–54

    Article  CAS  PubMed  Google Scholar 

  • Tani Y, Saito K, Imoto M, Ohno T (1998) Pharmacological characterization of nicotinic receptor-mediated acetylcholine release in rat brain--an in vivo microdialysis study. Eur J Pharmacol 351:181–188

    Article  CAS  PubMed  Google Scholar 

  • Terry AV, Buccafusco JJ, Decker MW (1997) Cholinergic channel activator, ABT-418, enhances delayed-response accuracy in rats. Drug Dev Res 40:304–312

    Article  CAS  Google Scholar 

  • Tota S, Nath C, Najmi AK, Shukla R, Hanif K (2012) Inhibition of central angiotensin converting enzyme ameliorates scopolamine induced memory impairment in mice: role of cholinergic neurotransmission, cerebral blood flow and brain energy metabolism. Behav Brain Res 232:66–76

    Article  CAS  PubMed  Google Scholar 

  • Vannucchi MG, Scali C, Kopf SR, Pepeu G, Casamenti F (1997) Selective muscarinic antagonists differentially affect in vivo acetylcholine release and memory performances of young and aged rats. Neuroscience 79:837–846

    Article  CAS  PubMed  Google Scholar 

  • Wanibuchi F, Nishida T, Yamashita H, Hidaka K, Koshiya K, Tsukamoto S, Usuda S (1994) Characterization of a novel muscarinic receptor agonist, YM796: comparison with cholinesterase inhibitors in in vivo pharmacological studies. Eur J Pharmacol 265:151–158

    Article  CAS  PubMed  Google Scholar 

  • Wilkie GI, Hutson P, Sullivan JP, Wonnacott S (1996) Pharmacological characterization of a nicotinic autoreceptor in rat hippocampal synaptosomes. Neurochem Res 21:1141–1148

    Article  CAS  PubMed  Google Scholar 

  • Wonnacott S, Soliakov L, Wilkie G, Redfern P, Marshall D (1996) Presynaptic nicotinic acetylcholine receptors in the brain. Drug Dev Res 38:149–159

    Article  CAS  Google Scholar 

  • Wu Y-J, Harp P, Yan X-R, Pope CN (2003) Nicotinic autoreceptor function in rat brain during maturation and aging: possible differential sensitivity to organophosphorus anticholinesterases. Chem Biol Interact 142:255–268

    Article  CAS  PubMed  Google Scholar 

  • Yoshida S, Suzuki N (1993) Antiamnesic and cholinomimetic side-effects of the cholinesterase inhibitors, physostigmine, tacrine and NIK-247 in rats. Eur J Pharmacol 250:117–124

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

Special thanks to Jamie Richards, Disha Goswami, Emily Pajerski, Huzefa Chinwala, Laura Manning, Sydney Muchnik, Heather Lin, and Fiona Weingartner for their valuable participation on this project.

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Correspondence to P. E. Gold.

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Supported by NSF IOS 13-18490, the Alzheimer’s Association, and the Syracuse University Center for Aging and Policy Studies (NIA P30 AG034464). L.A.N. was a postdoctoral trainee on NICHD Training Grant HD00733.

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Newman, L.A., Gold, P.E. Attenuation in rats of impairments of memory by scopolamine, a muscarinic receptor antagonist, by mecamylamine, a nicotinic receptor antagonist. Psychopharmacology 233, 925–932 (2016). https://doi.org/10.1007/s00213-015-4174-9

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  • DOI: https://doi.org/10.1007/s00213-015-4174-9

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