Abstract
Rationale
Preclinical and clinical studies suggest the potential use of memantine in the treatment of binge eating disorder. The aim of this study was to further investigate the mechanisms by which memantine influences the motivational aspects of ingestion through the analysis of licking microstructure. To interpret treatment effects in relation to drug action at specific functionally relevant times, we compared the effect of two different administration schedules.
Methods
Memantine was administered daily for a week, either 1 h before or immediately after a 30-min daily session. The effects on the microstructure of licking for a 10% sucrose solution in rats were examined in the course of treatment and for 15 days after treatment discontinuation.
Results
Treatment before testing reduced ingestion due to reduced burst size and increased latency in the first session. However, a progressive increase in burst number across sessions led to a full recovery of ingestion levels by the end of treatment. Daily post-session administration induced a dramatic decrease of activation of licking behaviour, indicated by reduced burst number, accompanied to reduced burst size. A slow recovery of ingestion took place after treatment discontinuation.
Conclusion
These results suggest a reduced hedonic/reward evaluation response, an effect likely due to NMDA receptor blockade occurring during the testing time and support the hypothesis that memantine interferes with the hedonic/non-homeostatic mechanisms regulating food intake and food-seeking. The effect of post-session administration might be explained by the development of conditioned taste aversion.
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References
Aguado L, del Valle R, Pérez L (1987) The NMDA-receptor antagonist ketamine as an unconditioned stimulus in taste aversion learning. Neurobiol Learn Mem 68:189–196
Arthurs J, Lin JY, Ocampo R, Reilly S (2017) Lactose malabsorption and taste aversion learning. Physiol Behav 180:39–44
Baird JP, St John SJ, Nguyen EA (2005) Temporal and qualitative dynamics of conditioned taste aversion processing: combined generalization testing and licking microstructure analysis. Behav Neurosci 119:983–1003
Berridge KC (2007) The debate over dopamine’s role in reward: the case for incentive salience. Psychopharmacology 191:391–431
Bisaga A, Danysz W, Foltin RW (2008) Antagonism of glutamatergic NMDA and mGluR5 receptors decreases consumption of food in baboon model of binge-eating disorder. Eur Neuropsychopharmacol 18:794–802
Bisaga A, Popik P (2000) In search of a new pharmacological treatment for drug and alcohol addiction: N-methyl-D-aspartate (NMDA) antagonists. Drug Alcohol Depend 59:1–15
Brennan BP, Roberts JL, Fogarty KV, Reynolds KA, Jonas JM, Hudson JI (2008) Memantine in the treatment of binge eating disorder: an open-label, prospective trial. Int J Eat Disord 41:520–526
Briscione MA, Serafine KM, Merluzzi AP, Rice KC, Riley AL (2013) The effects of the 5-HT3 receptor antagonist tropisetron on cocaine-induced conditioned taste aversions. Pharmacol Biochem Behav 105:112–117
Chen HS, Lipton SA (2006) The chemical biology of clinically tolerated NMDA receptor antagonists. J Neurochem 97:1611–1626
D’Aquila PS (2010) Dopamine on D2-like receptors “reboosts” dopamine D1-like receptor-mediated behavioural activation in rats licking for sucrose. Neuropharmacology 58:1085–1096
D’Aquila PS, Galistu A (2017) Within-session decrement of the emission of licking bursts following reward devaluation in rats licking for sucrose. PLoS One 12(5):e0177705
D’Aquila PS, Rossi R, Rizzi A, Galistu A (2012) Possible role of dopamine D1-like and D2-like receptors in behavioural activation and “contingent” reward evaluation in sodium-replete and sodium-depleted rats licking for NaCl solutions. Pharmacol Biochem Behav 101:99–106
Davis JD (1989) The microstructure of ingestive behavior. Ann N Y Acad Sci 575:106–119 discussion 120-121
Davis JD, Smith GP (1992) Analysis of the microstructure of the rhythmic tongue movements of rats ingesting maltose and sucrose solutions. Behav Neurosci 106:217–228
De Chiara L, Serra G, Koukopoulos AE, Koukopoulos A, Serra G (2014) Memantine in the treatment and prophylaxis of bipolar type II mood disorder and co-morbid eating disorder: a case report. Riv Psichiatr 49:192–194
Dou KX, Tan MS, Tan CC, Cao XP, Hou XH, Guo QH, Tan L, Mok V, Yu JT (2018) Comparative safety and effectiveness of cholinesterase inhibitors and memantine for Alzheimer's disease: a network meta-analysis of 41 randomized controlled trials. Alzheimers Res Ther 10(1):126
Dwyer DM (2012) EPS prize lecture. Licking and liking: the assessment of hedonic responses in rodents. Q J Exp Psychol 65:371–394
Foltin RW, Danysz W, Bisaga A (2008) A novel procedure for assessing the effects of drugs on satiation in baboons: effects of memantine and dexfenfluramine. Psychopharmacology 199:583–592
Freeman CR, Zehra A, Ramirez V, Wiers CE, Volkow ND, WangGJ (2018) Impact of sugar on the body, brain, and behavior. Front Biosci 23:2255–2266
Gaillard D, Stratford JM (2016) Measurement of behavioral taste responses in mice: two-bottle preference, Lickometer, and conditioned taste-aversion tests. Curr Protoc Mouse Biol 6:380–407
Galistu A, D’Aquila PS (2013) Dopamine on D2-like receptors “reboosts” dopamine D1-like receptor-mediated behavioural activation in rats licking for a isotonic NaCl solution. Psychopharmacology 229:357–366
Hayes MR, Covasa M (2005) CCK and 5-HT act synergistically to suppress food intake through simultaneous activation of CCK-1 and 5-HT3 receptors. Peptides 26:2322–2330
Hermanussen M, Tresguerres JA (2005) A new anti-obesity drug treatment: first clinical evidence that, antagonising glutamate-gated Ca2+ ion channels with memantine normalises binge-eating disorders. Econ Hum Biol 3:329–337
Higgs S, Cooper SJ (1998) Evidence for early opioid modulation of licking responses to sucrose and intralipid: a microstructural analysis in the rat. Psychopharmacology 139:342–355
Jackson A, Sanger DJ (1989) Conditioned taste aversions induced by phencyclidine and other antagonists of N-methyl-D-aspartate. Neuropharmacology 28:459–464
Johnson AW (2018a) Characterizing ingestive behavior through licking microstructure: underlying neurobiology and its use in the study of obesity in animal models. Int J Dev Neurosci 64:38–47
Johnson AW (2018b) Examining the influence of CS duration and US density on cue-potentiated feeding through analyses of licking microstructure. Lear Motiv 61:85–96
Keitz M, Martin-Soelch C, Leenders KL (2003) Reward processing in the brain: a prerequisite for movement preparation? Neural Plast 10:121–128
Kishi T, Matsunaga S, Oya K, Nomura I, Ikuta T, Iwata N (2017) Memantine for Alzheimer’s disease: an updated systematic review and meta-analysis. J Alzheimers Dis 60:401–425
Lee RH, Tseng TY, Wu CY, Chen PY, Chen MF, Kuo JS, Lee TJ (2012) Memantine inhibits α3β2-nAChRs-mediated nitrergic neurogenic vasodilation in porcine basilar arteries. PLoS One 7(7):e40326
Lin JY, Arthurs J, Reilly S (2017) Anesthesia-inducing drugs also induce conditioned taste aversions. Physiol Behav 177:247–251
Lu S, Nasrallah HA (2018) The use of memantine in neuropsychiatric disorders: an overview. Ann Clin Psychiatry 30:234–248
Lydall ES, Gilmour G, Dwyer DM (2010) Analysis of licking microstructure provides no evidence for a reduction in reward value following acute or sub-chronic phencyclidine administration. Psychopharmacology 209:153–162
Parsons CG, Stöffler A, Danysz W (2007) 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 53:699–723
Popik P, Kos T, Zhang Y, Bisaga A (2011) Memantine reduces consumption of highly palatable food in a rat model of binge eating. Amino Acids 40:477–485
Popik P, Wrobel M, Bisaga A (2006) Reinstatement of morphine-conditioned reward is blocked by memantine. Neuropsychopharmacology 31:160–170
Rammes G, Rupprecht R, Ferrari U, Zieglgänsberger W, Parsons CG (2001) The N-methyl-D-aspartate receptor channel blockers memantine, MRZ 2/579 and other amino-alkyl-cyclohexanes antagonise 5-HT(3) receptor currents in cultured HEK-293 and N1E-115 cell systems in a non-competitive manner. Neurosci Lett 306:81–84
Salamone JD, Cousins MS, Snyder BJ (1997) Behavioral functions of nucleus accumbens dopamine: empirical and conceptual problems with the anhedonia hypothesis. Neurosci Biobehav Rev 21:341–359
Salamone JD, Correa M, Farrar A, Mingote SM (2007) Effort-related functions of nucleus accumbens dopamine and associated forebrain circuits. Psychopharmacology 191:461–482
Sani G, Serra G, Kotzalidis GD, Romano S, Tamorri SM, Manfredi G, Caloro M, Telesforo CL, Caltagirone SS, Panaccione I, Simonetti A, Demontis F, SerraG GP (2012) The role of memantine in the treatment of psychiatric disorders other than the dementias: a review of current preclinical and clinical evidence. CNS Drugs 26:663–690
Schneider LH, Davis JD, Watson CA, Smith GP (1990) Similar effect of raclopride and reduced sucrose concentration on the microstructure of sucrose sham feeding. Eur J Pharmacol 186:61–70
Shore DM, Rafal R, Parkinson JA (2011) Appetitive motivational deficits in individuals with Parkinson’s disease. Mov Disord 26:1887–1892
Smith GP (2001) John Davis and the meanings of licking. Appetite 36:84–92
Smith KL, Rao RR, Velázquez-Sánchez C, Valenza M, Giuliano C, Everitt BJ, Sabino V, Cottone P (2015) The uncompetitive N-methyl-D-aspartate antagonist memantine reduces binge-like eating, food-seeking behavior, and compulsive eating: role of the nucleus accumbens shell. Neuropsychopharmacology 40:1163–1171
Spanagel R, Eilbacher B, Wilke R (1994) Memantine-induced dopamine release in the prefrontal cortex and striatum of the rat--a pharmacokinetic microdialysis study. Eur J Pharmacol 262:21–26
Spector AC, Klumpp PA, Kaplan JM (1998) Analytical issues in the evaluation of food deprivation and sucrose concentration effects on the microstructure of licking behavior in the rat. Behav Neurosci 112:678–694
Stojakovic A, Espinosa EP, Farhad OT, Lutfy K (2017) Effects of nicotine on homeostatic and hedonic components of food intake. J Endocrinol 235(1):R13–R31
Traverso LM, Ruiz G, De la Casa LG (2012) MK-801 induces a low intensity conditioned taste aversion. Pharmacol Biochem Behav 100:645–651
Traynelis SF, Wollmuth LP, McBain CJ, Menniti FS, Vance KM, Ogden KK, Hansen KB, Yuan H, Myers SJ, Dingledine R (2010) Glutamate receptor ion channels: structure, regulation, and function. Pharmacol Rev 62:405–496
Vardigan JD, Huszar SL, McNaughton CH, Hutson PH, Uslaner JM (2010) MK-801 produces a deficit in sucrose preference that is reversed by clozapine, D-serine, and the metabotropic glutamate 5 receptor positive allosteric modulator CDPPB: relevance to negative symptoms associated with schizophrenia? Pharmacol Biochem Behav 95:223–229
Wise RA (1982a) Common neural basis for stimulation reward, drug reward and food reward. In: Hoebel BG, Novin D (eds) The neural basis of feeding and reward. Haer Institute for Electrophysiological Research, Brunswick, ME, pp 445–454
Wise RA (1982b) Neuroleptics and operant behaviour: the anhedonia hypothesis. Behav Brain Sci 5:39–87
Wise RA, Spindler J, deWit H, Gerberg GJ (1978) Neuroleptic-induced “anhedonia” in rats: pimozide blocks reward quality of food. Science 201:262–264
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The present study was funded by the Fondazione di Sardegna, Sassari, Italy.
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Galistu, A., D’Aquila, P.S. Daily memantine treatment blunts hedonic response to sucrose in rats. Psychopharmacology 237, 103–114 (2020). https://doi.org/10.1007/s00213-019-05348-3
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DOI: https://doi.org/10.1007/s00213-019-05348-3