Abstract
Episodic memory retrieval is fundamental for daily activities of humans and animals. Muscarinic cholinergic signaling is important for memory functioning and shows gender-dependent response in episodic memory retrieval. Dopamine D2 receptors influence memory formation and retrieval by influencing cholinergic signaling in the brain. This study aimed to determine the gender-dependent effects of D2 and muscarinic activity on memory retrieval. Male and female mice were trained for Morris water maze test and contextual fear conditioning. Memory retrieval was assessed following sub-chronic treatment (for 5 days) with D2 antagonist (risperidone 2.5 mg/kg) alone or in combination with scopolamine (1 mg/kg) or donepezil (1 mg/kg). Open field test was performed prior to the retrieval test to evaluate effects of risperidone treatment on locomotor activity and exploratory behavior. Risperidone co-treatment with donepezil impaired spatial memory retrieval in males only. Muscarinic and D2 simultaneous antagonism tend to impair fear retrieval in males but significantly enhanced retrieval of fear memories in female mice. These results suggest that D2 signaling influence muscarinic receptor activity during memory retrieval in gender-dependent manner.
Similar content being viewed by others
References
Allain H, Tessier C, Bentue-Ferrer D, Tarral A, Le Breton S, Gandon M, Bouhours P (2003) Effects of risperidone on psychometric and cognitive functions in healthy elderly volunteers. Psychopharmacology 165:419–429
Aravagiri M, Marder SR (2002) Brain, plasma and tissue pharmacokinetics of risperidone and 9-hydroxyrisperidone after separate oral administration to rats. Psychopharmacology 159:424–431
Bezu M, Malikovic J, Kristofova M, Engidawork E, Hoger H, Lubec G, Korz V (2017) Spatial working memory in male rats: pre-experience and task dependent roles of dopamine D1- and D2-like receptors. Front Behav Neurosci 11:196
Carlsson A, Waters N, Holm-Waters S, Tedroff J, Nilsson M, Carlsson ML (2001) Interactions between monoamines, glutamate, and GABA in schizophrenia: new evidence. Annu Rev Pharmacol Toxicol 41:237–260
Chopko TC, Lindsley CW (2018) Classics in chemical neuroscience: risperidone. ACS Chem Neurosci 9:1520–1529
De Bundel D, Zussy C, Espallergues J, Gerfen CR, Girault JA, Valjent E (2016) Dopamine D2 receptors gate generalization of conditioned threat responses through mTORC1 signaling in the extended amygdala. Mol Psychiatry 21:1545–1553
Devanand DP, Mintzer J, Schultz S, Sultzer D, De La Pena D, Gupta S, Colon S, Schimming C, Pelton GH, Andrews H, Levin B (2012) The antipsychotic discontinuation in Alzheimer disease trial: clinical rationale and study design. Am J Geriatr Psychiatry 20:362–373
Drago F, Contarino A, Marino R, Anzallo C, Valerio C, Rampello L, Raffaele R, Scapagnini U (1997) Effects of acute or chronic administration of risperidone on motor and sexual behavior of male rats. Pharmacol Res 35:17–25
Durk MR, Deshmukh G, Valle N, Ding X, Liederer BM, Liu X (2018) Use of subcutaneous and intraperitoneal administration methods to facilitate cassette dosing in microdialysis studies in rats. Drug Metab Dispos 46:964–969
Fadok JP, Dickerson TM, Palmiter RD (2009) Dopamine is necessary for cue-dependent fear conditioning. J Neurosci 29:11089–11097
Farhat SM, Mahboob A, Ahmed T (2017) Cortex- and amygdala-dependent learning and nicotinic acetylcholine receptor gene expression is severely impaired in mice orally treated with AlCl3. Biol Trace Elem Res 179:91–101
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 U S A 98:15312–15317
Hartung CM, Widiger TA (1998) Gender differences in the diagnosis of mental disorders: conclusions and controversies of the DSM-IV. Psychol Bull 123:260–278
Hasselmo ME (2006) The role of acetylcholine in learning and memory. Curr Opin Neurobiol 16:710–715
Hertel P, Nomikos GG, Iurlo M, Svensson TH (1996) Risperidone: regional effects in vivo on release and metabolism of dopamine and serotonin in the rat brain. Psychopharmacology 124:74–86
Ichikawa J, Dai J, O’laughlin IA, Fowler WL, Meltzer HY (2002) Atypical, but not typical, antipsychotic drugs increase cortical acetylcholine release without an effect in the nucleus accumbens or striatum. Neuropsychopharmacology 26:325–339
Keiser AA, Turnbull LM, Darian MA, Feldman DE, Song I, Tronson NC (2017) Sex differences in context fear generalization and recruitment of hippocampus and amygdala during retrieval. Neuropsychopharmacology 42:397–407
Koponen M, Taipale H, Tanskanen A, Tolppanen AM, Tiihonen J, Ahonen R, Hartikainen S (2015) Long-term use of antipsychotics among community-dwelling persons with Alzheimers disease: a nationwide register-based study. Eur Neuropsychopharmacol 25:1706–1713
Kuroki T, Meltzer HY, Ichikawa J (1999) Effects of antipsychotic drugs on extracellular dopamine levels in rat medial prefrontal cortex and nucleus accumbens. J Pharmacol Exp Ther 288:774–781
Leaderbrand K, Chen HJ, Corcoran KA, Guedea AL, Jovasevic V, Wess J, Radulovic J (2016) Muscarinic acetylcholine receptors act in synergy to facilitate learning and memory. Learn Mem 23:631–638
Martorana A, Di Lorenzo F, Esposito Z, Lo Giudice T, Bernardi G, Caltagirone C, Koch G (2013) Dopamine D(2)-agonist rotigotine effects on cortical excitability and central cholinergic transmission in Alzheimer’s disease patients. Neuropharmacology 64:108–113
Menezes J, Alves N, Borges S, Roehrs R, De Carvalho Myskiw J, Furini CR, Izquierdo I, Mello-Carpes PB (2015) Facilitation of fear extinction by novelty depends on dopamine acting on D1-subtype dopamine receptors in hippocampus. Proc Natl Acad Sci U S A 112:E1652-1658
Nyberg L, Karalija N, Salami A, Andersson M, Wahlin A, Kaboovand N, Kohncke Y, Axelsson J, Rieckmann A, Papenberg G, Garrett DD, Riklund K, Lovden M, Lindenberger U, Backman L (2016) Dopamine D2 receptor availability is linked to hippocampal-caudate functional connectivity and episodic memory. Proc Natl Acad Sci U S A 113:7918–7923
Patel JC, Rossignol E, Rice ME, Machold RP (2012) Opposing regulation of dopaminergic activity and exploratory motor behavior by forebrain and brainstem cholinergic circuits. Nat Commun 3:1172
Raczka KA, Mechias ML, Gartmann N, Reif A, Deckert J, Pessiglione M, Kalisch R (2011) Empirical support for an involvement of the mesostriatal dopamine system in human fear extinction. Transl Psychiatry 1:e12
Rashid H, Ahmed T (2018) Gender dependent contribution of muscarinic receptors in memory retrieval under sub-chronic stress. Neurosci Lett 681:6–11
Rashid H, Ahmed T (2019) Muscarinic activity in hippocampus and entorhinal cortex is crucial for spatial and fear memory retrieval. Pharmacol Rep 71:449–456
Rashid H, Mahboob A, Ahmed T (2017) Role of cholinergic receptors in memory retrieval depends on gender and age of memory. Behav Brain Res 331:233–240
Rogoz Z, Skuza G (2011) Anxiolytic-like effects of olanzapine, risperidone and fluoxetine in the elevated plus-maze test in rats. Pharmacol Rep 63:1547–1552
Rossato JI, Bevilaqua LR, Izquierdo I, Medina JH, Cammarota M (2009) Dopamine controls persistence of long-term memory storage. Science 325:1017–1020
Santos-Casado M, Garcia-Avello A (2019) Systematic review of gender bias in the clinical trials of new long-acting antipsychotic drugs. J Clin Psychopharmacol 39:264–272
Sienkiewicz-Jarosz H, Czlonkowska AI, Siemiatkowski M, Maciejak P, Szyndler J, Plaznik A (2000) The effects of physostigmine and cholinergic receptor ligands on novelty-induced neophobia. J Neural Transm (Vienna) 107:1403–1412
Simon P, Dupuis R, Costentin J (1994) Thigmotaxis as an index of anxiety in mice. Influence of dopaminergic transmissions. Behav Brain Res 61:59–64
Uniyal A, Singh R, Akhtar A, Bansal Y, Kuhad A, Sah SP (2019) Co-treatment of piracetam with risperidone rescued extinction deficits in experimental paradigms of post-traumatic stress disorder by restoring the physiological alterations in cortex and hippocampus. Pharmacol Biochem Behav 185:172763
Wang JS, Ruan Y, Taylor RM, Donovan JL, Markowitz JS, Devane CL (2004) The brain entry of risperidone and 9-hydroxyrisperidone is greatly limited by P-glycoprotein. Int J Neuropsychopharmacol 7:415–419
Wellman CL, Izquierdo A, Garrett JE, Martin KP, Carroll J, Millstein R, Lesch KP, Murphy DL, Holmes A (2007) Impaired stress-coping and fear extinction and abnormal corticolimbic morphology in serotonin transporter knock-out mice. J Neurosci 27:684–691
Wen JL, Xue L, Wang RH, Chen ZX, Shi YW, Zhao H (2015) Involvement of the dopaminergic system in the consolidation of fear conditioning in hippocampal CA3 subregion. Behav Brain Res 278:527–534
White NM, Viaud M (1991) Localized intracaudate dopamine D2 receptor activation during the post-training period improves memory for visual or olfactory conditioned emotional responses in rats. Behav Neural Biol 55:255–269
Williams GV, Goldman-Rakic PS (1995) Modulation of memory fields by dopamine D1 receptors in prefrontal cortex. Nature 376:572–575
Wu L, Feng X, Li T, Sun B, Khan MZ, He L (2017) Risperidone ameliorated Abeta1-42-induced cognitive and hippocampal synaptic impairments in mice. Behav Brain Res 322:145–156
Zarrindast MR, Sattari-Naeini M, Motamedi F (1992) Effect of D-1 or D-2 receptor stimulation on memory retrieval in mice. J Psychopharmacol 6:526–531
Zarrindast MR, Sroushi A, Bananej M, Vousooghi N, Hamidkhaniha S (2011) Involvement of the dopaminergic receptors of the rat basolateral amygdala in anxiolytic-like effects of the cholinergic system. Eur J Pharmacol 672:106–112
Acknowledgements
We are thankful to the Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology (NUST), Pakistan, and Higher Education Commission (HEC) of Pakistan for supporting this study and providing the technical research facilities. We are also grateful to Dr. Sami Siraj, Associate Professor, and Dr. Muhammad Ibrahim Rashid, Assistant Professor, Khyber Medical University, and MediCraft Pharma Pvt Ltd. Peshawar, especially Mr. Muhammad Abdullah, Quality Control Manager MediCraft, for assistance in experiments.
Author information
Authors and Affiliations
Contributions
HR and TA designed the study. HR conducted behavior tests; HR and TA analyzed data. HR and TA wrote the manuscript.
Corresponding author
Ethics declarations
Ethical approval
All experimental procedures were approved by institutes Internal Review Board. Approval number: IRB-62.
Conflict of interest
The authors declare no competing interests.
Additional information
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Rashid, H., Ahmed, T. Gender dimorphic effect of dopamine D2 and muscarinic cholinergic receptors on memory retrieval. Psychopharmacology 238, 2225–2234 (2021). https://doi.org/10.1007/s00213-021-05847-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-021-05847-2