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Cannabinoid agonist WIN55,212-2 prevents scopolamine-induced impairment of spatial memory in rats.

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Title: Cannabinoid agonist WIN55,212-2 prevents scopolamine-induced impairment of spatial memory in rats.
Authors: Moreno-Rodríguez M; Department of Pharmacology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), Leioa, Spain., Bengoetxea de Tena I; Department of Pharmacology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), Leioa, Spain., Martínez-Gardeazabal J; Department of Pharmacology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), Leioa, Spain., Pereira-Castelo G; Department of Pharmacology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), Leioa, Spain., Llorente-Ovejero A; Department of Pharmacology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), Leioa, Spain., Manuel I; Department of Pharmacology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), Leioa, Spain; Neurodegenerative Diseases, BioBizkaia Health Research Institute, Barakaldo, Spain., Rodríguez-Puertas R; Department of Pharmacology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), Leioa, Spain; Neurodegenerative Diseases, BioBizkaia Health Research Institute, Barakaldo, Spain. Electronic address: rafael.rodriguez@ehu.eus.
Source: European journal of pharmacology [Eur J Pharmacol] 2025 Jul 05; Vol. 998, pp. 177612. Date of Electronic Publication: 2025 Apr 17.
Publication Type: Journal Article
Language: English
Journal Info: Publisher: Elsevier Science Country of Publication: Netherlands NLM ID: 1254354 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1879-0712 (Electronic) Linking ISSN: 00142999 NLM ISO Abbreviation: Eur J Pharmacol Subsets: MEDLINE
Imprint Name(s): Publication: 2005- : Amsterdam : Elsevier Science
Original Publication: Amsterdam, North Holland Pub. Co.
MeSH Terms: Spatial Memory*/drug effects , Cannabinoid Receptor Agonists*/pharmacology, Amnesia/chemically induced ; Amnesia/prevention & control ; Pattern Recognition, Physiological/drug effects ; Male ; Animals ; Rats ; Rats, Sprague-Dawley ; Scopolamine ; Drug Evaluation, Preclinical ; Morpholines ; Naphthalenes ; Benzoxazines
Abstract: The endocannabinoid system is involved in diverse processes, like learning and memory, governed by cholinergic neurotransmission. Recent research demonstrates that in a rat model of dementia derived from basal forebrain cholinergic degeneration, WIN55,212-2, a potent cannabinoid receptor agonist, improves cognition through increased cortical choline levels. However, the effect of cannabinoids on cholinergic deficits is still under investigation. In this work, we studied the effect of this treatment in a pharmacological rat model of transient cholinergic hypofunction by the acute administration of the muscarinic antagonist, scopolamine (2 mg/kg), in spatial, recognition and aversive memory tests. Scopolamine induced memory impairment was observed in the three tests and, importantly, the cannabinoid subchronic treatment with low doses of WIN55,212-2 (0.5 mg/kg) prevented this deleterious effect in spatial memory when evaluated in Barnes maze test. Autoradiographic studies indicate that, following the WIN55,212-2 treatment, cannabinoid receptor density increased in the motor and somatosensory cortices. In layers I-V of the motor cortex, the activity of cannabinoid and muscarinic receptors also increased. These results suggest that WIN55,212-2, through the activation of cannabinoid receptors, indirectly elevates the muscarinic tone in key cortical areas for learning and memory, preventing the memory deficits induced by scopolamine specifically in spatial memory. This highlights the importance of the crosstalk between the endocannabinoid and the cholinergic system for learning and memory processes and suggest that cannabinoid agonists might be an alternative for the treatment of cognitive deficits associated with cholinergic dysfunction.
(Copyright © 2025 The Authors. Published by Elsevier B.V. All rights reserved.)
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Rafael Rodriguez Puertas has patent #Tratamiento de la demencia con agonistas cannabinoides. Spain. 02-03-2017. University of the Basque Country. ES2638057. issued to ES2638057. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Contributed Indexing: Keywords: Autoradiographic studies; CB(1) receptors; Cannabinoid agonist; Central cholinergic system; Memory impairment; Scopolamine; Sprague-Dawley rats
Substance Nomenclature: 5H31GI9502 ((3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone)
0 (Cannabinoid Receptor Agonists)
DL48G20X8X (Scopolamine)
0 (Morpholines)
0 (Naphthalenes)
0 (Benzoxazines)
Entry Date(s): Date Created: 20250419 Date Completed: 20250718 Latest Revision: 20260127
Update Code: 20260130
DOI: 10.1016/j.ejphar.2025.177612
PMID: 40252898
Database: MEDLINE
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  – Url: https://www.doi.org/10.1016/j.ejphar.2025.177612?
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  Data: Cannabinoid agonist WIN55,212-2 prevents scopolamine-induced impairment of spatial memory in rats.
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  Data: <searchLink fieldCode="AU" term="%22Moreno-Rodríguez+M%22">Moreno-Rodríguez M</searchLink>; Department of Pharmacology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), Leioa, Spain.<br /><searchLink fieldCode="AU" term="%22Bengoetxea+de+Tena+I%22">Bengoetxea de Tena I</searchLink>; Department of Pharmacology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), Leioa, Spain.<br /><searchLink fieldCode="AU" term="%22Martínez-Gardeazabal+J%22">Martínez-Gardeazabal J</searchLink>; Department of Pharmacology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), Leioa, Spain.<br /><searchLink fieldCode="AU" term="%22Pereira-Castelo+G%22">Pereira-Castelo G</searchLink>; Department of Pharmacology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), Leioa, Spain.<br /><searchLink fieldCode="AU" term="%22Llorente-Ovejero+A%22">Llorente-Ovejero A</searchLink>; Department of Pharmacology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), Leioa, Spain.<br /><searchLink fieldCode="AU" term="%22Manuel+I%22">Manuel I</searchLink>; Department of Pharmacology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), Leioa, Spain; Neurodegenerative Diseases, BioBizkaia Health Research Institute, Barakaldo, Spain.<br /><searchLink fieldCode="AU" term="%22Rodríguez-Puertas+R%22">Rodríguez-Puertas R</searchLink>; Department of Pharmacology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), Leioa, Spain; Neurodegenerative Diseases, BioBizkaia Health Research Institute, Barakaldo, Spain. Electronic address: rafael.rodriguez@ehu.eus.
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  Data: <searchLink fieldCode="JN" term="%221254354%22">European journal of pharmacology</searchLink> [Eur J Pharmacol] 2025 Jul 05; Vol. 998, pp. 177612. <i>Date of Electronic Publication: </i>2025 Apr 17.
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  Data: <i>Publisher: </i><searchLink fieldCode="PB" term="%22Elsevier+Science%22">Elsevier Science </searchLink><i>Country of Publication: </i>Netherlands <i>NLM ID: </i>1254354 <i>Publication Model: </i>Print-Electronic <i>Cited Medium: </i>Internet <i>ISSN: </i>1879-0712 (Electronic) <i>Linking ISSN: </i><searchLink fieldCode="IS" term="%2200142999%22">00142999 </searchLink><i>NLM ISO Abbreviation: </i>Eur J Pharmacol <i>Subsets: </i>MEDLINE
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  Data: <i>Publication</i>: 2005- : Amsterdam : Elsevier Science<br /><i>Original Publication</i>: Amsterdam, North Holland Pub. Co.
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  Group: Su
  Data: <searchLink fieldCode="MM" term="%22Spatial+Memory%22">Spatial Memory*</searchLink>/<searchLink fieldCode="MM" term="%22Spatial+Memory+drug+effects%22">drug effects</searchLink> <br /><searchLink fieldCode="MM" term="%22Cannabinoid+Receptor+Agonists%22">Cannabinoid Receptor Agonists*</searchLink>/<searchLink fieldCode="MM" term="%22Cannabinoid+Receptor+Agonists+pharmacology%22">pharmacology</searchLink><br /><searchLink fieldCode="MH" term="%22Amnesia%22">Amnesia</searchLink>/<searchLink fieldCode="MH" term="%22Amnesia+chemically+induced%22">chemically induced</searchLink> ; <searchLink fieldCode="MH" term="%22Amnesia%22">Amnesia</searchLink>/<searchLink fieldCode="MH" term="%22Amnesia+prevention+%26+control%22">prevention & control</searchLink> ; <searchLink fieldCode="MH" term="%22Pattern+Recognition%2C+Physiological%22">Pattern Recognition, Physiological</searchLink>/<searchLink fieldCode="MH" term="%22Pattern+Recognition%2C+Physiological+drug+effects%22">drug effects</searchLink> ; <searchLink fieldCode="MH" term="%22Male%22">Male</searchLink> ; <searchLink fieldCode="MH" term="%22Animals%22">Animals</searchLink> ; <searchLink fieldCode="MH" term="%22Rats%22">Rats</searchLink> ; <searchLink fieldCode="MH" term="%22Rats%2C+Sprague-Dawley%22">Rats, Sprague-Dawley</searchLink> ; <searchLink fieldCode="MH" term="%22Scopolamine%22">Scopolamine</searchLink> ; <searchLink fieldCode="MH" term="%22Drug+Evaluation%2C+Preclinical%22">Drug Evaluation, Preclinical</searchLink> ; <searchLink fieldCode="MH" term="%22Morpholines%22">Morpholines</searchLink> ; <searchLink fieldCode="MH" term="%22Naphthalenes%22">Naphthalenes</searchLink> ; <searchLink fieldCode="MH" term="%22Benzoxazines%22">Benzoxazines</searchLink>
– Name: Abstract
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  Group: Ab
  Data: The endocannabinoid system is involved in diverse processes, like learning and memory, governed by cholinergic neurotransmission. Recent research demonstrates that in a rat model of dementia derived from basal forebrain cholinergic degeneration, WIN55,212-2, a potent cannabinoid receptor agonist, improves cognition through increased cortical choline levels. However, the effect of cannabinoids on cholinergic deficits is still under investigation. In this work, we studied the effect of this treatment in a pharmacological rat model of transient cholinergic hypofunction by the acute administration of the muscarinic antagonist, scopolamine (2 mg/kg), in spatial, recognition and aversive memory tests. Scopolamine induced memory impairment was observed in the three tests and, importantly, the cannabinoid subchronic treatment with low doses of WIN55,212-2 (0.5 mg/kg) prevented this deleterious effect in spatial memory when evaluated in Barnes maze test. Autoradiographic studies indicate that, following the WIN55,212-2 treatment, cannabinoid receptor density increased in the motor and somatosensory cortices. In layers I-V of the motor cortex, the activity of cannabinoid and muscarinic receptors also increased. These results suggest that WIN55,212-2, through the activation of cannabinoid receptors, indirectly elevates the muscarinic tone in key cortical areas for learning and memory, preventing the memory deficits induced by scopolamine specifically in spatial memory. This highlights the importance of the crosstalk between the endocannabinoid and the cholinergic system for learning and memory processes and suggest that cannabinoid agonists might be an alternative for the treatment of cognitive deficits associated with cholinergic dysfunction.<br /> (Copyright © 2025 The Authors. Published by Elsevier B.V. All rights reserved.)
– Name: Abstract
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  Data: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Rafael Rodriguez Puertas has patent #Tratamiento de la demencia con agonistas cannabinoides. Spain. 02-03-2017. University of the Basque Country. ES2638057. issued to ES2638057. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
– Name: SubjectMinor
  Label: Contributed Indexing
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  Data: <i>Keywords: </i>Autoradiographic studies; CB(1) receptors; Cannabinoid agonist; Central cholinergic system; Memory impairment; Scopolamine; Sprague-Dawley rats
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  Data: 5H31GI9502 ((3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone)<br />0 (Cannabinoid Receptor Agonists)<br />DL48G20X8X (Scopolamine)<br />0 (Morpholines)<br />0 (Naphthalenes)<br />0 (Benzoxazines)
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        Text: English
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      – SubjectFull: Amnesia chemically induced
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