Antidepressant effects of selective adenosine receptor antagonists targeting the A1 and A2A receptors administered jointly with NMDA receptor ligands: behavioral, biochemical and molecular investigations in mice.
BDNF
DPCPX
Forced swim test
Gene expression
Istradefylline
NMDA receptor ligands
Journal
Pharmacological reports : PR
ISSN: 2299-5684
Titre abrégé: Pharmacol Rep
Pays: Switzerland
ID NLM: 101234999
Informations de publication
Date de publication:
25 Jul 2024
25 Jul 2024
Historique:
received:
15
12
2023
accepted:
10
07
2024
revised:
10
07
2024
medline:
26
7
2024
pubmed:
26
7
2024
entrez:
24
7
2024
Statut:
aheadofprint
Résumé
The objective of the study was to ascertain the antidepressant potential of the co-administration of NMDA receptor ligands and selective adenosine A1 and A2A receptor antagonists. The forced swim test (FST) and spontaneous locomotor activity test were carried out in adult male naïve mice. Before the behavioral testing, animals received DPCPX (a selective adenosine A1 receptor antagonist, 1 mg/kg) or istradefylline (a selective adenosine A2A receptor antagonist, 0.5 mg/kg) in combination with L-701,324 (a potent NMDA receptor antagonist, 1 mg/kg), D-cycloserine (a partial agonist at the glycine recognition site of NMDA receptor, 2.5 mg/kg), CGP 37849 (a competitive NMDA receptor antagonist, 0.3 mg/kg) or MK-801 (a non-competitive NMDA receptor antagonist, 0.05 mg/kg). Additionally, serum BDNF level and the mRNA level of the Adora1, Comt, and Slc6a15 genes in the murine prefrontal cortex were determined. The obtained results showed that DPCPX and istradefylline administered jointly with NMDA receptor ligands (except for DPCPX + D-cycloserine combination) produced an antidepressant effect in the FST in mice without enhancement in spontaneous motility of animals. An elevation in BDNF concentration was noted in the D-cycloserine-treated group. Adora1 expression increased with L-701,324, DPCPX + D-cycloserine, and DPCPX + CGP 37849, while D-cycloserine, CGP 37849, and MK-801 led to a decrease. Comt mRNA levels dropped with DPCPX + L-701,324, istradefylline + L-701,324/CGP 37849 but increased with D-cycloserine, MK-801, CGP 37849 and DPCPX + MK-801/ CGP 37849. Slc6a15 levels were reduced by D-cycloserine, DPCPX + L-701,324 but rose with DPCPX + CGP 37849/MK-801 and istradefylline + D-cycloserine/MK-801/CGP 37849. Our study suggests that selective antagonists of adenosine receptors may enhance the antidepressant efficacy of NMDA receptor ligands highlighting a potential synergistic interaction between the adenosinergic and glutamatergic systems. Wherein, A2A receptor antagonists are seen as more promising candidates in this context. Given the intricate nature of changes in BDNF levels and the expression of Adora1, Comt, and Slc6a15 seen after drug combinations exerting antidepressant properties, further research and integrative approaches are crucial understand better the mechanisms underlying their antidepressant action.
Sections du résumé
BACKGROUND
BACKGROUND
The objective of the study was to ascertain the antidepressant potential of the co-administration of NMDA receptor ligands and selective adenosine A1 and A2A receptor antagonists.
METHODS
METHODS
The forced swim test (FST) and spontaneous locomotor activity test were carried out in adult male naïve mice. Before the behavioral testing, animals received DPCPX (a selective adenosine A1 receptor antagonist, 1 mg/kg) or istradefylline (a selective adenosine A2A receptor antagonist, 0.5 mg/kg) in combination with L-701,324 (a potent NMDA receptor antagonist, 1 mg/kg), D-cycloserine (a partial agonist at the glycine recognition site of NMDA receptor, 2.5 mg/kg), CGP 37849 (a competitive NMDA receptor antagonist, 0.3 mg/kg) or MK-801 (a non-competitive NMDA receptor antagonist, 0.05 mg/kg). Additionally, serum BDNF level and the mRNA level of the Adora1, Comt, and Slc6a15 genes in the murine prefrontal cortex were determined.
RESULTS
RESULTS
The obtained results showed that DPCPX and istradefylline administered jointly with NMDA receptor ligands (except for DPCPX + D-cycloserine combination) produced an antidepressant effect in the FST in mice without enhancement in spontaneous motility of animals. An elevation in BDNF concentration was noted in the D-cycloserine-treated group. Adora1 expression increased with L-701,324, DPCPX + D-cycloserine, and DPCPX + CGP 37849, while D-cycloserine, CGP 37849, and MK-801 led to a decrease. Comt mRNA levels dropped with DPCPX + L-701,324, istradefylline + L-701,324/CGP 37849 but increased with D-cycloserine, MK-801, CGP 37849 and DPCPX + MK-801/ CGP 37849. Slc6a15 levels were reduced by D-cycloserine, DPCPX + L-701,324 but rose with DPCPX + CGP 37849/MK-801 and istradefylline + D-cycloserine/MK-801/CGP 37849.
CONCLUSION
CONCLUSIONS
Our study suggests that selective antagonists of adenosine receptors may enhance the antidepressant efficacy of NMDA receptor ligands highlighting a potential synergistic interaction between the adenosinergic and glutamatergic systems. Wherein, A2A receptor antagonists are seen as more promising candidates in this context. Given the intricate nature of changes in BDNF levels and the expression of Adora1, Comt, and Slc6a15 seen after drug combinations exerting antidepressant properties, further research and integrative approaches are crucial understand better the mechanisms underlying their antidepressant action.
Identifiants
pubmed: 39048810
doi: 10.1007/s43440-024-00627-z
pii: 10.1007/s43440-024-00627-z
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Statutory Activity of Medical University of Lublin
ID : DS48
Informations de copyright
© 2024. The Author(s).
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