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Cross state-dependency of learning between tramadol and MK-801 in the mouse dorsal hippocampus: involvement of nitric oxide (NO) signaling pathway

Abstract

Rationale

Tramadol, an atypical μ-opioid receptor agonist, as a psychoactive drug, is frequently abused by human beings. Understanding the neurobiological mechanisms of drug-associated learning and memory formation may help prevent drug addiction and relapse. Previous study revealed that dorsal hippocampus (CA1) plays a crucial role in the retrieval of tramadol-associated memory and that its role depends on the expression of CA1 N-methyl-d-aspartate (NMDA) receptors (Jafari-Sabet et al. Can J Physiol Pharmacol 96:45-50, 2018).

Objective

To clarify the exact mechanisms involved, the activation of CA1 nitric oxide (NO) signaling pathway by l-arginine (a nitric oxide precursor) on the interaction between tramadol and MK-801 in memory retrieval was examined. The dorsal hippocampal CA1 regions of adult male NMRI mice were bilaterally cannulated and a single-trial step-down inhibitory avoidance apparatus was used for the assessment of memory retrieval.

Results

Post-training and/or pre-test microinjection of tramadol (0.5 and 1 μg/mouse) and/or a non-competitive NMDA receptor antagonist, MK-801 (0.25 and 0.5 μg/mouse), induced amnesia which were reversed when the same doses of the drugs were administered 24 h later in a pre-test session, suggesting tramadol state-dependent learning (SDL) and MK-801 SDL. The amnesia induced by post-training microinjection of tramadol (1 μg/mouse) was reversed by pre-test microinjection of MK-801 (0.25 and 0.5 μg/mouse). Pre-test microinjection of MK-801 (0.125 and 0.25 μg/mouse) with an ineffective dose of tramadol (0.25 μg/mouse) potentiated tramadol SDL. The amnesia induced by post-training microinjection of MK-801 (0.5 μg/mouse) was reversed by pre-test microinjection of tramadol (0.5 and 1 μg/mouse). Pre-test microinjection of tramadol (0.25 and 0.5 μg/mouse) with an ineffective dose of MK-801 (0.125 μg/mouse) potentiated MK-801 SDL. Pre-test microinjection of ineffective doses of l-arginine (0.125, 025, and 0.5 μg/mouse) improved amnesia induced by the co-administration of tramadol and MK-801. Pre-test microinjection of l-arginine (0.125, 025, and 0.5 μg/mouse) could not reverse amnesia induced by post-training microinjection of tramadol while same doses of l-arginine improved MK-801 response on tramadol SDL.

Conclusion

The results strongly propose that activation of CA1 NO signaling pathway has a pivotal role in cross SDL among tramadol and MK-801.

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Correspondence to Majid Jafari-Sabet.

Ethics declarations

All animal experiments were conducted in accordance with the UK Animals (Scientific Procedures) Act, 1986 and associated guidelines and EU Directive 2010/63/EU for animal experiments and approved by the local ethical committee.

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The authors declare that they have no conflict of interest.

Additional information

Research Highlights

• Tramadol and/or MK-801 induced amnesia and also state-dependent learning (SDL).

• Cross SDL occurred between tramadol and MK-801 in the mouse dorsal hippocampus.

• Intra-CA1 microinjection of l-arginine dose-dependently improved tramadol/MK-801-induced amnesia.

• Intra-CA1 microinjection of l-arginine dose-dependently increased MK-801 response upon tramadol-SDL.

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Jafari-Sabet, M., Amiri, S. & Ataee, R. Cross state-dependency of learning between tramadol and MK-801 in the mouse dorsal hippocampus: involvement of nitric oxide (NO) signaling pathway. Psychopharmacology 235, 1987–1999 (2018). https://doi.org/10.1007/s00213-018-4897-5

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  • DOI: https://doi.org/10.1007/s00213-018-4897-5

Keywords

  • Tramadol; MK-801
  • l-Arginine
  • State-dependent learning
  • Dorsal hippocampus
  • Mouse