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

• Published in: Psychopharmacology 2018-07, Vol.235 (7), p.1987-1999
• Main Authors: Jafari-Sabet, Majid, Amiri, Shiva, Ataee, Ramin
• Format: Article
• Language: English
• Subjects: Activation; Amnesia; Arginine; Biomedical and Life Sciences; Biomedicine; Dizocilpine; Dosage and administration; Drug abuse; Drug addiction; Drug dosages; Drug interactions; Glutamic acid receptors; Glutamic acid receptors (ionotropic); Health aspects; Hippocampus; Hippocampus (Brain); Learning; Memory; Microinjection; N-Methyl-D-aspartic acid receptors; Neurosciences; Nitric oxide; Observations; Opioid receptors; Original Investigation; Pharmacology/Toxicology; Psychiatry; Psychotropic drugs; Rodents; Signal transduction; State-dependent learning; Tramadol
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-018-4897-5

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.