Molecular determinants of behavioral changes induced by neonatal ketamine and dexmedetomidine application

J Neural Transm (Vienna). 2019 Dec;126(12):1577-1588. doi: 10.1007/s00702-019-02081-1. Epub 2019 Sep 14.

Abstract

Ketamine (KET), an anesthetic, analgesic, and a sedative N-methyl-D-aspartate (NMDA) receptor antagonist agent, exposure during neonatal period may lead to learning impairment, behavioral abnormalities, and cognitive decline in the later years of life. In recent studies, it has been reported that sedative-acting α2 agonist dexmedetomidine (DEX), which is commonly used in clinical practice with KET, has neuroprotective effects and prevents the undesirable effects of anesthesia. To elucidate the underlying mechanisms of these actions, we investigated the interaction between NMDA receptors α2 adrenoceptor and adulthood behaviors in neonatally KET and/or DEX administrated mice. Balb/c male mice were administrated with saline, KET (75 mg/kg), DEX (10 µg/kg), or KET + DEX (75 mg/kg + 10 µg/kg) on postnatal day 7. During adulthood (8-10 weeks old) mice were subjected to elevated plus maze, open field, and Morris water maze tests. After behavioral tests, hippocampus samples were extracted for mRNA expression studies of NMDAR subunits (GluN1, GluN2A, and GluN2B) and α2 adrenoceptor subunits (α2A, α2B, and α2C) by real-time PCR. Ketamine increased horizontal and vertical locomotor activity (p < 0.01) and impaired spatial learning-memory (p < 0.05). DEX increased anxiety-like behavior (p < 0.01), but did not affect spatial learning-memory and locomotor activity. KET + DEX impaired spatial learning-memory (p < 0.01), increased horizontal locomotor activity (p < 0.01), and anxiety-like behavior (p < 0.05). Our study implies that DEX cannot prevent the adverse effects of KET, on spatial learning-memory, and locomotor activity. In addition to this, it can be thought that during brain development, there is an interaction between NMDAR and α2 adrenoceptor systems.

Keywords: Dexmedetomidine; Ketamine; NMDA; Neonatal mice; Neurocognitive function; α2 adrenoceptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anesthetics, Dissociative / pharmacology*
  • Animals
  • Animals, Newborn
  • Behavior, Animal / drug effects*
  • Dexmedetomidine / pharmacology*
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Hypnotics and Sedatives / pharmacology*
  • Ketamine / pharmacology*
  • Male
  • Mice, Inbred BALB C
  • Receptors, Adenosine A2 / drug effects
  • Receptors, Adenosine A2 / metabolism
  • Receptors, N-Methyl-D-Aspartate / drug effects
  • Receptors, N-Methyl-D-Aspartate / metabolism

Substances

  • Anesthetics, Dissociative
  • Hypnotics and Sedatives
  • Receptors, Adenosine A2
  • Receptors, N-Methyl-D-Aspartate
  • Dexmedetomidine
  • Ketamine