Pharmacological modulators of nitric oxide signaling and contextual fear conditioning in mice

Jonathan B. Kelley, Karen L. Anderson, Yossef Itzhak

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Rationale: Nitric oxide (NO) produced by neuronal nitric oxide synthase (nNOS) is a retrograde neuronal messenger that participates in synaptic plasticity, including late-phase long-term potentiation (LTP) and long-term memory (LTM) formation. Our recent studies have shown that nNOS knockout (KO) mice have a severe deficit in contextual fear conditioning compared to wild type (WT) counterparts (Kelley et al. 2009). Objectives: Given the role of the nNOS gene in fear conditioning, we investigated whether systemic administration of modulators of NO signaling affect the formation of contextual and cued fear memories and the effects of these modulators on cyclic 3'5'-guanosine monophosphate (cGMP) levels in the hippocampus and amygdala. Methods: The preferential nNOS inhibitor S-methyl-L-thiocitrulline (SMTC; 10-200 mg/kg) was administered (IP) to WT mice, and the NO donor molsidomine (10 mg/kg) was administered (IP) to nNOS KO mice either 30 min pretraining or immediately posttraining. Results: Pretraining SMTC administration to WT mice impaired both short-and long-term memories of contextual (36% inhibition) but not cued fear conditioning. Pretraining molsidomine administration to nNOS KO mice improved their deficit in short-and long-term memories of contextual fear conditioning (46% increase). Posttraining drug administration had no effect on WT and nNOS KO mice. The systemic administration of SMTC dose-dependently decreased cGMP concentrations down to 25% of control, while molsidomine increased cGMP concentration (threeand five-fold) in amygdala and hippocampus, respectively. Conclusions: These findings suggest that neuronal NO and its downstream second messenger cGMP are important for acquisition and subsequent consolidation of LTM of contextual fear conditioning.

Original languageEnglish
Pages (from-to)65-74
Number of pages10
JournalPsychopharmacology
Volume210
Issue number1
DOIs
StatePublished - May 1 2010

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Nitric Oxide Synthase Type I
Fear
Nitric Oxide
Pharmacology
Long-Term Memory
Molsidomine
Knockout Mice
Amygdala
Short-Term Memory
Hippocampus
Neuronal Plasticity
Nitric Oxide Donors
Long-Term Potentiation
Second Messenger Systems
Conditioning (Psychology)
3'-guanylic acid
Pharmaceutical Preparations
Genes

Keywords

  • Amygdala
  • Fear conditioning
  • Hippocampus
  • Memory
  • Nitric oxide
  • Nitric oxide synthase

ASJC Scopus subject areas

  • Pharmacology

Cite this

Pharmacological modulators of nitric oxide signaling and contextual fear conditioning in mice. / Kelley, Jonathan B.; Anderson, Karen L.; Itzhak, Yossef.

In: Psychopharmacology, Vol. 210, No. 1, 01.05.2010, p. 65-74.

Research output: Contribution to journalArticle

Kelley, Jonathan B. ; Anderson, Karen L. ; Itzhak, Yossef. / Pharmacological modulators of nitric oxide signaling and contextual fear conditioning in mice. In: Psychopharmacology. 2010 ; Vol. 210, No. 1. pp. 65-74.
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abstract = "Rationale: Nitric oxide (NO) produced by neuronal nitric oxide synthase (nNOS) is a retrograde neuronal messenger that participates in synaptic plasticity, including late-phase long-term potentiation (LTP) and long-term memory (LTM) formation. Our recent studies have shown that nNOS knockout (KO) mice have a severe deficit in contextual fear conditioning compared to wild type (WT) counterparts (Kelley et al. 2009). Objectives: Given the role of the nNOS gene in fear conditioning, we investigated whether systemic administration of modulators of NO signaling affect the formation of contextual and cued fear memories and the effects of these modulators on cyclic 3'5'-guanosine monophosphate (cGMP) levels in the hippocampus and amygdala. Methods: The preferential nNOS inhibitor S-methyl-L-thiocitrulline (SMTC; 10-200 mg/kg) was administered (IP) to WT mice, and the NO donor molsidomine (10 mg/kg) was administered (IP) to nNOS KO mice either 30 min pretraining or immediately posttraining. Results: Pretraining SMTC administration to WT mice impaired both short-and long-term memories of contextual (36{\%} inhibition) but not cued fear conditioning. Pretraining molsidomine administration to nNOS KO mice improved their deficit in short-and long-term memories of contextual fear conditioning (46{\%} increase). Posttraining drug administration had no effect on WT and nNOS KO mice. The systemic administration of SMTC dose-dependently decreased cGMP concentrations down to 25{\%} of control, while molsidomine increased cGMP concentration (threeand five-fold) in amygdala and hippocampus, respectively. Conclusions: These findings suggest that neuronal NO and its downstream second messenger cGMP are important for acquisition and subsequent consolidation of LTM of contextual fear conditioning.",
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