PMID- 28240305
OWN - NLM
STAT- MEDLINE
DCOM- 20181101
LR  - 20181202
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 7
DP  - 2017 Feb 27
TI  - Increased PKC activity and altered GSK3beta/NMDAR function drive behavior cycling in 
      HINT1-deficient mice: bipolarity or opposing forces.
PG  - 43468
LID - 10.1038/srep43468 [doi]
LID - 43468
AB  - Mice with histidine triad nucleotide-binding protein 1 (HINT1) deletion exhibit 
      manic-like symptoms that evolve into depressive-like behavior in response to 
      stressful paradigms. Molecular and electrophysiological studies have indicated 
      that HINT1(-/-) mice exhibit increased PKC, PKA, and GSK3beta activities, as well as 
      glutamate N-methyl-D-aspartate receptor 
      (NMDAR)/alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic receptor (AMPAR) and 
      NR2B/NR2A subunit ratios. Pharmacological interventions stabilized their behavior 
      but through different mechanisms. GSK3beta inhibitors and valproate directly 
      attenuated the expression of the manic-like symptoms, whereas PKC inhibition, 
      lamotrigine, or risperidone promoted NMDAR-mediated depressive-like behaviors 
      that counterbalanced the preexisting manic-like symptoms. Naive HINT1(-/-) mice 
      exposed to stressful paradigms rapidly manifested depressive-like behaviors in 
      subsequent stressful situations, a capacity that persisted for a couple of weeks 
      thereafter. During the depressive-like phase, citalopram, amitriptyline and MK801 
      precipitated manic-like behaviors in stressed HINT1(-/-) mice. Notably, the 
      antagonism of NMDARs prevented HINT1(-/-) mice from alternating behaviors in 
      response to stress. A comparison with "manic" Black Swiss mice indicated that in 
      HINT1(-/-) mice, PKC supports manic-like symptoms and reduces the expression of 
      depressive-like behaviors via activation of GSK3beta and regulation of NR2B-enriched 
      NMDARs. HINT1(-/-) mice represent a suitable model for studying human BPD and may 
      facilitate the identification of novel targets and drugs to treat this mental 
      disorder.
FAU - Garzon-Nino, Javier
AU  - Garzon-Nino J
AD  - Neuropharmacology, Department of Translational Neurosciences, Instituto Cajal, 
      CSIC, Madrid E-28002, Spain.
FAU - Rodriguez-Munoz, Maria
AU  - Rodriguez-Munoz M
AD  - Neuropharmacology, Department of Translational Neurosciences, Instituto Cajal, 
      CSIC, Madrid E-28002, Spain.
FAU - Cortes-Montero, Elsa
AU  - Cortes-Montero E
AD  - Neuropharmacology, Department of Translational Neurosciences, Instituto Cajal, 
      CSIC, Madrid E-28002, Spain.
FAU - Sanchez-Blazquez, Pilar
AU  - Sanchez-Blazquez P
AD  - Neuropharmacology, Department of Translational Neurosciences, Instituto Cajal, 
      CSIC, Madrid E-28002, Spain.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20170227
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - 0 (Antidepressive Agents, Second-Generation)
RN  - 0 (Antimanic Agents)
RN  - 0 (Antipsychotic Agents)
RN  - 0 (Excitatory Amino Acid Antagonists)
RN  - 0 (Hint1 protein, mouse)
RN  - 0 (Nerve Tissue Proteins)
RN  - 0 (Neuroprotective Agents)
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - 0 (Triazines)
RN  - 0DHU5B8D6V (Citalopram)
RN  - 1806D8D52K (Amitriptyline)
RN  - 614OI1Z5WI (Valproic Acid)
RN  - 6LR8C1B66Q (Dizocilpine Maleate)
RN  - EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta)
RN  - EC 2.7.11.1 (Gsk3b protein, mouse)
RN  - EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases)
RN  - EC 2.7.11.13 (Protein Kinase C)
RN  - L6UH7ZF8HC (Risperidone)
RN  - U3H27498KS (Lamotrigine)
SB  - IM
MH  - Amitriptyline/pharmacology
MH  - Animals
MH  - Antidepressive Agents, Second-Generation/pharmacology
MH  - Antimanic Agents/pharmacology
MH  - Antipsychotic Agents/pharmacology
MH  - Bipolar Disorder/drug therapy/*genetics/metabolism/physiopathology
MH  - Citalopram/pharmacology
MH  - Cyclic AMP-Dependent Protein Kinases/genetics/metabolism
MH  - Disease Models, Animal
MH  - Dizocilpine Maleate/pharmacology
MH  - Excitatory Amino Acid Antagonists/pharmacology
MH  - Gene Expression Regulation
MH  - Glycogen Synthase Kinase 3 beta/*genetics/metabolism
MH  - Humans
MH  - Lamotrigine
MH  - Male
MH  - Mice
MH  - Mice, Knockout
MH  - Nerve Tissue Proteins/deficiency/*genetics
MH  - Neuroprotective Agents/pharmacology
MH  - Protein Kinase C/*genetics/metabolism
MH  - Receptors, N-Methyl-D-Aspartate/*genetics/metabolism
MH  - Risperidone/pharmacology
MH  - Signal Transduction
MH  - Stress, Psychological/*genetics/metabolism/physiopathology/prevention & control
MH  - Triazines/pharmacology
MH  - Valproic Acid/pharmacology
PMC - PMC5327482
COIS- The authors declare no competing financial interests.
EDAT- 2017/02/28 06:00
MHDA- 2018/11/02 06:00
PMCR- 2017/02/27
CRDT- 2017/02/28 06:00
PHST- 2016/08/22 00:00 [received]
PHST- 2017/01/25 00:00 [accepted]
PHST- 2017/02/28 06:00 [entrez]
PHST- 2017/02/28 06:00 [pubmed]
PHST- 2018/11/02 06:00 [medline]
PHST- 2017/02/27 00:00 [pmc-release]
AID - srep43468 [pii]
AID - 10.1038/srep43468 [doi]
PST - epublish
SO  - Sci Rep. 2017 Feb 27;7:43468. doi: 10.1038/srep43468.