PMID- 25446676
OWN - NLM
STAT- MEDLINE
DCOM- 20150715
LR  - 20191210
IS  - 1873-7064 (Electronic)
IS  - 0028-3908 (Print)
IS  - 0028-3908 (Linking)
VI  - 89
DP  - 2015 Feb
TI  - Knockdown of ventral tegmental area mu-opioid receptors in rats prevents effects 
      of social defeat stress: implications for amphetamine cross-sensitization, social 
      avoidance, weight regulation and expression of brain-derived neurotrophic factor.
PG  - 325-34
AB  - Social defeat stress causes social avoidance and long-lasting cross-sensitization 
      to psychostimulants, both of which are associated with increased brain-derived 
      neurotrophic factor (BDNF) expression in the ventral tegmental area (VTA). 
      Moreover, social stress upregulates VTA mu-opioid receptor (MOR) mRNA. In the 
      VTA, MOR activation inhibits GABA neurons to disinhibit VTA dopamine neurons, 
      thus providing a role for VTA MORs in the regulation of psychostimulant 
      sensitization. The present study determined the effect of lentivirus-mediated MOR 
      knockdown in the VTA on the consequences of intermittent social defeat stress, a 
      salient and profound stressor in humans and rodents. Social stress exposure 
      induced social avoidance and attenuated weight gain in animals with 
      non-manipulated VTA MORs, but both these effects were prevented by VTA MOR 
      knockdown. Rats with non-manipulated VTA MOR expression exhibited 
      cross-sensitization to amphetamine challenge (1.0 mg/kg, i.p.), evidenced by a 
      significant augmentation of locomotion. By contrast, knockdown of VTA MORs 
      prevented stress-induced cross-sensitization without blunting the 
      locomotor-activating effects of amphetamine. At the time point corresponding to 
      amphetamine challenge, immunohistochemical analysis was performed to examine the 
      effect of stress on VTA BDNF expression. Prior stress exposure increased VTA BDNF 
      expression in rats with non-manipulated VTA MOR expression, while VTA MOR 
      knockdown prevented stress-induced expression of VTA BDNF. Taken together, these 
      results suggest that upregulation of VTA MOR is necessary for the behavioral and 
      biochemical changes induced by social defeat stress. Elucidating VTA MOR 
      regulation of stress effects on the mesolimbic system may provide new therapeutic 
      targets for treating stress-induced vulnerability to substance abuse.
FAU - Johnston, Caitlin E
AU  - Johnston CE
AD  - Department of Basic Medical Sciences, University of Arizona College of Medicine, 
      Phoenix, AZ, USA.
FAU - Herschel, Daniel J
AU  - Herschel DJ
FAU - Lasek, Amy W
AU  - Lasek AW
FAU - Hammer, Ronald P Jr
AU  - Hammer RP Jr
FAU - Nikulina, Ella M
AU  - Nikulina EM
LA  - eng
GR  - R01 DA026451/DA/NIDA NIH HHS/United States
GR  - DA026451/DA/NIDA NIH HHS/United States
GR  - R01 MH073930/MH/NIMH NIH HHS/United States
GR  - AA016654/AA/NIAAA NIH HHS/United States
GR  - U01 AA016654/AA/NIAAA NIH HHS/United States
GR  - MH073930/MH/NIMH NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - England
TA  - Neuropharmacology
JT  - Neuropharmacology
JID - 0236217
RN  - 0 (Analgesics, Opioid)
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Central Nervous System Stimulants)
RN  - 0 (Receptors, Opioid, mu)
RN  - CK833KGX7E (Amphetamine)
SB  - IM
MH  - Amphetamine/*pharmacology
MH  - Analgesics, Opioid/pharmacokinetics
MH  - Animals
MH  - Body Weight/drug effects
MH  - Brain-Derived Neurotrophic Factor/*metabolism
MH  - Cell Count
MH  - Central Nervous System Stimulants/*pharmacology
MH  - Disease Models, Animal
MH  - Escape Reaction/drug effects/physiology
MH  - Handling, Psychological
MH  - Male
MH  - Motor Activity/drug effects
MH  - Protein Binding/drug effects
MH  - Rats
MH  - Rats, Long-Evans
MH  - Rats, Sprague-Dawley
MH  - Receptors, Opioid, mu/*deficiency/genetics
MH  - *Stress, Psychological/metabolism/pathology/prevention & control
MH  - Transduction, Genetic
MH  - Ventral Tegmental Area/*metabolism
PMC - PMC4293250
MID - NIHMS636700
EDAT- 2014/12/03 06:00
MHDA- 2015/07/16 06:00
PMCR- 2016/02/01
CRDT- 2014/12/03 06:00
PHST- 2014/06/30 00:00 [received]
PHST- 2014/09/14 00:00 [revised]
PHST- 2014/10/08 00:00 [accepted]
PHST- 2014/12/03 06:00 [entrez]
PHST- 2014/12/03 06:00 [pubmed]
PHST- 2015/07/16 06:00 [medline]
PHST- 2016/02/01 00:00 [pmc-release]
AID - S0028-3908(14)00374-8 [pii]
AID - 10.1016/j.neuropharm.2014.10.010 [doi]
PST - ppublish
SO  - Neuropharmacology. 2015 Feb;89:325-34. doi: 10.1016/j.neuropharm.2014.10.010.