Social defeat stress-induced sensitization and escalated cocaine self-administration: the role of ERK signaling in the rat ventral tegmental area.
BACKGROUND
Intermittent social defeat stress can induce neuroadaptations that promote compulsive drug taking. Within the mesocorticolimbic circuit, repeated cocaine administration activates extracellular signal-regulated kinase (ERK).


OBJECTIVE
The present experiments examine whether changes in ERK phosphorylation are necessary for the behavioral and neural adaptations that occur as a consequence of intermittent defeat stress.


METHODS
Rats were exposed to four brief intermittent defeats over the course of 10 days. Ten days after the last defeat, rats were challenged with cocaine (10 mg/kg, i.p.) or saline, and ERK activity was examined in mesocorticolimbic regions. To determine the role of ERK in defeat stress-induced behavioral sensitization, we bilaterally microinjected the MAPK/ERK kinase inhibitor U0126 (1 μg/side) or vehicle (20 % DMSO) into the ventral tegmental area (VTA) prior to each of four defeats. Ten days following the last defeat, locomotor activity was assessed for the expression of behavioral cross-sensitization to cocaine (10 mg/kg, i.p.). Thereafter, rats self-administered cocaine under fixed and progressive ratio schedules of reinforcement, including a 24-h continuous access "binge" (0.3 mg/kg/infusion).


RESULTS
We found that repeated defeat stress increased ERK phosphorylation in the VTA. Inhibition of VTA ERK prior to each social defeat attenuated the development of stress-induced sensitization and prevented stress-induced enhancement of cocaine self-administration during a continuous access binge.


CONCLUSIONS
These results suggest that enhanced activation of ERK in the VTA due to brief defeats is critical in the induction of sensitization and escalated cocaine taking.
Department of Psychology, Tufts University, Medford, MA, 02155, USA, jasmine.yap@ucdenver.edu.
Jasmine J
JJ
Yap
Elena H
EH
Chartoff
Elizabeth N
EN
Holly
David N
DN
Potter
William A
WA
Carlezon
Klaus A
KA
Miczek
D000818:Animals; D003042:Cocaine / Q000008:administration & dosage*; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006608:Hierarchy, Social; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D012054:Reinforcement, Psychology; D012646:Self Administration; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013315:Stress, Psychological / Q000378:metabolism*; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000378:metabolism*
D018765:Dopamine Uptake Inhibitors; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases; D003042:Cocaine