This study examined whether activation of extracellular signal-regulated kinase (ERK) contributes to the increased open-arm time observed in the elevated plus maze (EPM) during opioid withdrawal. We applied SL327, a selective ERK kinase (MEK) inhibitor, to specific limbic areas and examined the effect on EPM behaviors of controls and during naloxone-precipitated morphine withdrawal. We next confirmed that ERK activation increased in limbic areas of mice undergoing naloxone-precipitated morphine withdrawal. Direct injection of SL327 into the amygdala blocked the withdrawal-induced increase in open-arm time; however, injecting SL327 into the septum had no effect. Consistent with these results, both 0.2 and 2 mg/kg naloxone increased ERK activation in the central amygdala of morphine-dependent mice. In drug-naive mice, 2 mg/kg naloxone, but not 0.2 mg/kg, increased ERK activation in the central amygdala. During withdrawal, increased ERK activation was also observed in the lateral septum. In the locus coeruleus, a significant increase was observed only in morphine-dependent mice receiving 2 mg/kg, but not 0.2 mg/kg naloxone. In conclusion, ERK activation in limbic areas is likely involved in both the aversive properties of naloxone and in the affective/emotional symptoms of opioid withdrawal, including mediating EPM behaviors.
aDepartment of Psychology, Behavioral and Cellular Neuroscience, Texas A&M University, College Station, Texas
bDepartment of Psychiatry and Biobehavioral Sciences, UCLA, Neuropsychiatric Institute, Westwood Plaza, Los Angeles, California
cDepartment of Human Genetics, University of Chicago, CLSC, Chicago, Illinois, USA
Correspondence to Shoshana Eitan, PhD, Texas A&M University, Department of Psychology, 4235 TAMU, College Station, TX 77843, USA
Received 16 December 2008 Accepted as revised 7 May 2009