BEHAVIORAL NEUROSCIENCE Knockdown of tropomyosin-related kinase B receptor expression in the nucleus accumbens shell prevents intermittent social defeat stress-induced cross- sensitization to amphetamine in rats Junshi Wang, 1, * Robert W. Bina, 2 Jeffrey C. Wingard, 3 Ernest F. Terwilliger, 3 Ronald P. Hammer Jr 1,2,4 and Ella M. Nikulina 2 1 Neuroscience Program, Arizona State University, Tempe, AZ, USA 2 Department of Basic Medical Sciences, University of Arizona, College of Medicine, 425 N 5th Street, Phoenix, AZ, 85004, USA 3 Beth Israel Deaconess Medical Center, Boston, MA, USA 4 Departments of Pharmacology and Psychiatry, University of Arizona, College of Medicine, Phoenix, AZ, USA Keywords: brain-derived neurotrophic factor, cross-sensitization, nucleus accumbens, social stress, tropomyosin-related kinase B, ventral tegmental area Abstract The nucleus accumbens (NAc) is a critical brain region for the rewarding effects of drugs of abuse. Brain-derived neurotrophic factor (BDNF) can facilitate stress- and drug-induced neuroadaptation in the mesocorticolimbic system. BDNF-containing projec- tions to the NAc originate from the ventral tegmental area (VTA) and the prefrontal cortex, and BDNF release activates tropomyo- sin-related kinase B (TrkB). In this study, we examined the necessity for BDNF-TrkB signaling in the NAc shell during social defeat stress-induced cross-sensitization to amphetamine. Adeno-associated virus expressing short hairpin RNA directed against TrkB (AAV-shTrkB) was infused bilaterally into the NAc shell to knock down TrkB, whereas AAV-GFP (green fluorescent protein) was used as the control virus. Rats were exposed to intermittent social defeat stress or handling procedures; amphetamine chal- lenge was given at 10 days after the last defeat and locomotor activity was measured. Stressed rats that received the control virus showed cross-sensitization to amphetamine compared with the handled rats. In contrast, NAc TrkB knockdown prevented social defeat stress-induced cross-sensitization. TrkB knockdown in the NAc was found to reduce the level of phospho-extracellu- lar signal-regulated kinase 1 in this region. NAc TrkB knockdown also prevented stress-induced elevation of BDNF and the gluta- mate receptor type 1 (GluA1) subunit of AMPA receptor in the VTA, as well as DFosB expression in the NAc. These findings indicated that BDNF-TrkB signaling in the NAc shell was required for social defeat stress-induced cross-sensitization. NAc TrkB- BDNF signaling also appeared to be involved in the regulation of GluA1 in the VTA, as well as in the NAc DFosB accumulation that could trigger cross-sensitization after social defeat stress. Introduction Exposure to stress augments drug-induced mesolimbic dopamine transmission and locomotor activity (Sorg & Kalivas, 1991; Yap & Miczek, 2008), known as cross-sensitization. Among all types of stressors, social defeat has face validity to replicate aversive social interaction in humans (Koolhaas et al., 1997), and induces long-last- ing cross-sensitization to psychostimulants (Covington & Miczek, 2001; Nikulina et al., 2004). After intermittent social defeat stress, elevation of brain-derived neurotrophic factor (BDNF) expression in the ventral tegmental area (VTA) occurs with a time course similar to that of cross-sensitization to psychostimulants (Fanous et al., 2010). In the mesolimbic circuit, BDNF is synthesised in VTA dopamine neurons and transported anterogradely to the nucleus accumbens (NAc) (Altar et al., 1997), the brain region mediating the addictive effects of drugs of abuse. Previous studies have demonstrated the involvement of BDNF signaling in addiction-related behaviors using a drug self-administration model. It was shown that enhanced BDNF in the NAc can promote drug intake and drug-seeking behavior during the withdrawal period (Grimm et al., 2001; Lu et al., 2004; Graham et al., 2007, 2009). Enhanced BDNF signaling in the NAc facilitates the development of sensitization to cocaine (Horger et al., 1999). Also, NAc tropomyosin-related kinase B (TrkB) overexpression enhances sensitization to cocaine, which can be prevented by Correspondence: Ella M. Nikulina, as above. E-mail: nikulina@email.arizona.edu *Present address: Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425, USA. Received 15 August 2013, revised 20 October 2013, accepted 26 November 2013 © 2013 Federation of European Neuroscience Societies and John Wiley & Sons Ltd European Journal of Neuroscience, Vol. 39, pp. 1009–1017, 2014 doi:10.1111/ejn.12464