BDNF Over-Expression in the Ventral Tegmental Area Prolongs Social Defeat Stress-induced Cross-Sensitization to Amphetamine and Increases ΔFosB Expression in Mesocorticolimbic Regions of Rats (2013)

Neuropsychopharmacology. 2013 May 21. doi: 10.1038/npp.2013.130.

Wang J, Fanous S, Terwilliger EF, Bass CE, Hammer RP Jr, Nikulina EM.


1] Department of Basic Medical Sciences, University of Arizona College of Medicine, Phoenix, AZ, USA [2] Neuroscience Program, Arizona State University, Tempe, AZ, USA.


Social defeat stress induces persistent cross-sensitization to psychostimulants, but the molecular mechanisms underlying the development of cross-sensitization remain unclear. One candidate is brain-derived neurotrophic factor (BDNF). The present research examined whether ventral tegmental area (VTA) BDNF over-expression would prolong the time-course of cross-sensitization after a single social defeat stress, which normally produces transient cross-sensitization lasting less than one week.

ΔFosB, a classic molecular marker of addiction, was also measured in mesocorticolimbic terminal regions.

Separate groups of intact male Sprague-Dawley rats underwent a single episode of social defeat stress or control handling, followed by amphetamine challenge 3 or 14 days later. AMPH cross-sensitization was apparent 3 but not 14 days after stress. Intra-VTA infusion of adeno-associated viral (AAV-BDNF) vector resulted in a two-fold increase of BDNF level in comparison with the group receiving the control virus (AAV-GFP), which lasted at least 45 days.

Additionally, over-expression of BDNF in the VTA alone increased ΔFosB in the nucleus accumbens (NAc) and prefrontal cortex.

Fourteen days after viral infusions, a separate group of rats underwent a single social defeat stress or control handling and were challenged with amphetamine (AMPH) 14 and 24 days after stress. AAV-BDNF rats exposed to stress showed prolonged cross-sensitization and facilitated sensitization to the second drug challenge. Immunohistochemistry showed that the combination of virally enhanced VTA BDNF, stress, and AMPH resulted in increased ΔFosB in the NAc shell compared to other groups. Thus, elevation of VTA BDNF prolongs cross-sensitization, facilitates sensitization, and increases ΔFosB in mesocorticolimbic terminal regions. As such, elevated VTA BDNF may be a risk factor for drug sensitivity.

Neuropsychopharmacology accepted article preview online, 21 May 2013; doi:10.1038/npp.2013.130.