Neurotrophin-3 contributes to the initiation of behavioral sensitization to cocaine by activating the Ras/mitogen-activated protein kinase signal transduction cascade

These experiments were designed to assess the role of neurotrophins and the Ras/mitogen-activated protein kinase (MAP) signal transduction cascade in behavioral sensitization to cocaine. The first experiments evaluated the ef fect of three daily intra-ventral tegmental area (VTA) microinjections of n eurotrophin-3 (NT-3) or brain-derived neurotrophic factor (BDNF) on the beh avioral-activating effects of a subsequent challenge injection of cocaine i n rats. Results indicated that, although NT-3 did not influence behavior ac ross the three microinjection days, animals displayed a sensitized behavior al response to the subsequent cocaine challenge injection. In contrast, BDN F microinjections resulted in a progressive increase in behavioral activity but did not influence the subsequent behavioral response to cocaine. A sec ond series of experiments assessed the effect of inhibiting the MAP kinase signal transduction cascade on the initiation of behavioral sensitization t o cocaine. The MAP kinase kinase inhibitor PD98059, or its vehicle, was mic roinjected into the VTA before three daily cocaine injections. Although PD9 8059 did not influence the acute behavioral response to cocaine, it blocked sensitization. Finally, the effects of acute and repeated cocaine injectio ns on NT-3 and BDNF mRNA levels in the VTA, substantia nigra, and hippocamp us were assessed. Results indicated that an acute cocaine injection resulte d in a transient increase in NT-3 mRNA levels in the VTA. Collectively, the se results suggest that NT-3 contributes to the initiation of behavioral se nsitization to cocaine by activating the Ras/MAP kinase signal transduction system. The present data also indicate that BDNF itself produced a progres sive augmentation in behavioral activation with repeated administration.