Psychostimulants are widely abused, but the molecular mechanisms mediating addiction and craving remain largely unknown. First messengers mediating responses to psychostimulants include brain-derived neurotrophic factor (BDNF), and its signals are transduced via the receptor, trkB. Following administration of cocaine to rodents, BDNF elevations in the striatum are noted both acutely and during the withdrawal period. The effects of BDNF may be mediated pre-synaptically, on dopaminergic neurons in the substantia nigra (SN) and ventral tegmental area (VTA), and/or post-synaptically, directly on striatal medium size spiny neurons. To investigate the role of trkB-mediated signal transduction in the dorsal and ventral striatum in age-dependent differences in response to cocaine, this study will utilize a novel mouse model of selective, post-natal deletion of trkB receptors in these regions using the striatal-specific DARPP-32 promoter recently identified in this laboratory. Based on preliminary data, it is hypothesized that BDNF and dopamine may have similar actions via stimulation of shared signal transduction molecules and transcription factors, including cdk5/p35 and dFosB.
In SPECIFIC AIM 1, gene expression of molecules known to participate in behavioral and neuromolecular adaptations to cocaine will be measured in the dorsal and ventral striatum of male, homozygote, non-hypomorphic, floxed trkB/DARPP-32 Cre mice relative to controls. Baseline levels and those following acute and chronic exposure to cocaine will be determined.
In SPECIFIC AIM 2, the role of endogenous, post-synaptic trkB neurotransmission will be assayed as it pertains to behavioral adaptations in the mouse brain following chronic exposure to cocaine, and the correlations with neuromolecular adaptations. The significance of this research resides in the fact that the findings could have profound implications for the understanding of the molecular basis of addiction and for determining targets of therapeutic interventions. The molecular mechanisms leading to addiction are largely unknown, but one of the molecules implicated is BDNF, acting via trkB. This application is focused on the delineation of the site of action of trkB, and what other molecules regulated by trkB may be implicated in the behavioral responses to cocaine. ? ?
| Unterwald, Ellen M; Page, Michelle E; Brown, Timothy B et al. (2013) Behavioral and transcriptome alterations in male and female mice with postnatal deletion of TrkB in dorsal striatal medium spiny neurons. Mol Neurodegener 8:47 |
