The transition from recreational drug use to addiction is defined by an escalation in the intake of the drug and cravings during periods of withdrawal, leading to an increase in relapse. This transition is further marked by drug-induced neuroadaptations that promote changes in the expression of brain derived neurotrophic factor (BDNF), neuroplasticity, and neuron morphology. In order to understand how these molecular changes contribute to escalation in intake and the increase in the propensity for relapse, the proposed research will examine the role of tropomyosin-related kinase B (TrkB) receptors and its distinct signaling pathways in cocaine addiction.
Specific Aim I will create an adeno-associate virus (AAV) mediated gene transfer vector that will over express either wildtype or docking mutants that specifically mediate TrkB through phospholipase C-gamma (PLCy) or extracellular signal-regulated kinase(ERK)/phosphoinositide 3-kinase (PI3K), or a kinase dead (dominant negative) version of TrkB. The ability of AAV overexpression of wildtype TrkB and TrkB signaling mutants to selectively activate ERK and PLCy signaling pathways in the NAc will be verified by analysis of pathway specific phosphorylation of target substrates after BDNF challenge infusions. In addition, dendritic spine growth will be determined in infected GFP tagged neurons by confocal microscopy.
Specific Aim II will employ the viruses from Aim I to study how the expression of wildtype and docking mutants of TrkB effect self-administration under fixed and progressive ratio reinforcement schedules, or during withdrawal to study extinction and relapse behaviors. Manipulation of TrkB expression will help determine the contribution of each signaling pathway to escalation of cocaine intake, enhanced reinforcement, and a propensity for relapse shown previously to be induced by BDNF activity in the NAc. The proposed experiments directly address the mission of the NIH and general public health, since findings gained from these studies will increase the understanding of the transition from recreational to addictive drug taking. Insight gained about the involvement of TrkB and its signaling pathways may prove helpful when designing treatments targeting relapse. By decreasing drug-taking and relapse behaviors, the detriment to societal health and the financial burden will abate.
