The goal of the present proposal is to understand the cellular and synaptic events through which cocaine induces long-term plasticity at excitatory synapses in the ventral tegmental area (VTA) after a single in vivo exposure. The VTA considered to play a central role in the initiation of drug-related behaviors such as behavioral sensitization, but the cellular mechanisms that underlie the initiation of such behavioral phenomena are still obscure. Our preliminary data suggest that a single injection of cocaine produces a long-term potentiation (LTP) of AMPA-receptor-mediated post-synaptic currents in the VTA. Furthermore, when mice were challenged with a second injection of cocaine, they displayed context-dependent behavioral sensitization. Further, both cocaine-induced LTP and context-dependent behavioral sensitization are blocked by the NMDA receptor antagonist MK-801. Our first goal is to determine whether the expression of cocaine-induced LTP involves a change in AMPA receptor number, function, or both. Second, we will perform intra-VTA in vivo injections to understand whether intra-VTA injections of cocaine are sufficient for cocaine to induce LTP, and to define the receptors and second messengers involved in producing the cocaine-induced LTP. Third, we will use an in vitro model to study which receptors in the VTA are involved in producing the cocaine-mediated long-term potentiation. Fourth, we will determine whether such cocaine dependent LTP also occurs in tertiary cells, a group of VTA neurons whose function is still unknown. Our long-term goal is to understand the complete sequence of cellular and molecular events through which cocaine produces LTP at AMPA receptors in the VTA and the subsequent initiation of behavioral sensitization.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA015096-04
Application #
6878935
Study Section
Integrative, Functional and Cognitive Neuroscience 8 (IFCN)
Program Officer
Volman, Susan
Project Start
2002-04-01
Project End
2006-03-31
Budget Start
2005-04-01
Budget End
2006-03-31
Support Year
4
Fiscal Year
2005
Total Cost
$241,050
Indirect Cost
Name
Ernest Gallo Clinic and Research Center
Department
Type
DUNS #
173995366
City
Emeryville
State
CA
Country
United States
Zip Code
94608
Janak, Patricia H; Tye, Kay M (2015) From circuits to behaviour in the amygdala. Nature 517:284-92
Steinberg, Elizabeth E; Boivin, Josiah R; Saunders, Benjamin T et al. (2014) Positive reinforcement mediated by midbrain dopamine neurons requires D1 and D2 receptor activation in the nucleus accumbens. PLoS One 9:e94771
Steinberg, Elizabeth E; Keiflin, Ronald; Boivin, Josiah R et al. (2013) A causal link between prediction errors, dopamine neurons and learning. Nat Neurosci 16:966-73
Steinberg, Elizabeth E; Janak, Patricia H (2012) Establishing causality for dopamine in neural function and behavior with optogenetics. Brain Res :
Witten, Ilana B; Steinberg, Elizabeth E; Lee, Soo Yeun et al. (2011) Recombinase-driver rat lines: tools, techniques, and optogenetic application to dopamine-mediated reinforcement. Neuron 72:721-33
Tye, Kay M; Tye, Lynne D; Cone, Jackson J et al. (2010) Methylphenidate facilitates learning-induced amygdala plasticity. Nat Neurosci 13:475-81
Bowers, M Scott; Chen, Billy T; Bonci, Antonello (2010) AMPA receptor synaptic plasticity induced by psychostimulants: the past, present, and therapeutic future. Neuron 67:11-24
Borgland, Stephanie L; Chang, Shao-Ju; Bowers, M Scott et al. (2009) Orexin A/hypocretin-1 selectively promotes motivation for positive reinforcers. J Neurosci 29:11215-25
Chen, Billy T; Bowers, M Scott; Martin, Miquel et al. (2008) Cocaine but not natural reward self-administration nor passive cocaine infusion produces persistent LTP in the VTA. Neuron 59:288-97
Tye, Kay M; Stuber, Garret D; de Ridder, Bram et al. (2008) Rapid strengthening of thalamo-amygdala synapses mediates cue-reward learning. Nature 453:1253-7

Showing the most recent 10 out of 18 publications