Abstract

Dopamine neurons in the VTA play a very important role in a variety of physiological as well as addictive behaviors. The main goal of the present proposal is to elucidate the relationship between plasticity at excitatory synapses in the ventral tegmental area (VTA) and addictive behaviors such as behavioral sensitization and self-administration of cocaine. During the current funding period (April1st, 2002- February 2006), we have collected evidence that might explain the sequence of events leading from NMDAR activation in the VTA produced by acute cocaine application, to long-term potentiation of VTA neurons that results as a consequence of in vivo cocaine exposure. Further, our preliminary data suggest that long-term changes of excitatory synaptic transmission in the VTA are not only produced by passive cocaine administration (e.g. in vivo cocaine injections), but operant behaviors such as cocaine self-administration.
Specific aim 1 will test the hypothesis that in vivo cocaine-induced potentiation involves a direct action of cocaine in the VTA mediated by NMDARs, D5 receptors and the cAMP/PKA-dependent pathway.
Specific aim 2 will test the role and time-course of protein synthesis in mediating long-term plasticity at VTA synapses and behavioral sensitization. Finally, specific aim 3 will characterize whether long-term synaptic changes at glutamatergic synapses in the VTA are produced during forced abstinence or extinction of operant responding from either food or cocaine. Taken together, the results from these experiments will likely help us understand the role of plasticity at glutamatergic synapses in the VTA in mediating cocaine-dependent behaviors. ? ? ?

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
2R01DA015096-05A1
Application #
7208307
Study Section
Special Emphasis Panel (ZRG1-IFCN-A (04))
Program Officer
Volman, Susan
Project Start
2002-04-01
Project End
2011-11-30
Budget Start
2007-04-15
Budget End
2007-11-30
Support Year
5
Fiscal Year
2007
Total Cost
$318,000
Indirect Cost

  Institution

Name
Ernest Gallo Clinic and Research Center
Department
Type
DUNS #
173995366
City
Emeryville
State
CA
Country
United States
Zip Code
94608

  Publications

Fischbach-Weiss, Sarah; Reese, Rebecca M; Janak, Patricia H (2018) Inhibiting Mesolimbic Dopamine Neurons Reduces the Initiation and Maintenance of Instrumental Responding. Neuroscience 372:306-315
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

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