(provided by candidate): The overall goal for this project is to investigate the mechanisms by which drugs of abuse, such as morphine, cocaine and nicotine, alter forms of synaptic plasticity in brain regions relevant to drug addiction. While activation of brain reward pathways is a normal physiological process, exogenous compounds overwhelm endogenous signaling and function in these brain regions which may lead to addiction. Alterations in the signaling of neurons in the ventral tegmental area (VTA) induced by drugs of abuse may underlie addictive properties of abused drugs. Results obtained under this proposal will contribute to the addiction field by investigating the basic properties of inhibitory synaptic contacts in the VTA under naive and drug-treated conditions using electrophysiological and pharmacological tools.
The specific aims of this project are to (1) define the onset time and duration of morphine-induced blockade of long-term potentiation of GABAergic synapses (LTPGABA) in the VTA, (2) compare the efficacy of morphine blockade of LTPGABA in immature versus young adult rats, (3) determine whether drugs of abuse from differing classes (e.g. cocaine and nicotine) block LTPGABA, and (4) determine the mechanism by which morphine inactivates the nitric oxide-cyclic GMP signaling pathway to block LTPGABA- LTPGABA is a novel form of synaptic plasticity that may provide a new mechanism for understanding and treating opioid abuse. Neurons from brain slice preparations containing the VTA will be obtained from both immature and young adult rats, either drug treated or naive, for electrophysiological recordings. Brain slice recordings permit in vitro examination of the effects of drugs of abuse to identify and characterize cellular and molecular mechanisms involved in addiction. Rats from different age groups will provide complementary information on the effects of drugs of abuse on the nervous system during development. Elucidating the cellular mechanisms by which drugs of abuse alter the normal function of neurons in the VTA may provide novel therapeutic targets for preventing and treating drug addiction. Drug addiction is a disease that develops over time as the brain is changed by and adapts to the presence of drugs of abuse. This research project will provide a more complete understanding of how drugs of abuse modify the brain during the initial stages of addiction in order to discover new ways of preventing addiction and improving current therapies to treat drug addiction. ? ? ?
| Niehaus, Jason L; Murali, Manjari; Kauer, Julie A (2010) Drugs of abuse and stress impair LTP at inhibitory synapses in the ventral tegmental area. Eur J Neurosci 32:108-17 |
| Niehaus, Jason L; Cruz-Bermudez, Nelson D; Kauer, Julie A (2009) Plasticity of addiction: a mesolimbic dopamine short-circuit? Am J Addict 18:259-71 |
| Nugent, Fereshteh S; Niehaus, Jason L; Kauer, Julie A (2009) PKG and PKA signaling in LTP at GABAergic synapses. Neuropsychopharmacology 34:1829-42 |
