Identification of the mechanism(s) responsible for drug reinforcement is a key step in understanding the mechanism of reinforcement learning, but has so far proven elusive. The dopamine neurons of the ventral tegmental area and substantia nigra pars compacta, located within the ventral mesencephalon, are a central locus for drug reinforcement. Even a single exposure to cocaine is sufficient to alter synaptic transmission to dopamine neurons, with attention focused on postsynaptic mechanisms of plasticity mediated by AMPA receptors (AMPARs). Most AMPARs are impermeable to Ca2+ (CI-AMPAR) whereas receptors that lack the GluR2 subunit are permeable to Ca2+ (CP-AMPAR). A biophysical characteristic known as rectification is commonly used to differentiate CP-AMPARs from the more common CI-AMPARs . It is commonly accepted that cocaine exposure alters rectification of AMPAR synaptic currents on dopamine neurons without affecting measures of release probability, pointing to postsynaptic mechanisms of synaptic plasticity. However, our new data challenges the assumptions that rectification is sufficient to infer AMPAR subunit composition and that release probability is sufficient to assess presynaptic efficacy. Rather, our data shows that changes in the readily-releasable pool of vesicles can robustly alter presynaptic efficacy without a change in the release probability and that presynaptic mechanisms can affect rectification properties of AMPAR synaptic currents. Based on our data, we hypothesize that presynaptic mechanisms contribute to synaptic changes in dopamine neurons following cocaine exposure. We will first test AMPAR properties in dopamine neurons from nave and cocaine-treated mice under conditions that isolate postsynaptic mechanisms. We will then follow up to test whether presynaptic changes contribute to synaptic plasticity induced by cocaine exposure. Presynaptic efficacy and AMPAR subunit composition have important functional consequences ranging from regulating the ability of postsynaptic cells to precisely follow high-frequency synaptic activity and mediating Ca2+ influx that can trigger plasticity or pathology like addiction. Successful completion of the proposed studies has potential to reveal novel mechanisms underlying synaptic plasticity at synapses onto dopamine neurons following exposure to drugs of abuse.

Public Health Relevance

The dopamine neurons of the ventral tegmental area and substantia nigra pars compacta, located within the ventral mesencephalon, are the central locus for drug reinforcement. We propose that presynaptic mechanisms contribute to the cocaine-induced synaptic plasticity and AMPAR biophysical properties at glutamate synapses on dopamine neurons. Successful completion of the proposed studies will reveal novel mechanisms that are essential for understanding how drugs of abuse alter dopamine neuron function critical for reinforcement of drug-seeking behavior.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Exploratory/Developmental Grants (R21)
Project #
Application #
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Tsai, Shang-Yi Anne
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Alabama Birmingham
Schools of Medicine
United States
Zip Code