Cocaine modulation of synapses onto dopamine neurons

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 the biophysical properties of AMPA receptors (AMPARs) on dopamine neurons. AMPARs mediate the majority of excitatory glutamatergic synaptic transmission in the brain.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.Inward rectification of CP-AMPARs results from intracellular polyamines that act as open channel blockers to prevent outward current flux at positive membrane potentials.Thus. rectification. and sensitivity to antagonists that bind at the polyamine site. provide biophysical signatures of AMPAR subunit composition and hence Ca2+ permeability. These characteristics have been widely used to establish rules of postsynaptic AMPAR localization and plasticity.However. previous work and our preliminary data show that CP-AMPAR rectification and pharmacology are sensitive to presynaptic factors that potentially complicate the use of these biophysical properties as sole proxies of subunit composition.We hypothesize that presynaptic mechanisms contribute to the cocaine-induced shift in AMPAR biophysical properties at glutamate synapses to dopamine neurons in the ventral midbrain. where a continuum of rectifying and non-rectifying AMPARs are expressed.We will test the glutamate concentration dependence of AMPAR excitatory postsynaptic current (EPSC) properties in midbrain DA neurons. We will then follow up to test whether presynaptic changes in glutamate concentration alter AMPAR EPSC properties following prior cocaine exposure.AMPAR subunit composition has 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.Successful completion of the proposed research will reveal novel properties of AMPARs that are essential for understanding their function within synapses and how drugs of abuse may alter their function via presynaptic mechanisms.