Cocaine-Induced Structural and Functional Changes of Input-Specific Excitatory Synapses on Nigral Dopamine Neurons

Drug abuse has been well documented to affect the brain, causing plasticity changes that include changes in receptor expression, number of synapses, and even receptor function and composition. Cocaine induces plasticity in various neural pathways that deal with motivation and reward-association, specifically targeting dopaminergic neurons. One of the dopaminergic systems affected by cocaine is the substantia nigra pars compacta (SNc). The pedunculopontine nucleus (PPN) has excitatory glutamatergic innervations to the SNc, and our research focuses on how cocaine affects their relationship. Prior research has shown that the ionotropic glutamate receptors: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR) and N-methyl-D-aspartate receptors (NMDAR) are affected by cocaine use. Specifically, the AMPA-to-NMDA receptor-mediated current ratio is decreased due to an increase in NMDAR mediated current seen after an acute cocaine injection in mice. The reason for this increase in NMDAR mediated current became the focus of our research. We utilized optogenetics to selectively excite PPN pre-synaptic neurons and with electrophysiology recorded from SNc dopaminergic post-synaptic neurons from brain slices. NBQX was used to block AMPAR function in order to focus on NMDAR function. We measured the IV relationship of NMDAR-mediated current from mice exposed to saline or cocaine. Strontium was used as a substitute to calcium in order to cause asynchronous release of neurotransmitter from PPN neurons. From our measures of the size and frequency of asynchronous release events, we may determine a change in number of NMDAR at a synapse or number of synapses, respectively. While the project is still in progress, data seems to point towards a NMDAR subunit change, seeing increased activity in cocaine-treated mice when the membrane voltage is negative. These data bring up interesting effects of cocaine, such as subunit changes, increase in synapses, and increase in receptor number