Stochastic Model of Glutamatergic PFC-NAc Synapse Predicts Cocaine-Induced Changes in Receptor Occupancy

Neurotransmitter homeostasis in and around synapses involves random processes such as diffusion, molecular binding and unbinding. A three-dimensional stochastic diffusion model of a synapse was developed to provide molecular level details of neurotransmitter homeostasis not predicted by alternative models based on continuum approaches. This framework was used to estimate effective diffusion and provide a more accurate prediction of geometric tortuosity in the perisynaptic region. The stochastic model was used to predict the relative contributions of non-synaptic sources to extracellular concentration in control, natural reward seeking, and chronic cocaine cases; and estimation of molecular influx rates required to maintain tone on presynaptic autoreceptors. Also, this was the first stochastic model to confirm the prediction of down-regulation of glutamate transporters by 40% after chronic cocaine. The model can be further generalized to study the role of diffusion path length in supporting neurotransmitter gradients and isolating the synapse.