 Alone NMDA mediated activation of ERK is self-limited, as NMDA activation also inhibits PKA mediated inhibition of ERK deactivating phosphatases.However, when D1 and NMDA cascades are co-activated, they work synergistically, and the resultant activation of ERK regulates synaptic plasticity in the form of spine restructuring, transport of AMPA receptors, regulation of CREB, and increasing cellular excitability via inhibiting Kv4.2

The first clue to the presence of a reward system in the brain came with an accident discovery by James Olds and Peter Milner in 1954.They discovered that rats would perform behaviors such as pressing a bar, to administer a brief burst of electrical stimulation to specific sites in their brains.