State-dependent regulation of neuronal excitability by dopamine.

Since the discovery that the loss of the dopaminergic innervation of the striatum resulted in Parkinson's disease, physiologists have attempted to understand the role of dopamine on striatal activity. Hypotheses relying upon concepts derived from studies of fast synaptic transmission have consistently failed to explain the actions of dopamine or other receptors coupled to G-proteins which modulate the properties of voltage-dependent ionic conductances responsible for synaptic integration and spike activity. Recently, patch clamp studies have revealed that in medium spiny striatal neurons dopamine D1-class receptors modulate voltage-dependent Na+, K+ and Ca2+ channels. From a consideration of the biophysical properties of these channels and the state transitions that medium spiny neurons undergo while responding to cortical input, a novel picture of dopamine's actions is beginning to emerge. Our results and those of others suggest that D2-class receptors serve to make the transition to the depolarized 'upstate' from the hyperpolarized 'downstate' more probable in response to cortical input. But, once the transition has occurred, the alteration in excitability should be short-lived unless the neuron has recently been active. This state-dependent modulation provides a mechanism by which dopamine could shape global striatal activity governing the execution of motor behaviors.