Abnormal dopaminergic signaling has been implicated in schizophrenia . Some salient hypotheses regarding midbrain dopamine neurons and explored in our cellular models are as follows: 1) In the absence of afferent input, dopamine neurons exhibit spontaneous regular pacemaker firing; this background level of tonic firing ensures that dopaminergic signaling is bidirectional so that both positive and negative signals regarding the difference between expected and actual rewards can be transmitted. 2) Dopamine neurons can fire rapid bursts only in the presence of NMDA synaptic activation. 3) In vivo, a balanced state between excitation and inhibition enables tonic single spike firing and an imbalance results in a phasic signal in the form of a burst. 4) The complex contributions of the intrinsic currents to the neural dynamics allow for rich modulatory possibilities regarding the propensity of these neurons to transmit tonic or phasic signals.

Dopamine neurons in vitro go into depolarization block at applied current levels that are not sufficient to elicit the high frequency firing observed during bursts. The role of NMDA synaptic activation in bursting and the mechanism by which the limitation on firing rate is circumvented has been hotly debated. Also, induction of depolarization block in dopamine neurons has been correlated with the efficacy of antipsychotic drugs, and antipsychotics have been shown to rapidly induce depolarization block in a developmental rat model of schizophrenia. Applied depolarization does not cause neurons to enter depolarization block by simply biasing the cell above the region in which the sodium current activates regeneratively. Instead, the spike threshold gradually increases after pulse onset causing the interspike intervals to increase until the final depolarizing prepotential fails to reach threshold. Our modeling suggests that only a second slow component of the inactivation of the sodium channel can drive a pacemaker into depolarization block in this manner, and only a regenerative inward current like the NMDA current can circumvent this limitation. Finally, since antipsychotic drugs in general block the ether-a-gogo-related (ERG) potassium current, we examine the role of this current in limiting episodes of depolarization block.