Noradrenergic excitation of dopaminergic neurons

Dopaminergic neurons located in the ventral midbrain play a critical role in reward-based learning and drug-seeking behavior. The firing activity of these neurons, including the bursts and pauses, encode reward prediction error, and these firing patterns are profoundly altered by psychostimulant abuse. During psychostimulant administration several receptors located on dopaminergic neurons are activated and, specifically, the activation of noradrenergic receptors may play a role in psychostimulant-mediated modulation of dopamine function. Both in vitro and in vivo electrophysiology was used to demonstrate that cocaine increases both the pacemaker and burst firing frequency of dopaminergic neurons in vitro through an alpha1 adrenergic receptor-dependent mechanism. The pacemaker and burst firing are differently affected by alpha1 adrenergic receptor activation, with a decrease in the calcium-activated potassium channels (SK) conductance being solely responsible for the increase in the intra-burst firing frequency whereas the effect on pacemaker activity requires the modulation of both SK and the hyperpolarization-activated cation (Ih) currents. The observed increases in pacemaker and burst firing frequency are also shown to be preserved in the intact animal, and the cocaine-induced rise in dopamine levels in vivo is due to the activation of alpha1 adrenergic receptors located on dopaminergic neurons within the ventral midbrain. These results suggests that one of the primary mechanisms of action of cocaine is mediated through alpha1 adrenergic receptors that increase impulse-dependent activity of dopaminergic neurons, resulting in an increase in dopamine release in projection areas.