From the Cover: Firing properties of dopamine neurons in freely moving dopamine-deficient mice: Effects of dopamine receptor activation and anesthesia

Dopamine neurons fire in pacemaker, irregular, and bursting modes (1-6). Different modes of dopamine neuron activity are thought to lead to different forms of neuronal plasticity. For example, in molecular models of learning, long-term depression at corticostriatal synapses is induced by the release of low concentrations of dopamine (i.e., the pacemaker or irregular mode), whereas long-term potentiation is induced by the release of high concentrations of dopamine (i.e., the bursting mode) (7-13). These dopamine-dependent forms of synaptic plasticity provide a basis for context-dependent changes that may underlie reward-related learning. Behavioral evidence also supports a role for dopamine in reward-related learning (14). Specifically, burst firing of dopamine neurons (6, 15, 16) and transient increases in striatal dopamine concentration (17, 18) have been shown to correlate with behavioral adaptations during reward-related learning in primates and rodents. The DD mouse model provides an excellent opportunity to test whether behaviorally relevant burst firing of dopamine neurons is necessary for goal-directed, reward-related behaviors. In contrast to lesion models, dopamine neurons in DD mice are intact, and the ability to restore endogenous dopamine signaling is under experimenter control. DD mice were generated by the selective inactivation of the tyrosine hydroxylase gene in dopamine neurons (19). Endogenous dopamine signaling is restored in DD mice by administration of L-dopa, which is presumably taken up by dopamine neurons, converted to dopamine, packaged into vesicles, and released in a behaviorally relevant manner. After L-dopa administration, DD mice become hyperactive and hyperphagic, consuming all of their daily food within 6-9 h, after which they again become dopamine-depleted and thus hypoactive and hypophagic (19, 20). One objective of this study was to characterize the basal firing properties of dopamine neurons and their responses to dopamine receptor D1 (D1R) and dopamine receptor D2 (D2R) agonists. These characterization experiments were conducted to (i) permit comparison of recordings from freely moving mice with previously reported recordings from intact and dopamine-depleted rats (2-4, 21-27), (ii) compare the effects of exogenous dopamine receptor activation (agonist studies) to the effects of endogenous dopamine release (L-dopa studies), and (iii) provide a foundation from which to design future studies in DD mice that explore the role of dopamine in reward-related behaviors. In contrast to L-dopa, dopamine receptor agonists do not elicit sufficient feeding by DD mice for their survival, whereas both L-dopa and dopamine agonists stimulate locomotion (19, 20, 28). One interpretation of this phenomenon is that burst firing and transient activation of dopamine receptors, as achieved after L-dopa administration (but not with agonist treatment), is necessary for shaping and maintaining certain goal-directed behaviors, such as eating. Therefore, we investigated changes in dopamine neuron activity that accompany L-dopa-mediated restoration of goal-directed behaviors. We considered the following scenarios, while recognizing that many factors could affect the firing properties of dopamine neurons of DD mice. First, L-dopa administration to DD mice might restore burst firing along with behavioral activation and feeding. This possibility is based on our previous finding that dopamine neurons of anesthetized DD mice did not fire in bursts, unlike controls, and that L-dopa partially restored bursting activity (29). Second, the bursting activity and firing rate of dopamine neurons from DD mice might exceed that of controls, and L-dopa treatment might slightly dampen neural activity to match that of controls. This scenario assumes that the lack of burst firing reported previously was an artifact of anesthesia (30) and that dopamine dampens activity via D2 autoreceptors, as described by others (27, 31-35). Third, the bursting activity of dopamine neurons might be normal in the absence of dopamine but greatly suppressed by treatment with L-dopa as a consequence of the hypersensitive striatal projection neurons that inhibit dopamine neuron activity through long-loop, feedback pathways. This possibility is based on reports describing the effects of dopamine receptor agonists in dopamine-depleted rats (25, 26). The results support the third possibility, which indicates that life-sustaining behavioral activation obtained by restoration of dopamine signaling with L-dopa is accompanied by substantial inhibition of midbrain dopamine neuron activity.