In recent years, the population of neurons in the ventral tegmental area (VTA) and substantia nigra (SN) has been examined at multiple levels. The results indicate that the projections, neurochemistry, and receptor and ion channel expression in this cell population vary widely. This review centers on the intrinsic properties and synaptic regulation that control the activity of dopamine neurons. Although all dopamine neurons fire action potentials in a pacemaker pattern in the absence of synaptic input, the intrinsic properties that underlie this activity differ considerably. Likewise, the transition into a burst/pause pattern results from combinations of intrinsic ion conductances, inhibitory and excitatory synaptic inputs that differ among this cell population. Finally, synaptic plasticity is a key regulator of the rate and pattern of activity in different groups of dopamine neurons. Through these fundamental properties, the activity of dopamine neurons is regulated and underlies the wide-ranging functions that have been attributed to dopamine.

Midbrain dopamine neurons release dopamine from both axons and dendrites. The mechanism underlying release at these different sites has been proposed to differ. This study used electrochemical and electrophysiological methods to compare the time course and calcium dependence of somatodendritic dopamine release in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) to that of axonal dopamine release in the dorsal striatum. The amount of dopamine released in the striatum was ∼20-fold greater than in cell body regions of the VTA or SNc. However, the calcium dependence and time to peak of the dopamine transients were similar. These results illustrate an unexpected overall similarity in the mechanisms of dopamine release in the striatum and cell body regions. To examine how diffusion regulates the time course of dopamine following release, dextran was added to the extracellular solution to slow diffusion. In the VTA, dextran slowed the rate of rise and fall of the extracellular dopamine transient as measured by fast-scan cyclic voltammetry yet did not alter the kinetics of the dopamine-dependent IPSC. Dextran failed to significantly alter the time course of the rise and fall of the dopamine transient in the striatum, suggesting a more influential role for reuptake in the striatum. The conclusion is that the time course of dopamine within the extracellular space of the VTA is dependent on both diffusion and reuptake, whereas the activation of D₂receptors on dopamine neurons is primarily limited by reuptake.

Intravenous drug self-administration is considered the “gold standard” model to investigate the neurobiology of drug addiction in rodents. However, its use in mice is limited by frequent complications of intravenous catheterization. Given the many advantages of using mice in biomedical research, we developed a noninvasive mouse model of opioid self-administration using vaporized fentanyl. Mice readily self-administered fentanyl vapor, titrated their drug intake, and exhibited addiction-like behaviors, including escalation of drug intake, somatic signs of withdrawal, drug intake despite punishment, and reinstatement of drug seeking. Electrophysiological recordings from ventral tegmental area dopamine neurons showed a lower amplitude of GABA_B receptor–dependent currents during protracted abstinence from fentanyl vapor self-administration. This mouse model of fentanyl self-administration recapitulates key features of opioid addiction, overcomes limitations of the intravenous model, and allows investigation of the neurobiology of opioid addiction in unprecedented ways.

Mutations in the methyl-CpG-binding protein 2 (MeCP2) result in Rett syndrome (RTT), an X-linked disorder that disrupts neurodevelopment. Girls with RTT exhibit motor deficits similar to those in Parkinson's disease, suggesting defects in the nigrostriatal pathway. This study examined age-dependent changes in dopamine neurons of the substantia nigra (SN) from wild-type, presymptomatic, and symptomaticMecp2^+/−mice. Mecp2⁺neurons in the SN inMecp2^+/−mice were indistinguishable in morphology, resting conductance, and dopamine current density from neurons in wild-type mice. However, the capacitance, total dendritic length, and resting conductance of Mecp2⁻neurons were less than those of Mecp2⁺neurons as early as 4 weeks after birth, before overt symptoms. These differences were maintained throughout life. In symptomaticMecp2^+/−mice, the current induced by activation of D₂dopamine autoreceptors was significantly less in Mecp2⁻neurons than in Mecp2⁺neurons, although D₂receptor density was unaltered inMecp2^+/−mice. Electrochemical measurements revealed that significantly less dopamine was released after stimulation of striatum in adultMecp2^+/−mice compared to wild type. The decrease in size and function of Mecp2⁻neurons observed in adultMecp2^+/−mice was recapitulated in dopamine neurons from symptomaticMecp2^−/ymales. These results show that mutation inMecp2results in cell-autonomous defects in the SN early in life and throughout adulthood. Ultimately, dysfunction in terminal dopamine release and D₂autoreceptor-dependent currents in dopamine neurons from symptomatic females support the idea that decreased dopamine transmission due to heterogeneous Mecp2 expression contributes to the parkinsonian features of RTT inMecp2^+/−mice.