However, the precise mechanisms employed by DA to mediate these effects remain largely unknown owing to the multiplicity and complexity of its actions. DA signaling involves a plethora of molecules including kinases, phosphatases, transcription factors, ion channels, and membrane receptors. Moreover, DA’s actions have largely defied interpretation because they vary greatly between cell types, depend on the strength and duration of receptor stimulation, are influenced by current and past cellular states, and compete with other neuromodulatory systems impinging on similar pathways. Thus, despite extensive investigation, there is no unified view of dopamine’s actions in

the CNS, and many studies VX-770 in vivo have yielded contradictory conclusions. Here, we discuss dopamine’s ability to rapidly influence synaptic transmission, dendritic integration, and membrane excitability. The search for neurons that produce DA started in the early 1960s, after the remarkable finding that catecholamine-containing neurons could be visualized in tissue after chemical conversion of CAs into fluorescent molecules with formaldehyde (Carlsson et al., 1962; Falck

et al., 1982). Using this method, seventeen groups of CA cells (designated A1–A17) were initially identified in the CNS. Specific identification of DA-producing cells is complex even with modern techniques. Firmly establishing a dopaminergic identity necessitates the analysis of multiple cellular markers and ideally the demonstration of stimulus-evoked DA release from genetically defined neurons such as by combining optogenetics and carbon fiber voltammetry (e.g., www.selleckchem.com/products/17-AAG(Geldanamycin).html Stuber et al., 2010; Tecuapetla et al., 2010). Collectively, the available data support the existence of ten DA-producing nuclei in the mammalian brain (A8–A17). Neurons within each field can differ significantly with respect to axonal projection areas, electrophysiological properties, and the expression of synthetic enzymes, membrane and vesicular transporters, aminophylline neuropeptides, and other amino acid transmitters (Björklund

and Dunnett, 2007; Hnasko et al., 2010; Lammel et al., 2011). Midbrain DA neurons in the substantia nigra pars compacta (SNc; field A9) and ventral tegmental area (VTA; field A10) are perhaps the best studied of these because of their central roles in the pathology of PD and in reward signaling and reinforcement, respectively. These two centers provide the bulk of DA to the basal ganglia and forebrain and contain the vast majority of DA neurons in the CNS. In the rat, VTA and SNc each contain ∼20,000 neurons bilaterally (German and Manaye, 1993). Given their small numbers and powerful impact on many aspects of behavior, each midbrain DA neuron must exert influence over large brain areas and many cells. Indeed, individual SNc neurons extend impressive axons of half a meter in total length that densely ramify throughout up to 1 mm3 of tissue (Matsuda et al., 2009).