Dopamine – CNS P athways and Neurophysiology A A Grace, D J Lodge, and D M Buffalari , University of Pittsburgh, Pittsburgh, PA, USA ã 2009 Elsevier Ltd. All rights reserved. Introduction The dopa mine (DA) syst ems of the br ai n have been the topic of intensive investigation since the first report of this neur oc hemi cal as an inde pendent ne ur o- transmitter in the brain nearly 50 years ago. The DA systems have drawn the attention of investigators due to their known role in a variety of neurological and psychiatric disorders, including Parkinson’s disease, schizophr enia, and drug add ict ion . In thi s art icl e, we review the principal electrophysiological charac- teri sti cs of DA neurons, as well as the intr insi c and extrinsic regulation of their activity and firing patterns. Anatomy of DA Neuron Projections As wit h most monoami ne systems, ind ivi dual DA neuronsare bel ieve d to exhi bit den se coll ate rali zations, wi th si ng le neurons gi vi ng rise to 50 0 000 to 1 00 0 000 synaptic terminals. However, unlike other monoamine neurons, midbrain DA neurons have discrete, topo- gr aph ic pr oje ct ion s to the ir tar ge t re gio ns. Thr ee major DA neuronal systems have been identified that project to forebrain regions: (1) the nigrostriatal DA neuron projection, which arises from the substantia nigra (SN) and projects to the dorsal striatum; this system is involved in motor control and is known to degenerate in Parkinson’s disease; (2) the mesolimbic DA pr oje ction, whi ch ar ises fro m the ve ntr al teg me nta l ar ea (VT A) and pro je cts to limbic str uc turessuch as the ventral striatum, nucleus accumbens, amygdala, and other regions involved in control of affect and likely play a role in schizo phreniaand dru g abuse; and(3)the mesocortical DA system, which also arises from the VTA and pro ject s primaril y to fron tal cortex; this projection system is believed to be involved in higher process es related t o the control of executive function. Electrophysiology Identification Since the ventral mesencephalon is a heterogeneous region, the first challenge in examining the neuro- physiology of DA systems is to ensure that the neu- rons recorded are indeed DAergic in nature. The first extracellular recordings from putative DA neurons were performed in the 1970s. Through an examina- tion of the neurophysiological characteristics of DA neurons and subsequent histochemical verification, it was determined that DA neurons can be identified based solely on their electrophysiological character- istics. As such, one of the most distinct features ofDA neurons is the broad extracellular spike wave- form they produce ( Figure 1). Such waveforms are biphasic (þ/À), with an inflection in the rising phase (re pre sentative of the initial seg ment spi ke). The y ha ve a pr onounced nega tiv e phas e to the action potential, as well as a long ti me cour se (>2ms). More specifically, action potent ials consis t of a short -durat ion, smalle r- amplitu de initia l segment spike, foll owe d by a larg er and lon ger dura tionsomato - dendritic spike. Much of this unique waveform is a conse quence of the active memb rane prope rties of the neu ron, causing a train of act ion poten tials to be variable from one waveform to the next, and readily distinguishable by the long-duration negative phase, alt hou gh suc h dif ferences can be obs cured if improp er filter settings are employed. Passive Membrane Properties Intracellular recordings from identified DA neurons have provided important insights into the mechan- isms underlying action potential generation in these neuro ns. Intere stingl y , DA neuro ns record ed from mesen cepha lic slices after sever ing of affer ent pro- cesses continue to exhibit spontaneous activity that is derived from the active membrane properties ofthe neuron. One factor associated with spike genera- tion in DA neurons is a large-amp litude (10–1 5 mV), pac ema ker -lik e slow dep ola riz ing pot ent ial tha t bring s the membrane potent ial from rest ( c. –55 mV) to the comparatively high action potential threshold (c. –40 mV) . This slow depolarization is mediated by both sodi um and ca lcium conductances, as it can be blo cke d by tet rodotoxin (TTX) or cob alt , both of which also inhibit spontaneous spike firing. The resultant spike is followed by a negative shift in membrane potential accompanied by an inhibition of spike firing, or an afterhyperpolarization. This after- hyp erp ola riz ation is vol tag e dep end en t and mediated by a cal cium-activated pot assium conductan ce, as it can be blocked by tetraethylammonium (TEA) and atten uated by the calcium chelator ethylene glycol tetraacetic acid (EGTA). Furthermore, it is believed that the rebound from this hyperpolarization triggers the cal cium and sodium con duc tances compris ing the sl ow depolariz ation. It is this cy cl e that has Dopamine – CNS Path ways and Neu rophys iolog y 549
