Abstract
Midbrain dopaminergic neurons in the substantia nigra, pars compacta and ventral tegmental area are critically important in many physiological functions. These neurons exhibit firing patterns that include tonic slow pacemaking, irregular firing and bursting, and the amount of dopamine that is present in the synaptic cleft is much increased during bursting. The mechanisms responsible for the switch between these spiking patterns remain unclear. Using both in-vivo recordings combined with microiontophoretic or intraperitoneal drug applications and in-vitro experiments, we have found that M-type channels, which are present in midbrain dopaminergic cells, modulate the firing during bursting without affecting the background low-frequency pacemaker firing. Thus, a selective blocker of these channels, 10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone dihydrochloride, specifically potentiated burst firing. Computer modeling of the dopamine neuron confirmed the possibility of a differential influence of M-type channels on excitability during various firing patterns. Therefore, these channels may provide a novel target for the treatment of dopamine-related diseases, including Parkinson’s disease and drug addiction. Moreover, our results demonstrate that the influence of M-type channels on the excitability of these slow pacemaker neurons is conditional upon their firing pattern.
Highlights
Midbrain dopaminergic (DA) neurons sustain important physiological functions such as control of motricity and signalling of positive error in reward prediction in the mesolimbic system (Schultz, 2007)
Effect of systemic and local application of XE991 on the firing of DA neurons In a first series of experiments, we studied the impact of intraperitoneally administered XE991 (3 mg/kg i.p.) on the firing of DA neurons
In previous in vitro experiments, we had demonstrated that this compound is a specific blocker of the M current in these cells: it had no effect on the shape of action potentials, on the resting membrane potential or on the medium-duration afterhyperpolarization induced by the opening of SK channels (Hansen et al, 2006)
Summary
Midbrain dopaminergic (DA) neurons sustain important physiological functions such as control of motricity and signalling of positive error in reward prediction in the mesolimbic system (Schultz, 2007). Because burst firing increases synaptic concentrations of dopamine (Chergui et al, 1994), many studies have focused on the factors controlling the switch to this firing pattern It is generally agreed (see Overton and Clark, 1997) that bursting requires a glutamatergic input stimulating N-methyl-D-aspartate (NMDA) receptors. Activation of GABAA receptors inhibits bursting because of their shunting effect on the oscillatory behavior (Tepper and Lee, 2007) Both in vitro and in vivo experiments show that a reduction of a potassium conductance mediated by small conductance Ca2+-activated K+ (SK) channels greatly potentiates irregularity and/or bursting (Shepard and Bunney, 1988, 1991; Seutin et al, 1993; Nedergaard et al, 1993; Waroux et al, 2005; Ji and Shepard, 2006). This current had the typical electrophysiological signature (Brown and Adams, 1980; Kuffler and Sejnowski, 1983) and pharmacology of the M current, being enhanced by retigabine and blocked by 10,10-bis(4pyridinylmethyl)-9(10H)-anthracenone dihydrochloride (XE991)
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