Abstract
Dopamine (DA) containing midbrain neurons play critical roles in several psychiatric and neurological diseases, including schizophrenia and attention deficit hyperactivity disorder, and the substantia nigra pars compacta neurons selectively degenerate in Parkinson’s disease. Pharmacological modulation of DA receptors and transporters are well established approaches for treatment of DA-related disorders. Direct modulation of the DA system by influencing the discharge pattern of these autonomously firing neurons has yet to be exploited as a potential therapeutic strategy. Small conductance Ca2+-activated K+ channels (SK channels), in particular the SK3 subtype, are important in the physiology of DA neurons, and agents modifying SK channel activity could potentially affect DA signaling and DA-related behaviors. Here we show that cyclohexyl-[2-(3,5-dimethyl-pyrazol-1-yl)-6-methyl-pyrimidin-4-yl]-amine (CyPPA), a subtype-selective positive modulator of SK channels (SK3 > SK2 > > > SK1, IK), decreased spontaneous firing rate, increased the duration of the apamin-sensitive afterhyperpolarization, and caused an activity-dependent inhibition of current-evoked action potentials in DA neurons from both mouse and rat midbrain slices. Using an immunocytochemically and pharmacologically validated DA release assay employing cultured DA neurons from rats, we show that CyPPA repressed DA release in a concentration-dependent manner with a maximal effect equal to the D2 receptor agonist quinpirole. In vivo studies revealed that systemic administration of CyPPA attenuated methylphenidate-induced hyperactivity and stereotypic behaviors in mice. Taken together, the data accentuate the important role played by SK3 channels in the physiology of DA neurons, and indicate that their facilitation by CyPPA profoundly influences physiological as well as pharmacologically induced hyperdopaminergic behavior.
Highlights
Small conductance Ca2+-activated K+ channels (SK channels, KCa2, encoded by KCNN genes) are widely distributed in the central nervous system, with the SK1 and SK2 subtypes expressed mainly in cortical/limbic areas and SK3 mostly in the striatum, habenula, and in the monoaminergic nuclei (Sailer et al, 2004; Abbreviations: aCSF, artificial cerebrospinal fluid; AP, action potential; CyPPA, cyclohexyl-[2-(3,5-dimethyl-pyrazol-1-yl)-6-methyl-pyrimidin-4-yl]-amine; DA, dopamine; ECL, enhanced chemiluminescence; i.p., intraperitoneal; mAHP, medium duration afterhyperpolarization; NS8593, (R)-N -(benzimidazol-2-yl)1,2,3,4-tetrahydro-1-naphtylamine; SK, small conductance Ca2+ activated K+ conductance; s.c., subcutaneous; SNc, substantia nigra pars compacta; TH, tyrosine hydroxylase.Sarpal et al, 2004)
The DA neurons exhibited a spontaneous, slow (1.9 ± 0.5 Hz, n = 16) pacemaker discharge characterized by broad action potentials (>2.5 ms measured at 1/2 AP amplitude) separated by deep afterhyperpolarizations (AHP), and slowly ramping depolarizations leading to the spike, as illustrated in Figure 1A
Cells silenced by CyPPA returned to a spontaneous firing mode upon co-superfusion with NS8593, a negative SK channel gating modulator, or apamin, a SK channel blocker
Summary
Small conductance Ca2+-activated K+ channels (SK channels, KCa2, encoded by KCNN genes) are widely distributed in the central nervous system, with the SK1 and SK2 subtypes expressed mainly in cortical/limbic areas and SK3 mostly in the striatum, habenula, and in the monoaminergic nuclei (Sailer et al, 2004; Abbreviations: aCSF, artificial cerebrospinal fluid; AP, action potential; CyPPA, cyclohexyl-[2-(3,5-dimethyl-pyrazol-1-yl)-6-methyl-pyrimidin-4-yl]-amine; DA, dopamine; ECL, enhanced chemiluminescence; i.p., intraperitoneal; mAHP, medium duration afterhyperpolarization; NS8593, (R)-N -(benzimidazol-2-yl)1,2,3,4-tetrahydro-1-naphtylamine; SK, small conductance Ca2+ activated K+ conductance; s.c., subcutaneous; SNc, substantia nigra pars compacta; TH, tyrosine hydroxylase.Sarpal et al, 2004). In dopaminergic (DA) neurons of the substantia nigra pars compacta (SNc), cyclic activation of SK3 channels is important for timing and stability of the slow www.frontiersin.org. A current belief is that DA exerts two main actions: a tonic, far reaching influence caused by regularly firing DA neurons slowly releasing DA from sites weakly influenced by DA uptake such as varicosities and dendrites; and a phasic influence governed by synchronized burst firing, mediating a synaptic DA transmission temporally and spatially restricted by the activity of the DA transporter (Grace, 1991). A unifying mathematical model of DA neuron firing, release, uptake, and receptor activation confirmed that synchronized bursting can be the mechanism that modulates the balance between activation of D1 and D2 receptors (Dreyer et al, 2010). Emerging evidence suggest increased bursting of DA neurons in Parkinson’s disease (Bishop et al, 2010)
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