CyPPA, a Positive SK3/SK2 Modulator, Reduces Activity of Dopaminergic Neurons, Inhibits Dopamine Release, and Counteracts Hyperdopaminergic Behaviors Induced by Methylphenidate1

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

The economic well-being of nations is associated with positive daily situational experiences

People in economically advantaged nations tend to evaluate their life as more positive overall and report greater well-being than people in less advantaged nations. But how does positivity manifest in the daily life experiences of individuals around the world? The present study asked 15,244 college students from 62 nations, in 42 languages, to describe a situation they experienced the previous day using the Riverside Situational Q-sort (RSQ). Using expert ratings, the overall positivity of each situation was calculated for both nations and individuals. The positivity of the average situation in each nation was strongly related to the economic development of the nation as measured by the Human Development Index (HDI). For individuals’ daily experiences, the economic status of their nation also predicted the positivity of their experience, even more than their family socioeconomic status. Further analyses revealed the specific characteristics of the average situations for higher HDI nations that make their experiences more positive. Higher HDI was associated with situational experiences involving humor, socializing with others, and the potential to express emotions and fantasies. Lower HDI was associated with an increase in the presence of threats, blame, and hostility, as well as situational experiences consisting of family, religion, and money. Despite the increase in a few negative situational characteristics in lower HDI countries, the overall average experience still ranged from neutral to slightly positive, rather than negative, suggesting that greater HDI may not necessarily increase positive experiences but rather decrease negative experiences. The results illustrate how national economic status influences the lives of individuals even within a single instance of daily life, with large and powerful consequences when accumulated across individuals within each nation