Search

Rationale: The voltage-insensitive, small-conductance calcium-activated potassium (SK) channel is a key regulator of neuronal depolarization and is implicated in the pathophysiology of depressive disorders., Objective: We ascertained whether the SK channel is impaired in the chronic unpredictable stress (CUS) model and whether it can serve as a molecular target of antidepressant action., Methods: We assessed the depressive-like behavioral phenotype of CUS-exposed rats and performed post-mortem SK channel binding and activity-dependent zif268 mRNA analyses on their brains. To begin an assessment of SK channel subtypes involved, we examined the effects of genetic and pharmacological inhibition of the SK3 channel using conditional knockout mice and selective SK3 channel negative allosteric modulators (NAMs)., Results: We found that [ 125 I]apamin binding to SK channels is increased in the prefrontal cortex and decreased in the hippocampus, an effect that was associated with reciprocal levels of zif268 mRNA transcripts indicating abnormal regional cell activity in this model. We found that genetic and pharmacological manipulations significantly decreased immobility in the forced swim test without altering general locomotor activity, a hallmark of antidepressant-like activity., Conclusions: Taken together, these findings link depression-related neural and behavioral pathophysiology with abnormal SK channel functioning and suggest that this can be reversed by the selective inhibition of SK3 channels., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Rationale: Ethanol-induced behavioural sensitization (EBS) does not occur uniformly in mice exposed to the sensitization paradigm. This suggests innate differential responses to ethanol (EtOH) in the reward circuitry of individual animals., Objectives: To better characterize the adaptive differences between low-sensitized (LS) and high-sensitized (HS) mice, we examined excitatory amino acid (EAA) and inhibitory amino acid (IAA) neurotransmitter levels in the nucleus accumbens (NAc) during EBS expression., Methods: Male DBA/2J mice received five ethanol (EtOH) (2.2 g/kg) or saline injections, and locomotor activity (LMA) was assessed during EBS induction. EtOH mice were classified as LS or HS on the basis of final LMA scores. Following an EtOH challenge (1.8 g/kg) 2 weeks later, LMA was re-evaluated and in vivo microdialysis samples were collected from the NAc., Results: Most differences in amino acid levels were observed within the first 20 min after EtOH challenge. LS mice exhibited similar glutamate levels compared with acutely treated (previously EtOH naïve) mice, and generally increased levels of the IAAs GABA, glycine, and taurine. By contrast, HS mice exhibited increased glutamate and attenuated levels of GABA, glycine, and taurine., Conclusion: These data suggest that the profile of amino acid neurotransmitters in the NAc of LS and HS mice significantly differs. Elucidating these adaptive differences contributes to our understanding of factors that confer susceptibility/resilience to alcohol use disorder.