Neuropharmacology
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Hyperpolarizing synaptic inhibition through GABAA and glycine receptors depends on the presence of the neuronal cation-chloride-cotransporter protein, KCC2. Several transcriptional and post-transcriptional mechanisms have been shown to regulate KCC2 and thereby influence the polarity and efficacy of inhibitory synaptic transmission. It is unclear however whether regulation of KCC2 enables the transporter to attain different levels of activity thus allowing a neuron to modulate the strength of inhibitory synaptic transmission to its changing requirements. ⋯ Our results demonstrate that KCC2 transport can vary considerably in magnitude depending on the combination of alanine mutations present on the protein. Transport can be enhanced to sufficiently high levels that hyperpolarizing GABAA responses may be obtained even in neurons with an extremely negative resting membrane potential and at high extracellular K(+) concentrations. Our findings highlight the significant potential for regulating the inhibitory tone by KCC2-mediated chloride extrusion and suggest that cellular signaling pathways may act combinatorially to alter KCC2 phosphorylation/dephosphorylation and thereby tune the strength of synaptic inhibition.
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GABAA receptors are the major inhibitory neurotransmitter receptors in the brain and are the target for many clinically important drugs such as the benzodiazepines. Benzodiazepines act at the high-affinity binding site at the α+/γ- subunit interface. Previously, an additional low affinity binding site for diazepam located in the transmembrane (TM) domain has been described. ⋯ SJM-3 acts as a more efficient modulator than diazepam at the site in the trans-membrane domain. In contrast to low concentrations of benzodiazepines, SJM-3 modulates both synaptic and extrasynaptic receptors. A detailed exploration of the membrane site may provide the basis for the design and identification of subtype-selective modulatory drugs.
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Morphine excites dopamine (DA) neurons in the ventral tegmental area (VTA), an effect mediated by both local and systemic mechanisms. While the importance of the prefrontal cortex (PFC) - VTA circuit in opiate addiction is well established, little is known about how the PFC regulates the activity of VTA DA neurons upon morphine stimulation. One major challenge is that VTA DA neurons are highly heterogeneous in terms of projection and regulation, making their responses to PFC manipulations variable. ⋯ Using in vivo microdialysis, we find that inactivation of the PFC also reduces the morphine-induced elevation of DA levels in the nucleus accumbens (NAc). Furthermore, 24 h after only single morphine exposure, PFC-inactivation failed to prevent subsequent morphine challenge from exciting VTA DA neurons, which is paralleled by altered response of PFC pyramidal neurons to morphine stimulation. Our results indicate that the PFC gates acute morphine action on a subset of VTA DA neurons, which is highly plastic and can be functionally remodeled by morphine exposure.
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The main purpose of the present study is to investigate the influence of donepezil, a well-known acetylcholinesterase (AChE) inhibitor, on amyloid-β (Aβ)-associated mitochondrial dysfunction, in order to gain a better understanding of the neuroprotective effects of this clinically used anti-Alzheimer's disease (AD) drug. First, our study verifies the ameliorative effects of donepezil on behavioral deficits in both working memory and anxiety in APP/PS1 double transgenic mice, at a time point that AChE is not inhibited. Meanwhile, we demonstrate that donepezil enhances the resistance of brain mitochondria of APP/PS1 mice to the induction of mitochondrial permeability transition (MPT) by calcium ions. ⋯ In addition, donepezil treatment also significantly blocks the Aβ accumulation in the isolated mitochondria. Our study reported for the first time that the protective effects of donepezil against Aβ-associated mitochondrial dysfunction are closely associated with the reduction of Aβ accumulation in the mitochondria. Above observation led us to assume that, besides potent AChE inhibitory effect, other non-cholinergic mechanisms may be involved in the neuroprotective profiles of donepezil.