Prefrontal cortex nicotinic receptor inhibition by methyllycaconitine impaired cocaine-associated memory acquisition and retrieval

Abstract Background After chemotherapy, many cancer survivors suffer from long-lasting cognitive impairment, colloquially known as “chemobrain.” However, the trajectories of cognitive changes and the underlying mechanisms remain unclear. We previously established paclitaxel-induced inositol trisphosphate receptor (InsP3R)-dependent calcium oscillations as a mechanism for peripheral neuropathy, which was prevented by lithium pretreatment. Here, we investigated if a similar mechanism also underlay paclitaxel-induced chemobrain. Method Mice were injected with 4 doses of 20 mg/kg paclitaxel every other day to induced cognitive impairment. Memory acquisition was assessed with the displaced object recognition test. The morphology of neurons in the prefrontal cortex and the hippocampus was analyzed using Golgi-Cox staining, followed by Sholl analyses. Changes in protein expression were measured by Western blot. Results Mice receiving paclitaxel showed impaired short-term spatial memory acquisition both acutely 5 days post injection and chronically 23 days post injection. Dendritic length and complexity were reduced in the hippocampus and the prefrontal cortex after paclitaxel injection. Concurrently, the expression of protein kinase C α (PKCα), an effector in the InsP3R pathway, was increased. Treatment with lithium before or shortly after paclitaxel injection rescued the behavioral, cellular, and molecular deficits observed. Similarly, memory and morphological deficits could be rescued by pretreatment with chelerythrine, a PKC inhibitor. Conclusion We establish the InsP3R calcium pathway and impaired neuronal morphology as mechanisms for paclitaxel-induced cognitive impairment. Our findings suggest lithium and PKC inhibitors as candidate agents for preventing chemotherapy-induced cognitive impairment.

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Nicotinic Receptor Activation Increases [3H]Dopamine Uptake and Cell Surface Expression of Dopamine Transporters in Rat Prefrontal Cortex

Journal of Pharmacology and Experimental Therapeutics ◽

10.1124/jpet.108.147025 ◽

2008 ◽

Vol 328 (3) ◽

pp. 931-939 ◽

Cited By ~ 19

Author(s):

Jun Zhu ◽

Subbu Apparsundaram ◽

Linda P. Dwoskin

Keyword(s):

Prefrontal Cortex ◽

Cell Surface ◽

Nicotinic Receptor ◽

Surface Expression ◽

Receptor Activation ◽

Dopamine Uptake ◽

Cell Surface Expression ◽

Dopamine Transporters

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The α7 nicotinic receptor agonist SSR180711 increases activity regulated cytoskeleton protein (Arc) gene expression in the prefrontal cortex of the rat

Neuroscience Letters ◽

10.1016/j.neulet.2007.03.016 ◽

2007 ◽

Vol 418 (2) ◽

pp. 154-158 ◽

Cited By ~ 17

Author(s):

Søren E. Kristensen ◽

Morten S. Thomsen ◽

Henrik H. Hansen ◽

Daniel B. Timmermann ◽

Anders Hay-Schmidt ◽

...

Keyword(s):

Gene Expression ◽

Prefrontal Cortex ◽

Nicotinic Receptor ◽

Receptor Agonist ◽

Cytoskeleton Protein ◽

Arc Gene

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A Novel Multisensory Integration Task Reveals Robust Deficits in Rodent Models of Schizophrenia: Converging Evidence for Remediation via Nicotinic Receptor Stimulation of Inhibitory Transmission in the Prefrontal Cortex

Journal of Neuroscience ◽

10.1523/jneurosci.1628-16.2016 ◽

2016 ◽

Vol 36 (50) ◽

pp. 12570-12585 ◽

Cited By ~ 10

Author(s):

Jacob M. Cloke ◽

Robin Nguyen ◽

Beryl Y.T. Chung ◽

David I. Wasserman ◽

Stephanie De Lisio ◽

...

Keyword(s):

Prefrontal Cortex ◽

Multisensory Integration ◽

Nicotinic Receptor ◽

Rodent Models ◽

Receptor Stimulation ◽

Inhibitory Transmission ◽

Stimulation Of

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Layer- and subregion-specific differences in the neurophysiological properties of rat medial prefrontal cortex pyramidal neurons

Journal of Neurophysiology ◽

10.1152/jn.00146.2017 ◽

2018 ◽

Vol 119 (1) ◽

pp. 177-191 ◽

Cited By ~ 7

Author(s):

Chenghui Song ◽

James R. Moyer

Keyword(s):

Prefrontal Cortex ◽

Medial Prefrontal Cortex ◽

Pyramidal Neurons ◽

Conditioned Fear ◽

Input Resistance ◽

Underlying Mechanism ◽

Fear Memory ◽

Membrane Properties ◽

Spike Threshold ◽

Memory Acquisition

Medial prefrontal cortex (mPFC) is critical for the expression of long-term conditioned fear. However, the neural circuits involving fear memory acquisition and retrieval are still unclear. Two subregions within mPFC that have received a lot of attention are the prelimbic (PL) and infralimbic (IL) cortices (e.g., Santini E, Quirk GJ, Porter JT. J Neurosci 28: 4028–4036, 2008; Song C, Ehlers VL, Moyer JR Jr. J Neurosci 35: 13511–13524, 2015). Interestingly, PL and IL may play distinct roles during fear memory acquisition and retrieval but the underlying mechanism is poorly understood. One possibility is that the intrinsic membrane properties differ between these subregions. Thus, the current study was carried out to characterize the basic membrane properties of mPFC neurons in different layers and subregions. We found that pyramidal neurons in L2/3 were more hyperpolarized and less excitable than in L5. This was observed in both IL and PL and was associated with an enhanced h-current in L5 neurons. Within L2/3, IL neurons were more excitable than those in PL, which may be due to a lower spike threshold and higher input resistance in IL neurons. Within L5, the intrinsic excitability was comparable between neurons obtained in IL and PL. Thus, the heterogeneity in physiological properties of mPFC neurons may underlie the observed subregion-specific contribution of mPFC in cognitive function and emotional control, such as fear memory expression. NEW & NOTEWORTHY This is the first study to demonstrate that medial prefrontal cortical (mPFC) neurons are heterogeneous in both a layer- and a subregion-specific manner. Specifically, L5 neurons are more depolarized and more excitable than those neurons in L2/3, which is likely due to variations in h-current. Also, infralimbic neurons are more excitable than those of prelimbic neurons in layer 2/3, which may be due to differences in certain intrinsic properties, including input resistance and spike threshold.

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Dementia rating and nicotinic receptor expression in the prefrontal cortex in schizophrenia

Biological Psychiatry ◽

10.1016/s0006-3223(03)00348-2 ◽

2003 ◽

Vol 54 (11) ◽

pp. 1222-1233 ◽

Cited By ~ 69

Author(s):

Carmen M Martin-Ruiz ◽

Vahram H Haroutunian ◽

Philip Long ◽

Allan H Young ◽

Kenneth L Davis ◽

...

Keyword(s):

Prefrontal Cortex ◽

Nicotinic Receptor ◽

Receptor Expression

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Nicotinic receptor-mediated regulation of dopamine transporter activity in rat prefrontal cortex

Synapse ◽

10.1002/1098-2396(200010)38:1<10::aid-syn2>3.0.co;2-t ◽

2000 ◽

Vol 38 (1) ◽

pp. 10-16 ◽

Cited By ~ 63

Author(s):

Allison E. Drew ◽

Alicia E. Derbez ◽

Linda L. Werling

Keyword(s):

Prefrontal Cortex ◽

Dopamine Transporter ◽

Nicotinic Receptor

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Vortioxetine Subchronically Activates Serotonergic Transmission via Desensitization of Serotonin 5-HT1A Receptor with 5-HT3 Receptor Inhibition in Rats

International Journal of Molecular Sciences ◽

10.3390/ijms20246235 ◽

2019 ◽

Vol 20 (24) ◽

pp. 6235 ◽

Cited By ~ 7

Author(s):

Motohiro Okada ◽

Ruri Okubo ◽

Kouji Fukuyama

Keyword(s):

Prefrontal Cortex ◽

Medial Prefrontal Cortex ◽

Serotonin Transporter ◽

Raphe Nucleus ◽

Clinical Effects ◽

Partial Agonism ◽

Lower Affinity ◽

Receptor Inhibition ◽

Freely Moving ◽

Antidepressant Action

Vortioxetine is a novel, multimodal antidepressant with unique targets, including the inhibition of the serotonin transporter (SET), of serotonin 5-HT3 (5-HT3R), and of 5-HT7 (5-HT7R) receptors and partial agonism to serotonin 5-HT1A (5-HT1AR) receptors in humans. Vortioxetine has a lower affinity to 5-HT1AR and 5-HT7R in rats compared with humans, but several behavior studies have demonstrated its powerful antidepressant-like actions. In spite of these efforts, detailed effects of the subchronic administration of vortioxetine on serotonergic transmission remain to be clarified. This study examined the mechanisms underlying the clinical effects of vortioxetine by measuring the releases of 5-HT and GABA in the medial prefrontal cortex (mPFC) of freely moving rats compared with the selective SET inhibitor, escitalopram. Inhibition of 5-HT3R in the mPFC enhanced regional 5-HT release via GABAergic disinhibition. Activation of somatodendritic 5-HT1AR in the dorsal raphe nucleus (DRN) and presynaptic 5-HT1AR in the mPFC inhibited 5-HT release in the mPFC. Escitalopram subchronically activated mesocortical serotonergic transmission via desensitization of 5-HT1AR in the mPFC and DRN and of 5-HT3R in the mPFC; however, vortioxetine also subchronically activated mesocortical serotonergic transmission via desensitization of 5-HT1AR in the mPFC and DRN but not of 5-HT3R in the mPFC. These demonstrations, the desensitization of 5-HT1AR with the inhibition of 5-HT3R (without 5-HT3R desensitization), at least partially, contribute to the multimodal antidepressant action of vortioxetine in rats.

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