The novel α7 nicotinic acetylcholine receptor agonist EVP-6124 enhances dopamine, acetylcholine, and glutamate efflux in rat cortex and nucleus accumbens

Huang, Mei; Felix, Anna R.; Flood, Dorothy G.; Bhuvaneswaran, Chaya; Hilt, Dana; Koenig, Gerhard; Meltzer, Herbert Y.

doi:10.1007/s00213-014-3596-0

Cited by 45 publications

(23 citation statements)

References 53 publications

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“…As expected for an a7 nAChR agonist, RG3487 increased dopamine and ACh release in the rat hippocampus and prefrontal cortex (Huang et al, 2014b). Similarly, encenicline increased dopamine and ACh, as well as glutamate release in the prefrontal cortex (Huang et al, 2014a). Tested in clinical trials in schizophrenia patients, RG3487 showed no significant improvement of the cognitive deficit associated with schizophrenia, but patients with moderate negative symptoms exhibited a significant improvement in their symptoms (Umbricht et al, 2014).…”

Section: Gts-21mentioning

confidence: 58%

“…Development of compounds acting at the a7 nAChR might therefore also serve to alleviate NMDA receptor dysfunction, as hypothesized in schizophrenia. Indeed, glutamate release from prefrontal cortex was elevated after treatment with a7 nAChR agonists in rats and nonhuman primates Huang et al, 2014a). The recent hypothesis that ketamine might be used for the treatment of depression indicates that in view of the a7 nAChR/NMDA receptor interaction, additional targets might be envisaged to treat a wide range of psychologic afflictions.…”

Section: B Schizophreniamentioning

confidence: 99%

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Therapeutic Potential ofα7 Nicotinic Acetylcholine Receptors

et al. 2015

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Section: Gts-21mentioning

confidence: 58%

Section: B Schizophreniamentioning

confidence: 99%

Therapeutic Potential ofα7 Nicotinic Acetylcholine Receptors

et al. 2015

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“…Glutamatergic terminals express presynaptic α7 nAChRs in the rat VTA and PFC (Jones and Wonnacott, 2004, Huang et al, 2014). As shown in Figure 1, glutamate release via stimulating presynaptic α7 nAChRs in glutamate terminals may have an indirect action in dopamine release by activating ionotropic glutamate receptors (iGLURs) in dopaminergic terminals (Desce et al, 1992, Fu et al, 2000, Kaiser and Wonnacott, 2000).…”

Section: Role Of Nicotinic Acetylcholine Receptors In the Modulatimentioning

confidence: 99%

Targeting glutamate homeostasis for potential treatment of nicotine dependence

Alasmari

Al‐Rejaie

AlSharari

et al. 2016

Brain Research Bulletin

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Several studies demonstrated that impairment in glutamatergic neurotransmission is linked to drug dependence and drug-seeking behavior. Increased extracellular glutamate concentration in mesocorticolimbic regions has been observed in animals developing nicotine dependence. Changes in glutamate release might be associated with stimulatory effect of nicotinic acetylcholine receptors (nAChRs) via nicotine exposure. We and others have shown increased extracellular glutamate concentration, which was associated with downregulation of the major glutamate transporter, glutamate transporter 1 (GLT-1), in brain reward regions of animals exposed to drug abuse, including nicotine and ethanol. Importantly, studies from our laboratory and others showed that upregulation of GLT-1 expression in the mesocorticolimbic brain regions may have potential therapeutic effects in drug dependence. In this review article, we discussed the effect of antagonizing presynaptic nAChRs in glutamate release, the upregulatory effect in GLT-1 expression and the role of glutamate receptors antagonists in the treatment of nicotine dependence.

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“…Increased dopamine release within this pathway may target the negative symptoms of the disease [36]. Agonists targeting the alpha7 nicotinic acetylcholine receptor (a7-nAChR) increase dopamine release in both pathways [37,38]. While increased dopamine release in the mesocortical pathway could potentially improve emotional blunting and cognitive symptoms, increase dopamine release within the mesolimbic pathway could potentially exacerbate hallucinations.…”

Section: Nicotinic Receptors and Schizophreniamentioning

confidence: 99%

Targeting Functional Biomarkers in Schizophrenia with Neuroimaging

Wylie

Smucny²,

Legget³

et al. 2016

CPD

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Many of the most debilitating symptoms for psychiatric disorders such as schizophrenia remain poorly treated. As such, the development of novel treatments is urgently needed. Unfortunately, the costs associated with high failure rates for investigational compounds as they enter clinical trials has led to pharmaceutical companies downsizing or eliminating research programs needed to develop these drugs. One way of increasing the probability of success for investigational compounds is to incorporate alternative methods of identifying biological targets in order to more effectively screen new drugs. A promising method of accomplishing this goal for psychiatric drugs is to use functional magnetic resonance imaging (fMRI). fMRI investigates neural circuits, shedding light on the biology that generates symptoms such as hallucinations. Once identified, relevant neural circuits can be targeted with pharmacologic interventions and the response to these drugs measured with fMRI. This review describes the early use of fMRI in this context, and discusses the alpha7 nicotinic receptor agonist 3-(2,4-dimethoxybenzylidene) anabaseine (DMXB-A), as an example of the potential value of fMRI for psychiatric drug development.

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The novel α7 nicotinic acetylcholine receptor agonist EVP-6124 enhances dopamine, acetylcholine, and glutamate efflux in rat cortex and nucleus accumbens

Abstract: These results suggest increased cortical DA, ACh, and Glu release, which may contribute to the ability of the α7 nAChR agonist, EVP-6124, to treat cognitive impairment and possibly other dimensions of psychopathology.

Cited by 45 publications

References 53 publications

Therapeutic Potential ofα7 Nicotinic Acetylcholine Receptors

Therapeutic Potential ofα7 Nicotinic Acetylcholine Receptors

Targeting glutamate homeostasis for potential treatment of nicotine dependence

Targeting Functional Biomarkers in Schizophrenia with Neuroimaging

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