Effects of varenicline on alpha4-containing nicotinic acetylcholine receptor expression and cognitive performance in mice

Lange-Asschenfeldt, Christian; Schäble, Sandra; Suvorava, Tatsiana; Fahimi, Ehsan Gholamreza; Bisha, Marion; Stermann, Torben; Henning, Ulf; Kojda, Georg

doi:10.1016/j.neuropharm.2016.03.025

Cited by 21 publications

(8 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Data from other laboratories suggest that activation of α 7 (Roncarati R et al, 2009) or α 4 β 2 (Lange-Asschenfeldt et al, 2016) nicotinic receptors is capable of attenuating scopolamine-induced deficits in object recognition memory in rodents. However, whether vortioxetine’s effects on scopolamine-induced deficits are mediated via nicotinic receptor mechanisms or some other downstream mechanism cannot be evaluated based on the data presented in this work, and again these concepts are outside the intended scope of the present study.…”

Section: Discussionmentioning

confidence: 99%

Task- and Treatment Length-Dependent Effects of Vortioxetine on Scopolamine-Induced Cognitive Dysfunction and Hippocampal Extracellular Acetylcholine in Rats

Pehrson

Hillhouse

Haddjeri

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

View full text Add to dashboard Cite

Major depressive disorder (MDD) is a common psychiatric disorder that often features impairments in cognitive function, and these cognitive symptoms can be important determinants of functional ability. Vortioxetine is a multimodal antidepressant that may improve some aspects of cognitive function in patients with MDD, including attention, processing speed, executive function, and memory. However, the cause of these effects is unclear, and there are several competing theories on the underlying mechanism, notably including regionally-selective downstream enhancement of glutamate neurotransmission and increased acetylcholine (ACh) neurotransmission. The current work sought to evaluate the ACh hypothesis by examining vortioxetine’s ability to reverse scopolamine-induced impairments in rodent tests of memory and attention. Additionally, vortioxetine’s effects on hippocampal extracellular ACh levels were examined alongside studies of vortioxetine’s pharmacokinetic profile. We found that acute vortioxetine reversed scopolamine-induced impairments in social and object recognition memory, but did not alter scopolamine-induced impairments in attention. Acute vortioxetine also induced a modest and short-lived increase in hippocampal ACh levels. However, this short-term effect is at variance with vortioxetine’s moderately long brain half life (5.1 hours). Interestingly, subchronic vortioxetine treatment failed to reverse scopolamine-induced social recognition memory deficits and had no effects on basal hippocampal ACh levels. These data suggest that vortioxetine has some effects on memory that could be mediated through cholinergic neurotransmission, however these effects are modest and only seen under acute dosing conditions. These limitations may argue against cholinergic mechanisms being the primary mediator of vortioxetine′s cognitive effects, which are observed under chronic dosing conditions in patients with MDD.

show abstract

Section: Discussionmentioning

confidence: 99%

Task- and Treatment Length-Dependent Effects of Vortioxetine on Scopolamine-Induced Cognitive Dysfunction and Hippocampal Extracellular Acetylcholine in Rats

Pehrson

Hillhouse

Haddjeri

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

View full text Add to dashboard Cite

show abstract

“…Varenicline (Chantix®) is a pharmacotherapy that has increased the likelihood of successful quit attempts for tobacco users, in part, due to its pharmacological similarity to nicotine (Cahill, Stead, & Lancaster, 2010). Tobacco users who wish to maintain abstinence during a serious quit attempt may find that it alleviates craving for nicotine (Cahill et al, 2013;Lange-Asschenfeldt et al, 2016). Varenicline acts as a partial agonist on the α4β2containing nicotinic acetylcholine receptors (nAChRs) which may account for its increased efficacy when compared to less nicotine-like pharmacotherapies such as bupropion (Zyban®; Potts & Garwood, 2007).…”

Section: Introductionmentioning

confidence: 99%

Exploring the interoceptive stimulus effects of nicotine and varenicline

Thompson

Barrett

Bevins

2019

Pharmacology Biochemistry and Behavior

View full text Add to dashboard Cite

Learning processes associated with nicotine influence the development of addiction to tobacco products. In the present report, we are interested in the interoceptive stimulus effects of nicotine acquiring control over appetitive behaviors-specifically, reward seeking. Also of interest is the current smoking cessation drug, varenicline (Chantix®). Varenicline, with its nicotine-like stimulus effects, can decrease withdrawal and cravings for a subset of individuals addicted to nicotine, though relapse is still common. We trained rats (N=48) with nicotine (0.4 mg/kg, SC) as an excitatory stimulus (i.e., paired with sucrose) in a drug-discriminated goal-tracking (DGT) task. There was no access to sucrose on interspersed saline days. After acquisition of the initial nicotine-saline discrimination, rats were separated into four groups to test discrimination reversal and drug substitution. The control group maintained nicotine as the excitatory stimulus (NIC+). The substitution group had varenicline (1 mg/kg) replace nicotine as the stimulus paired with sucrose (VAR+). One reversal group had nicotine signal the absence of sucrose (i.e., now available on intermixed saline sessions; NIC-). The last group was similar to the NIC-group except varenicline replaced nicotine on non-reinforced sessions (VAR-). We found that varenicline fully substituted as the training stimulus when the drug-sucrose relation remained in place (VAR+). Both reversal groups acquired the new discrimination, albeit slowly and more variable for the VAR-group in comparison to NIC-. There was an effect of group during substitution testing. Specifically, nicotine fully substituted for varenicline regardless of condition. However, varenicline only partially substituted for the nicotine stimulus. At the start of extinction, responding mimicked that of the rats training condition. However, by extinction session 12, all groups maintained similarly low levels of responding. These findings show nicotine and varenicline share stimulus elements, yet the conclusion of partial to full substitution depends on the nature of the testing protocol.

show abstract

“…In 1851, Claude Bernard first discovered that nicotine directly activates muscle tissue, and nicotine was later proven to neurally stimulate common receptors through neurotransmitter release. Over the past two decades, clinical investigations have revealed that nicotinic acetylcholine receptors (nAChRs) play essential roles in mediating anti-nociception ( Marubio et al, 1999 ), cognitive performance ( Lange-Asschenfeldt et al, 2016 ), and oncogenic characteristics in lung, colon, and breast cancers ( Dasgupta et al, 2006 ; Wei et al, 2009 ; Lee et al, 2010 , 2011 ). Among all nAChRs, the homopentameric form of a7-nAChR and the heteropentameric form of a4b2-nAChR are the two most investigated nAChRs, as they are the focus of studies exploring the downstream signaling pathways and biofunctional properties of nAChRs.…”

Section: Introductionmentioning

confidence: 99%

Nicotinic Acetylcholine Receptor Subtype Alpha-9 Mediates Triple-Negative Breast Cancers Based on a Spontaneous Pulmonary Metastasis Mouse Model

Huang

Lin

Qiu

et al. 2017

Front. Cell. Neurosci.

View full text Add to dashboard Cite

Triple-negative breast cancer (TNBC) subtype is associated with poor prognosis and a high risk of recurrence-related death in women. Despite the aggressiveness of TNBCs, targeted TNBC therapy is not yet available in the clinic. To overcome this challenge, we generated highly metastatic TNBC cells (LM) derived from metastasized lung cells via a serial spontaneous pulmonary metastasis animal model to identify targetable molecules for attenuating the progression of TNBC metastasis. Gene analysis of primary tumor (P), first-round (1LM) and second-round (2LM) metastasized lung cells revealed that mesenchymal-related genes were significantly expressed in LM cells, especially in 2LM cells. Interestingly, α9-nAChR gene expression was also dramatically induced in LM cells, confirming our previous finding that α9-nAChR plays important roles in receptor-mediated carcinogenic signals in human breast cancer development. Using α9-nAChR as a biomarker, we transfected 2LM cells with CRISPR/Cas9 lentivirus targeting the α9-nAChR genomic region (2LM-α9-nAChR-null), showing that mesenchymal markers and the migration and invasion abilities of 2LM cells were significantly attenuated in 2LM-α9-nAChR-null cells both in vitro and in vivo. In addition, the high efficiency of editing the α9-nAChR gene using a CRISPR/Cas9 lentivirus was demonstrated by gene sequencing, genomic indel frequency and protein expression analyses. Collectively, these results confirmed those of our previous study that advanced-stage breast tumors are associated with substantially higher levels of α9-nAChR gene expression, indicating that α9-nAChR expression is essential for mediating TNBC metastasis during cancer development and may potentially act as a biomarker for targeted therapy in clinical investigations.

show abstract

Effects of varenicline on alpha4-containing nicotinic acetylcholine receptor expression and cognitive performance in mice

Cited by 21 publications

References 57 publications

Task- and Treatment Length-Dependent Effects of Vortioxetine on Scopolamine-Induced Cognitive Dysfunction and Hippocampal Extracellular Acetylcholine in Rats

Task- and Treatment Length-Dependent Effects of Vortioxetine on Scopolamine-Induced Cognitive Dysfunction and Hippocampal Extracellular Acetylcholine in Rats

Exploring the interoceptive stimulus effects of nicotine and varenicline

Nicotinic Acetylcholine Receptor Subtype Alpha-9 Mediates Triple-Negative Breast Cancers Based on a Spontaneous Pulmonary Metastasis Mouse Model

Contact Info

Product

Resources

About