Varenicline decreases ethanol intake and increases dopamine release via neuronal nicotinic acetylcholine receptors in the nucleus accumbens

Background and Purpose Varenicline, a neuronal nicotinic acetylcholine receptor (nAChR) modulator, decreases ethanol consumption in rodents and humans. The proposed mechanism of action for varenicline to reduce ethanol consumption has been through modulation of dopamine (DA) release in the nucleus a...

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Veröffentlicht in:British journal of pharmacology 2014-07, Vol.171 (14), p.3420-3431
Hauptverfasser: Feduccia, A A, Simms, J A, Mill, D, Yi, H Y, Bartlett, S E
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container_end_page 3431
container_issue 14
container_start_page 3420
container_title British journal of pharmacology
container_volume 171
creator Feduccia, A A
Simms, J A
Mill, D
Yi, H Y
Bartlett, S E
description Background and Purpose Varenicline, a neuronal nicotinic acetylcholine receptor (nAChR) modulator, decreases ethanol consumption in rodents and humans. The proposed mechanism of action for varenicline to reduce ethanol consumption has been through modulation of dopamine (DA) release in the nucleus accumbens (NAc) via α4*‐containing nAChRs in the ventral tegmental area (VTA). However, presynaptic nAChRs on dopaminergic terminals in the NAc have been shown to directly modulate dopaminergic signalling independently of neuronal activity from the VTA. In this study, we determined whether nAChRs in the NAc play a role in varenicline's effects on ethanol consumption. Experimental Approach Rats were trained to consume ethanol using the intermittent‐access two‐bottle choice protocol for 10 weeks. Ethanol intake was measured after varenicline or vehicle was microinfused into the NAc (core, shell or core‐shell border) or the VTA (anterior or posterior). The effect of varenicline treatment on DA release in the NAc was measured using both in vivo microdialysis and in vitro fast‐scan cyclic voltammetry (FSCV). Key Results Microinfusion of varenicline into the NAc core and core‐shell border, but not into the NAc shell or VTA, reduced ethanol intake following long‐term ethanol consumption. During microdialysis, a significant enhancement in accumbal DA release occurred following systemic administration of varenicline and FSCV showed that varenicline also altered the evoked release of DA in the NAc. Conclusion and Implications Following long‐term ethanol consumption, varenicline in the NAc reduces ethanol intake, suggesting that presynaptic nAChRs in the NAc are important for mediating varenicline's effects on ethanol consumption.
doi_str_mv 10.1111/bph.12690
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The proposed mechanism of action for varenicline to reduce ethanol consumption has been through modulation of dopamine (DA) release in the nucleus accumbens (NAc) via α4*‐containing nAChRs in the ventral tegmental area (VTA). However, presynaptic nAChRs on dopaminergic terminals in the NAc have been shown to directly modulate dopaminergic signalling independently of neuronal activity from the VTA. In this study, we determined whether nAChRs in the NAc play a role in varenicline's effects on ethanol consumption. Experimental Approach Rats were trained to consume ethanol using the intermittent‐access two‐bottle choice protocol for 10 weeks. Ethanol intake was measured after varenicline or vehicle was microinfused into the NAc (core, shell or core‐shell border) or the VTA (anterior or posterior). The effect of varenicline treatment on DA release in the NAc was measured using both in vivo microdialysis and in vitro fast‐scan cyclic voltammetry (FSCV). Key Results Microinfusion of varenicline into the NAc core and core‐shell border, but not into the NAc shell or VTA, reduced ethanol intake following long‐term ethanol consumption. During microdialysis, a significant enhancement in accumbal DA release occurred following systemic administration of varenicline and FSCV showed that varenicline also altered the evoked release of DA in the NAc. Conclusion and Implications Following long‐term ethanol consumption, varenicline in the NAc reduces ethanol intake, suggesting that presynaptic nAChRs in the NAc are important for mediating varenicline's effects on ethanol consumption.</description><identifier>ISSN: 0007-1188</identifier><identifier>EISSN: 1476-5381</identifier><identifier>DOI: 10.1111/bph.12690</identifier><identifier>PMID: 24628360</identifier><language>eng</language><publisher>England: Blackwell Publishing Ltd</publisher><subject>alcohol ; Alcohol Drinking - drug therapy ; Animals ; Benzazepines - administration &amp; dosage ; Benzazepines - pharmacology ; Dopamine ; Dopamine - secretion ; Dose-Response Relationship, Drug ; Ethanol ; Ethanol - administration &amp; dosage ; Ethanol - antagonists &amp; inhibitors ; fast‐scan cyclic voltammetry ; in vivo microdialysis ; Male ; microinfusion ; Microinjections ; nicotinic acetylcholine receptors (nAChRs) ; Nucleus Accumbens - drug effects ; Nucleus Accumbens - metabolism ; Quinoxalines - administration &amp; dosage ; Quinoxalines - pharmacology ; Rats ; Rats, Wistar ; Receptors, Nicotinic - metabolism ; Research Papers ; Rodents ; Structure-Activity Relationship ; Varenicline</subject><ispartof>British journal of pharmacology, 2014-07, Vol.171 (14), p.3420-3431</ispartof><rights>2014 The Authors. British Journal of Pharmacology published by John Wiley &amp; Sons Ltd on behalf of The British Pharmacological Society.</rights><rights>Copyright © 2014 The British Pharmacological Society</rights><rights>2014 The Authors. 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The proposed mechanism of action for varenicline to reduce ethanol consumption has been through modulation of dopamine (DA) release in the nucleus accumbens (NAc) via α4*‐containing nAChRs in the ventral tegmental area (VTA). However, presynaptic nAChRs on dopaminergic terminals in the NAc have been shown to directly modulate dopaminergic signalling independently of neuronal activity from the VTA. In this study, we determined whether nAChRs in the NAc play a role in varenicline's effects on ethanol consumption. Experimental Approach Rats were trained to consume ethanol using the intermittent‐access two‐bottle choice protocol for 10 weeks. Ethanol intake was measured after varenicline or vehicle was microinfused into the NAc (core, shell or core‐shell border) or the VTA (anterior or posterior). The effect of varenicline treatment on DA release in the NAc was measured using both in vivo microdialysis and in vitro fast‐scan cyclic voltammetry (FSCV). Key Results Microinfusion of varenicline into the NAc core and core‐shell border, but not into the NAc shell or VTA, reduced ethanol intake following long‐term ethanol consumption. During microdialysis, a significant enhancement in accumbal DA release occurred following systemic administration of varenicline and FSCV showed that varenicline also altered the evoked release of DA in the NAc. 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Allied Health Premium</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>British journal of pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Feduccia, A A</au><au>Simms, J A</au><au>Mill, D</au><au>Yi, H Y</au><au>Bartlett, S E</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Varenicline decreases ethanol intake and increases dopamine release via neuronal nicotinic acetylcholine receptors in the nucleus accumbens</atitle><jtitle>British journal of pharmacology</jtitle><addtitle>Br J Pharmacol</addtitle><date>2014-07</date><risdate>2014</risdate><volume>171</volume><issue>14</issue><spage>3420</spage><epage>3431</epage><pages>3420-3431</pages><issn>0007-1188</issn><eissn>1476-5381</eissn><abstract>Background and Purpose Varenicline, a neuronal nicotinic acetylcholine receptor (nAChR) modulator, decreases ethanol consumption in rodents and humans. The proposed mechanism of action for varenicline to reduce ethanol consumption has been through modulation of dopamine (DA) release in the nucleus accumbens (NAc) via α4*‐containing nAChRs in the ventral tegmental area (VTA). However, presynaptic nAChRs on dopaminergic terminals in the NAc have been shown to directly modulate dopaminergic signalling independently of neuronal activity from the VTA. In this study, we determined whether nAChRs in the NAc play a role in varenicline's effects on ethanol consumption. Experimental Approach Rats were trained to consume ethanol using the intermittent‐access two‐bottle choice protocol for 10 weeks. Ethanol intake was measured after varenicline or vehicle was microinfused into the NAc (core, shell or core‐shell border) or the VTA (anterior or posterior). The effect of varenicline treatment on DA release in the NAc was measured using both in vivo microdialysis and in vitro fast‐scan cyclic voltammetry (FSCV). Key Results Microinfusion of varenicline into the NAc core and core‐shell border, but not into the NAc shell or VTA, reduced ethanol intake following long‐term ethanol consumption. During microdialysis, a significant enhancement in accumbal DA release occurred following systemic administration of varenicline and FSCV showed that varenicline also altered the evoked release of DA in the NAc. Conclusion and Implications Following long‐term ethanol consumption, varenicline in the NAc reduces ethanol intake, suggesting that presynaptic nAChRs in the NAc are important for mediating varenicline's effects on ethanol consumption.</abstract><cop>England</cop><pub>Blackwell Publishing Ltd</pub><pmid>24628360</pmid><doi>10.1111/bph.12690</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record>
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source Wiley Free Content; MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Wiley Online Library All Journals; PubMed Central; Alma/SFX Local Collection
subjects alcohol
Alcohol Drinking - drug therapy
Animals
Benzazepines - administration & dosage
Benzazepines - pharmacology
Dopamine
Dopamine - secretion
Dose-Response Relationship, Drug
Ethanol
Ethanol - administration & dosage
Ethanol - antagonists & inhibitors
fast‐scan cyclic voltammetry
in vivo microdialysis
Male
microinfusion
Microinjections
nicotinic acetylcholine receptors (nAChRs)
Nucleus Accumbens - drug effects
Nucleus Accumbens - metabolism
Quinoxalines - administration & dosage
Quinoxalines - pharmacology
Rats
Rats, Wistar
Receptors, Nicotinic - metabolism
Research Papers
Rodents
Structure-Activity Relationship
Varenicline
title Varenicline decreases ethanol intake and increases dopamine release via neuronal nicotinic acetylcholine receptors in the nucleus accumbens
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