Role of estradiol in women smokers' acute HPA axis hormone response to naltrexone

University Of Chicago, Chicago IL

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Abstract

DESCRIPTION (provided by applicant): endogenousopioidsystemisinvolvedinacuteresponsetonicotineandthedevelopmentand maintenanceofnicotinedependence.Accordingly,onedrugbeinginvestigatedforsmokingcessation treatmentisnaltrexone,aopioidreceptorantagonist.However,recentclinicaltrialsexaminingtheefficacyof adjunctivetreatmentwithnaltrexoneinsmokingcessationhaveyieldedmixedresultsand,therefore,further researchisneeded.Ofpotentialrelevancetotheseclinicaloutcomes,boththeendogenousopioidsystemand nicotinehaveactiononthehypothalamicpituitaryadrenal(HPA)axis,asystemthatisprimarilyassociated withresponsetostress.SmokershaveanacutelyunderresponsiveHPAaxistostressorsor pharmacologicalactivationcomparedtononsmokers.Importantly,thisHPAaxisdysfunctionmayplayarole inmaintenanceofaddictionandsusceptibilitytorelapse.NaltrexoneacutelyactivatestheHPAaxisandithas beenpreviouslyhypothesizedthatthisincreaseinHPAaxisactivitymayunderlienaltrexone'sefficacyfor treatmentofalcoholismandpossiblysmoking.However,therelationshipbetweennaltrexone'sactiononthe HPAaxisanditsreductionofsmokingbehaviorhasnotbeeninvestigated.Finally,theremaybeimportant,yet unexploredsexdifferencesinsmokers'responsetonaltrexone.Womensmokershaveshownmoreacute sensitivitytonaltrexonethanmenintermsofsubjective,behavioral,andHPAaxishormonemeasures,aswell asbetterquitratesinsmokingcessationtrialsusingnaltrexone.Thesereportedsexdifferencesmaybe relatedtodifferencesinlevelsofestradiol,thepredominantestrogeninhumans,betweenmenandwomen.In women,fluctuationsinestradiollevelsacrossthemenstrualcyclemayaffecttheamountofavailableopioid receptorsand,therefore,mayaffecttheefficacyofnaltrexone.Thestudiesinthisapplicationaredesignedto testtheeffectsofnaltrexoneontheHPAaxisandsmokingbehaviorinmaleandfemalesmokers,andto examinehowestradiollevelaffectstheseresponsestonaltrexoneinfemalesmokers.Inordertoexaminethe effectofestradiolonresponsetonaltrexone,womenwillbetestedattwodifferentstagesofthemenstrual cycle:theearlyfollicularphase(thelowestlevelofestradioloccurringduringthemenstrualcycle)andthelate follicularphase(thehighestoccurringlevelofestradiol).Theresultsofthisstudywouldpotentiallyprovide evidenceforestradiollevelasamechanismunderlyingsexdifferencesinresponsetonaltrexoneandmay havetranslationalclinicalimplicationsfortheuseofnaltrexoneinsmokingcessation.