Anti-VAChT vesicular acetylcholine transporter, NeuroMab ...
WSU 2014 Drug toxicity vs reward - Washington State...
Transcript of WSU 2014 Drug toxicity vs reward - Washington State...
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Recrea&onal*drug*use:*does*drug*toxicity*explain*more*than*drug*reward?*
Edward*H.*Hagen*Casey*J.*Roule>e*
*Department*of*Anthropology*Washington*State*University*
*
Roger*J.*Sullivan**
Department*of*Anthropology*California*State*University*Sacramento*
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Tobacco*use*is*responsible*for*1*in*5*deaths*in*high*income*countries,*and*more*than*1*in*10*deaths*globally.*
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The*mainstream*“reward”*model*Recrea&onal*drugs*increase*mesolimbic*dopamine*
Dopamine)False*signal*of*fitness*benefit*
Drugs)=)sugar)
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Reasons*to*doubt*reward*model*
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Most drugs are plant defensive toxins
Nico&ne*in*tobacco*Cocaine*in*coca*THC*in*cannabis*Caffeine*in*coffee*Arecoline*in*betel*nut*
These*evolved*to*harm*plant*consumers,*not*reward*them*
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Nico&ne*as*a*model*drug*
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Nico&ne*is*extremely*toxic*
Toxin Recreational dose Lethal dose
Hydrogen cyanide 50 mg Nicotine 1-4 mg 30-60 mg
*One*cigare>e*contains*10S20*mg*nico&ne,*enough*to*kill*a*child*
***
This*acute*toxicity*plays*almost*no*role*in*mainstream*drug*use*theory**
(Nico&ne*is*not*a*carcinogen)*
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Nico&ne*ac&vates*virtually*all*known*toxin*defense*mechanisms*
Bi>er*taste*receptors*Gastrointes&nal*�taste��receptors*Nocicep&ve*(pain)*neurons*Xenobio&cSsensing*nuclear*receptors*Xenobio&c*metabolizing*enzymes*Aversion*circuitry*in*the*CNS*Condi&oned*taste*avoidance*Nausea*Vomi&ng*
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Hypothesis*
Drug*toxicity*explains:**Age*differences*in*use*Sex*differences*in*use**Use*
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Age*differences*in*substance*use*
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Cumula&ve*distribu&on*of*age*at*first*use*(self*report)*
Degenhardt*et*al.*2008*WHO*World*Mental*Health*Surveys**N*=*85,052*
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Co&nine*vs.*age*(Co&nine*is*a*nico&ne*metabolite)*
NHANES)199962010)*
N*=*18,382**
Age*3S10**
N*=*5932*Smoker*in*household:*1111*
Co&nine*half*life*�*18*hours*
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Reward*models*of*low*child*use:**
Reduced*reward*func&on*in*children?*
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Sugar*consump&on*vs.*age*
NHANES*1999S2004,*Wang*et*al.*2008* NHANES*2005S2008,*Ervin*et*al.*2012*
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“Imbalance”*model*Chambers*et*al.*2003,*Casey*et*al.*2008,*Steinberg*2008*
Mesolimbic*dopamine*system*(MDS)**Reward*Reinforcement*
Prefrontal*cortex*(PFC)**SelfSregula&on*Abstract*reasoning*Delibera&on*Response*inhibi&on*Planning*ahead**
Pro*drug*signals* An&*drug*signals*
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“Imbalance”*model*Chambers*et*al.*2003,*Casey*et*al.*2008,*Steinberg*2008*
Childhood*MDS*and*PFC**in*balance*
Adolescence*MDS*and*PFC**out*of*balance*
Adulthood*MDS*and*PFC**back*in*balance*
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Imbalance*model*of*low*child*use:***
Social*restric&ons**
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US*tobacco*control*programs*$500*million/year*
Mass*media*an&Stobacco*campaigns*Dissemina&on*of*health*warnings*via,*e.g.,*cigare>e*packages*and*adver&sing*Enforcing*bans*on*tobacco*marke&ng*Monitoring*tobacco*use*Enforcing*some*smokeSfree*legisla&on*Providing*some*tobacco*cessa&on*health*care*programs.**Tobacco*taxes*also*deter*use.*
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Caffeine*
Caffeine*is*a*bi>erStas&ng*plant*toxin*Caffeine*increases*dopamine*in*the*MDS*Few*formal*controls*on*child*caffeine*consump&on*
Caffeine*added*to*many*sog*drinks*marketed*to*children*
Social*control*model:*children*should*consume*as*much*caffeine*as*adults.*
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Coffee*intake*vs.*age*Pa>ern*very*similar*to*tobacco*use*
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Toxicity*model*of*low*child*use**
*The*costs*of*neurotoxin*consump&on*are*high*in*childhood*but*decrease*with*age*
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Brain development and acetylcholine
Acetylcholine plays a critical role in brain maturation from early embryogenesis to adolescence.
nACHRs detectable before neuralation Acetylcholine promotes switch from replication to differentiation Acetylcholine modulates axonogenesis and synaptogenesis Acetylcholine promotes/prevents neuronal apoptosis
Interference with cholinergic signaling disrupts final architectural assembly of brain regions with cholinergic target zones, such as those that control learning and memory.
Slotkin 2004
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Heightened*child*toxin*defense*mechanisms*
Avoidance*******Detec&on*******Elimina&on*
Higher*density*of*taste*buds*on*the*&p*of*the*tongue.**Greater*bi>er*taste*sensi&vity*
Greater*neophobia*and*“pickiness.”*
Larger*liver/body*ra&o**Higher*drug*clearance*rates*
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US*nonSfatal*poisoning*rate*vs.*age*
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Adolescent*onset:*Brain*matura&on*
Longitudinal*fMRI*(Lenroot*and*Giedd*2006)*
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Sex*differences*in*substance*use*
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Female*vs.*male*prevalence*of*tobacco*use*N*=*157*countries*
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No*sex*difference*in*consump&on*of*added*sugar*NHANES*2005S2010*
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Sex*differences*in*reinforcement*learning?*
Many*sex*differences*in*spa&al*and*aversive*learning*(Dalla*and*Shors*2009)**Sex*differences*in*appe&&ve*learning?*
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Toxicity*model***
Costs*of*neurotoxin*consump&on*are*higher*for*women*(pregnancy*and*fetal*exposure)*
S>*Less*female*drug*use*
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Heightened*female*toxin*defense*mechanisms*
Avoidance*******Detec&on*******Elimina&on*
Higher*density*of*taste*buds*on*the*&p*of*the*tongue.**Greater*bi>er*taste*sensi&vity*
Food*aversions*in*pregnancy*
Larger*liver/body*ra&o**Higher*drug*clearance*rates,*especially*in*pregnancy*
?*******?*******?*
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Xenobio&c*metabolism*accelerated*during*pregnancy*(mostly)*
+*++*+*S*S*+*+/S*+*
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US*nonSfatal*poisoning*rate*vs.*age*
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Female*vs.*male*prevalence*of*tobacco*use*N*=*157*countries*
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Female*vs.*male*prevalence*of*tobacco*use*N*=*157*countries*
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Female*vs.*male*prevalence*of*tobacco*use*N*=*157*countries*
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Female*smoking*prevalence*vs.*TFR*
Generalized*linear*mixed*model*(GLMM)*with*spa&al*correla&on
Coefficients: Value SE DF t-value p-value
(Intercept) 4.58 3.90 139 1.17 0.243WECO 1.65 0.78 139 2.11 0.037tfr1975 -1.19 0.48 139 -2.48 0.014Male prevalence 0.31 0.06 139 5.48 0.000
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Female*Aka*smoker*status*by*age*(selfSreport)*
Female smoker status ~ age + mother_smoker
*Coefficients: Estimate Std. Error z value Pr(>|z|) (Intercept) 4.52726 1.18191 3.830 0.000128 *** age -0.07406 0.02582 -2.869 0.004123 ** mother_smokeryes -2.59852 0.72489 -3.585 0.000337 ***
*
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Prevalence*by*age*and*sex*(US)*NHANES*1999S2010*co&nine*conc.*>*3*ng/ml*
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Ra&o*of*smoking*prevalence*45S64*years/25S44*years**13*countries*in*Global*Adult*Tobacco*Survey*(WHO)*
With*former*Soviet*Block*countries*(N=13)*
Without*former*Soviet*Block*countries*(N=10)*
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A*regulatory*model*
The*brain*is*regula&ng,*not*elimina&ng,*exposure*to*plant*neurotoxins*
***
But*why?*
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Honest*signal*of*brain*maturity*
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Honest*signal*of*brain*maturity*
Cost*of*substance*use*is*high*for*individuals*with*s&llSdeveloping*brains*vs.*those*with*completed*brain*development.*
Substance*use*is*honest*signal*of*brain*matura&on.*
Maturity*important*criterion*for*mate*choice*and*social*partner*choice**
HunterSgatherers*typically*do*not*keep*track*of*chronological*age*Considerable*individual*varia&on*in*brain*matura&on*(Giedd*2008)*If*young*men*ranged*widely*in*search*of*mates,*young*women*would*have*to*assess*“maturity”*on*the*basis*of*limited*observa&ons.*
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Ma&ng*and*substance*use*
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Age*started*regular*smoking*vs.*first*sex*
Males* Females*
NHANES*1999S2010,*Controlling*for*ethnicity*and*current*age*of*par&cipant*
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Maturity,*ma&ng*and*substance*use*
Smoking*ini&a&on*is*significantly*influenced*by*perceived*benefits,*such*as*looking*cool,*looking*grown*up,*being*popular*(HalpernSFelsher*et*al.*2004;*Morrell*et*al.*2010;*Song*et*al.*2009;*Borrelli*et*al.*2010)*
Smoking*associated*with*early*sexual*behavior*(Sussman*2005)*
Higher*ma&ng*effort*associated*with*higher*smoking*(Jones*and*Figueredo*2007),*other*drug*use*(Richardson*et*al.*2012),*and*more*lenient*aotudes*towards*drug*use*(Kurzban*et*al.*2010).*
*
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Parasite*defense*
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Plant neurotoxins (e.g., recreational drugs) evolved to harm plant parasites
Arthropods Nematodes
Did animals evolve to take advantage of 400+ million years of pharmacological �R&D� by plants?
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Species*known*to*selfSmedicate*against*parasites*(Zoopharmocognosy,*Pharmacophagy)*
Primates*Fruit*flies*Ants*Moths*Bu>erflies*Honeybees*Birds*Sheep*Goats*
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*Pharmacophagy*hypothesis*
*Recrea&onal*drug*use*is*an*(unconscious)*form*of*
selfSmedica&on*against*helminths*and*other*macroparasites*
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Chemoprophylaxis & Chemotherapy
Chemoprophylaxis: recreational drug use deters infection by pathogens with nervous systems Chemotherapy: recreational drug use treats infection by pathogens with nervous systems
Psychoac&ve*drugs*
=
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Efficacy of nicotine against helminths
Many commercial anthelmintics (e.g., levamisole, pyrantel) attack same neuroreceptor system as nicotine (nAChRs).
Nicotine sulfate was widely used to de-worm livestock.
Aqueous tobacco extracts still used in developing world to de-worm livestock.
Tobacco widely reported as an anthelmintic in the ethnomedical literature.
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Helminth*burden*and*immune*response*vs.*age*
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Study population: Aka foragers of the Central African Republic
Aka camp
Study)site)ra<onale)*High*levels*of*intes&nal*parasites**Heavy*tobacco*and*cannabis*use*among*men*(very*low*use*among*women).**Almost*no*access*to*commercial*anthelmin&cs.*
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Predic&ons*
Chemotherapy*Inverse*correla&on*between*smoking*levels*and*worm*burden.**
Trea&ng*helminth*infec&ons*will*reduce*smoking*rela&ve*to*placebo*controls.*
Slow*nico&ne*metabolizers*will*have*lower*worm*burdens.*
Chemoprophylaxis*Among*Aka*treated*for*helminths,*smoking*levels*in*year*1*will*be*inversely*correlated*with*reinfec&on*by*year*2.*
Countries*with*higher*helminth*diversity*will*have*higher*smoking*prevalence.*
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2010-2011
206 Aka males 3 neighboring populations of Aka
Up to 9 saliva and stool samples per person
Controls (age, region, wealth & acculturation)
Experimental and observational designs
1 2 3
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Smoking levels
Salivary cotinine – Nicotine metabolite – Half life ~ 18 hrs (nicotine half life ~ 2 hrs) – Indexes level of recent nicotine exposure
Saliva collection tube
Barry Hewlett and Casey Roulette interviewing Aka about tobacco use
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Worm burden
Appreciable levels of three types Hookworm Ancylostoma duodenale, Necator americanus Ascaris lumbricoides Whipworm Trichuris trichiura
Egg counts measured with 3 techniques
Direct examination Kato technique Concentration by sedimentation
Semi-quantified on a 10 point scale for each species for each technique Worm burden score: sum all scores for all species for all techniques.
Stool collection kit Formalin/PVA
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Chemotherapy: Observational study
Interview upon entrance to study 3 saliva and 3 stool samples per subject over ~ 6 days
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Controls
Material wealth Radio Flashlight Watch Sets of clothes
Acculturation
Prefer forest or village Schooling (y/n) Church attendance (y/n)
Region 1: Near village 2, 3: ~20 Km W, SE
Age
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Chemotherapy: Observational study
Worm*burde
n*score*
Worm*burde
n*score*
Age* Square*root*of*co&nine*concentra&on*
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Generalized additive model
Family: Negative Binomial(1.904) Link function: log
Formula:worm ~ village + acculturation + wealth + s(age) + s(cotinine) + offset(log(stool_count))
Parametric coefficients: Estimate Std. Error t value Pr(>|t|) (Intercept) 2.78046 0.18384 15.124 <2e-16 ***villageTRUE 0.28057 0.12250 2.290 0.0232 * acculturation 0.09957 0.09683 1.028 0.3053 wealth -0.03064 0.04700 -0.652 0.5153 ---Signif. codes: 0 ‘***’ 0.001 ‘**’ 0.01 ‘*’ 0.05 ‘.’ 0.1 ‘ ’ 1
Approximate significance of smooth terms: edf Ref.df F p-value s(age) 2.464 3.116 2.483 0.04512 *s(cotinine) 2.549 3.200 4.719 0.00281 **---Signif. codes: 0 ‘***’ 0.001 ‘**’ 0.01 ‘*’ 0.05 ‘.’ 0.1 ‘ ’ 1
R-sq.(adj) = 0.146 Deviance explained = 13.7%UBRE score = 1.054 Scale est. = 1 n = 176
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Limitations
Males only Observational study (worm score vs. cotinine)
Correlation ≠ Causation Limited controls (age, wealth, acculturation) Negative correlation for heavier smokers only Unexplained flat or positive relationship at low cotinine levels
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Testing the chemotherapy hypothesis with a randomized control trial
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Predictions
Infec&on*with*helminths*should*increase*smoking**
Elimina&on*of*helminths*should*decrease*smoking*
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Randomize into treatment and placebo control groups (double-blind)
400 mg albendazole Placebo
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Randomized control trial
Administer 400 mg albendazole or placebo (double-blind)
~ 2 weeks
3 saliva/stools 3 saliva/stools
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Prediction
Albendazole treatment group will have reduced salivary cotinine relative to placebo control group
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Manipulation check
Worm burden
t = 7.0537, df = 86.781, p-value = 2.001e-1095 percent confidence interval: 7.78 Inf sample estimates: mean in group control mean in group treatment 13.66 3.47
t
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RCT results
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Limita&ons*
Cause(s)*of*treatment*effect*might*be*unrelated*to*selfSmedica&on*
Is*treatment*effect*due*to*changes*in*smoking*behavior*or*changes*in*metabolism?*
Why*does*control*group*co&nine*increase*preS*to*postSinterven&on*for*those*with*high*baseline*worm*burden?*
Biased*a>ri&on*(but*no*significant*difference*in*treatment*vs.*control*group)*
*
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CYP2A6*genotype*
CYP2A6*metabolizes*nico&ne*to*co&nine*Polymorphisms*increase/decrease*metabolism*
Cheek*swabs*(Whatman*FTA*cards)*
Dried*blood*spots*
Predict*phenotype*Fast*metabolizing*alleles*=*1*
Normal*alleles*(wildtype)*=*0*
Slow*alleles*=*S1*
Sum*two*alleles*
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Genotype*study*predic&ons*
Slow*phenotypes*will*have*higher*co&nine*levels*(reflec&ng*higher*nico&ne*exposure)*and*lower*worm*burden*
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Aka*metabolic*phenotype*vs.*co&nine*
Robust*F*=*3.03,*p=.076**
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Aka*metabolic*phenotype*vs.*worm*burden*
Normal*metabolizers*
Slow*metabolizers*
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Limita&ons*
1. We*tested*for*common*slow*and*fast*2A6*alleles,*but*it*is*likely*that*the* default* *1A* wildtype* allele* category* comprises* a* mix* of*wildtype*and*uniden&fied*slow*and*fast*alleles.*
2. We* assume* that* the* rela&onship* between* 2A6* phenotype* and*worm*burden*was*mediated*by*nico&ne*exposure,*but*the*Aka*diet*might*contain*other*substrates*of*2A6*that*might*account*for*this*effect.**
3. 2A6*is*involved*in*the*biosynthesis*and*metabolism*of*endogenous*signaling*molecules*that*might*play*a*role*in*immunity*to*helminths*(e.g.,* steroids).*Allelic*varia&on* in*2A6*might* thus*have*numerous*influences*on*vulnerability*to*helminth* infec&on* in*addi&on*to,*or*other*than,*its*effect*on*nico&ne*metabolism;*or*it*might*simply*be*confounded*with*other*factors*influencing*worm*burden.*
4. Currently,* Aka* exposure* to* nico&ne* is* primarily* from* the* New*World* tobacco* plant* (probably).* It* is* not* clear* what* substrate* in*the*diet,*if*any,*influenced*selec&on*on*2A6*in*the*Aka*or*any*other*popula&on.*
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Chemoprophylaxis:*reinfec&on*study*
Predic&on:*Among*the*uninfected,*higher*smoking*reduces*risk*of*(re)infec&on.**Specifically,*year*1*and*year*2*smoking*levels*will*be*inversely*correlated*with*reinfec&on*by*year*2.*
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Reinfec&on*study*
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Reinfection study
r = -0.42, p = .02
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Reinfection study
r = -0.47, p = .01
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Limita&ons*
Even*though*longitudinal,*s&ll*a*correla&on*study*(correla&on*≠*causa&on)*
*
Small*sample*size*Cannot*control*for*confounds.*
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CrossSna&onal*test*of*chemotherapy*
Predic&on:*Countries*with*higher*parasite*diversity*will*have*higher*smoking*prevalence*
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Cross national data: Males
lm(formula = Percentage_smokers_male ~ LnGNP * Latitude^2 + RicArthropode + RichVirus + RichParasites, data = bio)
Coefficients: Estimate Std. Error t value Pr(>|t|)(Intercept) 74.72263 9.96451 7.50 1.8e-11 ***LnGNP 0.57758 1.11946 0.52 0.60693Latitude^2 0.01395 0.00364 3.83 0.00021 ***RicArthropode -7.07995 1.71151 -4.14 6.9e-05 ***RichVirus -1.04143 0.28156 -3.70 0.00034 ***RichParasites 1.29529 0.23681 5.47 2.9e-07 ***LnGNP:Latitude^2 -0.00373 0.00108 -3.45 0.00081 ***---Signif. codes: 0 ‘***’ 0.001 ‘**’ 0.01 ‘*’ 0.05 ‘.’ 0.1 ‘ ’ 1
Residual standard error: 9.9 on 110 degrees of freedom (106 observations deleted due to missingness)Multiple R-squared: 0.47, Adjusted R-squared: 0.442F-statistic: 16.3 on 6 and 110 DF, p-value: 2.39e-13
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Cross national data: Females
lm(formula = Percentage_smokers_female ~ LnGNP + Latitude^2 + RicArthropode + RichVirus + RichParasites, data = bio)
Coefficients: Estimate Std. Error t value Pr(>|t|)(Intercept) 15.91894 8.88752 1.79 0.07602 .LnGNP 2.29394 0.94081 2.44 0.01636 *Latitude^2 0.00383 0.00110 3.47 0.00074 ***RicArthropode -2.07676 1.63166 -1.27 0.20577RichVirus 0.04887 0.26472 0.18 0.85387RichParasites -0.18692 0.22008 -0.85 0.39754---Signif. codes: 0 ‘***’ 0.001 ‘**’ 0.01 ‘*’ 0.05 ‘.’ 0.1 ‘ ’ 1
Residual standard error: 9.5 on 110 degrees of freedom (107 observations deleted due to missingness)Multiple R-squared: 0.374, Adjusted R-squared: 0.346F-statistic: 13.2 on 5 and 110 DF, p-value: 4.79e-10
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Neurotoxin*regula&on*model*
Tobacco*users*&trate*nico&ne*intake**Some*dopamine*neurons*in*the*MDS*respond*to*aversive*s&muli**Inflammatory*signals*reinforce*opium*and*ethanol*consump&on*in*rodents*(Hutchinson*et*al.*2012,*Blednov*et*al.*2011,*2012)**Infec&on*induces*broad*downSregula&on*of*CYP*P450*metabolism,*increasing*plasma*concentra&ons*of*drug*(Morgan*et*al.*2008).*
“A*major*development*in*drug*addic&on*research*in*recent*years*has*been*the*discovery*that*immune*signaling*within*the*central*nervous*system*contributes*significantly*to*mesolimbic*dopamine*reward*signaling*induced*by*drugs*of*abuse,*and*hence*is*involved*in*the*presenta&on*of*reward*behaviors.”*Hutchinson*and*Watkins*2014.*
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Conclusions*
Large*age*and*sex*differences*in*substance*use**Few*age*or*sex*differences*in*reward*or*reinforcement*learning**Age*and*sex*differences*in*substance*use*parallel*age*and*sex*differences*in*the*costs*of*neurotoxin*consump&on**Higher*co&nine*associated*with*lower*worm*burden*and*less*reinfec&on**Trea&ng*worms*reduces*exposure*to*nico&ne**Parasite*biodiversity*posi&vely*correlated*with*male*smoking*prevalence*