Early Life Lead Exposure and Substance Abuse: is there a …. toms r. guilarte. universidad... ·...

Early Life Lead Exposure andSubstance Abuse: is there a

connection??

Tomás R. Guilarte, PhDDean, Robert Stempel College of Public Health &

Social WorkProfessor, Department of Environmental &

Occupational HealthProfessor, Cognitive Neuroscience & Imaging

Member, Biomolecular Sciences InstituteFlorida International University

Miami, FL

oAt least 4 million households havechildren living in them that are beingexposed to high levels of lead.

oThere are approximately half amillion U.S. children ages 1-5 withblood lead levels (BLL) above 5µg/dL, the reference level at whichCDC recommends public healthactions to be initiated.

https://www.cdc.gov/nceh/lead/

Lead ExposureLead is one of ten chemicalsidentified by the World HealthOrganization (WHO, 2010) as beingof “major public health concern”and in need of action (World HealthOrganization, 2010).

CDC: Center for Disease Control and Prevention

Lead Exposure

October 22-28 is National Lead Poisoning Prevention CDC: Center for Disease Control and Prevention

Lead Exposure

CDC

The economic impact of leadexposure in US and Europe: $50.9and $55 billion, respectively.

(Attina & Trasande, 2013)

Lead Exposure and Drug Addiction

Childhood lead intoxication has been associated with learning deficits, antisocialbehaviors, and juvenile delinquency. This study found that heroin users had bonelead levels higher than age-matched controls.

The study suggests an association between lead exposure and substance abuse

What is Drug Addiction?

Drug addiction is a worldwide epidemic, affecting millions of individuals across theglobe. Substance abuse and addiction can result in serious repercussions in medical,financial, legal, and social domains and cost our society roughly $193 billion annuallyin healthcare, crime and lost work productivity (NIDA, 2016).

NIDA: National Institute on Drug Abuse

Addiction is defined as a chronic, relapsingbrain disease characterized by compulsivedrug seeking and use, despite harmfulconsequences. It is considered a braindisease because drugs change the brain; theychange its structure and how it works.

These brain changes can be long lasting andcan lead to many harmful, often self-destructive, behaviors (NIDA, 2016).

o In 2014, there were anestimated 1.5 million currentcocaine users aged 12 or older

Cocaine Use

o Adults aged 18 to 25 yearshave a higher rate of currentcocaine use than any otherage group

https://www.drugabuse.gov/publications/research-reports/cocaine/what-scope-cocaine-use-in-united-states

Drug Addiction

How we can identifya relationshipbetween Pb2+-exposure and

predisposition todrug addiction?

Lead Exposure Paradigm

ControlPb2+

(1500 ppm)

MatingExposure

Birth WeaningSex & cull

PN-0 PN-21 PN-28 PN-50

BehavioralEndpoints

* *

Males Females

PN-28 Mean (µg/dL) ± S.E.MControl

Pb2+ 1500 ppm≤ 1.9ƚ (n=20)

20.38 ± 0.61 (n=25)≤ 1.9ƚ (n=18)

26.55 ± 1.55 (n=22)

Males Females

PN-50 Mean (µg/dL) ± S.E.MControl

Pb2+ 1500 ppm≤ 1.9ƚ (n=20)

19.8 ± 0.6 (n=25)≤ 1.9ƚ (n=18)

21.75 ± 1.55 (n=22)

Blood Lead Levels

60 minutes

-Habituation

i.p.

-Drug administration

- Saline- 5 or 15 mg/kgcocaine-HCl.

-Locomotor activity

60 minutesTotal distance travelled

Locomotor Activity

Acute locomotor responses arean indicator of drug sensitivity

Most drugs of abuse stimulatelocomotor behavior through activationof the dopaminergic circuits thatcontribute to their reinforcing effects(Wise 1987; Di Chiara 1995).

Cocaine typically increase motoractivity in two ways:

At lower doses (<20 mg/kg) , theambulatory activity is increased, this ismeasured as an increase in distancetraveled.

At higher doses (>20 mg/kg),locomotor behavior decreases andstereotypic behavior emerges, which ismanifested as an increase in sniffing,grooming, head bobbing, or otherrepetitive behaviors and a decrease indistance traveled.

n=15, 15, 15 n=14, 16, 17Two Way ANOVA, posthoc: BonferroniTreatment F 1,89= 5.049, p=0.027Drugs F 2,89 = 29.113, p≤0.001 Two Way ANOVA, posthoc: BonferroniTreatment F 1,76 = 7.496, p=0.008Drugs F 2,76 = 49.55, p≤0.001

n= 13, 13, 13 n=15, 15, 13

Locomotor ActivityPN-28

84% 60%

Locomotor ActivityPN-50

n=15, 15, 15 n=17, 17, 17

Two Way ANOVA, posthoc: BonferroniTreatment F 1,90= 7.664, p=0.007Drugs F 2,90= 57.539, p≤0.001

Two Way ANOVA, posthoc: BonferroniTreatment F 1,99= 3.608, p=0.060Drugs F 2,99= 61.511, p≤0.001

n= 18, 17, 18 n=17, 16, 19

55%

Lead Exposure and Drug Addiction

Summary

o Psychostimulant effects of cocaine are higher in lead exposed ratscompared to control

o Psychostimulant effects of cocaine are higher in adolescent lead exposedrats compared to adults

o In adults, the acute psychostimulant effects of cocaine are higher in malelead-exposed than females

o Lead exposed animals have a higher rate of cocaine self-administration

Substance use in adolescence is a key predictor of latersubstance use and related health consequences,including substance use disorders, mental illness, loweducational achievement, and incarceration (Aarons et al., 1999;Hall et al., 2016; Hussong et al., 2017).

Summary

Cocaine effect on the dopaminergic system

60 minutes

-Habituation -Locomotor activity

60 minutes

Total distance travelled

i.p.

-Drug administration

15 mg/kg cocaine-HCl.

SCH-23390(0, 0.05 or 0.1 mg/kg, i.p.)Raclopride(0, 0.05 or 0.1 mg/kg, i.p)

-15 min

D1-D2 Receptor Antagonist Treatment

D1 Receptor Antagonist, PN-28

n=10, 10, 10 n=10, 10, 10 n= 10, 10, 10 n=10, 10, 10

A

BB

B B

C

A

A

BB B B

[3H]-SCH23390 AutoradiographyMales and females, PN-28

D1R Males Females

Mean fmol/mg of tissue ± S.E.

Control n= 8Pb n =7

Control n= 7Pb n=6

StriatumControl

Pb

*, p= 0.0225107.4 ± 4.92127.1 ± 5.92

*, p=0.0127107 ± 3.72

120.6 ± 1.85

NAcControl

Pb

**, p= 0.0014104.6 ± 2.9126.3 ± 4.28

ns115.6 ± 5.74

130 ± 5.7

OTControl

Pb

***, p= 0.0002104.9 ± 4.95143.1 ± 5.48

**, p= 0.007112. 4± 7.4

151.4 ± 7.98


Summary

o Psychostimulant effects of cocaine are mainly mediated by D1Rin adolescent and adult rats

oD1R levels were increased in the STR, NAc and OT of PN-28 ratsand in the OT of PN-50 rats

oNo changes in D2R levels were detected in any of the brainregions at the ages

The Opioid Epidemic

Karila et al., 2019

The US Opioid Epidemic

https://www.hhs.gov/opioids/

The CDC estimates that the total "economic burden" of prescription opioid misusealone in the United States is $78.5 billion/year,

https://www.drugabuse.gov/drugs-abuse/opioids/opioid-overdose-crisis

The Opioid EpidemicUnited States

2000 2009 2016

Estimated Age-Adjusted Death Rate per 100,000

Source: National Center for Health Statistics, National Vital Statistics System, mortality dataRossen et al., 2017

Numerous studies have implicated all three opioid receptors inbehavioral effects including: analgesia, reward, depression, anxiety,and addiction.

µ,

Opioid Receptor mediated signaling

The most commonly used opioids for pain management act on μ-opioid receptor (MOR) systems.

[3H]-DAMGO AutoradiographyAnatomical Regions

https://instruct.uwo.ca/anatomy/530/ratpix.pdf

LPTN: Lateral post-thalamic nucleiVPM/VPL: Ventral posteromedial and lateromedialthalamic nucleusZID/ZIV: Zona Incerta (dorsal and ventral part)

[3H]-DAMGO Autoradiography PN-28

0 fmol/mg tissue

CONTROL Pb2+

208 fmol/mg tissue

https://instruct.uwo.ca/anatomy/530/ratpix.pdf

Striatum

[3H]-DAMGO AutoradiographyAnatomical Regions

0 fmol/mg tissue

CONTROL Pb2+

208 fmol/mg tissue

MALE

FEMALE


[3H]-DAMGO Autoradiography PN-28 MALES

Hypothalamus Thalamus BasolateralAmygdala

Striatum

Lateralposthalamic nuclei

Striamedullaris ofthe thalamus

Ventralposteromedial

thalamic nucleus

NucleusAccumbens

n=7-8*p<0.05 ,**p<0.01and ,***p<0.001

[3H]-DAMGO Autoradiography PN-28 FEMALES

Hypothalamus Thalamus BasolateralAmygdala

Striatum

Lateralposthalamic nuclei

Striamedullaris ofthe thalamus

Ventralposteromedial

thalamic nucleus

NucleusAccumbens

n=6-8*p<0.05 ,**p<0.01and ,***p<0.001

Summary

o Lead exposure increases the number of MOR in brain regionsthat are relevant to drug use and abuse in adolescent rats

o The increase in MOR makes it possible to increase thesusceptibility of lead-exposed experimental animals/humans tobe more sensitive/susceptible to opioid drugs

oCollectively, these studies suggest that exposure to lead mayincrease the susceptibility of drug use and abuse inadolescence and in young adults.

THANK YOU!


n=15, 14, 14 n=13, 12, 12 n= 11, 10, 12 n=10, 10, 10


D1R Males Females

Mean fmol/mg of tissue ± S.E.

Control n= 8Pb n =7

Control n= 7Pb n=6

StriatumControl

Pb

ns219.7 11.9231.9 8.4

ns243.7 ± 7.97229.8 ± 11.4

NAcControl

Pb

ns229.0 10.04249.8 12.30

ns222.8 ± 8.03226 ± 17.23

OTControl

Pb

**, p= 0.01198.3 11.9250.0 9.1

ns221± 11.5

214.7 ± 28.2


Cocaine effects on the Brain

Cocaine enhances dopamine-mediated neurotransmission by elevatingsynaptic levels of dopamine within the mesocorticolimbic pathway, the majorneuroanatomical circuit mediating drug reward.

This pathway originates from dopaminergic-containing cell bodies in theventral tegmental area (VTA) and projects to a number of forebrain areasincluding the frontal cortex, nucleus accumbens, caudate putamen, olfactorytubercle, hippocampus, and amygdala (Fallon and Moore, 1978).

What dopamine receptor subtype mediates thecocaine-induced increase in locomotor activity?

From Korpi et al., 2015

cAMP cAMP

Dopamine

How to study Drug Abuse using Animal models

REPEATED INTAKERECREATIONAL USE

Stable Self-administration

INITIALEXPERIMENTATION

ConditionedAversion

ConditionedPreference

AcuteLocomotion

Acquisition ofself

administration

COMPULSIVE DRUGSEEKING

Self-adminw/permutations

modelingcompulsion

Sensitization

Modified from Schramm-Sapyta et al., 2009

ATTEMPTEDCESSATION,

WITHDRAWALWithdrawalin animals

Opioid Receptor mediated signaling

Opioid peptides and their receptors are expressed throughout thenociceptive neural circuitry and in regions involved in reward andemotion-related brain structures.

MOR are of the most effective analgesics, they are alsoefficacious mood enhancers and cause activation of centraldopamine reward pathways that modulate euphoria.

Beyond the rewarding aspect of drugconsumption, pharmacological studies have alsosuggested a role for this receptor in themaintenance of drug use, as well as craving andrelapse

MOR mediated signaling

n=10, 10, 10 n=10, 10, 10 n= 10, 10, 10 n=10, 10, 10

A

A

A

A

A

AA A

A

B

A, B

A, B


[3H]-Raclopride Autoradiography,Males and Females, PN-28

https://epi.envirocenter.yale.edu/2018-epi-report/heavy-metals

Lead-Polluted Sites

Behavioral Sensitization

60 minutes-Habituation

-Drugadministration 15 mg/kg cocaine-HCl

i.p.

-Locomotoractivity

60 minutesTotal

distancetravelled

Repeated exposure to Cocaine canlead to a phenomenon calledsensitization, in which the ambulatory orstereotypic response to a repeated lowdose is augmented (Segal andKuczenski, 1992).

Sensitization is a manifestation ofneuroplastic changes in response torepeated exposure, and someresearchers have hypothesized that it isa behavioral correlate of increaseddrug craving and development ofdependence (Robinson and Berridge 1993,2000, 2001, 2008).

Sensitization represents a lastingneuroplastic change that is easilymeasured.

5 DAYSAbstinence 2 Days

Reinstatement

Two Way RM ANOVA, posthoc: BonferroniTreatment F 1,90=3.087, p= 0.096Days F 5,90=5.844, p<0.001

Two Way RM ANOVA, posthoc: BonferroniTreatment F 1,85=0.000135, p= 0.991Days F 5,85=10.231, p<0.001

Behavioral Sensitization,PN-28

Behavioral Sensitization,PN-50

Two Way RM ANOVA, posthoc: BonferroniTreatment F 1,90= 1.624, p=0.219Days F 5,90= 8.327, p<0.001

Two Way RM ANOVA, posthoc: BonferroniTreatment F 1,95=7.129, p=0.015Days F 5,95=22.034, p<0.001

Summary

o Developmental Pb2+ exposure increases the response to thepsychostimulant effects of cocaine in male and femaleadolescent rats

o Developmental Pb2+ exposure increases the response to thepsychostimulant effects of cocaine in male adult rats

o The enhancement of the cocaine-induced locomotor activity inPb2+ exposed rats is mainly mediated by D1R

o Developmental Pb2+ exposure could predispose to drug use inearly adolescence.

0 fmol/mg tissue

CONTROL Pb2+

208 fmol/mg tissue

MALE

FEMALE


[3H]-DAMGO Autoradiography

PN-28

Hypo Thal BLA

% increase 126 809 167p value 0.0778 0.0015 0.0024

Control n= 8Pb n = 7



LPTN SM VPM/VPL

% increase 104 205 235p value 0.0032 0.0026 0.0379

LPTN: Lateral post-thalamic nucleiSM: Stria MedullarisVPM/VPL: Ventral posteromedial and lateromedial thalamic nucleusZID/ZIV: Zona Incerta (dorsal and ventral part)

PN-28

PN-28

Hypo Thal BLA% increase 244 104 157

p value 0.0344 0.0023 0.042



LPTN SM VPM/VPL% increase 112 85 326

p value 0.0064 0.0653 0.025


LPTN: Lateral post-thalamic nucleiSM: Stria MedullarisVPM/VPL: Ventral posteromedial and lateromedial thalamic nucleusZID/ZIV: Zona Incerta (dorsal and ventral part)


PN-28


n=10, 10, 10 n=10, 10, 10 n= 10, 10, 10 n=10, 10, 10

[3H]-Raclopride Autoradiography,Males and Females, PN-50

0102030405060708090

100

74dB 78dB 82dB 86dB 90dB

% In

hibi

tion

PN28Control Male1500ppm Male

0102030405060708090

100


% In

hibi

tion

PN28Control Female1500ppm Female

Control: n=18; 1500ppm: n=19 Control: n=19; 1500ppm: n=19

dB Levels: F(2.56, 92.28) = 42.74; p<0.001Treatment: F(1,36) = 0.01; p=0.942dB Levels x Treatment: F(2.56, 92.28) = 0.17; p=0.888


020406080

100120140160

Control Male 1500ppm Male

Sta

rtle

Res

pons

e (m

V)

T-test (Two-Sample Assuming Unequal Variances): p= 0.462 T-test (Two-Sample Assuming Unequal Variances): p= 0.311

0

20

40

60

80

100

120

140

Control Female 1500ppm Female

Sta

rtle

Res

pons

e (m

V)

-100

102030405060708090

100


% In

hibi

tion

PN50Control Male1500ppm Male

0102030405060708090

100


% In

hibi

tion





T-test (Two-Sample Assuming Unequal Variances): p= 0.770 T-test (Two-Sample Assuming Unequal Variances): p= 0.861

0

50

100

150

200

250


Sta

rtle

Res

pons

e (m

V)

0

50

100

150

200

250


Sta

rtle

Res

pons

e (m

V)

0102030405060708090

100


% In

hibi

tion

PN120Control Male1500ppm…



T-test (Two-Sample Assuming Unequal Variances): p= 0.730

0100200300400500600700800


Sta

rtle

Res

pons

e (m

V)

0102030405060708090

100


% In

hibi

tion


dB Levels: F(2.82, 104.17) = 57.96; p<0.001Treatment: F(1,37) = 0. 02; p=0.878dB Levels x Treatment: F(2.82, 104.17) = 0.61; p=0.597

0

100

200

300

400

500


Sta

rtle

Res

pons

e (m

V)

T-test (Two-Sample Assuming Unequal Variances): p= 0.481

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Early Life Lead Exposure and Substance Abuse: is there a …. toms r. guilarte. universidad... ·...

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