Alcohol and AdolescenceAlcohol and Adolescence

Linda Patia SpearBinghamton University

Edited by:Susan Tapert

Univ. of California at San Diego

Adolescence

• Transition between childhood/immaturity and adulthood/maturity

• Timing varies (nutrition, gender, genetics, environment)

• Soft signs: no events signal onset/offset• Prototypic age ranges:

• Humans: 12-18 yrs (early as 8; late as 25)• Rats: 28-42 days (early as 23; late as 55+) • Primates: varies with species

(“older juvenile” and early “subadult” stages)

• Highly conserved physiological transitions and behavioral characteristics

Physiological ChangesPhysiological Changes During AdolescenceDuring Adolescence

HormonalHormonal Body size and Body size and CharacteristicsCharacteristics

Neural Neural AlterationsAlterations

AdrenarcheAdrenarche(early)(early)

adrenal adrenal androgensandrogens

GonadarcheGonadarche(puberty)(puberty)

LH, FSH,LH, FSH,estrogen,estrogen,

testosteronetestosterone

OtherOtherGH andGH and

stress-inducedstress-inducedcorticoidcorticoid releaserelease

Gray Matter Maturation

(Gogtay et al., 2004, Proc. Natl. Acad. Sci.)

Forebrain Changes in Adolescents

• Prefrontal cortex (PFC)– Reduced excitatory drive (humans, primates, rodents)– Decrease in PFC volume (humans & rodents)– Peak of DA innervation (humans, primates, rats)– High DA turnover early followed by decline (rats)

• Nucleus accumbens– Low DA turnover early followed by increase (rats)

• Hippocampus sprouting and myelination (humans, rodents)

• Amygdala activity (humans, rodents) and PFC connectivity

(rodents)

• Ventral pallidum / olfactory tubercles oxytocin receptor binding (rodents)

• Relationship to hormonal reawakening of puberty?

• Support continued cognitive/emotional development

• Facilitate highly conserved adolescent behaviors social interactions with peers risk-taking, novelty-seeking, sensation seeking

Functional Consequences of Adolescent Brain Sculpting

Ancillary Consequence of Adolescent Brain Sculpting

Altered sensitivity to alcohol/drugs• Multiple neural systems affected by ethanol

differ ontogenetically between adolescents and adult

-Altering ethanol sensitivity and adaptations

-Possibly increasing propensity for use

Adolescent alcohol intakeM

ean

drin

ks/o

ccas

ion

(SAMHSA Survey data, 2003)

Male Female0

2

4

6

8

10

12

12-20 yrs

21 and over

Humans

Male Female

g/kg

EtO

H I

ntak

e

0

2

4

6

8

10

12 Adult

Adolescent

Rats

(Doremus et al. 2005)

• Lessened sensitivity to ethanol-induced:– Sedation

– Dysphoria

– Social inhibition

– Motor impairment

– Anxiolytic effects

– Analgesia

– Hangover effects

Adolescent-Related Alterations in Ethanol Sensitivity:

Ethanol Sedation

5.04.54.03.500

100

200

300

400

500

600

Dose of Ethanol (g/kg)

Rec

over

y T

ime

(min

)

Adults

Adolescents

(Silveri & Spear, 1998)

• Lessened sensitivity to ethanol-induced:– Sedation

– Dysphoria

– Motor impairment

– Hypothermia

– Social inhibition

– Analgesia

– Hangover effects

Adolescent-Related Alterations in Ethanol Sensitivity:

Pharmacokinetics?

Rate of Ethanol Metabolism

P16 P26 P36 P560

10

20

30

40

50

60

Age

mg/

dl/h

r

P16 P26 P36 P56

BEC-derived BrEC-derived

(Silveri & Spear, 2000)

• Greater sensitivity to ethanol-induced:– Impairment in LTP and

spatial water maze performance

– Facilitation of social behavior

• Lessened sensitivity to ethanol-induced:– Sedation

– Dysphoria

– Social inhibition

– Motor impairment

– Anxiolytic effects

– Analgesia

– Hangover effects

Adolescent-Related Alterations in Ethanol Sensitivity:

Alcohol and Spatial Learning

Adolescent Adult

Saline1.0 g/kg EtOH2.0 g/kg EtOH

0

5000

10000

15000

20000

25000

30000

35000

Dis

tanc

e S

wam

to

Crit

erio

n (c

m

SE

M)

(Markwiese et al., 1998)

Ethanol-Induced Social Facilitation

0 0.25 0.5 0.75 1 2 3 4

Dose of Ethanol (g/kg)

Fre

qu

ency

/ 1

0 m

in

0

20

40

60

80

100

120

Overall Social Activity

(Varlinskaya & Spear, 2001)

0 0.5 2 3 0

30

60

90

120

150

Dose of Ethanol (g/kg)

Fre

quen

cy /

10

min

0 0.5 2 3

Partner Cotton ball

Overall Activity

(Varlinskaya & Spear, 2001)

Familiar Social Situation

0

20

40

60

80

100

Dose of Ethanol (g/kg)

Fre

quen

cy /

10

min

0 0.25 0.5 0.75 1

Adolescents

*

0 0.25 0.5 0.75 1

Adults

*

*

(Varlinskaya & Spear, 2002)

• Greater sensitivity to ethanol-induced:– Impairment in LTP and

spatial water maze performance

– Facilitation of social behavior

• Lessened sensitivity to ethanol-induced:– Sedation– dysphoria– Social inhibition– Motor impairment– Anxiolytic effects– Analgesia– Hangover effects

opiate + NMDA-R function GABAAR immaturity

Adolescent-Related Alterations in Ethanol Sensitivity:

Acute Tolerance

Time

Blo

od E

than

ol C

once

ntra

tion

(Mellanby, 1919)

Acute Tolerance: Sedation

P16 P26 P36 P46 P56 P96

-5

0

5

10

15

20

25

30bloodbrain

Postnatal Day (P)

Slo

pe

of R

eg

ress

ion

(alc

oh

ol l

eve

l ve

rsu

s d

ose

)

(Silveri & Spear, 1998)

Do Human Adolescents Differ from Adults in Alcohol Sensitivity?

• Increased sensitivity: – to alcohol-induced memory impairment?

Alcohol effects on performance of:

placebo 0.6 g/kg7

8

9

10

11

12

13

14

15

16

17

18T

otal

Cor

rect

(+

/- S

EM

)Complex Figures Task

placebo 0.6 g/kg5

6

7

8

9

10

11

12

13

Verbal Learning Test

21-24 yr.25-29 yr.

(Acheson et al, 1998, Alcoholism: Clin.Exp.Res., 22:1437-1442.)

Do Human Adolescents Differ from Adults in Alcohol Sensitivity?

• Increased sensitivity:

– to alcohol-induced memory impairment?

– to alcohol-induced social facilitation?

Drinking for Social Facilitation

• “…the literature suggests that most students drink for primarily social purposes…” (Berkowitz & Perkins, 1986)

• Principle components analysis of HS survey data revealed:

“the most important factor across all of the measures of alcohol abuse was drinking for social facilitation” (Beck et al, 1993)

• Less sensitivity to motor impairing/ intoxicating effects?

Do Human Adolescents Differ from Adults in Alcohol Sensitivity?

• Increased sensitivity:

– to alcohol-induced memory impairment?

– to alcohol-induced social facilitation?

Reduced Alcohol Sensitivity

• First intoxicating experience of boys– 8-15 yrs old; 0.5 ml/kg; peak BAC 34-35 mg%– No significant consequences: clinically, subjectively, or on

objective test

• “…these children exhibited a smaller behavioral change than expected for their BAL”

• “None behaved grossly ‘intoxicated’ as our adult…subjects were”

• “We were impressed by how little gross behavioral change occurred in the children…after a dose … intoxicating in an adult population.”

(Behar et al., 1983)

Drinks/occasion and use days/month

12-2021 and over

Female

drinks/occasion days used0

2

4

6

8

10

12

Avera

ge N

um

ber 12-20

21 and over

Male

drinks/occasion days used0

2

4

6

8

10

12

SAMHSA Survey Data (2003)

How Might Adolescent Alcohol Sensitivity Contribute to Problems?

• Decreased response to alcohol is a risk factor: – “lower sensitivity to moderate doses of alcohol is associated

with a significant increase in the risk of future alcoholism, perhaps through increasing the chances that a person will drink more heavily…” (Schuckit, 1994)

• Lowered sensitivity to alcohol seen:– Developmentally: in adolescence– Genetically: in offspring with family history of alcoholism– As function of history/environment:

• prior ethanol use (tolerance)• early experience?• stress during adolescence?

Together, may serve as permissive factors to promote

high levels of adolescent alcohol use

• Yet, adolescents more sensitive to alcohol-induced disruptions in memory and brain

How Might Adolescent Alcohol Sensitivity Contribute to Problems?

• Alcohol-induced social facilitation may encourage elevated drinking of adolescents

Adverse Effects

• Impact on functioning during adolescence: – Greater sensitivity to alcohol-induced disruptions

• Memory • Brain plasticity

– Mutual synergism: alcohol risk-taking – Circumvention of normal developmental tasks?– Increased level of stress?

• Lasting consequences:– Lasting neurocognitive consequences?– Increased susceptibility to alcohol use disorders?

Lifetime Prevalence of Alcohol Dependence by Age at First Drink

0

10

20

30

40

50

60

Age at First Drink

MalesFemales

3028262422201816141210

%

[Prescott & Kendler (1999)ACER, 23, 101-107]

Early alcohol use as marker vs. causality?

Alcohol Withdrawal & Spatial Skills

(Tapert & Brown, 1999)

30

35

40

45

50

55

60

Treatment (ns)

4-Year Follow-Up(p<.01)

Vis

uo

sp

ati

al T

-sc

ore

Good treatmentoutcome(n=32)

Post-txwithdrawal(n=48)

Ethanol-Induced Brain Damage

(Crews et al., 2000)

Silv

er-S

tain

ed

Are

a

Adolescent Adult0

200

400

600

800Anterior Piriform

0

200

400

600

Adolescent Adult

Olfactory Tubercle

Adolescent Adult0

250

500

750

1000

Middle Piriform

ControlEthanol

Adolescent Adult0

200

400

600

800Posterior Piriform

Adolescent Adult 0

200

400

600

Anterior Perirhinal

Adolescent Adult0

1000

2000

3000

4000

Entorhinal

Summary• Adolescence:

– Highly conserved period across species– Numerous brain and behavioral similarities

• Adolescents exhibit:– Age-related neural alterations and enhanced acute tolerance

associated with:– Less sensitivity to alcohol cues that moderate drinking– Greater sensitivity to ethanol-induced social stimulation and

disruption in brain plasticity and memory

• Attenuated sensitivity to ethanol effects:– May permit relatively high alcohol intake in adolescence– Potentially lead to adverse consequences during and after

adolescence