Transcript Exercise - Virginia Commonwealth University

Exercise as an Intervention and
Prevention Strategy for
Nicotine Use in Adolescents
Darlene H. Brunzell, Ph.D.
Associate Professor of Pharmacology and Toxicology
Virginia Commonwealth University
Wendy Lynch, Ph.D.
Associate Professor of Psychiatry
University of Virginia
Why Study Exercise as
a Cessation Strategy
During Adolescence?
 A healthy option to pharmacological therapies that may
affect development of the adolescent brain
 Nicotine and exercise regulate similar hormones and
signaling pathways suggesting an overlap of these two
systems
 Potential secondary benefit to prevent obesity, the
second leading preventable cause of death
Why Study Sex
Differences in
Nicotine Use During
Adolescence?
 Adolescent males and females are different
 Most individuals initiate smoking during their teens
 The hormone transition phase during adolescence may
provide insight into biological basis of sex differences
in smoking behavior observed in adults
Rat Nicotine Self
Administration as a Model
for Adolescent Smoking
• Like humans smokers, rats
voluntarily self administer
nicotine
• Similar to smoking, i.v.
administration of nicotine
provides fast delivery of the
drug to the brain
• Rodents have similar
circulating hormones, brain
areas, and neurotransmitters
thought to control smoking in
humans
Behavioral Studies
Nicotine Use
Females > Males
Nicotine Abstinence
Exercise
Nicotine Seeking
Males?
NIC versus SAL
Wheel versus Sedentary
Females?
Extinction
?
Wheel running
prevents nicotine
Nicotine-Seeking:
Resultsseeking?
Sanchez et al. 2014 Psychopharmacology
•
Males: Exercise attenuates
nicotine-seeking during
extinction
•
Females: Low levels of
nicotine-seeking under both
unlocked and locked wheel
conditions.
Wheel running prevents nicotine seeking
Sanchez et al. 2014 Psychopharmacology
•
Males: Exercise attenuates
nicotine-seeking during
extinction
•
Females: Low levels of
nicotine-seeking under both
unlocked and locked wheel
conditions.
•
Wheel access attenuates
nicotine-seeking in females
Adolescent females rats were more
active than males during wheel access
Number of wheel rotations
Female NIC
Male NIC
10000
5 mg/kg
Female SAL
Male SAL
10 mg/kg
PND 45-56
Exercise
Wheel
2 hr/day
8000
6000
4000
2000
0
1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10
Age (Postnatal Day)
…but exercise-dependent decreases in nicotine
seeking were not individually correlated with
level of exercise
Number of Lever Presses
200
Female NIC r = 0.01
Male NIC r = 0.18
PND 57
Extinction of
Nicotine
SA
150
100
50
0
0
5000 10000 15000 20000
Wheel Rotations
A little exercise can go a long way
30 minutes of structured exercises 3 to 4 times a week
can improve health and promote weight loss. Those who
include exercise in their daily routine not only lose
weight quicker but are more likely to keep the weight
off.
Mechanistic Studies
Cytokines, Neurotransmitters, Growth Factors and
Second Messengers Regulated by
Nicotine and Exercise
Species
Neurochemical
Agent
Mediated by
Exercise
Associated with
Nicotine
Use/Dependence
Human
Cytokines
TNF-a, IL6
IL2, IL6,
Growth Factors
BDNF
Trk2 (BDNF) receptors
Neurotransmitters
Dopamine
Dopamine, Glutamate
transporter
Second
Messengers
ERK (skeletal muscle)
ERK (epithelial lung
cells)
Cytokines
TNF-a, IL1b, IL6
TNF-a, IL1, IL10, IL12
Growth Factors
BDNF, NGF, VGF
BDNF, FGF2
Neurotransmitters
Dopamine, Glutamate
Dopamine
Second
Messengers
ERK, CREB
ERK, CREB
Rodent
Mesocorticolimbic Dopamine Pathway
Supports the Reinforcing Effects of
Nicotine
Prefrontal Cortex
(PFC)
Nucleus
Accumbens
(NA)
Ventral Tegmental
Area (VTA)
What are the changes in intracellular
signaling that support nicotine-associated
neural plasticity
Prefrontal Cortex
(PFC)
Nucleus
Accumbens
(NA)
Ventral Tegmental
Area (VTA)
Exercise and nicotine affect neurotransmitters and
neurotrophins that converge on the Extracellular
Regulated Kinase (ERK1/2) signaling pathway
Dopamine
BDNF
CREB
Brunzell, Drug Abuse Handbook, 2007
Is ERK activation necessary for nicotine-associated
changes in Signaling and Behavior?
U0126
Brunzell, Drug Abuse Handbook, 2007
Nicotine Use
NIC versus SAL
Nicotine Abstinence
Wheel versus Sedentary
Extinction
Does ERK 1/2 in the NAc shell regulate
nicotine use following protracted abstinence?
Pre-Abstinence
Post Nicotine-Abstinence
Modified from Korhonen et al, Tobacco Induced Disease 2005
Modified from Bedi et al, Biological Psychiatry 2011
20
BDNF?
ERK?
Exercise as a prevention strategy for nicotine use
Exercise
Nicotine Use
Males?
Wheel versus Sedentary
?
NIC versus SAL
Acquisition: Experimental Design
PND 22
28
45
30
Acclimation
Surgery Exercise: 2-hr/day prior to self-administration
Acquisition testing: FR-1schedule, 21-hr/day
•
Exercise: unlocked running
•
Sedentary:
(1) locked wheel access
(2) no wheel access
Acquisition: Results
A locked wheel does not
affect acquisition
Sanchez et al, 2015 Drug and Alcohol Dependence
Exercise significantly reduced
nicotine reinforcement in male rats
A locked wheel does not
affect acquisition
Exercise robustly
decreases acquisition
Sanchez et al, 2015 Drug and Alcohol Dependence
Exercise reduced motivation to
self-administer nicotine
Exercise had robust and persistent
effects on motivation for nicotine
Higher levels of exercise were
associated with greater decreases in
motivation for nicotine
Sanchez et al, 2015 Drug and Alcohol Dependence
Does Exercise During
Adolescence Protect
Against Tobacco Use?
• Exercise is an effective intervention and prevention strategy to
reduce nicotine use during adolescence
• Exercise and nicotine regulate ERK in the brain areas that
support tobacco dependence
Acknowledgements
Collaborators/Consultants
Wendy Lynch
Edmund Acevedo
Justin Polkis
Brunzell Lab
Karen Boschen
Yun Ding
Jennifer Lee
Lauren Thompson
Lynch Lab
Florence Breslin
Vivian Hofler
Victoria Sanchez