Post on 14-Apr-2018
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NEUR 3306
Lecture 3
The neural basis of nicotine addiction
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Videos!First, some comedy.
Then, Nicotine A Love Affair
http://www.youtube.com/watch?v=23mjOOdRrfg
Question: Knowing what you (hopefully) knowabout the theories of addiction, why do people
smoke?
Nicotine. Priming Addiction Pathways.
http://www.youtube.com/watch?v=YXtzH54Qv5o
http://www.youtube.com/watch?v=23mjOOdRrfghttp://www.youtube.com/watch?v=YXtzH54Qv5ohttp://www.youtube.com/watch?v=YXtzH54Qv5ohttp://www.youtube.com/watch?v=23mjOOdRrfg7/27/2019 Lec 3 Sept 20 Slides
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Nicotine: Epidemiology
One of the most widely used psychoactive drugs Seemed to be on the decline:
~50 percent in 1965 to ~25 percent in 1998
However:
The number of smokers is expected toincrease to 1.6 billion people by 2025 as a
result of growth in adult population and
increased tobacco consumption
Smoking is the leading cause of preventabledeath - 4.3 million people worldwide die every
year as a result of cigarette smoking
Avg starting age declining
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1828: Nicotine isolated from tobacco (1 of ~4,000 compounds released
by burning)
Nicotine is a highly toxic, colorless,
volatile, liquid alkaloid; not well
absorbed from digestive tract
Nicotine is the addictive (reinforcing)
component in cigarettes (& others) Each cigarette contains 6-11 mg
nicotine; only 1-3 mg reaches the
blood
Also carbon monoxide and tar
What is Nicotine?
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Nicotine: Pharmacokinetics
Method of Administration:
Inhalation (8 seconds to brain) Effect on brain very rapid:
blood from capillaries in lungs
goes straight to left side of
heart and out to body
Absorption:
Nicotine suspended in smoke in the form of minute
particles; quickly absorbed from bloodstreamAmount of nicotine actually delivered depends on
how the cigarette is smoked
Only about 20% (~0.5-2 mg to brain) of nicotine
in a cigarette is actually inhaled and absorbed
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Nicotine: Pharmacokinetics
Metabolism: Liver metabolizes 8090 percentbefore excretion by kidneys
Nicotine is metabolized by the hepatic (liver)
enzyme CYP2A6
Smoking increases the cytochrome P450
enzymes, which also metabolize antidepressants
and caffeine (enzyme induction)
Elimination half-life is ~2 hours Major metabolite is cotinine,
which is basis for tests
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Behavioural Effects
Mild euphoria
Increased energy
Heightened arousal
-HR increases by 5-40 bpm
BUT reduced stress/anxiety
-Nesbitts paradox: more
arousal but less emotion
Reduced appetite
Improved attention/cognition
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Nicotinic Receptors
The receptors always
contain 2 (or more) subunits, which are
critical in nicotine binding
The binding site is
comprised of a dimerformed by the subunits
(principal component)
plus an adjacent subunit
Binding to both sites
required for channel to
open
Pentameric ligand-
gated ion channels
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Nicotinic Receptors Lots of diversity in neural nAChRs, with 2
through 10 and 2 through 4 subunitsidentified in brain tissues
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42 nAChRs play central role inaddiction highest affinity
Can incorporate other subunits
Genetic KO no nicotinereinforcement
2 KO no VTA DA release restored by reintroduction
4 hypersensitivity nicotine CPP Divergent expression patterns (on
DA vs GABA vs Glu neurons) may
play role in addiction
nAChRs
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Nicotine: Where? The primary neural pathway for nicotine
reinforcement = mesocorticolimbic dopamine
tract: DAergic axons project from cell bodies in
VTA to NAc and PFC
6-OHDA lesions,
antagonism of DA
eliminate
reinforcing
effects
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Video
Nicotine: The physiologic mechanism of tobacco
dependence
http://www.youtube.com/watch?v=yd46Hs7pTo
w
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Measuring nicotine motivation
Intracranial self stimulation (ICSS)- nicotine withdrawal produces dose-
dependent increase in brain reward
thresholds (decreased reward)
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Conditioned place aversion
Animals will avoid the environment paired
with nicotine withdrawal
Motivational withdrawal separate from
somatic withdrawal
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Self-administration
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Conditioned Taste Aversion
Selectively samples the aversive properties of
a drug
Drug Vehicle
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Acute nicotine: Pharmacodynamics
**VTA**
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DAergic activation by tobacco smoke
VTA
SN
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But, some say the TPP is important
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Dual motivational effects of acute
nicotine Lav & VDK
All studies showing DA involved in acute
nicotine reward were because of TPP
mediated GABA inhibition of DA release
Or, for SA studies, the animal was dependent
mediated by DA
Reward = GABA (TPP)
Aversion = DA
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DifferenceScore
Intra-VTA nicotine dose (nmol/hemisphere)
Control
Neuroleptic
TPP lesion
Acute Nicotine Motivation
300
200
100
0
-100
-2000
0.
0008
0.
008
0.
08
0.
8
2
8
24
48
80
Control
Neuroleptic
TPP lesion
Preference (+)
Aversion (-)
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Dependence
Withdrawal symptoms inhumans:
High irritability
Malaise
Craving
Somatic withdrawal symptoms in rats:
Paw tremor/wet dog shakes
Rearing/jumping
Ptosis
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Laviolette & van der Kooy
Nondependent
Dependent
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Alternative: Chronic nic Long-term
reduction in baseline DA signaling
BUT both agonist & antagonist reduce craving
DA neurons fire in two characteristic states:
-Phasic (bursting)
-Tonic (baseline)
Top: Sal (ctrl)
Acute nic
Chronic nic
Bottom: Nic WD
2mV
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0
1
2
3
4
5
Saline
Control
Acute
Nicotine
Nicotine
Dependent
Nicotine
Withdrawal
To
nicfiring
(Hz)
Tonic DA activity
*
Nicotine dependent mice: decrease in tonic firing
- further decreased in rats undergoing withdrawal
from chronic nicotine
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Chronic nicotine and withdrawal did not alter
phasic firing, while acute nicotine increased phasic
activity in DA neurons
010
20
3040
50
Saline
Control
Acute
Nicotine
Nicotine
Dependent
Nicotine
Withdrawal
B
ursts/mi
n
Phasic DA activity
*
Ch i i i (d d d
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-300
-250
-200
-150
-100
-50
0
50
100
Vehicle D1R
agonist A-77636
D1R
antagonistSCH23390
D2R
agonistQuinpirole
D2R
antagonistEticlopride
Diff
erenceScore
Chronic nicotine (dependent and
withdrawn)
* *
Therefore withdrawal is signaled by a specific PATTERN
of tonic DA activity at D2Rs
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DA Rs
DA Rs (mostly D2) upregulated in brains ofsmokers
Antagonism of D2Rs (or D2R KO) prevents CPA to
nicotine withdrawal Blockade of D3 Rs prevented drug-induced
relapse to nicotine seeking role in craving
PATTERN of DA release onto Rs
Signal of dependence/withdrawal?
Ad i DA i t ti
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Adenosine-DA interactions
DA D2Rs and
adenosine A2ARs are
colocalized as
antagonistic allosteric
receptorheterodimers on
neurons within the
mesolimbic DA system
Effect on pattern
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nAChRs (Penton & Lester)
Single nucleotide polymorphisms (SNPs)
within the 3-5-4 gene cluster located on
chromosome 15
Correlate with nicotine intake
Genetic factors at the level of nAChRs may
predispose certain individuals to nicotine
addiction
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Volkow et al.
3 5 4
Increased risk
of nicotine
dependence
Lung cancer
Peripheral
arterial
disease
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Upregulation of nAchRs
Long-term exposureto nicotine
increases number of
nAChRs in the brain Correlation between
increased number
of receptors andamount of nicotine
exposure
Not permanentLighter = more binding
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High affinity nAChR upregulation
Concentration of nicin smokersbloodstreamselectivelyupregulates HS overLS nAChRs black line
Assembled R divertedfrom degradativepathway (green line)
Further stabilizationmay occur (red line)
GABA VTA neurons
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Also some data showing 6 (and others like 3
and 7) upregulation
Requires high nic concentrations because
lower affinity of Rs
Chronic nic downstream changes in Ca and
K channels, systems that degrade proteins, Ca
flux
General conclusion: All these things lead to a
decreased output of DA!!
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Review: Glutamate Rs
Ionotropic: 3 typesAMPA, NMDA, Kainate
Metabotropic Glu Rs (mGluRs) - 8 subtypes withdifferent functions (activate, inhibit; presynaptic,postsynaptic)
- G-protein coupled (slower acting)
- Widespread, differential distribution subtlealteration in glu transmission, no big side effects
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Markou
Avoidance of WD (and positive subjective
effects) motivates nicotine use
Nic enhances rewarding properties of other
stimuli (more so than other drugs of abuse)
Learning (about predictive stimuli) contributes
to nicotine seeking
/
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PFC NAc
VTAAmyg
24 hr WD from nicmGlu2/3 receptor downregulation
Nic = black, food = white
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mGlu2/3 Rs = inhibitory autoreceptors control glutamate release
Decrease in mGlu2/3 R function indicates impairednegative feedback control on glu terminals possibly to counteract the decreased glutransmission characterizing nic WD
Single injection of Glu2/3 R antagonist attenuatedbrain reward threshold elevations observed in ratsundergoing nic WD
24 hrs WD increased ionotropic Glu Rs in VTA,amygdala, NAc compensation for decreased glu
BUT decreased in PFC different brain sites for
different aspects of WD/dependence
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GABA
Ionotropic R = GABAA
Metabotropic R = GABAB
Both inhibitory, found pre & postsynaptically
Increased GABA transmission by GABAB R
antagonism decreases nic reward.BUT side effects (locomotion, anhedonia)
Penton & Lester came after (nAChR stuff)
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Ray, Schnoll, & Lerman Reward = VTA DA, disinhibition of GABA,
upregulation of glu Rs
Upregulation of 7 & 42 nAChRsmore DArelease, decreased DA during WD
Abstinence increased unbound nAChRs-correlated with urges-returned to normal after 3 weeks
Increases or decreases in PFCactivity-dependent on region ACC &OFC showed activation during
craving decision-making
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Genetics
Genetics 56-70% for dependence
Environmental factors important too:
CYP2A6 enzymemetabolizes nicotine
-Genetic WTs = fast metabolizers smoke
more, less likely to quit
Also associations with DA R, transporter,
enzyme genes, opioids, others
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Stress (CRF)
Extended amygdala (CeA, BNST, NAc) and
projections
Allostasis
Withdrawal
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CRF antagonist in CeA blocks nic WD
CRF antagonist in VTA blocks WD (not reward)
-300
-200
-100
0
100
200
300
a-process b-process
D
ifferencescore(s) Vehicle
CRF1R antagonist
*
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CRF mRNA is expressed in DAergic VTA neurons
Electrophys shows increased GABAergic firing
Link between brain stress and brain reward systems!
CRF administration decreases VTA DA firing
d d l f h l
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An integrated model of the neural
basis of nicotine addiction?