lec 3 sept 20 slides

7/27/2019 Lec 3 Sept 20 Slides

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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=23mjOOdRrfg


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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?

lec 3 sept 20 slides

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