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Pharmacology For the Addiction Professional
The Neuroscience of Addiction 2014:
The Anti-Reward Brain System – Part 3
Dr. Merrill Norton Pharm.D.,D.Ph.,ICCDP-D Clinical Associate Professor University of Georgia College of Pharmacy Athens, Georgia [email protected] Merrill Norton Pharm.D.,D.Ph.,ICCDP-‐D 1
Marijuana Spect Scans
Dr. Merrill Norton Pharm.D.,D.Ph.,ICCDP-D 2
With Permission Amens Clinics
4 Years 7 Years 9 Years 12 Years
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Stimulant Spect Scans
Cocaine Use 3 years Methamphetamine Use 1 Year
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Opioids Spect Scans
Normal Brain- 25 years old Hydrocodone 3 Years
Oxycodone 2 Years
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Alcohol Spect Scans
Alcohol Use of 7 Years
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prolonged drug use changes!the brain in fundamental!
and long-lasting ways!
Science has generated much!evidence showing that… !
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DA
D2
Rec
epto
r Ava
ilabi
lity
Control Addicted
Cocaine
Alcohol
DA!
DA!DA! DA !DA !
DA!
Reward Circuits
DA !DA ! DA !DA !
DA !
Reward Circuits
DA!
DA!
DA!
DA! DA !
DA!
Drug Abuser
Non-Drug Abuser
Heroin
Meth
Dopamine D2 Receptors are Lower in Addiction
DA!
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Dopamine Transporters in Methamphetamine Abusers
Normal Control
Methamphetamine Abuser
Motor Task!Loss of dopamine !transporters in the meth !abusers may result in !slowing of motor !reactions.!
Memory task!Loss of dopamine transporters !in the meth abusers may result !in memory impairment.!
7 8 9 10 11 12 13 1.0 1.2 1.4 1.6 1.8 2.0
Time Gait (seconds)
4 6 8 10 12 14 16 1.0 1.2 1.4 1.6 1.8 2.0
Delayed Recall (words remembered)
Dop
amin
e Tr
ansp
orte
r B
max
/Kd
Volkow et al., Am. J. Psychiatry, 2001. .!7/2/14! 8!Dr. Merrill Norton Pharm.D.,D.Ph.,ICCDP-D!
Implication:!
Brain changes resulting from !prolonged use of drugs !
may compromise !mental and motor functions
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Definition of Cross Addiction � When we give up the drug of our choice, a void is
created. The initial struggle to abstain from marijuana use often leaves us vulnerable. To fill this void we may start to use, or increase the use of, other substances such as alcohol, cocaine, pills, or other self-prescribed drugs. Although we may not now be addicted to these substances, their use can lower our inhibitions, leaving us open to repeating old patterns of thinking and behaving that can lead back to marijuana use. The fact that we became addicted to marijuana reflects a tendency towards behavior that may lead to cross addiction or substitution addiction to these substances.
� Marijuana Anonymous Literature
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Progression of Drug Dependence
From: Heilig M and Koob GF, Trends Neurosci, 2007, 30:399-406.
Stages of the Addiction Cycle
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Neurobiology of Addiction
Koob, G. F. and Volkow. N. D. Neurocircuitry of Addiction, Neuropsychopharmacology reviews 35 (2010) 217-238
Converging Acute Actions of Drugs of Abuse on the Ventral Tegmental Area and Nucleus Accumbens
From: Nestler EJ, Nat Neurosci, 2005, 8:1445-1449.
Cross Addic*on
• Many people who begin the process of becoming clean and sober cling to the idea that they can con*nue to hold on to some parts of their drinking/using lifestyle, especially their friends who might s*ll be using.
• Though each class of addic*ve drugs has its own unique area, or nucleus, in which it exerts its ac*ons, there is a common nerve pathway that acts to increase the release of dopamine in the pleasure center of the brain, following the use of any of these drugs. Interes*ngly, the pleasure center of the brain is a group of nuclei located in the same area in which the drive for survival resides. The nucleus accumbens and the Ventral tegmental areas are the primary sites responsible for dopamine release causing pleasure and relaxa*on. This release of dopamine in the reward center of the brain creates a desire, or reinforcement to repeat a par*cular ac*vity. In the same fashion that certain pleasurable ac*vi*es cause a surge of dopamine, drugs of abuse in certain individuals trigger a far greater release and/or response to the dopamine release. We think this is one reason some people may be more predisposed to addic*ve behavior than others.
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Merrill Norton Pharm.D.,D.Ph.,ICCDP-D
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The Nervous System!§ Neural Networks!
§ interconnected neural cells !
§ with experience, networks can learn, as feedback strengthens or inhibits connections that produce certain results !
§ computer simulations of neural networks show analogous learning!
Inputs Outputs
Neurons in the brain connect with one
another to form networks
The brain learns by modifying certain connections in response to feedback
Cross-addiction can occur by different mechanisms. A person in solid alcohol recovery, for instance, may go to the dentist and be prescribed some pain medicine along with an antibiotic. He may take this exactly as prescribed thinking nothing of it. He may then, without considering what is happening, begin to increase the dosage and/or frequency of the medication and may even seek a refill although the pain does not warrant a narcotic. This person, who was previously doing well as a recovering alcoholic may be on the path to developing a dependency on narcotics or, at very least, is on a slippery slope for an alcohol relapse.
Memory
• Memory – persistence of learning over time via the storage and retrieval of information
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Memory • Encoding
– the processing of information into the memory system
• Storage – the retention of encoded information over time
• Retrieval – process of ge;ing information out of memory
The Modal Memory System
Stage 3: Long Term Memory
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Explicit Memory
• Explicit memory involves the processes used to remember specific information which can be declared
• Episodic memory is personal
• Semantic memory involves knowledge of facts
Implicit Memory • Implicit memory is the pervasive process by which people show without awareness that they are remembering something
• Implicit memory does not require a;ention and is automatic
• Consider “procedural memory”
• Repetition priming
Retrieval • Recall – retrieve information learned earlier
• Recognition – identify items previously learned
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Amnesia
• Retrograde Amnesia – Loss of past memory
• Anterograde Amnesia – Can’t form new memories Anterograde Amnesia
Merrill Norton Pharm.D.,D.Ph.,ICCDP-D
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The Nervous System!§ Neural Networks!
§ interconnected neural cells !
§ with experience, networks can learn, as feedback strengthens or inhibits connections that produce certain results !
§ computer simulations of neural networks show analogous learning!
Inputs Outputs
Neurons in the brain connect with one
another to form networks
The brain learns by modifying certain connections in response to feedback
Cocktail Party Phenomenon
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Cross addiction or Cross-tolerance means that when you develop a tolerance to a drug you will also have a tolerance to closely related drugs--but not to totally dissimilar drugs. The more closely related the two drugs are the stronger the cross tolerance effect will be. For example, Valium, Librium, Xanax, Ativan and Klonopin are all closely related drugs which belong to the benzodiazepine family of drugs. These drugs all affect the GABA receptors in your brain. If you become addicted to any one of these benzodiazepines then you can substitute any other because there is cross-tolerance. Since alcohol also affects GABA receptors there is some cross-tolerance with alcohol but not as much with each other since alcohol affects many different receptors. However you cannot substitute heroin for Valium because heroin does not affect the GABA receptor. There is no cross tolerance between heroin and Valium.
Brain Reward Pathways
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Memories Appear to Be A Critical Part of Addiction!
“Its about people, places and things…”!
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Cocaine Film
Cocaine Craving: Population (Cocaine Users, Controls) x Film (cocaine, erotic)
Garavan et al., Am. J. Psychiatry, 2000.
IFG
Ant. Cing.
Cingulate
Sign
al In
tens
ity (A
U)
Cocaine FilmErotic Film
Controls Cocaine Users 7/2/14! 31!Dr. Merrill Norton Pharm.D.,D.Ph.,ICCDP-D!
Drugs Are Usurping ! Brain Circuits!
and !Motivational ! Priorities
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Drugs!
Brain Mechanisms!
Behavior!
Environment!
Historical!
Environmental!
- Prior experience - Expectation - Learning!
- Social interactions- Stress- Conditioned stimuli!
- Genetics- Circadian rhythms- Disease states- Gender!
Physiological!
Drug Addiction: A Complex Behavioral and Neurobiological Disorder!
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Source: Adapted from Volkow et al., Neuropharmacology, 2004.!
Drive Saliency
Memory
Control
Non-Addicted Brain
NOT GO
Addicted Brain
Drive
Memory
Control
GO Saliency
Addiction Changes Brain Circuits!
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Full recovery is a challenge but it is possible …!
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The Neurochemistry of Recovery and Discovery
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Dr. Merrill Norton Pharm.D.,D.Ph.,ICCDP-‐D 37
ANTI-‐REWARD The concept of an an*-‐reward system was developed to explain one component of *me-‐dependent neuroadapta*ons in response to excessive u*liza*on of the brain reward system. The brain reward system is defined as ac*va*on of circuits involved in posi*ve reinforcement with an overlay of posi*ve hedonic valence. The neuroadapta*on simply could involve state-‐shiNs on a single axis of the reward system (within-‐ system change; dopamine func*on decreases). However, there is compelling evidence that brain stress/emo*onal systems are recruited as a result of excessive ac*va*on of the reward system and provide an addi*onal source of nega*ve hedonic valence that are defined here as the an*-‐reward system (between-‐system change; cor*cotropin-‐releasing factor func*on increases). The combina*on of both a deficit in the reward system (nega*ve hedonic valence) and recruitment of the brain stress systems (nega*ve hedonic valence) provides a powerful mo*va*onal state mediated in part by the an*-‐reward system. (Koob & Le Moal 2005).
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38 Georgia Prescription Drug Abuse Prevention Initiative Pharmacists’ Training Module 7/21/2013
Thinking Brain Judgment Brain
Instinctual Brain
Pleasure Brain
“I want a beer”
“It makes me feel goooood” “Miller Lite”
Nucleus Accumbens
Prefrontal Cortex
Ventral Tegmental Area
Slide used with permission from DVD series “From DisGrace To Grace: The Hijacking of the Brain” By Dr. Merrill Norton, Pharm.D., D.Ph., ICCDP-D, University of Georgia, College of Pharmacy Athens,
Georgia
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Basolateral Amygdala!
Prefrontal Cortex!
Mediodorsal Thalamus!
Motor Nuclei!
Ventral Pallidum!
Nucleus Accumbens!
Ventral Tegmental Area!
GABA and Glutamate Role in Motivation!
Adapted from Kalivas and Nakamura, Curr. Opin. Neurobiol., 1999.!
Dopamine!
Glutamate!GABA !!
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A Major Reason People Take a Drug is They Like What it Does to Their Brains
Increased cAMP produced in post-‐synap*c cell
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Circuits Involved In Drug Abuse and Addiction!
All of these must be considered!in developing strategies to effectively treat addiction !7/2/14 43 Dr. Merrill Norton Pharm.D.,D.Ph.,ICCDP-‐D
0!
50!
100!
150!
200!
0! 60! 120! 180!Time (min)!
% o
f Bas
al D
A O
utpu
t!
NAc shell !
Empty!Box!Feeding!
Di Chiara et al., Neuroscience, 1999.!
FOOD!
Mounts!Intromissions!Ejaculations!
Fiorino and Phillips, J. Neuroscience, 1997.!
Natural Rewards Elevate Dopamine Levels!
100!
150!
200!
DA
Con
cent
ratio
n (%
Bas
elin
e)!
15!
0!5!10!
Copulation Frequency!
Sample!Number! 1! 2! 3! 4! 5! 6! 7! 8!
SEX!
Female Present!
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0!100!200!300!400!500!600!700!800!900!
1000!1100!
0! 1! 2! 3! 4! 5 hr!Time After Amphetamine!
% o
f Bas
al R
elea
se!
DA!DOPAC!HVA!
Accumbens! AMPHETAMINE!
0!
100!
200!
300!
400!
0! 1! 2! 3! 4! 5 hr!Time After Cocaine!
% o
f Bas
al R
elea
se!
DA!DOPAC!HVA!
Accumbens!COCAINE!
0!
100!
150!
200!
250!
0! 1! 2! 3! 4! 5hr!Time After Morphine!
% o
f Bas
al R
elea
se! Accumbens!
0.5!1.0!2.5!10!
Dose (mg/kg)!MORPHINE!
0!
100!
150!
200!
250!
0! 1! 2! 3 hr!Time After Nicotine!
% o
f Bas
al R
elea
se!
Accumbens!Caudate!
NICOTINE!
Di Chiara and Imperato, PNAS, 1988!
Effects of Drugs on Dopamine Release!
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prolonged drug use changes!the brain in fundamental!
and long-lasting ways!
Science has generated much!evidence showing that… !
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This is your brain
This is your brain ANer drugs
Think about it as what happens when you fail to fer*lize, water, and prune your garden.
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Questions?????????!
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