Psychopharmacology:. Neuroscience,.Addic7on,.and. Romance ... Handouts 2017.pdf · causing...

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Psychopharmacology: Neuroscience, Addic7on, and

Romance, With Humor

Dr. Merrill Norton Pharm.D.,D.Ph.,ICCDP-‐D Clinical Associate Professor

University of Georgia College of Pharmacy [email protected]

The Neuroscience and Pharmacology of Addic7on 2016

1/23/17 2 Dr. Merrill Norton Pharm.D.,D.Ph.,ICCDP-‐D

•  Epocrates •  Monthly Prescribing

Reference

•  Facts and Comparisons

•  Stahl’s Essen7al Psychopharmacology 4rd Edi7on

•  T-‐MAY Treatment of Maladap7ve Aggression in Youth* Updated 2015

•  The Principles of Addic7on Medicine 4th edi7on ASAM

•  Clinical Handbook of Psychotropic Drugs

•  Adults-‐21th Edi7on •  Children and Adolescents •  3rd Edi7on •  Updated Bi-‐Yearly

Merrill Norton Pharm.D., D.Ph.,ICCDP-‐D

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So What’s New in Psychopharmacology?

•  Vilazodone (Viibryd)

•  Levomilnacipran (Fetzima)

•  Vor7oxe7ne( Brintellix)

•  Asenapine (Saphris) •  Iloperadine (Fanapt)

•  Lurasidone (Latuda)

•  Zolpidem Spray (Zolpimist)

•  Clozapine Oral Suspension (Versacloz)

•  Cannabis Products

•  Fentanyl Oral Tablets (Abstral and Fentora)

•  Fentanyl Nasal Spray (Lazandra)

•  Fentanyl Buccal Film (Onsolis)

•  Buprenorphine Transdermal (Butrans)

•  Buprnorpine SL Tablets( Zubslov)

•  Tapentadol(Nucynta)

•  Hydrocodone (Zohydro)

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So What’s New in Psychopharmacology?

•  *Aristada (aripiprazole lauroxil) extended-‐release injectable; Alkermes; For the treatment of schizophrenia, Approved October 2015

•  •  *Belbuca (buprenorphine) ; Endo

PharmaceuQcals; For the management of severe pain, Approved October 2015

•  Nuplazid (pimavanserin); Acadia Pharmaceu7cals; For the treatment of hallucina7ons and delusions associated with Parkinson’s disease psychosis, Approved May 2016

•  Rexul7 (brexpiprazole); Otsuka; For the treatment of depression and schizophrenia, Approved July 2015

•  •  *Vraylar (cariprazine); Allergan; For the

treatment of schizophrenia and bipolar disorder, Approved September 2015

•  Aptensio XR •  methylphenidate

•  New extended-‐release capsule formulaQon for ADHD. •  Dyanavel XR •  amphetamine

•  New extended-‐release oral suspension for ADHD. •  Invega Trinza •  paliperidone •  New longer-‐acQng (e.g., 3 month) injectable atypical

anQpsychoQc. •  Morphabond •  morphine

•  An extended-‐release tablet formulaQon for severe chronic pain.

•  Tuzistra XR

•  codeine polisQrex/chlorpheniramine polisQrex •  An opioid/anQhistamine combinaQon for relief of

cough.

•  Brintellix renamed Trintellix

Addic7on is a Complex Illness

…with biological, sociological and

psychological components

1/23/17 Dr. Merrill Norton Pharm.D.,D.Ph.,ICCDP-‐D

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Neurobiology of the Addicted Brain

Dr. Merrill Norton Pharm.D.,D.Ph.,ICCDP-D Clinical Associate Professor University of Georgia College Of Pharmacy

Students of PHRM 5180 Class ( Pharm.D. Candidates) Huda Abdi, Daniel Anderson, Marissa Buscemi, Shelby Bridges, Grace Cooksey, Demetrios Gavalas, Ben Holley, & Yelena Lugin

Dynorphin, Dysphoria, and Dependence: the Stress of Addiction

The hypothesis that the dynorphin-kappa opioid receptor system may be a key component of the neuroplasticity associated with stress-induced mood disorders and the ‘dark side’ of addiction (withdrawal-negative affect stage) continues to gain preclinical and clinical experimental support. The endogenous kappa opioid peptides derived from prodynorphin encode the dysphoric, anxiogenic, and cognitive disrupting responses to behavioral stress exposure (Bruchas et al, 2010; Carroll and Carlezon, 2013)

Neuropsychopharmacology 41, 373-374 (January 2016) | doi:10.1038/npp.2015.258.

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Charles Chavkin and George F Koob

Addiction is Greater Than a Mother’s Love (Dynorphin)

  The reason for the that addicts can not stop using is once the dopaminergic system is deactivated (depleted) due to multiple neurobiological reasons- the reinforcing effects of the drug becomes more powerful than a mother’s love for her children. In 2016, the potencies of most street drugs (marijuana/heroin) have increased. This increased potency creates the increased reinforcing effects of dopamine thus increasing the addiction liability of the drug on the brain.

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The Brain The brain is the most complex organ in the body. Necessary to do and enjoy daily activities such as to create art, to interpret and respond to experiences, to breath…

We will explain to you

•  How different parts of the brain work in a team to coordinate and perform different functions.

•  How drugs alter important areas necessary for life sustaining functions.

•  How these changes to the brain can drive compulsive drug use that marks addiction.

Brain Region Overview

Prefrontal (choices/good/bad) → nucleus accumbens (reward pathways) --> Ventral Tegmental Area (memory)

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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Prefrontal Cortex

Used in planning, decision making, and alignment of actions with goals.

Normal brain: Contributes to social behavior and planning for enjoyment.

Addicted brain: Drugs become the primary motivator at the expense of the aspects of normal life activities.

Main part of the reward pathway of the brain.

Normal brain: Processes the rewarding aspect of experiences such as food, water, sex, and exercise.

Addicted brain: Sure of dopamine from some drugs cause a depletion of natural dopamine production so reward is only stimulated through drugs.

Nucleus Accumbens

Involved in dopamine production, memory, mood, and strong emotions. It sends these signals to the prefrontal cortex and nucleus accumbens.

Normal brain: Sends the reward signal when stimuli is presented that cause the brain to remember strong emotions such as love.

Addicted brain: Dopamine produced from drug use causes the lack of ability to respond to other stimuli because of a dopamine deficit.

Ventral Tegmental Area (Memory Systems)

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Dopamine Primary chemical in the brain responsible for activating the reward pathway

During the preoccupation phase of addiction, dopamine is being released stimulating desire for a drug

During the intoxication phase, all the dopamine in the brain is released giving the user a euphoric feeling

During the withdrawal phase, the brain has run out of dopamine and can not function properly until more is made

Opioid Receptors (Euphoria Receptors) !  µ (mu): Dopamine

!  Activated by morphine: analgesia !  Primary action site of all opioids !  Distribution: primarily in CNS and also GI !  Linked to substance use disorders

!  δ (delta): for endogenous peptides-Endorphins/Enkelphins Nerve Conduction- slows pain signal between the peripheral nervous system and the central nervous system(brain, hypothalamus, spinal cord)

!  κ (kappa): Dynorphins analgesia, endocrine changes and dysphoria (brain-amygdala, spinal cord) Stress Reduction

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Substance Use Disorders Change the following:

Opioid Receptors (mu, kappa, delta)-euphoria;

The Endogenous Opioid Peptide System( Endorphins/Dynorphins);

Cellular Membrane Action- down-regulation of ATP to ADP (release of beta-arrestins (2 & 3) that is responsible for opioid tolerance);

Dopamine Pathways- decreased production, storage, and transport;

Brain Derived Neurotropic Factors changes that may cause psychiatric mood dysregulation.

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Opioid Receptors ( I ) !  Five classes of opioid receptor

!  Mu(µ), Delta(δ), Kappa(κ) Nociceptin Subtypes (σ, ε receptors

!  Subtype of µ, δ, κ receptor

!  Structural characteristics** ( The more characteristics- the higher addiction liability) !  Typical G-protein-coupled receptor

!  Seven hydrophobic region !  Three intracellular loops !  Three extracellular loops !  Intracellular carboxy-terminal tail !  Extracellular amino-terminal tail

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Opioid Receptors ( II )

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The Basic Pharmacology of the Endogenous Opioids

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Fig.8

1.)Behaviors-Pleasure 2.)Euphoria-Addiction 3.)Movement-Parkinson’s Disease-EPS 4.)Perception-Psychosis

Dopamine Neural Pathways

1

2 3

4

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Instinctual Brain

Pleasure Brain

“I want a beer”


Nucleus Accumbens

Prefrontal Cortex



Georgia

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  Circuit #1 Use Dopamine (MU)-Euphoria   Relief/Like

  Pleasure/Pain circuit

Meso-accumbens

  Circuit #2 Regular Pattern Use-Endorphins(Delta/Kappa) Reduced Nerve Conduction   Repeat/Want

  Desire and urge circuit Basolateral n. of amygdala

  Circuit #3 Repeated Use Addiction-Dynorphin A/B (Kappa)- Reduced Stress   Need/Craving

  Pathologic desire & demand circuit Periaqueducal gray of brain stem Stimulation of the periaqueductal gray matter of

the midbrain activates enkephalin-releasing neurons that project to the raphe nuclei in the brainstem.

Enkephalin (endogenous opioid neurotransmitter), binds to mu opioid receptors.

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Role of Glutamate and Dopamine Neurotransmission in Relapse

to Drug-Seeking Behavior

From: Cornish JL and Kalivas PW, J Addict Dis, 2001, 20:43-54.


Instinctual Brain

Pleasure Brain

“I want a beer”


Nucleus Accumbens

Prefrontal Cortex



Georgia

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Neurobiology of Addiction 2016 !  Addiction is increasingly understood as a neurobiological illness where repetitive

substance abuse corrupts the normal circuitry of rewarding and adaptive behaviors causing drug-induced neuroplastic changes.

!  The addictive process can be examined by looking at the biological basis of substance initiation to the progression of substance abuse to dependence to the enduring risk of relapse.

!  Critical neurotransmitters and neurocircuits underlie the pathological changes at each of these stages.

!  Enhanced dopamine transmission in the nucleus accumbens is part of the common pathway for the positively rewarding aspects of drugs of abuse and for initiation of the addictive process. γ-Aminobutyric acid, opioid peptides, serotonin, acetylcholine, the endocannabinoids, and glutamate systems also play a role in the initial addictive process.

!  Dopamine also plays a key role in conditioned responses to drugs of abuse, and addiction is now recognized as a disease of pathological learning and memory.

!  In the path from substance abuse to addiction, the neurochemistry shifts from a dopamine-based behavioral system to a predominantly glutamate-based one marked by dysregulated glutamate transmission from the prefrontal cortex to the nucleus accumbens in relation to drug versus biologically oriented stimuli. This has been called the anti-reward brain.

!  This is a core part of the executive dysfunction now understood as one of the hallmark features of addiction that also includes impaired decision making and impulse dysregulation.

!  Understanding the neurobiology of the addictive process allows for a theoretical psychopharmacological approach to treating addictive disorders, one that takes into account biological interventions aimed at particular stages of the illness.

!  The Neurobiology of Addictive Disorders ,Ross, Stephen MD; Peselow, Eric MD

Merrill Norton Pharm.D.,D.Ph.,ICCDP-D 27

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Substance Use Disorder - A maladaptive pattern of substance use leading to clinically significant impairment or distress, as manifested by 2 (or more) of the following, occurring within a 12-month period:

1.recurrent substance use resulting in a failure to fulfill major role obligations at work, school, or home (e.g., repeated absences or poor work performance related to substance use; substance-related absences, suspensions, or expulsions from school; neglect of children or household)

2.recurrent substance use in situations in which it is physically hazardous (e.g., driving an automobile or operating a machine when impaired by substance use)

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Prevention Initiative Training 28

3.continued substance use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of the substance (e.g., arguments with spouse about consequences of intoxication, physical fights)

4.tolerance, as defined by either of the following: a need for markedly increased amounts of the substance to achieve intoxication or desired effect

b. markedly diminished effect with continued use of the same amount of the substance (Note: Tolerance is not counted for those taking medications under medical supervision such as analgesics, antidepressants, ant-anxiety medications or beta- blockers.)



"  5. Withdrawal is manifested by either of the following: "  a. The characteristic withdrawal syndrome for substance

used; "  b. Medication or closely related is taken to relieve or avoid

withdrawal symptoms;

"  6. There is a persistent desire or unsuccessful efforts to cut down or control use;

"  7. Substance taken in larger amounts or over a longer period than intended;

"  8 . Spend lots of time obtaining the substance, using the substance, or recovering from its effects;



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"  9. Important social, occupational, or recreational activities are given up or reduced because of substance use;

"  10. The substance use is continued despite knowing you have a serious physical or psychological problem that is likely to have been caused or made worse by the substance;

"  11. Craving or a strong desire or urge to use a specific substance.


+ Cravings

!  Craving: memory of the rewarding aspects of drug use superimposed on a negative emotional state !  Compels drug-seeking in dependent individuals

!  3 Types of Cravings !  Withdrawal induced

!  Drug-induced

!  Cue-induced

+ Cravings

!  Craving: memory of the rewarding aspects of drug use superimposed on a negative emotional state !  Compels drug-seeking in dependent individuals

!  3 Types of Cravings !  Withdrawal induced

!  Drug-induced

!  Cue-induced

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Reward Craving-Type 1

•  “Craving”- induced by stimuli that have been paired with drug self-administration such as environmental cues

•  An animal model of craving- type 1 is cue induced reinstatement where a cue previously paired with access to drug reinstates responding for a lever that has been extinguished.

•  Neurobiological substrates include glutamatergic projections from medial prefrontal cortex and basolateral amygdala to nucleus accumbens

Role of Glutamate and Dopamine Neurotransmission in Relapse

to Drug-Seeking Behavior

From: Cornish JL and Kalivas PW, J Addict Dis, 2001, 20:43-54.

Relief Craving-Type 2

•  State of protracted abstinence in subjects with addiction or alcoholism weeks after acute withdrawal.

•  Conceptualized as a state change characterized by anxiety and dysphoria or a residual negative emotional state that combines with Craving-Type 1 situations to produce relapse to excessive drug taking

•  Animal models of Craving-Type 2 include stress-induced reinstatement and increased drug taking in animals during protracted abstinence

•  Neurobiological substrates include residual activation of brain stress systems including corticotropin releasing factor and norepinephrine in the extended amygdala

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Positive and Negative Reinforcement- Definitions

Positive Reinforcement — defined as the process by which presentation of a stimulus (drug) increases the probability of a response (non dependent drug taking paradigms).

Negative Reinforcement —defined as a process by which removal of an aversive stimulus (negative emotional state of drug withdrawal) increases the probability of a response (dependence-induced drug taking)

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Drug-induced Craving

High

Craving

Dr. Merrill Norton Pharm.D.,D.Ph.,ICCDP-D

DSM 5 Addiction Severity Levels

•  Mild: 2-3 criteria•  Moderate: 4-5 criteria•  Severe: 6 or more

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Biology/genes

Environment

Biology/ Environment Interactions

1/23/17 Dr. Merrill Norton Pharm.D.,D.Ph.,ICCDP-D

Dr. Merrill Norton Pharm.D.,D.Ph.,ICCDP-‐D

Factors Contribu7ng to Vulnerability to Develop a Specific Addic7on

use of the drug of abuse essential (100%)

Genetic (25-50%)• DNA• SNPs• other polymorphisms

Drug-Induced Effects (very high)

Environmental(very high)• prenatal• postnatal• contemporary• cues• comorbidity

Kreek et al., 2000

• mRNA levels• peptides• proteomics

• neurochemistry• behaviors

1/23/17 42Dr. Merrill Norton Pharm.D.,D.Ph.,ICCDP-D

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We know that despitetheir many differences,

most abused substances enhance the dopamine and

serotonin pathways

1/23/17 43Dr. Merrill Norton Pharm.D.,D.Ph.,ICCDP-D

Alcohol

Benzodiazepines

Valium

Xanax

Ativan

Non benzodiazepine

Ambien

Sonata

Barbiturates

Fiorinal

Soma

Cocaine

Amphetamine

Methamphetamine

Ephedrine

Ritalin

Ecstasy

Mescaline

DOM

LSD

Psilocibin

DMT

Ibogaine

PCP

Ketamine

Opioids

Opiates

Heroin

Buprenex

Oxycontin

Nicotine

Marijuana

GABA Norepinephrine Serotonin

Cannabinoid- Anandamide

Opiate NMDA Acetylcholine

GHB

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“The Essential Eleven” •  Norepinephrine/Epinephrine-stimulant,anger,fear,anxiety,fight,flight •  Serotonin-depressant,sleep,calm,pleasure •  GABA-relaxant,stress reduction,seizure threshold •  Endorphins-pain relief,pleasure •  Acetylcholine-involutary actions,memory,motivation •  Anandamide-memory,new learning,calmness •  Glutamate-organization of brain signaling,memory,pain •  Dopamine-perception,movement,pleasure •  Dynorphins- stress reduction, bonding •  Histamine- It is a mediator of "wakefulness" and its activity is necessary to maintain

wakefulness, alertness, and reaction time.

•  PIP- loving of one’s self,others,GOD


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Neurotransmitters of Dependence

PIP Dopamine Glutamate

Acetylcholine Anandamide

Endorphins / Enkelphins GABA

Serotonin Histamine

Dynorphins Epinephrine / Norepinephrine

Addiction Recovery

Depletion may take less than 12 months

Replenishment may take 5 to 7 years

“Human Doing” “Human Being”



  Pleasure/Pain circuit

Meso-accumbens




  Pathologic desire & demand circuit Periaqueducal gray of brain stem Stimulation of the periaqueductal gray matter of

the midbrain activates enkephalin-releasing neurons that project to the raphe nuclei in the brainstem.

Enkephalin (endogenous opioid neurotransmitter), binds to mu opioid receptors.

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Schick Shadel Hospital, 2009 1/23/17 48

Dr. Merrill Norto

n Pharm.D.,D.

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The Anti-Reward Brain •  1. A key element of addiction is the

development of a negative emotional state during drug abstinence.

•  2. The neurobiological basis of the negative emotional state derives from two sources: decreased reward circuitry function and increased anti-reward circuitry function.

•  3. The anti-reward circuitry function recruited during the addiction process can be localized to connections of the extended amygdala in the basal forebrain.

•  4. Neurochemical elements in the antireward system of the extended amygdala have as a focal point the extrahypothalamic corticotropin-releasing factor system.

•  5. Other neurotransmitter systems implicated in the anti-reward response include norepinephrine, dynorphin, neuropeptide Y, and nociceptin.

•  6. Vulnerability to addiction involves multiple targets in both the reward and anti-reward system, but a common element is sensitization of brain stress systems.

•  7. Dysregulation of the brain reward system and recruitment of the brain anti-reward system are hypothesized to produce an allostatic emotional change that can lead to pathology.

•  8. Nondrug addictions may be hypothesized to activate similar allostatic mechanisms.


Dr. Merrill Norton Pharm.D.,D.Ph.,ICCDP-D 50

ANTI-‐REWARD The concept of an an7-‐reward system was developed to explain one component of 7me-‐dependent neuroadapta7ons in response to excessive u7liza7on of the brain reward system. The brain reward system is defined as ac7va7on of circuits involved in posi7ve reinforcement with an overlay of posi7ve hedonic valence. The neuroadapta7on simply could involve state-‐shids on a single axis of the reward system (within-‐ system change; dopamine func7on decreases). However, there is compelling evidence that brain stress/emo7onal systems are recruited as a result of excessive ac7va7on of the reward system and provide an addi7onal source of nega7ve hedonic valence that are defined here as the an7-‐reward system (between-‐system change; cor7cotropin-‐releasing factor func7on increases). The combina7on of both a deficit in the reward system (nega7ve hedonic valence) and recruitment of the brain stress systems (nega7ve hedonic valence) provides a powerful mo7va7onal state mediated in part by the an7-‐reward system. (Koob & Le Moal 2005).

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Reynolds & Berridge, 2003

Aversive fear (bite, distress, ‘dislike’)

Posterior

Appetitive positive (eat, prefer, ‘like’)

Anterior

Nucleus Accumbens shell Bivalent emotion from corticolimbic tweaks

(Glutamate AMPA blockade by shell DNQX)

Front Back

• Ambivalent middle: +/- both together

• No neutral center

• Positive front , Negative back

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+ Desire Corresponds with Drug Use

Liking • Non-problematic Use

Wanting • Abuse

Craving • Addiction

Desire Corresponds with Drug Use

Liking • Non-problematic Use

Wanting • Abuse

Craving • Addiction

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Addiction and the Brain Anti-Reward System

Dr. Merrill Norton Pharm.D.,D.Ph.,ICCDP-D Clinical Associate Professor

University of Georgia College of Pharmacy

Koob,G. LeMoal,M.,Addiction and the Antireward Brain System,Annu. Rev. Psychol. 2008.59:29-53

Brain Under the Influence

Receptor Sensitization

Liking

Wanting

Craving

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Downward spiral of reward

With normally rewarding things like food and sex, we usually have a pretty good idea of how good it will be. It’s when the reward exceeds our expectations that the dopamine circuitry really lights up big time. Conversely, if our expectations aren’t met, dopamine activity drops off.

But cocaine, heroin, alcohol and nicotine directly activate the circuit — they goose dopamine secretion — regardless of how high the expectation was. “Every time you take it, you activate that dopamine activity, so you’re getting a readout that says, ‘Wow, this was even better than I thought it would be,’

The experience is remembered as always getting better — even if, paradoxically, it’s actually not so great anymore. (“Tolerance mechanisms” within the brain can cause a drug’s pleasant effect to diminish with repeated use.)

What is Addiction? The Clinical Syndrome

Drug addiction (substance dependence) is characterized by:

Compulsion to seek and take the drug

Loss of control in limiting intake

Emergence of a negative emotional state when drug access prevented

Amygdala •  Memories •  Decision making •  Emotional reactions Ventral

Tegmental Area (VTA)

Hippocampus •  Turning short-

term memories into long-term memories

Nucleus Accumbens (NAcc) •  Pleasure (Reward) center

Prefrontal Cortex •  Planning complex

behavior •  Decision making

Dopamine Pathway

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Ventral Tegmental Area (VTA)





Amygdala •  Memories •  Decision making •  Emotional reactions


Dopamine Pathway

Amygdala •  Memories •  Decision making •  Emotional reactions

Ventral Tegmental Area (VTA)






Other Pathways

Opioid receptors

Nicotine receptors

GABAA receptors

Cannabinoid receptors

CNS Actions of Corticotropin Releasing Factor (CRF)

Merrill Norton D.Ph.,NCAC II,CCS

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Stages of the Addiction Cycle

Theory of Euphoria Opioid Receptors ( I ) !  Five classes of opioid receptor !  Mu(µ), Delta(δ), Kappa(κ), Nociceptin Subtypes (σ, ε

receptors

!  Subtype of µ, δ, κ receptor

!  Structural characteristics** ( The more charateristics- the higher addiction liability) !  Typical G-protein-coupled receptor

!  Seven hydrophobic region !  Three intracellular loops !  Three extracellular loops !  Intracellular carboxy-terminal tail !  Extracellular amino-terminal tail

Opioid Receptors ( II ) “Dynamite with Lit Fuse”

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aa

Synaptic Arrangement of Dorsal Horn

FromNociceceptors

EnkephalinDynorphin or GABA

Substance P andother transmitters

To Reticular Formation,Thalamus

Serotonin

Descending Projections from Raphe' N.

Dorsal Root Ganglion

ExcitatorySynapses

InhibitorySynapses

Serotonin

Pain

Opioid Receptors ( III ) !  Most of available opioid analgesics

!  Act at µ-opioid(mu) receptor( low, moderate, high doses) !  Morphine prototype

!  Activation of µ-opioid receptor → analgesia, euphoria, respiratory depress, nausea, vomiting,

decreased gastrointestinal motility, tolerance, dependence

!  δ(Delta), κ-opioid(Kappa) receptor agonist !  Produce analgesia( moderate, high doses) !  THC, CBD, NSAIDs, Duloxetine????, trazodone?? !  Not cause respiratory depression (high doses) or to decease GI

motility (high doses) → Analgesia without µ-opioid side effect

Opioid Receptors ( IV )

! κ-opioid receptor agonist !  Produce dysphoria and hallucination !  Focus

!  Not cross BBB, act only at pph κ-opioid receptor

! Morphine !  µ, δ, κ receptor activation( low, moderate, high) !  Heroin (diacetylmorphine)

!  Fentanyl, sufentanyl !  More selective µ-receptor agonist !  High effective analgesia

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Endogenous Opioid Peptides (Euphoria (Body’s Opioid System)

! Pain modulation in brain- Kappa and Delta Receptors !  Endogenous Opioid Peptide : opioid-like

pharmacologic activity !  Three Types- endorphins (Kappa),

enkelphins(Kappa), dynorphins (Delta) !  Cleaved from three primary precursor protein ( proopiomelanocortin, proenkephalin, prodynorphine) !  Methionine-enkephalin and leucine-enkephalin

Pharmacodynamics

•  Endorphin agonists/mimics endorphins •  Endorphins: endogenous morphine (3-‐4x more potent)

–  Regulate pain transmission from peripheral NS to CNS –  Also involved in mood regulaQon and cardiovascular, respiratory and

endocrine regulaQon

•  Increases endorphin neurotransmission •  Increases dopamine in the mesolimbic dopaminergic pathway via

inhibiQon of GABA in the ventral tegmental area

71 Dr. Merrill Norton,Pharm.D., D.Ph., ICCDP-‐D

and Caitlin Payne, Research Assistant

Predisposition & Progression

Genetics / Environment

Ini7a7on Use Heavy Use Substance Use Disorders

Substance Use ……………Substance Use Disorder

1.) Substance Use / 2.) Substance Abuse( Paberns Develops)

3.)Substance Use Disorders / AddicQon

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The Basic Pharmacology of the Endogenous Opioids

Heroin Addicts Energy

74

Fig.8

Normal Pleasure

Enhanced Pleasure-‐AddicQon

Movement

PercepQon


  Pleasure/Pain circuit Meso-accumbens




  Pathologic desire & demand circuit Periaqueducal gray of brain stem

Stimulation of the periaqueductal gray matter of the midbrain activates enkephalin-releasing neurons that project to the raphe nuclei in the brainstem.

Enkephalin (endogenous opioid neurotransmitter), binds to mu opioid receptors. 1/23/17

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Receptor Sensitization

Liking- Occassional Use

Wanting- Use with a Pattern

Craving-Compulsive Use

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The Addiction Cycle

Withdrawal/Negative

Effect

Preoccupation/anticipation

Binge/Intoxication

Koob,GF, Addiction is a reward deficit and stress surfeit disorder; Frontiers in Psychiatry | Addictive Disorders and Behavioral Dyscontrol August 2013 | Volume 4 | Article 72

•  The “lows” get lower •  The body’s baseline of what it considers normal gets adjusted to allostatic points

•  The dose that used to bring euphoria is now used just to feel normal •  Koob,GF, Addiction is a reward deficit and stress surfeit disorder; Frontiers in Psychiatry | Addictive Disorders and Behavioral

Dyscontrol August 2013 | Volume 4 | Article 72

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GDPGTP

GTP

PO4

GDP GDP

K+

Endogenous Opioids and their Receptors

LaForge, Yuferov and Kreek, 2000

Extracellular fluid

cell interior

cell membrane

AA identical in 3 receptors

AA identical in 2 receptors

AA different in 3 receptors

HOOC

H2N

S

S

µ δκ

Opioid Classes

EndorphinsEnkephalinsDynorphins

Endomorphins (?)

OpioidReceptorTypes

MuDelta

Kappa

Natural History of Drug Abuse and Addictions

Initial Use ofDrug of Abuse

SporadicIntermittent

Use

RegularUse

Addiction EarlyWithdrawal

(abstinence)

ProtractedAbstinence

WITHOUT PHARMACO-

THERAPY, RELAPSE

TO ADDICTION*

>80%

SUSTAINED ABSTINENCE*<20%

*with no medicationsADDICTION: Compulsive drug seeking behavior and drug self-administration, without regard to negative consequences to self or others (adapted from WHO).

PrimaryPrevention

Possible Utility of Vaccinesand Selected Medications

Medications Usefuland Needed

Kreek et al., Nature Reviews Drug Discovery, 1:710, 2002; 2007

For entry into opioid agonist pharmacotherapy (methadone or LAAM maintenance) (U.S. Federal Regulations), above criteria, plus multiple daily self-administration of opiates for one year or more. For entry into opioid partial agonist pharmacotherapy (buprenorphine), meeting DSM-IV criteria for dependence.

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Human Mu Opioid Receptor:Location of Coding Region SNPs (Single Nucleotide

Polymorphisms-DNA)(SNPs Resulting in Amino Acids Changes

or Synonymous Mutation)

Kreek, LaForge, Yuferov, 2005

Mu- Dopamine

Delta- Endorphins/Enkelphins

Kappa-Dynorphin A/B Increased Stress (Norepinephrine)

The An7-‐Reward Brain •  1. A key element of addic7on is the

development of a nega7ve emo7onal state during drug abs7nence.

•  2. The neurobiological basis of the nega7ve emo7onal state derives from two sources: decreased reward circuitry func7on and increased an7-‐reward circuitry func7on.

•  3. The an7-‐reward circuitry func7on recruited during the addic7on process can be localized to connec7ons of the extended amygdala in the basal forebrain.

•  4. Neurochemical elements in the an7reward system of the extended amygdala have as a focal point the extrahypothalamic cor7cotropin-‐releasing factor system.

•  5. Other neurotransmiier systems implicated in the an7-‐reward response include norepinephrine, dynorphin, neuropep7de Y, and nocicep7n.

•  6. Vulnerability to addic7on involves mul7ple targets in both the reward and an7-‐reward system, but a common element is sensi7za7on of brain stress systems.

•  7. Dysregula7on of the brain reward system and recruitment of the brain an7-‐reward system are hypothesized to produce an allosta7c emo7onal change that can lead to pathology.

•  8. Nondrug addic7ons may be hypothesized to ac7vate similar allosta7c mechanisms.

Merrill Norton Pharm.D.,D.Ph.,ICCDP-‐D 84

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Peaks of Brain Plasticity The word “plasticity” is a term used to describe the brain’s ability to physically change its internal structure (by making more dendrites) when we learn new things or have new experiences.

During peaks of plasticity the brain must make key neural connections to wire us to become a responsible, thoughtful, intelligent adults

Drinking alcohol during peak periods of plasticity can seriously damage brain wiring

Levels in the brain of a healthy non-drinker (left)……and that of a sober 21-year old with a 4 year history of heavy alcohol use (right). *The “holes” indicate areas of significantly reduced brain activity

Dark Side of Addiction   Defined as the development of the aversive

emotional state that drives the negative reinforcement of addiction

  Withdrawal/negative affect stage- chronic irritability, emotional pain, malaise, dysphoria, alexithymia, and loss of motivation for natural rewards

  The combination of decreases in reward function and recruitment of anitreward systems provides a powerful source of negative reinforcement that contributes to drug seeking behavior and addiction

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88

Koob.G 2008


89

Koob,G 2008


90

Koob,G 2008

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Neural Bases of Protracted Abstinence and Relapse

!  Dark side may contribute to chronic relapse

!  Hypofunctioning and reorganized prefrontal system drive drug-, cue-, and stress-induced reinstatement neurocircuits, which can cause vulnerability to craving

!  Animal models of craving: !  Drug seeking induced by stimuli paired with drug

taking !  Drug seeking induced by an acute stressor or state of

stress


92

Koob, G 2008

Vulnerability to Addiction

!  Factors that contribute to vulnerability for drug use or relapse !  Genetic background and environmental history !  Comorbidity with psychopathological conditions !  Temperamental and personality traits and genetic

factors, developmental factors, and socioeconomic status

!  Stress and life events

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94

Sensitivity to Anti-Reward Neuroadaptations

!  Preadolescent and adolescent exposure to alcohol, tobacco, or drugs of abuse significantly increases the propensity for dependence in adulthood

!  Adolescents first intoxicated with alcohol at age 16 or younger are 2-3 times more likely to develop dependence (similar to tobacco)

!  Early onset of drug use is a predictor of subsequent drug problems


96

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Genetic and Epigenetic Mechanisms

!  There is no single gene for addiction

!  Stress, trauma, prenatal stress, and early-life rearing experiences may alter addiction pathology later in life, via gene expression changes

!  Chronic use of drugs can even lead to DNA modification at particular target genes

Personalized Medicine

Courtesy of Felix W. Frueh US FDA

Anticipated Benefits of Genomics

!  Earlier detection of genetic predispositions

!  Improved diagnostic accuracy and speed

!  Gene therapies

!  Decrease in healthcare costs

!  Personalized treatment plans

!  Rational drug design

Available at ornl.gov/hgmis. Accessed on 12.28.13.

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Available at http://rogermontgomery.com/wp-content/uploads/2012/05/biotech-Fig-5.png. Accessed on 12.28.13.

Personalized Medicine!  Medicine is personal:

!  We are all different.!  Some of our differences translate into how we react to drugs as

individuals.!  This is why personalized medicine is important to everyone.

!  Why does someone need twice the standard dose to be effective?

!  Why does this drug work for you but not me?

!  Why do I have side-effects and you don’t?

!  Why do some people get cancer and others don’t?

!  Why is anecdotal information irrelevant to your own health and treatment?

The Goal of Personalized Medicine

!  The Right Dose of

!  The Right Drug for

!  The Right Indication for

!  The Right Patient at

!  The Right Time.

Courtesy Felix W. Frueh

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Homeostasis to Allostasis of the Reward System

!  Allostasis !  Defined as stability through change !  Involves a feed-forward mechanism rather than

negative feedback mechanisms of homeostasis !  Continuous re-evaluation of need and continuous

readjustment of all parameters toward new set points !  Thus, a fine matching of resources to needs

Homeostasis to Allostasis of the Reward System

!  Allostatic state !  State of chronic deviation of the regulatory system

from its normal (homeostatic) operating level.

!  Allostatic Load !  Long-term cost of allostasis that accumulates over

time and reflects accumulation of damage that can lead to pathological states

Temporal Dynamics of Allostasis !  The same physiological mechanism that allows rapid

response to environmental challenges becomes the engine of pathology if adequate time or resources are not available to shut off the response

!  Two components are hypothesized to adjust to challenges to the brain produced by drugs of abuse !  Overactivation of brain reward transmitters and circuits !  Recruitment of the brain antireward or brain stress systems

! Which leads to the compulsivity of drug seeking and drug taking

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Nondrug Addictions !  Impulse control disorders with characteristics similar to

drug addiction !  Kleptomania !  Trichotillomania !  Pyromania !  Compulsive gambling

!  Other disorders outside of accepted diagnostic disorders !  Compulsive shopping, compulsive sexual behavior,

compulsive eating, compulsive exercise, etc.

Psychopharmacology:. Neuroscience,.Addic7on,.and. Romance ... Handouts 2017.pdf · causing...

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