the anti reward brain system

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The Neuroscience of Chemical Dependence 2012:

The Anti-Reward Brain System

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

The Neuroscience and Pharmacology of Chemical Dependence 2012

11/27/12 2 Dr. Merrill Norton Pharm.D.,D.Ph.,ICCDP-D

Chemical Dependence is a Complex Illness

…with biological, sociological and

psychological components

11/27/12 Dr. Merrill Norton Pharm.D.,D.Ph.,ICCDP-D

The Addicted Brain- 2012


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“Street Drugs”-‐2012

  Absinthe   Alcohol*   Bath Salts*   Caffeine   Cannabis*   Cocaine   DXM   GHB   Heroin   Inhalants   Ketamine

  LSD   MDMA   Mescaline   Meth   Mushrooms   Nutmeg   Opiates*   Peyote   Salvia*   Spice*   Tobacco

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Bath Salts


Methylenedioxypyrovelerone (MDPV)   Street names: Bath Salts, Ivory Wave, Plant Fertilizer, Plant Food, Vanilla Sky, Energy-‐1

  Designer drug developed to get around drug control laws

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MDPV – “Bath Salts”

  Effects: similar to cocaine, amphetamine, or MDMA   Positive: mental and physical stimulation, euphoria, creativity, feelings of empathy, increased sociability and productivity, sexual arousal

  Negative: tightened jaw muscles, grinding teeth, loss of appetite, disturbed sleep patterns, involuntary body movements, confusion, GI disturbance, muscle tension, headache, harsh comedown effects, tachycardia, hypertension, vasoconstriction, psychotic behavior, residual depression, anxiousness/paranoia


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  Routes of Administration: most often insufflated (snorted), but can be smoked, injected, or ingested orally; usual amounts 5 mg or less (active ingredient)

  Duration of action: 3 to 4 hours for subjective effects, 6 to 8 hours for side effects

  Legal status: Not federally controlled, several states have banned either bath salts or chemicals used to make MDPV. Georgia has proposed a bill to ban sale of bath salts, but they have been commonly available in convenience stores and head shops



  Prevalence of use: Information is currently very limited, data is not yet reported by any national drug study programs due to relative newness of drug

  Used predominantly in youth population   Increasingly cases are being reported of overdose on MDPV leading to death – 2 men in Pennsylvania and 1 woman in Illinois in April 2011, and 1 man in Michigan in May 2011



  Chemistry and Pharmacology   Related in chemical structure to MDMA and cathinone

  MDPV administered to mice increased dopamine levels 60 minutes after administration, though not as markedly as increases induced by methamphetamine or MDMA

  Has a “cousin” mephedrone: also found in bath salts with same effects and dangers



  Availability: Typically sold in smoke shops or convenience stores as a “bath salt” under the product names Ivory Wave or Vanilla Sky. It is marked “for novelty use only” and has no instructions on dosing.

  Also sold online as “Energy 1” on UK based websites or as “Plant Food”


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  Addiction Potential: No studies have shown addiction potential as of yet, but self-‐report from users indicate the high is so addictive they can not stop using.   Intense cravings have been reported   Some users have sought professional help after only one month of abuse

  No information available on withdrawal or tolerance



  Long-‐term effects: Unknown – Bath salts have only come into spotlight within last 2 years, so no studies are available

  Toxicity and overdose:   Severe and life-‐threatening toxic effects that do not respond to conventional medical treatment   Usually non-‐responsive to sedatives  When users present with psychosis, psychotic state returns when sedatives and antipsychotics withheld, even after days

  Toxic and lethal doses are unknown



  Drug Testing   Not commonly tested for in standard and extended drug screens

  Redwood Toxicology Lab has a 2-‐panel urine drug screen that tests for MDPV and mephedrone, as well as an extended 14-‐panel screen that includes these drugs

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Cannabis-‐Tetrahydrocannabinols

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Cannabis Effects by Erowid

Onset 0-10 minutes

Coming Up 5-10 minutes

Plateau 15-30 minutes

Coming Down 45-60 minutes

After Effects 30-60 minutes


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 Opiates(Opium Poppy Extracts/Modifed Extracts)

 Morphine(Various) = 1.0  Codeine(Tylenol #3) = 0.4  Opium(Paregoric) = 0.8  Diacetylmorphine(Heroin) = 1.5  Hydrocodone(Vicodin) = 3.0  Oxycodone(Oxycontin,Percodan) = 4.0  Hydromorphone(Dilaudid) = 5.0 11/27/12 20 Merrill Norton

Pharm.D.,D.Ph.,ICCDP-D

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  Meperidine(Demerol) = 1.0   Propoxyphene(Darvon) = 0.7   Pentazocine(Talwin) = 0.5   L acetyl alpha methadol(LAAM)= 2.0   Methadone (Dolophine) = 3.0   Levomethadyl acetate HCl (Orlaam) = 3.0   Fentanyl(Sublimase) = 50.0   Sufentanyl(Various) = 100.0   Alpha Sufentanyl (Various) = 200.0

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A Dangerous Legal High


Salvia Divinorum

  Street names: Salvia, Diviner’s Sage, Ska Maria Pastora, Seer’s Sage, The Sheperdess

  Perennial herb in mint family, native to areas of Sierra Mazateca region of Oaxaca, Mexico


Salvia Divinorum

  Effects: Psychedelic experiences – causes dramatic changes in perception and sometimes frightening hallucinations that often deter users from repeated use

  “20 minute acid trip” – primary effects last 5 to 15 minutes, followed by 20 – 40 minutes of “comedown” period


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Salvia Divinorum


Salvia Divinorum

  Routes of administration: smoking out of a pipe or bong, vaporization, extracting juices to make a tea, or sublingual consumption by chewing the leaves (much larger doses: ~20 leaves vs. 1 leaf for smoking)

  Legal status: not federally controlled; however 15 states have placed Salvia on Schedule I lists – Georgia and 8 other states restrict its distribution, but it remains legal to possess


Salvia Divinorum

  Prevalence of use: In 2008, estimated 1.8 million persons aged 12 or older have used Salvia in their lifetime; approx. 750,000 in past year.

  More common among young adults aged 18 to 25 than those over 25, and more common in males than females


Salvia Divinorum

  Chemistry and Pharmacology:   Salvinorin A (or Divinorin A) is compound responsible for hallucinogenic effects

  Salvinorin A is a potent and selective kappa opioid receptor agonist   Other drugs that act at this receptor produce hallucinogenic effects and dysphoria similar to Salvinorin A

  Does not activate serotonin 2A receptor, which mediates the effects of other Schedule I hallucinogens


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Salvia Divinorum

  Availability: Sold as dried leaf ($50 -‐ $100 per ounce), concentrated extracts ($20 -‐ $50 per gram), and live plants (prices vary)

  Sold in smoke shops or online


Salvia Divinorum

  Long-‐term effects: No overall consensus; studies in rats show “depression-‐like” effects   One report of salvia precipitating psychosis in a patient genetically predisposed to schizophrenia

  No hangover effects reported by most users   Low toxicity   Feelings of déjà vu have been reported in long-‐term


Salvia Divinorum

  Addiction potential: not currently known to be physically addicting or cause psychological dependence

  Withdrawal effects have not been reported

  Appears to be no tolerance – experience can be extended or amplified with increased dose


Salvia Divinorum

  Toxicity and Overdose   No reports of either toxicity or overdose   Danger comes from need for “babysitters” to watch over first time users   Can have frightening experiences that mimic psychoses

  Can also precipitate psychotic episodes in those predisposed to schizophrenia


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Salvia Divinorum

  Drug Testing   Salvia is not commonly tested for in standard drug tests or extended drug tests

  It can be detected by liquid chromatography/mass spectrometry and gas chromatography/mass spectrometry; however these tests are expensive and impractical

  Elimination half-‐life of Salvinorin A is very short (less than an hour), so the detection window is likely less than 12 hours


Spice

  A Dangerous Legal High


Synthetic Cannabinoids

  Street names: K2 and Spice

  Marketed as “herbal incense”; claims to be a blend of traditionally used medicinal herbs but instead is laced with synthetic cannabinoids that are not naturally in the herbs it is labeled to possess


Spice

  Effects: has marijuana-‐like psychoactive effects in humans – decreased activity, analgesia, decreased body temperature, euphoria, anxiety, altered perception

  Does not induce “the munchies” in most users

  When used with alcohol, exacerbates hangovers and causes headaches at base of skull that last for hours


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Spice

  Routes of Administration: smoking in pipes, bongs, or joints

  Duration of Action: the high lasts an average of 10 minutes, and no longer than 30 minutes

  Legal status: As of March 1, 2011, synthetic cannabinoids have been temporarily placed in Schedule I federally, but has been illegal on a state level in Georgia since May 2010


Spice

  Prevalence of use: primary abusers are youth purchasing these substances from Internet sites, gas stations, convenience stores, and smoke shops


Spice

  Chemistry and Pharmacology   The chemical structure of synthetic cannabinoids shares similarities with THC as seen on the next slide, but is not classified as a THC

  Synthetic cannabinoids bind to the brain cannabinoid receptor CB1 and peripheral receptor CB2 with higher affinity than THC, suggesting it would have the same effects as THC in vivo


Spice

  Comparison of chemical structure of THC (left) and HU-‐210, a synthetic cannabinoid (right)


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Spice

  Availability: With the temporary Schedule I status federally, it should no longer be possible to purchase these compounds in retail stores; however many websites still operate that sell these drugs

  Cost: More expensive than real marijuana – one gram is sold for about $25, as opposed to $14/gram for potent marijuana on the street


Spice

  Addiction potential: unknown, though based on the similarity to THC in vivo it can be supposed that the addiction potential is likewise similar to marijuana

  No official information available on withdrawal or tolerance, though one case of withdrawal after daily use of Spice Gold for 3 months is reported; physicians treating the user noted his use showed signs associated with addiction


Spice

  Long-‐term effects: as yet unknown; still relatively new (Spice first appeared in 2004)   As with any smoked product, has detrimental effect on lungs – reported to cause more burning in throat and aching in lungs than marijuana

  Toxicity and overdose:   Extremely large doses may cause negative effects in humans that are generally not noted in marijuana users – increased agitation and vomiting

  Potential for overdose unknown


Spice

  Drug Testing   Spice and the synthetic cannabinoids do not cause a user to test positive for cannabis or other illegal drugs on a standard or extended drug screen, or even with gas or liquid chromatography/mass spectrometry testing

  Dominion Diagnostics and NMS Labs have developed tests that identify metabolites of some of the synthetic cannabinoids as of September 2010


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

DEFINITIONS OF PSYCHOACTIVE CHEMICAL USE, ABUSE, AND

DEPENDENCE "   Psychoactive Chemical Use

"   This term can be applied to a single episode of psychoactive chemical self-administration. Psychoactive chemical use can have adverse consequences that require treatment, and it can lead to psychoactive chemical abuse or dependence, but it may also be self-limiting and have no adverse effects. Psychoactive chemical use has no diagnostic criteria in the DSM-IV.


Psychoactive Chemical Use

"   Single episode

"   May have consequences-allergic reactions

"   May lead to abuse , addiction , and dependence


Endorphins/Dopamine Receptors

USE 1 Cortex


Psychoactive Chemical Abuse

"   Failure to meet a role obligation

"   Placing yourself or others in physically hazardous situations

"   Legal problems

"   Repeat of the above

"   12 Month Period

"   Estimate 50% Population US meet criteria

DSM IV TR Criteria

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ABUSE 2 Midbrain

Physical Dependence

Physical and Psychological Dependence


Psychoactive Chemical Dependence

"   Tolerance

"   Physical Withdrawal

"   Chemical taken longer/larger amounts than intended

"   Preoccupation

"   Time acquiring,using,recovering from drug

"   Important people,places,things become less important

"   Compulsivity DSM IV TR Criteria

Biology/genes

Environment

Biology/ Environment Interactions


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

Factors Contribu.ng to Vulnerability to Develop a Specific Addic.on

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"

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11/27/12" 53"Dr. Merrill Norton Pharm.D.,D.Ph.,ICCDP-D"

We know that despite"their many differences,

most abused substances enhance the dopamine and

serotonin pathways"


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


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Neurotransmitters of Dependence

PIP Dopamine Glutamate

Acetylcholine Anandamide

Endorphins / Enkelphins GABA

Serotonin Epinephrine / Norepinephrine

Dependence Recovery

Depletion may take less than 12 months

Replenishment may take 5 to 7 years

“Human Doing” “Human Being”


Schick Shadel Hospital, 2009 11/27/12 58

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

The An.-‐Reward Brain •  1. A key element of addic.on is the

development of a nega.ve emo.onal state during drug abs.nence.

•  2. The neurobiological basis of the nega.ve emo.onal state derives from two sources: decreased reward circuitry func.on and increased an.-‐reward circuitry func.on.

•  3. The an.-‐reward circuitry func.on recruited during the addic.on process can be localized to connec.ons of the extended amygdala in the basal forebrain.

•  4. Neurochemical elements in the an.reward system of the extended amygdala have as a focal point the extrahypothalamic cor.cotropin-‐releasing factor system.

•  5. Other neurotransmiOer systems implicated in the an.-‐reward response include norepinephrine, dynorphin, neuropep.de Y, and nocicep.n.

•  6. Vulnerability to addic.on involves mul.ple targets in both the reward and an.-‐reward system, but a common element is sensi.za.on of brain stress systems.

•  7. Dysregula.on of the brain reward system and recruitment of the brain an.-‐reward system are hypothesized to produce an allosta.c emo.onal change that can lead to pathology.

•  8. Nondrug addic.ons may be hypothesized to ac.vate similar allosta.c mechanisms.

Merrill Norton Pharm.D.,D.Ph.,ICCDP-‐D 59 Dr. Merrill Norton Pharm.D.,D.Ph.,ICCDP-‐D 60

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-‐shiXs 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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0 100 200 300 400 500 600 700 800 900

1000 1100

0 1 2 3 4 5 hr Time AXer Amphetamine

% of B

asal Release

AMPHETAMINE

0 50 100 150 200

0 60 120 180 Time (min)

% of B

asal Release

Empty Box Feeding

Di Chiara et al.

FOOD

VTA/SN nucleus accumbens

frontal cortex

These prescription drugs, like other drugs of abuse (cocaine, heroin, marijuana) raise brain dopamine levels

Dopamine Neurotransmission

Why Do People Abuse Prescription Drugs?

BUT dopamine is also elevated by natural re-enforcers

0 100 200 300 400 500 600 700 800 900

1000 1100

0 1 2 3 4 5 hr Time After Amphetamine

% of

Bas

al Relea

se

AMPHETAMINE

0 50 100 150 200

0 60 120 180 Time (min)

% of

Bas

al Relea

se

Empty Box Feeding

Di Chiara et al.

FOOD

VTA/SN nucleus accumbens

frontal cortex

These prescription drugs, like other drugs of abuse (cocaine, heroin, marijuana) raise brain dopamine levels

Dopamine Neurotransmission

Why Do People Abuse Prescription Drugs?

BUT dopamine is also elevated by natural re-enforcers

Merrill Norton D.Ph.,NCAC II,CCS 63

CNS Actions of Corticotropin Releasing Factor (CRF) 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

Binge/Intoxication Stage


Withdrawal/Negative Affect Stage


Preoccupation/Anticipation “Craving” Stage


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Positive Reinforcement

Negative Reinforcement

Non-dependent

Negative Reinforcement

Positive Reinforcement

Dependent

Brain Arousal-Stress System Modulation in the Extended Amygdala

From: Koob, G.F. 2008 Neuron 59:11-34

Merrill Norton D.Ph.,NCAC II,CCS 71 Merrill Norton D.Ph.,NCAC II,CCS 72

Allostasis - Definition

“The ability to achieve stability through change”

“To obtain stability, an organism must vary all of the parameters of its internal milieu and match them appropriately to environmental demands.”

From: Sterling P and Eyer J, Allostasis: a new paradigm to explain arousal pathology. In Fisher S and Reason J (eds), Handbook of Life Stress, Cognition and Health, John Wiley, New York, 1988, pp. 629-647.

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The Brain has a Hedonic “Set Point” Another “set point” in the brain . . .

High stress hormone levels reset the brain’s pleasure “set point”

Change in Hedonic Set Point:"Old pleasures don’t show up

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Anhedonia: Pleasure “deafness”

•  The patient is no longer able to derive normal pleasure from those things that have been pleasurable in the past

•  Addiction is a stress-induced “hedonic dysregulation”

Hedonic Allostasis Theory (Koob & LeMoal)

•  With continued drug use and withdrawal, the “anti-reward” system is recuited to counter-balance excess Dopamine (with the stress hormone CRF)

•  Brain is unable to maintain normal “homeostasis” •  So the brain reverts to “allostasis” - change of the

hedonic “set point” under stress in a desperate attempt to maintain stability

•  Current Rx/Tx focus: CRF1-antagonists as anti-craving drugs

Pharmacokinetics in Human Brain

[11C]Cocaine [11C]Methylphenidate

"High" "High" 0

20

40

60

80

100

0

20

40

60

80

100

0 10 20 30 40 50 60 70 80

% P

eak

[11C]Cocaine

Time (min)

[11C]Methylphenidate

0 10 20 30 40 50 60 70 80

Relationship Between Drug Pharmacokinetics and the “High”

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cAMP

BDNF

CREB

Addic.on = Depression 2012 Definitions"•  cAMP- Cyclic adenosine

monophosphate used for intracellular signal transduction"

•  BDNF- Brain-derived neurotrophic factor-encourage the growth and differentiation of new neurons and synapses."

•  CREB-(cAMP Response Element Binding)-neuronal plasticity and long-term memory formation in the brain."

Brain Derived Neurotrophic Factor and neuronal plasticity

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11p14 11p13 CHROMOSOME 11

PROMOTER

5´

1 297 1040 1353 BP

START CODON STOP CODON

681 468 492

G492 → A492 ⇓

Val66 → Met66 MAY BE EXTRACELLULARLY ACTIVE AT TrkB RECEPTORS

proBDNF (32 kDa)

TRUNCATED proBDNF (28 kDa) SIGNAL PEPTIDE

ACTIVITY UNKNOWN

Val66 → Met66

MATURE BDNF (14 kDa) SIGNAL PEPTIDE

ESSENTIAL ROLE IN DEVELOPMENT, SURVIVAL

AND FUNCTION OF NEURONS

Val66 → Met66

CLEAVED IN ENDOPLASMIC RETICULUM

CLEAVED IN TRANS-GOLGI NETWORK

AND/OR IMMATURE VESICLES OR

This is your brain"

This is your brain"Thanks to balanced"

BDNF"Think of it like fertilizing and pruning your rose bushes"

Molecular Biology of Addiction: Addiction is a form of drug-induced neural plasticity

•  Upregulation of cAMP pathway –  Occurs in response to chronic administration of drugs –  Resulting activation of transcription factor CREB

(cAMP response element-binding) –  Both mediate aspects of tolerance and dependency

•  Induction of another transcription factor, d FosB –  Exerts opposite effects –  May contribute to sensitized responses to drug

exposure Ref: Nestler, Eric - Molecular Biology of Addiction. Am J of Addictions 10:201-217, 2001

THE RECEPTOR SENSITIVITY HYPOTHESIS

 Supersensitivity and up-regulation of post-synaptic receptors leads to depression

 Suicidal and depressed patients have increased 5HT-α2 receptors

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Basis for Plasticity: Summary

•  Drugs enter the brain and bind to an initial protein target

•  Binding perturbs synaptic transmission which in turn cause the acute behavioral effects of the drug

•  Acute effects of the drug do not explain addiction by themselves

Ref: Nestler, Eric - Molecular Biology of Addiction. Am J of Addictions 10:201-217, 2001

Basis for Plasticity: Summary

•  Drugs enter the brain and bind to an initial protein target

•  Binding perturbs synaptic transmission which in turn cause the acute behavioral effects of the drug

•  Acute effects of the drug do not explain addiction by themselves


•  Addiction produces a change in brain structure and function (adaptation to the drug) •  molecular and cellular changes in particular neurons alter functional neural circuits •  This leads to changes in behavior consistent with addicted states •  Addiction is therefore a form of drug induced neural plasticity


?

The Neurochemistry of Recovery and Discovery

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Storage"

Synthesis"

Precursor"

Release"Reuptake"

Degradation"

Synaptic Cleft"

= vesicle "= neurotransmitters"= receptor "


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Merrill Norton 97"

Neural Communication"


98"


  Action Potential "  a neural impulse; a brief electrical charge that

travels down an axon"  generated by the movement of positively

charged atoms in and out of channels in the axonʼs membrane"

  Threshold "  the level of stimulation required to trigger a

neural impulse"


99"


Cell body end of axon"

Direction of neural impulse: toward axon terminals Merrill Norton 100"

Neural Communication"  Synapse [SIN-aps]"

  junction between the axon tip of the sending neuron and the dendrite or cell body of the receiving neuron"

  tiny gap at this junction is called the synaptic gap or cleft!  Neurotransmitters"

  chemical messengers that traverse the synaptic gaps between neurons"

  when released by the sending neuron, neurotransmitters travel across the synapse and bind to receptor sites on the receiving neuron, thereby influencing whether it will generate a neural impulse"

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Merrill Norton 101"


Merrill Norton 102"


Serotonin Pathways Dopamine Pathways

Merrill Norton 103"


Merrill Norton Pharm.D.,D.Ph.,ICCDP-D 104"

The Nervous System"

Central (brain and

spinal cord)

Nervous system

Autonomic (controls self-regulated action of

internal organs and glands)

Skeletal (controls voluntary movements of

skeletal muscles)

Sympathetic (arousing)

Parasympathetic (calming)

Peripheral

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Merrill Norton 105"

The Nervous System"

Merrill Norton 106"

The Nervous System"

Merrill Norton 107"

The Nervous System"  Reflex"

  a simple, automatic, inborn response to a sensory stimulus"

Skin receptors

Muscle

Sensory neuron (incoming information)

Motor neuron (outgoing information)

Brain

Interneuron

Spinal cord

Merrill Norton 108"

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

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Merrill Norton 109"

The Endocrine System"

  Endocrine System"  the bodyʼs “slow”

chemical communication system"

  a set of glands that secrete hormones into the bloodstream"

Merrill Norton 110"

Major Classes of Psychoactive Chemicals

• CNS Depressants •  CNS Stimulants •  Narcotics •  Hallucinogens •  Cannabis •  Solvents/ Inhalant •  Steroids •  Psychotropics

Merrill Norton 111"

CENTRAL NERVOUS SYSTEM (CNS) STIMULANTS SUMMARY

•  Pharmacological Actions ! ! ! !Withdrawal effects"

•  " Constricted blood vessels " " "Normal or decreased vessel tone"

•  " Increased blood pressure " " "Normal or decreased pressure"

•  " Increased energy " " " ""Fatigue"

•  " Increased strength " " " "Weakness"•  " Euphoria " " " " "

"Depression, anxiety"•  " Increased alertness " " " "Trouble

concentrating"•  " Decreased appetite " " " "Increased

appetite"

Merrill Norton 112"

NARCOTICS

•  . Naturally Occurring - Codeine, Morphine, Opium, Thebaine"

•  B. Semisynthetic - Dilaudid, Heroin (Horse, Junk, Smack, Skag), Percodan , Oxycontin"

•  C. Synthetic - Darvon, Demerol, Fentanyl, Methadone"

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113"

NARCOTIC SUMMARY •  Symptoms of users - Drowsiness, lethargy,

euphoria, slurred speech, bobbing head (nodding), flushing of skin of face, neck, chest, pinpoint pupils, constipation, and nausea. The duration of psychoactive chemical effect varies from 3-6 hours for Codeine to 12-36 hours for methadone."

•  How used - Injected - (I.V. or “skin popping”)"•  Orally or Smoked (Opium)"•  Physical dependence - YES (Very Rapid)"•  Psychological dependence - YES (High

Degree)"•  Tolerance - YES (Very Rapid)"

Merrill Norton 114"

HALLUCINOGENS

•  Examples"•  LSD, MDSA, MDMA (Adam, Ecstasy),

MDEA (EVE), MBDB, DMT, STP, Mescaline, Psilocybin, etc."

•  Spice"•  Bath Salts"•  Salvia"

Merrill Norton 115"

HALLUCINOGENS SUMMARY •  Physical and Mental Effects"•  Distortions in perception;"•  Euphoria;"•  Impaired short-term memory;"•  Increased pulse;"•  Disturbed judgement;"•  Withdrawal and tolerance;"•  Method of ingestion;"•  Specific effects of PCP;"•  Severe adverse effects possible:"

–  Anxiety reaction;"–  Depression;"–  Schizophrenia-like episode, usually paranoid; sometimes

long-lasting and difficult to treat;"–  Accidents;"–  “Flashbacks”"–  Extremely low effective dose;"–  Taken sporadically."

Merrill Norton 116"

CANNABIS: MARIJUANA, HASHISH

•  (Cannabis Sativa and Indica) Called Pot, Reefer, Dope, Weed, or Grass. Usually a mixture of the leaves, flowering tops, stems and seeds of the cannabis plant. The plant contains about 60 cannabinols to which the intoxicating properties are attributed. "

•  Tetrahydrocannabinol, or THC, is the most prevalent and most potent of the cannabinols found in the marijuana plant. The potency of marijuana is usually measured by the concentration of THC in the plant, cigarette or extract. There has been a dramatic increase in the potency of marijuana confiscated over the last 15 years."

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Merrill Norton 117"

CANNABIS SUMMARY •  Concentrations of THC"•  " Marijuana- (4-8 % THC) Hashish (up to 12% THC) Hash

Oil (up to 30% THC)"•  Symptoms of users—Altered time sense (time appears slow),

reddening of the eyes, confusion, paranoia, increased appetite, mood swings, drowsiness, vision may seem sharper and sounds may seem more distinct, increased reaction time, increased heart rate."

•  How used"•  When smoked—Onset of effect is within minutes, peak intensity is

within 70 minutes, decline is within 2 hours, clearing of the effects within 6 hours. "

•  When eaten—Only 1/3 to 1/4 of THC reaches the blood stream. Onset is from 30-120 minutes; duration of effect is 8-12 hours. "

•  Physical dependence—Suggested"•  Psychological dependence—YES"•  Tolerance—Plasma half-life of THC is shorter in chronic users than in

non-users. Users tend to increase daily intake by shortening the interval between highs or by increasing total numbers of cigarettes used. "

•  Withdrawal symptoms—Irritability, restlessness, nervousness, insomnia, dysphoria."

Merrill Norton 118"

SOLVENTS AND INHALANTS

•  Organic Solvents (hydrocarbons) are industrial solvents and aerosol sprays "

•  Volatile Nitrates"•  Nitrate “poppers” are used to enhance

sexual behavior performance. It is now a prescription substance. Butyl and Isobutyl, “Locker Room”, “Rush”, “Bolt”, “Quick Silver” and “Zoom” are used to enhance sexual pleasure."

•  Nitrous Oxide "

Merrill Norton 119"

"STEROIDS (Anabolic)

•  These psychoactive chemicals are male hormones that increase muscle mass. Names are: Testosterone, Dianabol. Effects include: elevated mood, aggressiveness, high risk of injury because muscle mass is all that increases while tendon strength remains the same; masculinization of women (body hair and baldness), feminization of males (atrophy of the gonads), and liver cancer. These compounds are currently on the Control Substance Schedule III listing."

Merrill Norton 120"

OVER-THE-COUNTER PSYCHOACTIVE CHEMICALS •  Allergy Treatment Products/Cough/Cold

Remedies containing Caffeine, Codeine, Pseudoephedrine derivatives. "

•  Antidiarrheal products containing Paregoric."•  Antitussives containing Codeine and

Pseudoephedrine."•  Sedatives and Sleep Aids/Appetite

Suppressants containing Codeine and Pseudoephedrine ."

•  Appetite Suppressants/Diet Control Medications containing Caffeine, Codeine, Psuedoephedrine and Phenylephrine derivatives. "

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USE OF PHARMACEUTICALS •  These are some precautions that will help avert

problems with prescribed psychoactive medications:"•  Avoid any medications that contain alcohol such as

prescription cough syrups, liquid vitamin supplements, and any other preparations containing alcohol."

•  Avoid any medications that contain any central nervous system stimulants such as prescription appetite suppressants and antihistamines."

•  Avoid any medications that contain a narcotic that is used for pain relief or as an anti-diarrheal."

•  Avoid any medications that contain a central nervous system depressant used for anxiety or as a sedative-hypnotic."


CENTRAL NERVOUS SYSTEM (CNS) DEPRESSANTS

•  Alcohol- Ethyl alcohol, Ethanol (Beer, Liquors, Wine)"

•  B. Barbiturates- Amytal, Nembutal, Phenobarbital, Seconal, Tuinal"

•  C. Benzodiazepines- Valium, Librium, Ativan, Serax, Xanax, Tranxene, Klonopin"

•  D. Other CNS Depressants- Ambien, Chloral Hydrate, Doriden, Meprobamate, Noludar, Paraldehyde, Placidyl, Quaaludes"


CENTRAL NERVOUS SYSTEM DEPRESSANT SUMMARY

•  Physical and Mental Effects"•  Tolerance"•  Generally useful only for brief therapy"•  Other effects"•  Varying lengths of action and medical uses"•  Withdrawal"•  Potentiation with other depressants"•  Release inhibition, hostility, agitation"•  Depression, brain damage with chronic use"•  Habituation"•  Neuroadaptation"


124"

CENTRAL NERVOUS SYSTEM STIMULANTS •  Amphetamines (Synthetic)-d,l

amphetamine, Dextroamphetamine, Methamphetamine"

•  B. Naturally Occurring-Caffeine, Cocaine, Nicotine"

•  C. Synthetic Agents Like Amphetamines - Methylphenidate, Phentermine HCl"

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Natural Rewards"• Food"• Sex"• Excitement"• Comfort"


Dopamine Spells REWARD"

Release

Activate

Recycle



Brain Reward Pathways"


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Activation of Reward"


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Drug-induced Craving

High

Craving

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

Thinking Brain

Judgment Brain

Ins.nctual Brain

Pleasure Brain

“I want a beer”

“It makes me feel goooood”

“Miller Lite”

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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Marijuana Spect Scans

Dr. Merrill Norton Pharm.D.,D.Ph.,ICCDP-D 133

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


Opioids Spect Scans

Normal Brain- 25 years old Hydrocodone 3 Years

Oxycodone 2 Years


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… "


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"


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. ."11/27/12" 139"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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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.

11/27/12 141 Dr. Merrill Norton Pharm.D.,D.Ph.,ICCDP-‐D

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.

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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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)

Controls Cocaine Users 11/27/12" 146"Dr. Merrill Norton Pharm.D.,D.Ph.,ICCDP-D"


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"


Full recovery is a challenge but it is possible …"


?

The Neurochemistry of Recovery and Discovery

Dr. Merrill Norton Pharm.D.,D.Ph.,ICCDP-‐D 152

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-‐shiXs 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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Thinking Brain

Judgment Brain

Ins.nctual Brain

Pleasure Brain

“I want a beer”

“It makes me feel goooood”

“Miller Lite”

11/27/12 153 Dr. Merrill Norton Pharm.D.,D.Ph.,ICCDP-D 11/27/12 154 Dr. Merrill Norton Pharm.D.,D.Ph.,ICCDP-‐D

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 ""


A Major Reason People Take a Drug is They Like What it Does to Their Brains

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Increased cAMP produced in post-‐synap.c cell Circuits Involved In Drug Abuse and Addiction"

All of these must be considered"in developing strategies to effectively treat addiction "11/27/12 158 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 (%

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elin

e)"

15"

0"5"10"

Copulation Frequency"

Sample"Number" 1" 2" 3" 4" 5" 6" 7" 8"

SEX"

Female Present"

11/27/12 159 Dr. Merrill Norton Pharm.D.,D.Ph.,ICCDP-‐D 11/27/12 160 Dr. Merrill Norton Pharm.D.,D.Ph.,ICCDP-‐D

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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"

11/27/12 161 Dr. Merrill Norton Pharm.D.,D.Ph.,ICCDP-‐D 11/27/12 162 Dr. Merrill Norton Pharm.D.,D.Ph.,ICCDP-‐D

prolonged drug use changes"the brain in fundamental"

and long-lasting ways"

Science has generated much"evidence showing that… "


This is your brain

This is your brain AXer drugs

Think about it as what happens when you fail to fer.lize, water, and prune your garden.


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Questions?????????"

11/27/12" Dr. Merrill Norton Pharm.D.,D.Ph.,ICCDP-D" 165"

the anti reward brain system

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