Lecture 9Substance Abuse

and Addiction

David Saffen, Ph.D.Principal Investigator

Department of Cellular and Genetic MedicineFudan University, Shanghai, China

Email: saffen@fudan.edu.cn

Substance abuse

The use of therapeutic drugs or illegal substances with the goal of producing altered psychological states, including hallucinations, euphoria or reduced anxiety.

Substance abuse also includes the use of drugs and other agents to gain unfair advantage in sports or other competitive activities.

Substance abuse often (but not always) results in “addiction” to the drug or illegal substance.

AddictionAddiction is a chronic, often relapsing brain disease that causes compulsive drug seeking and use, despite harmful consequences to the addicted individual and to those around him or her. Although the initial decision to take drugs is voluntary for most people, the brain changes that occur over time challenge an addicted person‟s self control and hamper his or her ability to resist intense impulses to take drugs. (NIDA, NIH)

Drug addition often involves both:

Physical dependence characterized by uncomfortable (and

sometimes) dangerous physiological responses to drug

withdrawal.

Psychological dependence characterized by “craving:” an intense,

urgent „abnormal desire‟ (longing or yearning) for drugs.

Substance abuse and addictionas diseases of the brain

• Until the last half of the 20th century, substance abuse and addiction were primarily considered to be the consequences of “weak personality” or “moral failure” rather than physical/ psychological diseases.

• Research during the last 50-60 years, however, has elucidated many physiological changes brought on by the use of drugs, including physical and neurological adaptations that generate dependence and behavioral and psychological changes that maintain addiction.

• The current hope is that basic research into the molecular and genetic mechanism underlying the substance abuse and addiction will lead to novel strategies for the treatment and prevention of these disorders.

Comorbidities:Substance abuse and addiction are often accompanied

by serious mental and physical illnesses

• Psychotic disorders

• Mood and anxiety disorders

• Physical complaints

• Infectious diseases:

- hepatitis

- HIV/AIDS Source: NIND, NIH

Substance-induced disorders

- intoxication

- withdrawal

- other substance/medication-induced disorders, including:

psychotic disorders

bipolar and related disorders

depressive disorders

anxiety disorders

obsessive-compulsive and related disorders

sleep disorders

sexual dysfunctions

delirium

neurocognitive disorders

Social costs and epidemiology of substance abuse and addiction

Substance abuse-related impact on public health (WHO 2002 survey)

Disability- Adjusted Life Years (DALY),

a measure of the burden of disease; one

DALY = one year of “healthy” life lost.

= no data

= < 40 per 100,000

= 40 – 160 “

= 160 – 320 “

= 320 – 440 “

= > 440 “Nutt D, et al, Lancet, 2007

Substance abuse

DSM-5: 10 classes of abused drugs

• Alcohol

• Caffeine

• Cannabis

• Hallucinogens

(phencyclidine, other hallucinogens)

• Inhalants

• Opioids

• Sedatives, hypnotics and anxiolytics

• Stimulants

(amphetamine-type substances, cocaine, other substances)

• Tobacco/nicotine

• Other substances (e.g. anabolic steroids)

Alcohol (ethanol)

• Alcohol abuse, which can lead to alcoholism, is a pattern of drinking that results in harm to one's health, interpersonal relationships, or ability to work.

• Alcoholism or alcohol dependence is a diagnosable disease characterized by a strong craving for alcohol, and/or continued use despite harm or personal injury.

• “Moderate” drinking: 1 (women) or 2 (men) drinks/day; “heavy” drinking: exceeding the above amounts. 1 drink = 14 grams of ethanol ~ 355 ml beer; 148 ml wine; 44.4 ml 80-proof distilled alcoholic drink or liquor.

Recorded annual alcohol consumption(liters per person; 2004)

Caffeine (and derivatives)

• Central nervous system stimulants; promotes wakefulness and alertness

• Antagonize adenosine receptor

(A1 and A2a subtypes)

• Indirectly stimulate the release of dopamine, glutamate and acetylcholine.

• One cup of regular coffee (8 oz = 240 ml) contains 60 - 130 mg caffeine; Tea: 40 -50 mg/8 oz; Colas: (Pepsi and Coca Cola) ~ 40- 50 mg/12 oz can and “energy” drinks: 80 - 120 mg/8 oz serving

• Caffeine withdrawal symptoms include: headaches, depressed mood, irritability, muscle pain and stiffness, lethargy

Psychoactive caffeine metabolites produced in liver

Cannabis (Marijuana)

• Most commonly abused illegal drug in the US. (Recently legalized for medical or recreational use in some states)

• Binds brain CB1 and immune system CB2 cannabinoid receptors.

• Can produce distorted perceptions, impaired coordination, difficulty thinking and solving problems, disruptions of learning and memory

• Has worrisome association with schizophrenia

Tetrahydro-cannabinol (THC)

Anandamides: endogenouscannabinoid receptor ligands

Cannabidiol

Hallucinogens I(phencyclidine and other arylcyclohexylamines)

• Non-competitive antagonists of the NMDA glutamate receptor: bind within the ion channel

• Produce visual or aural hallucinations; feeling of “dissociation” or being “out of body.”

• Cognitive dysfunctions similar to those observed in schizophrenia.

• At high-doses: psychosis similar to that observed in schizophrenia and bipolar disorder.

(Rolicyclidine)

(Tenocyclidine)

(Eticyclidine)

Hallucinogens II (other hallucinogens)

Mescaline(from peyote

Cactus)5-HT2A partial agonist

Dimethyltryptamine(DMT) 5-HT2A

partial agonist

Psilocybin(from mushrooms)

5-HT2A partial agonist

lysergic aciddiethylamine (LSD)

5-HT2A partial agonist

3,4-methylenedioxy-N-methylamphetamine

(MDMA; aka “ecstacy” or“molly”) an “empathogen”

dextromethorphan(DXM; an antitussive

At low doses;a “dissociative” drug

at high doses

Salvinorin A(k-opiate receptor

antagonist)

Intoxicative inhalants

Aliphatic Hydrocarbonse.g., gasoline

Kerosene, butane

Aromatichydrocarbonse.g., toluene

Ketones,e.g., acetone

Nitrites, alkyl nitritese.g., amyl nitrite

nitrous oxide

Haloalkanese.g, tricholoroethyene

Opioids(m-opioid receptor agonists/partial agonists)

Heroin MorphineHydrocodoneaka: Vicodin

MethadoneBuprenorphine(SuboxoneTM)

Sedatives, hypnotics & anxiolytics(including benzodiazepines: non-competitive

agonists of GABAA receptors)

Alprazolam(XanaxTM)

MethaqualoneQuaaludeTM

AmobarbitalAmytalTM

Gamma-hydroxy-butyric acid (GHB)

Diazepam(ValiumTM)

Clonazepam(KlonoponTM)

Lorazopam(AtivanTM)

Stimulants(often agents that rapidly increase extracellular

levels of dopamine, epinephrine and serotonin)

Amphetamine Methamphetamine

Cocaine MephedroneA synthetic stimulant with

structure similar to cathinone. Synthetic cathinones are

collectively known as“bath salts.”

Cathinonefrom Catha edulis

(aka: qat, khat)

2,5-dimethoxy-4-Methylamphetamine

(aka DOM or STP: “Serenity, Tranquility, Peace”)

Tobacco/nicotine

• Nicotine: agonist of nicotinic acetylcholine receptors; a parasympathomimetic and central nervous system agent; stimulates the release of dopamine and norepinephrine at low doses and serotonin and endogenous opiates at higher doses.

• Produces both stimulant and relaxant effects; suppresses appetite

• Highly addictive

• 1 cigarette yields ~ 1 mg absorbed nicotine

Nicotine

Other substances

Performance-enhancing drugs

Lean mass builders

-anabolic steroids, beta-agonists, elective androgen receptor modulators (SARMs), human growth hormone

Stimulants

- caffeine, amphetamine, methamphetamine

Painkillers

- buprenorphine and other opioids

Sedatives

- diazepam, propranolol, cannabis

Diuretics

- amiloride, furosemide,

Blood boosters

- erythropoietin (EPO)

Masking drugs

- epitestosterone

Testosterone(natural)

Methandrostenolone(synthetic; DianabolTM)

Epitestosterone

Normal(T/E) ratio

~ 1.0

MethylationIncreases

bioavailability

A recent attempt to quantify the relative harm

associated with abuse of different

substances

(Nutt D, et al, Lancet, 2007)

4-MTA: 4-methythioamphetamineA selective serotonin releasing agent (SSRA)

Methylphenidate: A stimulant used in the treatment of ADHD

Addiction

Stage 1: drug exposure stimulates the release of high levels of dopamine in the extended amygdala, ventral pallidum, n. accumbens, and PFC activating D1 dopamine receptors, resulting in increased synthesis of cAMP, activation of PKA and induction of gene expression.

Stage 2: Chronic stimulation of D1 receptors lead to the expression of DFosB, a stable transcription factor that mediates neuroplastic changes in n. accumbens circuitry.

Stage 3: A long-lasting state characterized by craving, relapse, reduced ability to suppress drug-seeking behavior, reduced pleasure

from drug.

Three stages ofdrug addiction

Slightly different definition of 3 stages1. Binge/intoxication2. Withdrawal/negative effects3. Preoccupation/anticipation (craving)

Mesocorticolimbic reward pathway

= midbrain

Limbic system targets(via medial forebrain bundle):- Medial PFC and anterior

cingulate gyrus- Amygdala- Hippocampus- Nucleus accumbens- Ventral globus pallidus

Limbic system circuitry:mediates the influences of motivation, emotion,

context, affect and information on behavior

mPFC = medialprefrontalcortex

AC = anteriorcingulategyrus

aka: medialdorsal thalamus

dopamine

GABA

glutamate

Aka: ventralglobuspallidus

AC

(ventral striatum)

Medialforebrain

bundle

Amygdala

Ledoux J, Current Biology, 2007

Extended amygdala

Comprises: - Central nucleus of the amygdala - Bed nucleus of the stria terminalis (BNST)- Medial shell subregion of the nucleus accumbens

Inputs from limbic structures, including:- basolateral amygdala- hippocampus

Outputs:- medial part of ventral pallidum - lateral hypothalamus

Implicated in the creation of negative states that promote negative-reinforcement mechanisms implicated in addiction (e.g., drug seeking behavior to avoid unpleasant psychological states associated with abstinence).

Bed nucleus of the stria terminalis (BNST)

Sokolowski K and Corbin JG, Frontiers in Molecular Neuroscience, 2012

MB =mammillary body

Hypo = hypothalamus

PAG = periaqueductal gray

MOB = main olfactory bulbs

Nucleus accumbens(a component of the “ventral striatum”)

AcbC = accumbens coreAcbSh = accumbens shellCaud = caudate; Put = putamenIc = internal capsule

• Schematic illustrating the connections of the VS. Blue arrows=inputs; gray arrows=outputs;

Amy=amygdala; BNST=bed nucleus stria terminalis; dACC=dorsal anterior cingulate cortex;

Hipp=hippocampus; hypo=hypothalamus; MD=medio-dorsal nucleus of the thalamus; OFC=orbital

frontal cortex; PPT=pedunculopontine nucleus; S=shell; SNc=substantia nigra, pars compacta;

STN=subthalamic nucleus; Thal=thalamus; VP=ventral pallidum; VS=ventral striatum;

VTA=ventral tegmental area; vmPFC=ventral medial prefrontal cortex

Habner SN and Knutsen B, Neuropsychopharmacology Reviews, 2010

Neural circuits central to the three stages of addiction

(1)(2)

(3)

Koob GF and Volkow ND, 2010

Addiction, stage 1 (Binge/intoxication):focal points: ventral tegmental area (VTA),

nucleus accumbens (Acb shell & core), dorsal striatum

SNc = Substantia nigra parscompacta

VGP = ventral globus pallidusDVP = dorsal globus pallidus

Addiction, Stage 2 (Withdrawal/negative effects)Focal point: extended amygdala

CeA = Central nucleus of amygdala

BNST = bed nucleus of stria terminalis

CRF = corticotropin-releasing factor

NE = norepinephrine

Addiction, Stage 3 (preoccupation/anticipation “craving”)craving: orbitofrontal cortex-dorsal striatum, prefrontal cortex, basolateral

amygdala (BLA), hippocampus, insula; inhibitory control: cingulate gyrus, dorsolateral prefrontal cortex and inferior frontal cortex

Hypothesized sequential cascade of neuroplasticity underling addiction

Summary• Addiction is a disease caused by maladaptive neuroplastic changes in

brain circuitry

• Neuroplasticity occurs in distinct neuronal systems during three (partially overlapping) phases of addiction.

1) Stage 1 (Binge/intoxication): VTA and ventral and dorsal striatum

2) Stage 2 (Withdrawal/negative effects): Extended amygdala

3) Stage 3 (Craving): OFC-dorsal striatum, PFC, BLA, Hipp, insula;

(Inhibitory control deficits): cingulate gyrus, dlPFC,

inferior frontal cortex

• The overall shift in motivation to take addicting drugs is from positive rewards (e.g. euphoria) to avoidance of the negative effects of abstinence.

• Knowledge of the neuronal networks underlying addiction opens the door to novel pharmacologic and behavioral therapies and preventive strategies.

References (1)• Nutt D, et al, Development of a rational scale to assess the harm of drugs of

potential misuse, Lancet 369, 1047-53, 2007

• Sinha R, The clinical neurobiology of drug craving, Current Opinion in Neurobiology 23, 649 – 654, 2013

• Kalivas PW and Volkow ND, The neural basis of addiction : a pathology of motivation and choice, American Journal of Psychiatry 162, 1403 - 1413, 2005

• Koob GF and Volkow ND, Neurocircuitry of Addiction , Neuropsychopharmacology Reviews 35, 217 – 238, 2010

• Pierce RC and Kumaresan V, The mesolimbic dopamine system: the final common pathway for the reinforcing effect of drugs of abuse?, Neuroscience and Biobehavioral Reviews 30, 215-239, 2006

• LeDoux J, The amygdala, Current Biology 17, R868 – R874, 2007

• Robinson AJ and Nestler EJ, Transcriptional and epigenetic mechanisms of addiction, Nature Reviews Neuroscience 12, 623-637, 2012

References (2)

• Kreek MJ et al., Opiate addiction and cocaine addiction: underlying molecular neurobiology and genetics, Journal of Clinical Investigations 122, 3387-3393, 2012

• Mazei-Robison MS and Nestler EJ, Plasticity of ventral tegmental area and locus ceruleus catecholamine neurons, Cold Spring Harbor Perspectives in Medicine 2, a012070, 1-16, 2012

• Zhang L et al, Src Phosphorylation of mu-receptor is responsible for the receptor switching from an inhibitory to a stimulatory signal, Journal of Biological Chemistry 284, 1990-2000, 2009

• Zhang L et al, a novel noncanonical signaling pathway for the mu-opioid receptor, Molecular Pharmacology 84, 844-853, 2013

• Monfils MH et al, Extinction-reconsolidation Boundaries: Key to persistent attenuation of fear memories, Science 324, 951-955, 2009

• Hutton-Bedbrook K and McNally GP, The promises and pitfalls of retrieval-extinction procedures in preventing relapse to drug seeking, Frontiers in Psychiatry 4, article 4, 1-4, 2013

Journal Presentations,

• Milton AL and Everitt BJ, Wiping Drug Memories, Science336, 167-168, 2012

• Xue YX, et al, A memory retrieval-extinction procedure to prevent drug craving and relapse, Science 336, 241-245, 2012

Internet resources

• National Institute on Drug Abuse (NIDA) http://www.drugabuse.gov/

• National Institute on Alcohol Abuse and Alcoholism (NIAAA)

http://www.niaaa.nih.gov/

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