Drugs and Addiction

Neuropsychiatry Lecture11.21.12

Jeannine Foley

Which of the following treatments for opioid dependence is both an opioid receptor agonist and antagonist?

• A Clonidine• B Methadone• C Lofexidine• D. Naltrexone• E. Buprenorphine

Which of the following treatments for opioid dependence is both an opioid receptor agonist and antagonist?

• A Clonidine• B Methadone• C Lofexidine• D. Naltrexone• E. Buprenorphine

The CAGE Questionnaire surveys an individual's relationship between alcohol and

• A. concentration.• B gambling.• C. anxiety.• D eating• E. guilt.

The CAGE Questionnaire surveys an individual's relationship between alcohol and

• A. concentration.• B gambling.• C. anxiety.• D eating• E. guilt.

Chronic abuse of which of the following drugs can cause intracerebral vasculitis / or hemorrhage, or subarachnoid hemorrhage?

• A Heroin• B. Marijuana• C. d-Amphetamine• D. Phencyclidine• E. Lysergic acid diethylamide

Chronic abuse of which of the following drugs can cause intracerebral vasculitis / or hemorrhage, or subarachnoid hemorrhage?

• A Heroin• B. Marijuana• C. d-Amphetamine• D. Phencyclidine• E. Lysergic acid diethylamide

Dopamine has been shown to inhibit the release of:

• A follicle-stimulating hormone.• B. antidiuretic hormone• C. testosterone.• D. prolactin• E. thyroxin

Dopamine has been shown to inhibit the release of:

• A follicle-stimulating hormone.• B. antidiuretic hormone• C. testosterone.• D. prolactin• E. thyroxin

Abrupt drug withdrawal is most likely to be life-threatening for a person addicted to.

• A. heroin.• B. cocaine.• C. naloxone.• D. amobarbital.• E. phencyclidine (PCP).

Abrupt drug withdrawal is most likely to be life-threatening for a person addicted to.

• A. heroin.• B. cocaine.• C. naloxone.• D. amobarbital.• E. phencyclidine (PCP).

Severe opiate overdose is appropriately treated with:

• A. naloxone.• B. naltrexone.• C. pentazocine.• D. buprenorphine.• E. levo-alpha-acetylmethadol.

Severe opiate overdose is appropriately treated with:

• A. naloxone.• B. naltrexone.• C. pentazocine.• D. buprenorphine.• E. levo-alpha-acetylmethadol.

Elevation of which of the following laboratory tests is most useful in detecting chronic alcohol abuse?

• A. Alkaline phosphatase• B. White blood cell count• C Creatinine phosphokinase • D. Gamma-glutamyl transferase

Elevation of which of the following laboratory tests is most useful in detecting chronic alcohol abuse?

• A. Alkaline phosphatase• B. White blood cell count• C Creatinine phosphokinase • D. Gamma-glutamyl transferase

Select a function for the gamma-aminobutyric acid-A (GABA-A) receptor

• A. Depolarizes cells by opening channels that principally allow calcium to enter the cell

• B. Gates channels that allow sodium, but not calcium, to cross the cell membrane

• C. Gates chloride channels• D. Activates G proteins and modulates calcium

and potassium channels• E. Activates adenylyl cyclase and raises cyclic

adenosine monophosphate (cAMP)

Select a function for the gamma-aminobutyric acid-A (GABA-A) receptor

• A. Depolarizes cells by opening channels that principally allow calcium to enter the cell

• B. Gates channels that allow sodium, but not calcium, to cross the cell membrane

• C. Gates chloride channels• D. Activates G proteins and modulates calcium

and potassium channels• E. Activates adenylyl cyclase and raises cyclic

adenosine monophosphate (cAMP)

Select a function for the Dopamine (Dl) receptor

• A. Depolarizes cells by opening channels that principally allow calcium to enter the cell

• B. Gates channels that allow sodium, but not calcium, to cross the cell membrane

• C. Gates chloride channels• D. Activates G proteins and modulates calcium

and potassium channels• E. Activates adenylyl cyclase and raises cyclic

adenosine monophosphate (cAMP)

Select a function for the Dopamine (Dl) receptor

• A. Depolarizes cells by opening channels that principally allow calcium to enter the cell

• B. Gates channels that allow sodium, but not calcium, to cross the cell membrane

• C. Gates chloride channels• D. Activates G proteins and modulates calcium

and potassium channels• E. Activates adenylyl cyclase and raises cyclic

adenosine monophosphate (cAMP)

Which of the following substances contributes most to premature death anddisability in the United States?

• A Heroin• B. Cocaine• C. Alcohol• D Nicotine• E Amphetamine

Which of the following substances contributes most to premature death anddisability in the United States?

• A Heroin• B. Cocaine• C. Alcohol• D Nicotine• E Amphetamine

The cycle of addiction

Human vs Mouse Brain Anatomy

Addiction Circuitry

Kauer and Malenka, 2007

DopamineGlutamateGABAOrexin

Modeling Addictive behavior

Image from NIAAA

• To model relapse behavior, train animals in apparatus with contingent or non-contingent cocaine exposure and withdraw them for a period of time.

• Induce relapse via stress, drug administration, or cue

Drug/Alc

Psychomotor Sensitization

Addictive drugs enhance DA neurotransmission

1. Increased extracellular DA in the striatum2. Increased SA when DA Rs are partially

antagonized, with cessation at more complete blockade

3. Inhibition of SA when DA synthesis is blocked4. Cessation of SA when DA neurons have axons

ablated

Nutt D, King LA, Saulsbury W, Blakemore C (March 2007)

The most addictive drugs tend to be the most harmful

Ethanol

• ½ Americans over 12 consume alcohol• ¼ Americans binge drink• 3 drinks increases DA by 138% in men and

69% in women• 5-20mM induces reinforcing DA concentration• Causes GABA disinhibition• Directly activates VTA DA neurons

Ethanol increases DA to a different extent in different species of rats

Bustamante et al., 2009

Nicotine

• 1/3 of the population over 13 uses it• Most common cause of drug-induced

premature death and disability• Enhances excitatory output to DA neurons• Acts on presynaptic Rs on DA terminals• 240nM/cigarette max brain concentration– Decreases to 25nM overnight

Chronic stress blocks the nicotine induced increase in striatal dopamine

Opioids

-Increase burst firing of VTA DA neurons-Disinhibition by inactivation of GABA neurons

DopamineGABA

Morphine increases DA in the NAc

Ogawa et al., 2007 PNAS

Cocaine and Amphetamines

Cocaine injections cause rapid dopamine release in the NAc and VTA

Bradberry and Roth, 1989 Neurosci Letters

Cocaine-Induced Glutamate Signaling in the NAc

McFarland et al., 2003 Cornish and Kalivas, 2000

Glutamate in NAc

Increasing GABA Concentrations Attenuate Cocaine Seeking Behavior

McFarland and Kalivas, 2001

Plasticity is attenuated in the NAc After Extinction

Moussawi et al., 2009

Modulation of synaptic function and plasticity in the VTA

Synaptic strength measured by the AMPAR/NMDAR ratio

Orexin enhances NMDAR EPSCs in VTA neurons

Modulation of synaptic function and plasticity in the NAc

Mesolimbic system on drugs

Glia surround synapses and release glutamate

Glutamate homeostasis hypothesis of addiction

Effects of Cocaine on Spine Morphology

Addiction: pathological synaptic plasticity

• Reward behavior circuits become habitually active and have decreased response to environmental stimuli and top down processing

• Behavior starts as drug seeking and is easily influenced by external stimuli. Changes in D2R levels in NAc alter behavioral circuits which become habitual then compulsive

• People with abnormal D2R concentrations may be more vulnerable to addiction

• Differential effects of drugs

PFC activity is reduced in subjects which abuse cocaine

Decreased D2 receptors in the ventral striatum have been found in alcoholics and addictive users of other drugs as well as in obese individuals

PET scanning in monkey basal ganglia

Treatment

• psychotherapy • methadone for heroin addicts • nausea-inducing Antabuse for alcoholics• TMS- stimulate PFC->VTA->DA in NAc to accoutn

for decreased DA in addicts• Vaccines like TA-CD (for cocaine) prevent the

addictive substance from ever reaching the user's brain

• Pharmacotherapy

GABA therapies• GABAa receptor antagonists that bind at or near the active site, such as

picrotoxin and bicuculline, have been found to reduce self-administration of ethanol and cocaine. – Nowak et al. reported that microinjections of picrotoxin or of bicuculline into

the VTA resulted in decreases in ethanol consumption, but that microinjections in regions outside the VTA failed to decrease ethanol intake

• Compared to rats that were in the lowest 15th percentile of ethanol self administration (LES), the rats that were in the highest 15th percentile (HES) had significantly higher GABAA receptor mRNA levels in the dorsal raphe, medial raphe, cerebellum, and hippocampus (Tyndale and Tomkins). – (Thus, elevated GABAA receptor mRNA associated with an increased density of

GABAa receptors, may predispose to the development of an addictive process.)

GABA therapies

•Gabapentin (~1200mg/day) decreased alcohol craving and increased sleep quality in double blind placebo controlled human studies•Topiramate increases GABAa activation and decreases AMPA/Kainate activatin which decreases DA release in the Nac•GABAb receptor agonist baclofen has been found to attenuate self-administration of cocaine, heroin, ethanol, nicotine, and d-amphetamine.

Ion Channel Targeting Drugs

• L-type Calcium channel blockers– DHP decreases drug related behavior in rodents

but human studies are lacking• SK-Type calcium activated potassium channels– Chronic EtOH exposure in rodents decreases SK

currents– Decreased alcohol and cocaine creaving and intake

in human addicts with bipolar and some evidence for decreased alcohol intake in schizophrenics

AMPAR/NMDAR ratio is increased after withdrawal from chronic cocaine

Kourrich et al., 2007

Increase in AMPAR/NMDAR ratio is Reversed by Cocaine Challenge

Cocaine-Induced AMPAR Plasticity in the NAc is Mediated by NMDARs

Schumann and Yaka, 2009