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Drugs and Addiction. Neuropsychiatry Lecture 11.21.12 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.

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Drugs and addiction

Drugs and Addiction

Neuropsychiatry Lecture

11.21.12

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

  • A. concentration.

  • B gambling.

  • C. anxiety.

  • Deating

  • E. guilt.


The cage questionnaire surveys an individual s relationship between alcohol and1
The CAGE Questionnaire surveys an individual's relationship between alcohol and

  • A. concentration.

  • B gambling.

  • C. anxiety.

  • Deating

  • E. guilt.


Chronic between alcohol abuse of which of the following drugs can cause intracerebralvasculitis / or hemorrhage, or subarachnoid hemorrhage?

  • A Heroin

  • B. Marijuana

  • C. d-Amphetamine

  • D. Phencyclidine

  • E. Lysergic acid diethylamide


Chronic between alcohol abuse of which of the following drugs can cause intracerebralvasculitis / 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
Dopamine between alcohol 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 of1
Dopamine between alcohol 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
Abrupt between alcohol 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 to1
Abrupt between alcohol 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
Severe between alcohol opiate overdose is appropriately treated with:

  • A. naloxone.

  • B. naltrexone.

  • C. pentazocine.

  • D. buprenorphine.

  • E. levo-alpha-acetylmethadol.


Severe opiate overdose is appropriately treated with1
Severe between alcohol opiate overdose is appropriately treated with:

  • A. naloxone.

  • B. naltrexone.

  • C. pentazocine.

  • D. buprenorphine.

  • E. levo-alpha-acetylmethadol.


Elevation between alcohol 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-glutamyltransferase


Elevation between alcohol 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-glutamyltransferase


Select a function for the gamma aminobutyric acid a gaba a receptor
Select between alcohol 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 receptor1
Select between alcohol 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
Select between alcohol 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 receptor1
Select between alcohol 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 between alcohol 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 between alcohol 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
The cycle of addiction between alcohol


Human vs mouse brain anatomy
Human between alcohol vs Mouse Brain Anatomy


Addiction circuitry
Addiction Circuitry between alcohol

Dopamine

Glutamate

GABA

Orexin

Kauer and Malenka, 2007


Modeling addictive behavior
Modeling Addictive behavior between alcohol

Drug/Alc

  • 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

Image from NIAAA


Psychomotor sensitization
Psychomotor Sensitization between alcohol


Addictive drugs enhance da neurotransmission
Addictive drugs enhance DA neurotransmission between alcohol

  • Increased extracellular DA in the striatum

  • Increased SA when DA Rs are partially antagonized, with cessation at more complete blockade

  • Inhibition of SA when DA synthesis is blocked

  • Cessation of SA when DA neurons have axons ablated


The most addictive drugs tend to be the most harmful between alcohol

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


Ethanol
Ethanol between alcohol

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

Bustamante et al., 2009


Nicotine
Nicotine species of rats

  • 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



Opioids
Opioids striatal dopamine

-Increase burst firing of VTA DA neurons

-Disinhibition by inactivation of GABA neurons

Dopamine

GABA


Morphine increases da in the nac
Morphine increases DA in the striatal dopamineNAc

Ogawa et al., 2007 PNAS


Cocaine and amphetamines
Cocaine and Amphetamines striatal dopamine


Cocaine injections cause rapid dopamine release in the nac and vta
Cocaine injections cause rapid dopamine release in the striatal dopamineNAc and VTA

Bradberry and Roth, 1989 Neurosci Letters


Cocaine induced glutamate signaling in the nac
Cocaine-Induced Glutamate Signaling in the striatal dopamineNAc

Glutamate in NAc

Cornish and Kalivas, 2000

McFarland et al., 2003


Increasing gaba concentrations attenuate cocaine seeking behavior
Increasing GABA Concentrations Attenuate Cocaine Seeking Behavior

McFarland and Kalivas, 2001


Plasticity is attenuated in the nac after extinction
Plasticity is attenuated in the BehaviorNAc After Extinction

Moussawi et al., 2009




Orexin enhances nmdar epscs in vta neurons
Orexin Behavior enhances NMDAR EPSCs in VTA neurons



Mesolimbic system on drugs
Mesolimbic Behavior system on drugs





Addiction pathological synaptic plasticity
Addiction: pathological synaptic plasticity Behavior

  • 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



Decreased BehaviorD2 receptors in the ventral striatum have been found in alcoholics and addictive users of other drugs as well as in obese individuals



Treatment
Treatment Behavior

  • 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
GABA therapies Behavior

  • 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 therapies1
GABA therapies Behavior

  • Gabapentin (~1200mg/day) decreased alcohol craving and increased sleep quality in double blind placebo controlled human studies

  • Topiramate increases GABAa activation and decreases AMPA/Kainateactivatin 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
Ion Channel Targeting Drugs Behavior

  • 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




Cocaine induced ampar plasticity in the nac is mediated by nmdars
Cocaine-Induced AMPAR Plasticity in the ChallengeNAc is Mediated by NMDARs

Schumann and Yaka, 2009


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