Drugs and addiction
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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 BMethadone C Lofexidine D.Naltrexone E.Buprenorphine.

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Drugs and addiction

Drugs and Addiction

Neuropsychiatry Lecture

11.21.12

Jeannine Foley


Drugs and addiction

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

  • AClonidine

  • BMethadone

  • CLofexidine

  • D.Naltrexone

  • E.Buprenorphine


Drugs and addiction

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

  • AClonidine

  • BMethadone

  • CLofexidine

  • 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.

  • Bgambling.

  • 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.

  • Bgambling.

  • C.anxiety.

  • Deating

  • E.guilt.


Drugs and addiction

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

  • AHeroin

  • B.Marijuana

  • C.d-Amphetamine

  • D.Phencyclidine

  • E.Lysergic acid diethylamide


Drugs and addiction

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

  • AHeroin

  • B.Marijuana

  • C.d-Amphetamine

  • D.Phencyclidine

  • E.Lysergic acid diethylamide


Dopamine has been shown to inhibit the release of

Dopamine has been shown to inhibit the release of:

  • Afollicle-stimulating hormone.

  • B.antidiuretic hormone

  • C.testosterone.

  • D.prolactin

  • E.thyroxin


Dopamine has been shown to inhibit the release of1

Dopamine has been shown to inhibit the release of:

  • Afollicle-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 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 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 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 opiate overdose is appropriately treated with:

  • A.naloxone.

  • B.naltrexone.

  • C.pentazocine.

  • D.buprenorphine.

  • E.levo-alpha-acetylmethadol.


Drugs and addiction

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-glutamyltransferase


Drugs and addiction

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-glutamyltransferase


Select a function for the gamma aminobutyric acid a gaba a receptor

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 receptor1

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

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 receptor1

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)


Drugs and addiction

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

  • AHeroin

  • B.Cocaine

  • C.Alcohol

  • DNicotine

  • E Amphetamine


Drugs and addiction

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

  • AHeroin

  • B.Cocaine

  • C.Alcohol

  • DNicotine

  • E Amphetamine


The cycle of addiction

The cycle of addiction


Human vs mouse brain anatomy

Human vs Mouse Brain Anatomy


Addiction circuitry

Addiction Circuitry

Dopamine

Glutamate

GABA

Orexin

Kauer and Malenka, 2007


Modeling addictive behavior

Modeling Addictive behavior

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


Addictive drugs enhance da neurotransmission

Addictive drugs enhance DA neurotransmission

  • 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


Drugs and addiction

The most addictive drugs tend to be the most harmful

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


Ethanol

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

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

Bustamante et al., 2009


Nicotine

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

Chronic stress blocks the nicotine induced increase in striatal dopamine


Opioids

Opioids

-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 NAc

Ogawa et al., 2007 PNAS


Cocaine and amphetamines

Cocaine and Amphetamines


Cocaine injections cause rapid dopamine release in the nac and vta

Cocaine injections cause rapid dopamine release in the NAc and VTA

Bradberry and Roth, 1989 Neurosci Letters


Cocaine induced glutamate signaling in the nac

Cocaine-Induced Glutamate Signaling in the NAc

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 NAc After Extinction

Moussawi et al., 2009


Modulation of synaptic function and plasticity in the vta

Modulation of synaptic function and plasticity in the VTA


Synaptic strength measured by the ampar nmdar ratio

Synaptic strength measured by the AMPAR/NMDAR ratio


Orexin enhances nmdar epscs in vta neurons

Orexin enhances NMDAR EPSCs in VTA neurons


Modulation of synaptic function and plasticity in the nac

Modulation of synaptic function and plasticity in the NAc


Mesolimbic system on drugs

Mesolimbic system on drugs


Glia surround synapses and release glutamate

Glia surround synapses and release glutamate


Glutamate homeostasis hypothesis of addiction

Glutamate homeostasis hypothesis of addiction


Effects of cocaine on spine morphology

Effects of Cocaine on Spine Morphology


Addiction pathological synaptic plasticity

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

PFC activity is reduced in subjects which abuse cocaine


Drugs and addiction

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

PET scanning in monkey basal ganglia


Treatment

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

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 therapies1

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/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

  • 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

AMPAR/NMDAR ratio is increased after withdrawal from chronic cocaine

Kourrich et al., 2007


Increase in ampar nmdar ratio is reversed by cocaine challenge

Increase in AMPAR/NMDAR ratio is Reversed by Cocaine Challenge


Cocaine induced ampar plasticity in the nac is mediated by nmdars

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

Schumann and Yaka, 2009


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