Chapter 12: Psychomotor Stimulants Flashcards

1
Q

Cocaine- HCl

A
  • Oral, intranasal, IV
  • Vulnerable to heat

Free base:

   - dissolve in H2O, NaHCO3
   - heat and dry= “crack”

Lipophilic
- easily crosses BBB

Metabolites:

     - benzoylecgonine
     - coc + EtOH —> cocaethylene
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2
Q

Ephedrine

A
  • Decreased appetite; increased energy
  • Bronchodilator

Amph:
- oral, IV

Meth:

  - from pseudo- ephedrine
  - smoked, intranasal

Metabolism:

  - about 50% excreted unchanged
  - half life 7-30 hrs
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3
Q

Primary drug actions of cocaine are:

A

Inhibition of neurotransmitter transporters

   - low affinity for DAT
   - higher affinity for NET and SERT

Increased DA release independent of DAT
- inhibition of NET in PFC drives excitation of VTA (increased frequency of DA release)

Inhibition of VGNaC in nerve axons (local anesthetic)
- procaine (Novocain) and lidocaine (Xylocaine)

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4
Q

Cocaine increased DA release independent of actions on DAT

A
  1. LC fibers project to the PFC, where they release NE onto excitatory a1-AR on glutamatergic pyramidal neurons
  2. NET inhibition by COC augments (increases) NE effects and actions of a1-AR in PFC

Increased excitation in PFC stimulates DA neurons in the VTA and elevates release of DA in NAcc

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5
Q

The primary drug actions of AMPH/mAMPH are

A
  • inhibition of neurotransmitter transporters
    - DAT, NET, and SERT (similar to COC)
  • increased DA release by reversal of DAT
    - AMPH and mAMPH are substrates for VMAT and DAT (takes up AMPH and gets into neuron)
    - m/AMPH are taken into vesicles, disrupt H+ gradient, reduce transport of DA into vesicles by VMAT; increases intracellular DA levels, because we can’t pump them into vesicles
    - DAT runs in reverse, releasing DA into synapse
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6
Q

AMPH and mAMPH disrupt the monoamine transport cycle

A
  1. m/AMPH enters DA nerve terminals in part through uptake by DAT
  2. m/AMPH provoke DA release from the synaptic vesicles into the cytoplasm
  3. DAT functions in reverse, releasing DA into the extracellular fluid
  4. The combined effect of these processes is a massive increase in synaptic DA levels
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7
Q

The behavioral effects of COC include

A

Euphoric “high”
-exhilaration, more energy, less fatigue, reinforcing, self-administered

Behavioral Activation

   - repetitive, stereotypes behaviors 
   - locomotion, rearing, sniffing

Sympathetic Arousal
- tachycardia, vasoconstriction, hypertension, hyperthermia

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8
Q

AMPH produces other effects

A

Other behavioral effects:

     - increased alertness, decreased sleep and improvised performance
     - sustained physical effort without need for sleep

Therapeutic uses:

    - Weight loss
    - ADHD
    - Narcolepsy
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9
Q

Psychostimulant microinjection: Nucleus accumbens

A

Increased locomotor behavior

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10
Q

Psychostimulant microinjection: Striatum

A

Increased stereotyped behaviors

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11
Q

6-OHDA lesion: Nucleus accumbens

A
  • decreased locomotor response following systematic administration of a low-dose psychostimulant
  • decreased reinforcing effectiveness of systemically administered psychostimulants
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12
Q

Cocaine and Amphetamine microinjection

A

Nucleus accumbens

Reinforcing to animal

  • NAcc DA (either D1 or D2 receptors) has been implicated in COC reward as model of relapse
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13
Q

COC-insensitive DAT-ki mice do not self-administer COC

A

DAT “knock-in”

   - transport DA
   - but not blocked COC

WT and HET mice
- show dose-dependent SA of COC

DAT-ki mice do not

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14
Q

Variations in DAT expression underlie behavioral response to COC

A

2 mechs:

     1. Differing DAT levels
     2. Differing levels of baseline DA release

LCR: increased DAT, less sensitive to COC
HCR: decreased DAT, more sensitive to COC

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15
Q

DA receptors in COC

A

D1 KO:

  • required for COC-induced behavioral activation
  • do not self-administer COC
  • drug’s ability to promote conditioned associations with environmental cues are dependent on activating D1 receptors

D2 or D3 KO:

  • not required for behavioral effects of COC
  • persist in COC self-administration
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16
Q

Chronic COC use alters brain function

A
  • occasional COC use may escalate to abuse and dependence
  • chronic COC use leads to tolerance and sensitization
  • hypofunction of the PFC caused by chronic COC
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17
Q

As COC dose increases

A

Locomotion, rearing, sniffing —> focus stereotypies

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18
Q

[…]% of COC users eventually abuse COC

A
  • rewarding properties
  • binge use
  • switch to smoking, IV administration
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19
Q

Binge use

A

Episodic bouts of repeated uses lasting hours/days with little or no sleep

20
Q

Abstinence Syndrome

A
  1. Crash- exhausted, depressed
  2. Withdrawal- anhedonia, anergia, anxiety, growing craving
  3. Extinction- symptoms subside
21
Q

CS (or US) exposure induces craving

A
  • incubation of craving

- mesolimbic DA release in NAcc(US,CS) —> increases craving

22
Q

Incubation of craving

A

Cravings and relapse increase over time following withdrawal

23
Q

Mesolimbic DA release —> increases craving

A

Increased in dorsal and ventral striatum, hippocampus, amygdala, and PFC

24
Q

Cue-induced cocaine craving is associated with heightened […]

A

Cue-induced cocaine craving is associated with heightened striatal DA release

25
Q

COC Sensitization

A

Once-daily injections
Response to drug becomes amplified (aka reverse tolerance)

Two phases:

  1. Induction
  2. Expression- sensitized response is manifested
26
Q

COC Tolerance

A

Continuous infusion

27
Q

Molecular adaptations in NAcc underlying tolerance

A
  • Reduced intracellular DA and reduced DA release
  • Reduced baseline rate of DA uptake
  • Reduced potency of cocaine to inhibit DA reuptake by DAT
  • Reduced D2 autoreceptors
28
Q

Neuroadaptations following chronic AMPH resemble chronic COC

A

COC-like adaptations

  • reduced DA release
  • reduced D2 autoreceptors
  • tolerance and sensitization

AMPH-specific adaptations

  • increased intracellular DA
  • AMPH potency for DAT remains unchanged
29
Q

Gray matter volume […] correlates with duration of chronic COC use

A

Gray matter volume reduction correlates with duration of chronic COC use

  • long-term use associated with less gray matter
30
Q

PFC is […] in compulsive seeking (shock-resistant) rats

A

PFC is hypoactive in compulsive seeking (shock-resistant) rats

31
Q

Hypofunction of the PFC caused by chronic COC

A
  • COC abusers show deficits in several cognitive control tasks (poor impulse control, poor decision making)
  • May contribute to COC-indices psychotic disorder
32
Q

Chronic m/AMPH use is associated with numerous adverse events

A
  • Dependence
  • Cognitive deficits
  • Psychosis
  • Neurotoxicity
  • Somatic outcomes
33
Q

Dependence

A

More likely in females

May lead to cognitive decline

34
Q

Psychosis

A

Visual/ auditory hallucinations

35
Q

Neurotoxicity

A

Long lasting reductions in levels of DA, TH, and DAT in dorsal striatum

  • decreased striatal DA levels, DAT binding, and D2/D3 receptor binding
36
Q

Somatic Outcomes

A

Cardiovascular (bp, MI, atherosclerosis) and stroke risk, “meth mouth”

37
Q

Psychostimulants […] symptoms of ADHD

A

Psychostimulants improve symptoms of ADHD

38
Q

ADHD Medications

A
  • amphetamine
  • methylphenidate
  • a2 AR agonists
  • NRI
39
Q

Methylphenidate (Ritalin)

A

Binds DAT and NET (blocks reuptake)

40
Q

Modafinil (Provigil)

A

Increased locomotor activity, but also antagonized barbituate-induced sedation (narcolepsy)

41
Q

Synthetic Cathinones

A

Substrates for DAT, NET, SERT:

  • Mephedrone
  • Methylone

Block monoamine transporters

  • MDPV
  • a-PVP
42
Q

Amphetamine Stereoisomers

A

L-AMPH: Benzedrine

D-AMPH: Dexedrine

43
Q

[…] and […] have similar structure to m/AMPH

A

Cathinone and ephedrine have similar structure to m/AMPH

44
Q

Smoking is effective route of mAMPH administration because:

A

It vaporizes at low temperatures and isn’t readily broken down by heat

45
Q

Amphetamines have […] half-life than COC

A

Amphetamines have longer half-life than COC

46
Q

AMPH is indirect agonists of catecholaminergic systems

A
  • Blocks catecholamine reuptake and release catecholamines from NT
  • Inhibit catecholamine metabolism using MAO