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Molecular Neuroscience III > 7 - Psychostimulants > Flashcards

7 - Psychostimulants Flashcards

Know striatal circuitry, as shown in slide 8

1
Q

What does cocaine do, roughly?

A

Inhibits dopamine reuptake.

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2
Q

What do amphetamines and their derivatives do, roughly?

A

Inhibit dopamine reuptake and degradative enzymes.

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3
Q

What is the biggest goal in pharmaceutical research on psychostimulants?

A

Achieving stimulating effects without addiction or other deleterious effects

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4
Q

True or false? As a requirement for a drug to be a psychostimulant, there needs to be release of dopamine. From where and to where?

A

True

From VTA to nucleus accumbens, which in turns projects to prefrontal cortex

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5
Q

What are the two parts of the nucleus accumbens? What is the consequence of this on psychostimulants?

A

Outer shell - reward
Inner core - Locomotion

Must test psychostimulants for effects on locomotion, as well as reward/stimulation

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6
Q

What type of neurons in the caudate putamen do VTA DA neurons stimulate in response to psychostimulants? (3)

A

Some GABAergic neurons expressing enkephalins, some co-express dynorphin and substance P

Small number of ACh neurons

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7
Q

What are trace amine receptors?

A

Endogenous G-protein coupled receptors that may have binding properties with amphetamines/psychostimulants

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8
Q

In what two areas of the brain are increased dendritic spine changes observed after long term exposure to psychostimulants?

A
  • Nucleus accumbens

- Prefrontal cortex

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9
Q

How does the shape of dendrites change after long term use of psychostimulants?

A
  • Become thinner
  • Less AMPA receptors on surface in NAc
  • More NMDA receptors in NAc
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10
Q

What systems does MDMA modulate? (2)

A
  • Dopaminergic system (through DATs)

- Serotonergic system (through 5-HT2a receptors)

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11
Q

True or false? Nicotine abuse results in tolerance and desensitization of the drug?

A

False, sensitization is pretty stable. However, nicotine receptor concentrations increase in certain areas.

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12
Q

List 5 plant psychostimulants and 1 synthetic psychostimulant.

A

Plant

  • Caffeine
  • Nicotine
  • Ephedrine
  • Khat
  • Cocaine

Synthetic
- Amphetamine and derivatives (eg. methamphetamine and MDMA)

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13
Q

List 5 acute effects of psychostimulants

A
  • hyperactivity
  • well-being and euphoria
  • increased energy and concentration
  • decreased sleepiness
  • decreased appetite
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14
Q

What does chronic abuse of psychostimulants cause? (4)

A

Disruption of circuits:
• reward - NAc and ventral pallidum
• motivation/drive - orbitofrontal cortex (OFC) and subcallosal cortex
• memory and learning - hippocampus, amygdala, and dorsal striatum
• inhibitory control – prefrontal cortex (PFC), the anterior cingulate cortex (ACC), and the lateral orbitofrontal cortex (OFC).

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15
Q

What is the main/broad mechanism for the effects of psychostimulants?

A

They induce dopamine release

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16
Q

Psychostimulant mediated release of dopamine in these two areas of the nucleus accumbens causes what:

  • Shell
  • Core
A

Shell: reward
Core: Locomotion

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17
Q

Which neurotransmitters does cocaine, methylphenidate (ritalin) and amphetamines block reuptake of?

What is seen in DAT KO mice?

NET KO mice?

A
  • Dopamine
  • Norepinephrine
  • Serotonin (except methylphenidate)
  • Dopamine transporter (DAT) knockout mice continue to administer cocaine, which indicates an interaction with other transporters. DAT-KO is hyperactive and stimulants have calming effect.
  • Norepineprine transporter (NET) knockout mice given cocaine show significantly higher and dose dependent increase in the locomotion.
  • Apart from action on neurotransmitter uptake, amphetamines are also agonists of the recently discovered trace amine receptors.
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18
Q

Describe signal transduction upon activation of dopamine receptors by psychostimulants in D1 (2) and D2 (4)

A

D1 mechanisms:

  • Activation of CREB is neuronal adaptation in the NAc to psychostimulants
  • PKA activation induces DARPP-32 (hyperlocomotor effects)

D2 mechanisms:

  • β-arrestins cause receptor internalization and activate serine/threonine kinase Akt
  • Akt phosphorylates GSK-3 (glycogen synthase kinase-3), resulting in GSK-3 inactivation
  • Akt phosphorylation/activation is reduced by amphetamine treatment
  • Suppression of GSK-3 activity inhibited locomotor hyperactivity in DAT-KO or amphetamine treated mice
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19
Q

What is Cdk5?

A

Cdk5 is a cellular kinase that is involved in negative feedback of PKA signalling. Inhibition of Cdk5 enhances cocaine-induced behavioral sensitization.

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20
Q

Describe morphological changes after chronic exposure to psychostimulants

A
  • Increase in dendritic spines in PFC, NAc and VTA
  • Chronic expo- sure to cocaine induces surface expression of NMDA and disappearance of AMPA glutamate receptors in NAc
  • Early withdrawal induces long-term depression whereas late withdrawal is connected to longterm potentiation and morphological changes observed as a mushroom-shaped spine.
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21
Q

List four psychostimulant anti-addictive mediators and three pro-addictive mediators

A

Anti:

  • Shati
  • Piccolo
  • TNF-α
  • Glial cell line-derived neurotrophic factor (GDNF)

Pro:

  • Matrix metalloproteinases (MMPs)
  • Tissue plasminogen activator (tPA)
  • Brain-derived neurotrophic factor (BDNF)
22
Q

What is shati?

A

a protein that contains sequences of N-acetyltransferases. Repeated methamphetamine treatment dose-dependently induces expression of shati mRNA in the nucleus accumbens. Shati antisense oligonucleotides inhibit expression of shati mRNA and enhance methamphetamine-induced hyperlocomotion, sensitization, and conditioned place preference (CPP).

23
Q

What is piccolo?

A

a component of the presynaptic active zone with proposed scaffolding role. Immunoreactivity to piccolo and tyrosine hydroxylase overlap. The expression of piccolo mRNA increases after repeated treatment with methamphetamine and piccolo-antisense enhance methamphetamine-induced behavioral sensitization and CPP. Piccolo may act as a cytoskeletal regulator for DAT membrane trafficking.

24
Q

How is TNF-α an anti-addictive mediator for psychostimulants?

A

Tumor Necrosis Factor-α (TNF- α) is a pro-inflammatory cytokine produced by macrophages and circulating monocytes. Methamphetamine or cocaine induces the expression of TNF-α mRNA in human brain endothelium. Responses to methamphetamine are enhanced in TNF-α(−/−) mice.

25
Q

How is Glial cell line–derived neurotrophic factor (GDNF) an anti-addictive mediator for psychostimulants?

A

promotes the survival and function of dopamine neurons in vivo. GDNF(+/-) mice show no changes after acute administration of cocaine but are hypersensitive to repeated cocaine. Partial reduction in the expression of GDNF potentiates methamphetamine self administration in rats. A dipeptide Leu-Ile, which is both a TNF-α inducer and GDNF inducer may have a therapeutic potential. However TNF-α is known to stimulate production of pro- inflammatory cytokines.

26
Q

How are Brain-derived neurotrophic factors (BDNF) pro-addictive mediators for psychostimulants?

A

activates receptor tyrosine kinase TrkB and activates intracellular signaling via mitogen-activated protein kinase (MAPK/ERK) and phosphatidylinositol 3-kinase (PI-3K). BDNF null mice are not viable. Heterozygous BDNF+/- mice are less sensitive to the locomotor stimulant effect of cocaine and show delayed development of locomotor sensitization to the drug. MAPK/ERK and PI-3K overexpressed during withdrawal which may indicate their role in the relapse to the drug.

27
Q

What are Tissue plasminogen activators (tPA)?

A

Serine proteases that catalyzes the conversion of plasminogen to plasmin (important for fibrinolysis). Repeated but not single methamphetamine treatments dose-dependently induce the expression of tPA mRNA in the frontal cortex, nucleus accumbens, striatum, and hippocampus. tPA knockout is no different from wt after single dose of methamphetamine but shows reduced conditioned place preference (CPP) and behavioral sensitization after multiple treatment with methamphetamine.

28
Q

What are Matrix metalloproteinases (MMPs)?

A

A group of enzymes that cleave extracellular matrix proteins and cell-surface components. Overexpressed in the chronic methamphetamine treatment. MMP-2(−/−) or MMP-9(−/−) mice show attenuated methamphetamine-induced behavioral sensitization and CPP.

29
Q

What is observed with D2 receptor density after long term cocaine administration?

A

Research in humans and laboratory animals shows correlation of reduced availability of striatal D2 with increased vulnerability to drug addiction. Also healthy non- abusing volunteers expressing low levels of D2 receptors report more pleasant experiences when taking drugs of abuse

30
Q

How is brain activity in cocaine abusers different from non-addicted subjects?

A
  • Decrease of relative glucose metabolism in the cortex of a cocaine abuser
  • Cocaine induces activation of the cortex and the mesolimbic DA subcortical brain areas in drug addict
  • DA receptor availability increases in cocaine addicts when watching a video of a person taking drugs
31
Q

Methamphetamine induces degeneration of what types of neurons? (2)

A
  • Dopaminergic

- Serotonergic

32
Q

What is 3,4-methylenedioxymethamphetamine

(MDMA)?

A

“Ecstasy” - a psychostimulant, related structurally to methamphetamine.
• Mixed stimulant and mild hallucinogenic actions via stimulation of 5-HT2A receptors. Serotonergic component is responsible for elevation of mood, improved social relations and hallucinations.
• Induces downregulation of postsynaptic 5-HT2A receptors.
• Induces downregulation of tryptophan hydroxylase.
• Induces severe hyperthermia.
• Users show severely impaired memory.
• Neurotoxic to serotonergic axons and dendrites.
• Dangerous interactions with other drugs eg. MAO inhibitors
• SERT knockout shows reduced locomotor response to MDMA but not to other psychostimulants. SERT-KO also do not self-administer MDMA.

33
Q

List some treatments for psychostimulant addiction (6)

A
  • Dopamine agonists to decrease craving and withdrawal
  • Dopamine receptor antagonists as antipsychotic agents (unsuccessful)
  • Modafinil to release monoamines and reduce withdrawal
  • Psychostimulant substitution
  • Disulfiram, which blocks alcohol metabolizer aldehyde dehydrogenase and dopamine β-hydroxylase
  • Immunotherapy to stimulate immune system to produce antibodies against abused drugs
34
Q

Describe immunotherapy to treat psychostimulant addiction (2)

A
  • Drugs alone do not usually induce the immune reaction. To stimulate production of antibodies (active immunization method), drugs are conjugated to a molecule that will trigger the immune reaction. The produced antibodies present in the circulation will bind the drug and this complex will not pass the blood-brain- barrier.
  • Most advanced vaccine is TA-CD, vaccinated mice using cocaine linked to deactivated cholera toxin B subunit protein (clinical trials in humans in progress)
  • Active immunization requires 2–3 months period of injecting with a drug–protein conjugate before a long-lasting immunologic memory against the drug of abuse is established. Currently under development are monoclonal antibodies that can be engineered for immediate and longterm protection against meth, without creating an immunologic memory.
35
Q

List three psychostimulants used as pharmaceuticals

A

Methylphenidate (Ritalin), amphetamine (adderall) - ADHD • Sibutramine – anorexant – withdrawn (strokes)
• Ampakines eg. aniracetam – increase attention

36
Q

What is khat? (4)

A

A drug most often confiscated at the border

  • Plant cultivated in north east Africa and Arabian Peninsula
  • Cathinone is main active compound (metabolized to NE) along with cathine (amphetamine like properties)
  • Chewing for spiritual or anti-depressive properties
  • Recent abuse has led to legal classification
37
Q

Describe tobacco smoking as psychostimulant abuse (4)

A
  • The main active ingredient is nicotine, an agonist of cholinergic nicotinic receptors.
  • Genetic risk of smoking - association with neuronal nicotinic acetylcholine receptor genes and also polymorphism of the dopamine b-hydroxylase or tryptophan hydroxylase genes.
  • Nicotine induces release of various neurotransmitters in the brain and this is a reason for variety of physiological effects observed after its application.
  • Nicotine administration to mice upregulates levels of the type2 ryanodine receptor (RyR2), a Ca2+ -release channel present on the endoplasmic reticulum, in a number of brain areas associated with cognition and addiction. Nicotine-ryanodine receptor interaction is dependent on a4b2-nAChR subtype.
38
Q

What does chronic nicotine administration cause? Is this reversible?

A
  • Chronic nicotine administration produces AchR upregulation
  • Nicotine receptors number is increased in human postmortem prefrontal cortex, hippocampus, entorhinal cortex, and, to a lesser extent, striatum of smokers. The most upregulated are α4β2 nicotinic receptors.
  • Nicotine receptors number is normalized in ex-smokers, indicating the process is reversible. These results were confirmed in laboratory animal nicotine-addiction models.
39
Q

Which transcription factors does nicotine strongly induce expression of?

A

Nicotine induces c-fos and fos-related antigen (FRA) transcription factor expressions
- Acute nicotine increases c-fos and FRA reactivity in most of the brain regions, especially the striatum, the shell and core of the nucleus accumbens, the lateral septum, the prefrontal cortex, and the cingulate cortex. In contrast to acute nicotine, chronic nicotine self-administration did not increase c-fos immunoreactivity in the hypothalamus, locus coeruleus, amygdala, and dentate gyrus.

40
Q

How does nicotine affect the reward system?

Go into detail on nicotine receptor knockouts and how they influence nicotine reinforcement (6)

A
  • DA release in nucleus accumbens
  • If expression of α4β2 nicotinic receptors is abolished, nicotine no longer has reinforcing properties
  • β2 nicotine receptor subunit knockouts have reduced DA release in the nucleus accumbens in response to nicotine. β2−/− mice are also a model of sudden infant death syndrome (SIDS).
  • α5 subunit KO mice self administer more nicotine. Humans with mutated CHRNA5, the gene encoding α5 subunit, also consume more nicotine.
  • β4 subunit overexpression in mice significantly reduces consumption of nicotine. The β4 –mediated nicotine aversion is also dependent on α5 subunit function.
  • Mice lacking the α6 subunit do not acquire intravenous nicotine self-administration.
  • 6-hydroxydopamine (neurotoxin) lesions of nucleus accumbens dopaminergic neurons significantly attenuate both responding for nicotine in rats trained to lever press for the drug and the locomotor stimulant response (the increase in spontaneous locomotion) to nicotine.
41
Q

List four neurotransmitter systems that nicotine interacts with and briefly describe the interaction.

A
  • Norepinephrine (Increased TH levels)
  • 5-HT (inhibited released in hippocampus, partially alleviates depression symptoms)
  • Opioid peptides (increases β-endorphin in hypothalamus and Met-enkephaline in striatum. Naloxone (μ antagonist) reduces nicotine withdrawal)
  • GABA (GABA increase blocks nicotine induced DA release in NAc and development of nicotine induced conditioned place preference
42
Q

How does nicotine affect attention and cognition?

A
  • Enhances attention and cognitive performance
  • α4β2, α3β2, and α7 receptors located in the hippocampus play an important role in the effects of nicotine on working memory.
  • Nicotine, through stimulation of nicotinic receptors, may also influence the expression and the processing of amyloid precursor protein (APP), increasing the secretion of neuroprotective soluble APP.
43
Q

How does tobacco smoking affect MAO expression? Why?

A
  • MAO is decreased in tobacco smokers
  • Interestingly it is not nicotine but 2,3,6-trimethyl-benzoquinone and 2-naphthylamine, which are present in tobacco smoke and are responsible for MAO blockade.
44
Q

What is treatment for nicotine addiction? (6)

A
  • Replacement therapy
    • α4β2 nicotinic agonist varenicline, and bupropion (nicotinic receptor antagonist and also NA- DA uptake inhibitor respectively) are also useful
  • Antibodies elicited by a nicotine vaccine can present in the blood stream and bind to the nicotine as it enters the circulation through the lungs. The nicotine-antibody complex cannot cross the blood–brain barrier due to its size therefore nicotine is not inducing brain stimulation.
  • Nicotine Qbeta
  • NicVAX: a bacterial exoprotein conjugate vaccine
  • TA-NIC: cholera toxin conjugate vaccine
45
Q

What are some challenges to developing a nicotine vaccine?

A

The vaccination poses ethical and legal challenges. For example treatment of adolescents with vaccines can effect in smoking more cigarettes in order to overcome the nicotine blockade, and as a results significant increase of ingested carcinogens.

46
Q

How is the insular cortex involved in nicotine addiction? (4)

A
  • Insula is an invagination of the cerebral cortex between frontal, parietal and temporal lobes.
  • Some tobacco smokers who suffered injury to the insula quit smoking without withdrawal symptoms.
  • This indicates that insula may be involved in mediating the addiction to nicotine.
  • The accidents involving damage to insula are not common (luckily) therefore there is still not enough data to confirm this hypothesis.

Stimuli which activate the right anterior insular cortex (AIC) are mostly arousing to the body whereas left AIC is activated by positive and emotional feelings. Studies in cigarette smokers who experienced brain injury to the insula show that these damages disrupted their smoking habit. This effect was observed in both left and right insular injuries but it was observed twice more often when the injured was the right insula.
Lesions of this region in rats disrupted well-established addiction to amphetamine.

47
Q

What is arecoline? (4)

A
  • An agonist of muscarinic and nicotinic receptors
  • Found in areca palm nuts
  • In the South Asia usually chewed together with betel leafs and/or tobacco and lime for its stimulating effects.
  • Palm nut is strong carcinogen
48
Q

How does caffeine work?

A

An antagonist of inhibitory adenosine receptors

49
Q

What are four positive effects of coffee drinking?

A
  • Increased alertness after single dose
  • Reduced chance to get Alzheimer’s disease
  • Reduced chance to develop some forms of cancer
  • Reduced suicidal rate (antidepressant action)
50
Q

How can adenosine differentially reduce or stimulate Glutamate release in the striatum?

A

It was proposed that dual A1 and A2A receptors present on the glutamatergic terminals in the striatum act as a switch, where low concentration of adenosine activates predominantly A1 receptors whereas high concentration of adenosine are required to stimulate A2A receptors and as an effect adenosine can either reduce or stimulate the GLU release.

May have consequence for effects of caffeine and genetic predisposition for caffeine susceptibility.

Molecular Neuroscience III (8 decks)

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