the rest of neuropharmacology chapter 18 and 19 slides

  1. A series of endogenous inverse agonists, called _____, produces extreme anxiety and an overwhelming sense of panic. These inverse agonists are presumed to uncouple the GABA receptors from the Cl- channels so that GABA is less effective in causing entry of Cl- into the cell, leading to increased membrane excitability.
    β-carbolines
  2. Neuropharmacologically, a specific BDZ receptor antagonist, ______, was developed. ______ prevents the effects of BDZ binding but has no effect on the GABA receptor.
    flumazenil
  3. pregnenolone, allopregnanolone, tetrahydrodeoxycorticosterone, and dehydroepiandrosterone (DHEA), are synthesized from cholesterol in both the CNS and PNS.
    A family of neurosteroidsNeuroactive steroids bind to a site on the GABAA receptor that is not the GABA biding site and potentiate the effect of GABA by increasing the duration of GABA induced Cl- channel opening. The role of neurosteroid majorly seen in panic disorder: when a panic attack occurs as an episode in panic disorder patients, the levels of neurosteroids drop; these signals reduce GABA control of the anxiety. Since there is no change in health subjects even when they experience similar levels of panic anxiety, it suggests that neurosteroids in healthy people are not reduced by anxiety stimuli. Thus, reduced neurosteroids may represent the underlying pathophysiology of the panic disorder.
  4. , baseline levels of neurosteroids are _____ compared with controls in panic disorder


     neurostetoid levels tend to be _____ in individuals treated for Generalized Anxiety Disorder and phobia.
    elevated (cuz body's natural defense against spontaneous panic attack)

    lower
  5. Higher activity of DAergic neurons to stress: Stress, such as forced swimming, increases firing of ______ neurons and increases _____ in the prefrontal cortex (PFC);
    mesocortical dopaminergic

    dopamine turnover
  6. What effects on dopamine?

    Increase anxiety (β-carboline -> anxiogenic)

    Diazepam (anxiolytic) blocks the anxiety responses to the stressors and to β-carboline treatment
    Increase dopamine metabolism in prefrontal cortex.

    Decrease dopamine turnover
  7. oNormally, the PFC normally produces descending inhibitory control of emotional reactions elicited by the amygdala. However, this descending inhibition is suggested to be interrupted by the above enhanced dopaminergic activity. That is; increased mesolimbic pathway via D1 or D2 receptors at the amygdala “interrupts” the PFC descending inhibition on the amygdala.

    dopamine metabolism/ activity/ turnover = anxiety

    inhibited dopamine metablism/ activity/ turnover = anxiolytic
    oNormally, the PFC normally produces descending inhibitory control of emotional reactions elicited by the amygdala. However, this descending inhibition is suggested to be interrupted by the above enhanced dopaminergic activity. That is; increased mesolimbic pathway via D1 or D2 receptors at the amygdala “interrupts” the PFC descending inhibition on the amygdala. 

    dopamine metabolism/ activity/ turnover = anxiety

    inhibited dopamine metablism/ activity/ turnover = anxiolytic  (((prefrontal cortex)))
  8. _____ is a 5-HT1A receptor partial agonist that initially stimulates 5-HT1A somatodendritic autoreceptors, which would acutely reduce 5-HT transmission. However, the use of it is actually a chronic treatment that would produce down-regulation of 5-HT1A autoreceptors (desensitization) causing increase in 5-HT release. This should be the mechanism of anxiolytic.

    Chronic _____ desensitizes terminal 5-HT autoreceptors (but not 5-HT2 receptors) in orbitofrontal cortex after a full 8 weeks of treatment, when improvement  in OCD symptoms occurs. Autoreceptors are desensitized by accumulated 5-HT. Desensitized autoreceptors (by tolerance) means more 5-HT is released to act on postsynaptic 5-HT2 receptors
    Buspirone - desensitizes serotonin 1A (5-HT1A) autoreceptors so more serotonin released to stop anxiety

    SSRI- after autoreceptors desensitized more serotonin and act on serotonin 2 (5-HT2) receptors
  9. Timing: Brain abnormalities depend on the timing of exposure of the brain to stress. The developmental stage of the brain that is highly vulnerable to stress is _____ or early _____.
    prenatal

    postnatal
  10. chronic stress causes shrinking and simplification of dendritic arbors as well as loss of dendritic spines in the PFC of male rats. In contrast, in females, similar stress causes estrogen-dependent enhancement of dendritic trees of neurons that project to the amygdala.
    chronic stress causes shrinking and simplification of dendritic arbors as well as loss of dendritic spines in the PFC of male rats. In contrast, in females, similar stress causes estrogen-dependent enhancement of dendritic trees of neurons that project to the amygdala.
  11. A typical case that the individual experiences both panic (fear, in the form of individual attacks) and anticipatory anxiety in where an individual may have been previously attacked in a place that is not safe (that is cue evoked) is called ______, a fear of public places and subsequent avoidance of many common situation.
    agoraphobia
  12. children who have parents with PTSD have an increased risk for PTSD and also tend to have a ________
    lower-than-normal blood cortisol
  13. these two drugs bind to BDZ receptor and reduce anxiety at low concentrations indicating high therapeutic index
    clonazepam & flunitrazepam
  14. Drugs treating anxiety effect on GABA receptor:

    increasing the number of times the channel opens for Cl- ions

    prolonging the opening of GABA-activated chloride channels rather than the number of openings
    benzodiazepines

    barbiturates
  15. why barbiturates can be lethal while BDZs are not?

    also why are BDZ safer? 3 reasons
    directly opening the Cl- channel without GABA.

    BDZs do not increase the number of liver microsomal enzymes that normally metabolize the drugs, they are safer than barbiturates.

    BDZs have almost no effect on the respiratory center in the medulla, lethal overdose is extremely rare unless the drugs are taken in combination with other CNS depressants such as alcohol. So, they have the high therapeutic index

    less withdrawal symptoms
  16. 3 differences in barbiturates side chains?
    length, complexity, lipid solubility
  17. _______ was first BDZ. Within a few years diazepam (Valium), oxazepam (Serax), flurazepam (Dalmane), and at least a dozen other chemically related drugs were developed.
    Chlordiazepoxide (Librium)
  18. BDZs are featured by true anxiolytic that target anxiety without producing excessive sedation because of an indirect effect on GABAARs. The feature are: 1) , 2)  and, 3)
    low incidence of tolerance

    a less severe withdrawal syndrome than barbiturates

    a very safe therapeutic index because of low tolerance
  19. The long-acting BDZs undergo several metabolic steps to produce multiple active metabolites that may have half-lives up to 60 h or more before ____ in the liver. These can be problematic for elderly individuals, who may rapidly accumulate drug in the body because of their reduced metabolic capacity.
    conjugating with glucuronide
  20. _________ is a way of inactivating drugs in the liver.
    Glucuronidation
  21. BDZs are also the drugs of choice in preventing acute alcohol or barbiturate withdrawal symptoms, including seizures. This action is based on the _____; hence withdrawal from any one of them can be terminated by administration of any of the others. This may also imply that BDZs somehow have withdrawal symptoms even though are mild
    cross dependence of these three drugs
  22. Buspirone advantages and disadvantages over BDZ
    advantage-

    useful in treating depression that comes with anxiety


    Since buspirone is not a CNS-depressant, it has less mentally effects. Its anxiety reduction is done by correcting the mood disorder, and not accompanied by sedation, confusion, or mental clouding.


    Buspirone, as well as other structurally related drugs (gepirone and ipsapirone), does not show cross-tolerance or cross-dependence with BDZs or sedative-hypnotics;

    disadvantages-

    cant control seizures, insomnia, or muscle tension and has long onset of effectiveness so not ideal for ppl who want immediate relief
  23. clomipramine (CMI), an SSRI that selectively blocks 5-HT reuptake is more effective in relieving symptoms of OCD than desipramine (DMI), an NE reuptake inhibitor



    shows the selective effect of the serotonergic antidepressant.
    clomipramine (CMI), an SSRI that selectively blocks 5-HT reuptake is more effective in relieving symptoms of OCD than desipramine (DMI), an NE reuptake inhibitor



    shows the selective effect of the serotonergic antidepressant.
  24. SSRIs: With the mechanism of enhancing 5-HT function by blocking reuptake of 5-HT.

       SSRIs, like clomipramine (CMI, Anafranil), fluoxetine (Prozac), fluvoxamine (Luvox), and sertraline (Zoloft), have been found effective in reducing symptoms of obsessive-compulsive disorder (OCD);

    Tricyclic and MAO-Is antidepressants: such as imipramine (tricyclic), and phenelzine and tranylcypromine (MAO-Is), are also often effective in treating some anxiety disorders, including panic, phobic disorders and GAD, although side effects are often troublesome



    However, SSRIs are always the first choice because of its less side effects and less abuse potential. In addition, SSRIs may be used on occasions when benzodiazepine dependence is a concern.
    SSRIs: With the mechanism of enhancing 5-HT function by blocking reuptake of 5-HT. 

       SSRIs, like clomipramine (CMI, Anafranil), fluoxetine (Prozac), fluvoxamine (Luvox), and sertraline (Zoloft), have been found effective in reducing symptoms of obsessive-compulsive disorder (OCD);

    Tricyclic and MAO-Is antidepressants: such as imipramine (tricyclic), and phenelzine and tranylcypromine (MAO-Is), are also often effective in treating some anxiety disorders, including panic, phobic disorders and GAD, although side effects are often troublesome



    However, SSRIs are always the first choice because of its less side effects and less abuse potential. In addition, SSRIs may be used on occasions when benzodiazepine dependence is a concern.
  25. Which of the following is true about the barbiturates?

    A)
    Ultrashort-acting barbiturates have poor lipid penetration, so they are the most likely to be abused

    B)

    Short/intermediate-acting barbiturates are most likely to be prescribed for insomnia

    C)

    Long-acting barbiturates are highly lipid soluble

    D)
     Long-acting barbiturates are poorly lipid soluble, so they are quickly metabolized

    E)


    Ultrashort-acting barbiturates have high lipid penetration, so they are not readily to be metabolized
    B)

    Short/intermediate-acting barbiturates are most likely to be prescribed for insomnia

    (ALSO most likely to be abused)
  26. Which of the following statements about CRF is false?

    A)
    CRF acts as both a hormone and a neurotransmitter.

    B)
    Hormonal CRF activates the pituitary glands during stress.

    C)
    CRF antagonists reduce stress or anxiety by binding to CRF receptors in the adrenal glands.

    D)
    High levels of CRF receptors are found in brain regions involved in anxiety.
    • C)
    • CRF antagonists reduce stress or anxiety by binding to CRF receptors in the adrenal glands.
  27. Which of the following about the endocannabinoids is false?

    a
    They are synthesized by FAAH.

    b
    They include arachidonic derivatives such as 2-AG and anandamide.

    c
    They are not stored in vesicles.

    d
    They are synthesized and released when needed, probably in response to Ca2+.
    • a
    • They are synthesized by FAAH.
  28. All of the following are effects that have been correlated with chronic use of marijuana except

    a- development of anxiety disorders
    b- adverse cardiac effects
    c- immune system suppression 
    d- damage to lung tissue
    e- all of the above
    a- development of anxiety disorders
  29. Thoughts of suicide: _____% of depressed individuals commit suicide due to self-devaluation and loss of self-esteem.
    7-15%
  30. Incidence of major depression _____ %

    age of onset major depression _____

    Incidence of bipolar ______%

    age of onset bipolar _____
    15-20%

    27 years

    10%

    20-30 years
  31. Mood disorder concordance rate for monozygotic twins _____

    Mood disorder concordance rate for dizygotic twins ______
    65%

    20%
  32. which has a higher genetic contribution, bipolar disorder or major depression?
    bipolar disorder
  33. Abnormal ______ is the most critical pathology for abnormal HPA axis
    circadian rhythm

    high level of cortisol in depressed patients
  34. _______ is a synthetic glucocorticoid that should act as a negative-feedback stimulus to suppress continuously hypothalamic release of CRF and pituitary release of ACTH, which in turn results in decreased cortisol level.
    Dexamethasone (DEX)
  35. abnormalities in sleep rhythm of depressed
    • - longer sleep onset
    • - more awakenings
    • - less slow wave deep sleep stage 3/4
    • - early REM onset (may enter immediately) 
    • -  increased eye movement
    • - increased REM sleep
  36. _____ prevents monoamines dopamine, norepinephrine, and serotonin from being packaged in vesicles leaving them in the cytoplasm to be degraded 

    - show that low levels of norepinephrine and serotonin may be involved in depression
    reserpine
  37. norepinephrine metabolite ______

    and serotonin metabolite ______

    in the CSF, plasma, or urine of depressed patients may indicate depression
    methoxyhydroxyphenylglycol (MHPG)

    5-hydroxyindoleacetic acid (5-HIAA)
  38. Low blood level of 5-HT precursor, _____: i) frequently appears low in depressed patients compared to controls

    relapse of depressive symptoms if NE synthesis is prevented by depletion of the NE precursor ____
    tryptophan

    tyrosine
  39. antidepressants 

    ___ days and no change in serotonin autoreceptor sensitivity 

    __ days and moderate change sensitivity 

    ___ days and significant change and sensitivity
    2 days

    4-7 days

    15 days
  40. brain region that excites and inhibits CRF in stress response
    excites - amygdala

    inhibits - hippocampus
  41. depression = high cortisol levels = what effect on hippocampus?
    reduces the formation of new hippocampal cells

    small reductions in hippocampal volume are found
  42. Cell loss including loss of hippocampal cells after stress can be due to deficits in neurotrophic factors such as ______
    BDNF (brain-derived neurotrophic factor).
  43. _____ suggests that low BDNF

    may be responsible for the loss in dendritic branches

    and spines and that antidepressants may protect

    vulnerable cells by preventing the decrease in BDNF.
    The neurotrophic hypothesis
  44. Up-regulation occurs in several stages of the cascade, including enhanced coupling between G protein and adenylyl cyclase, increase in cAMP-dependent protein kinase (PKA), and increase in cAMP response element binding protein _____, which is a transduction factor that _____.
    (CREB)

    induces protein synthesis of BDNF (increase cAMP)
  45. The MAO in the liver is responsible for de-aminating tyramine, which is a naturally occurring amine formed as a by-product of fermentation in many foods, including cheeses, certain meats, pickled products, and other food. These foods must be avoided by individuals using MAO-Is.

        Elevated tyramine levels due to inhibition of MAO trigger the release the higher-than-normal stores of NE at nerve endings, causing a dramatic increase in blood pressure. Blood pressure may reach critical levels and is accompanied by headache, sweating, nausea, vomiting, and sometimes stroke.



    Thus, tyramine acts as a catecholamine-releasing agent that can enhance the release of catecholamines.

       However, tyramine is unable to cross the blood-brain-barrier (BBB), so it results in only non-psychoactive peripheral sympathomimetic effects.
    The MAO in the liver is responsible for de-aminating tyramine, which is a naturally occurring amine formed as a by-product of fermentation in many foods, including cheeses, certain meats, pickled products, and other food. These foods must be avoided by individuals using MAO-Is.

        Elevated tyramine levels due to inhibition of MAO trigger the release the higher-than-normal stores of NE at nerve endings, causing a dramatic increase in blood pressure. Blood pressure may reach critical levels and is accompanied by headache, sweating, nausea, vomiting, and sometimes stroke.



    Thus, tyramine acts as a catecholamine-releasing agent that can enhance the release of catecholamines.

       However, tyramine is unable to cross the blood-brain-barrier (BBB), so it results in only non-psychoactive peripheral sympathomimetic effects.
  46. Tricyclic antidepressants (TCA) mechanism?
    Inhibitors of monoamine transmitter reuptake: acting by binding to the presynaptic transporter proteins and inhibiting reuptake of transmitters into the presynaptic terminal.
  47. Tricyclic antidepressants:

    Which ones selectively block reuptake of serotonin and which selectively block reuptake of norepinephrine?

    amitriptyline

    clomipramine 

    imipramine 

    nortriptyline

    fluoxetine

    sertraline 

    maprotiline
    amitriptyline - norepinephrine

    clomipramine - serotonin 

    imipramine - norepinephrine 

    nortriptyline - norepinephrine


    fluoxetine - serotonin 


    sertraline - serotonin 

    maprotiline - norepinephrine
  48. tricyclic antidepressants 

    The receptor blocking activity contributes to side effects, which includes blockade of histamine, cholinergic, and α1-adrenergic receptors. As a result, the symptoms may be different depending upon individual’s sensitivity to a specific TCA and doses one takes, as well as the length of drug taking; 



    üHistamine receptor blockade: Histamine-mediated arousal is blocked - sedation and fatigue;

    ü Cholinergic blockade: dry mouth, constipation, urinary retention, dizziness, confusion, impaired memory, and blurred vision;

    The α1 receptor blockade: hypotension, tachycardia and arrhythmia;



    Toxicity following overdose contributes to cardiovascular depression, delirium, convulsions, respiratory depression, and coma.
    The receptor blocking activity contributes to side effects, which includes blockade of histamine, cholinergic, and α1-adrenergic receptors. As a result, the symptoms may be different depending upon individual’s sensitivity to a specific TCA and doses one takes, as well as the length of drug taking;  



    üHistamine receptor blockade: Histamine-mediated arousal is blocked - sedation and fatigue; 

    ü Cholinergic blockade: dry mouth, constipation, urinary retention, dizziness, confusion, impaired memory, and blurred vision; 

    The α1 receptor blockade: hypotension, tachycardia and arrhythmia;



    Toxicity following overdose contributes to cardiovascular depression, delirium, convulsions, respiratory depression, and coma.
  49. _______ is characterized by

    severe agitation, disorientation and confusion,

    ataxia, muscle spasms, and exaggerated

    autonomic nervous system functions including

    fever, shivering, chills, diarrhea, elevated blood

    pressure, and increased heart rate.
    Serotonin syndrome
  50. üWhile the antidepressant action may be related to increased 5-HT function at serotonergic receptors, increased 5-HT activity at a variety of 5-HT receptor subtypes causes many kinds of side effects: anxiety, restlessness, movement disorders, muscle rigidity, nausea, headache, insomnia, and sexual dysfunction (occurs in 40-70% of patients).
    üWhile the antidepressant action may be related to increased 5-HT function at serotonergic receptors, increased 5-HT activity at a variety of 5-HT receptor subtypes causes many kinds of side effects: anxiety, restlessness, movement disorders, muscle rigidity, nausea, headache, insomnia, and sexual dysfunction (occurs in 40-70% of patients).
  51. 3rd generation



    _____ administered iv at sub-anesthetic doses has been shown to produce a rapid (generally within hours) and prolonged reduction in depression symptoms for 65-70% of treatment-resistant patients. This is an advantage compared with the late onset effects (4-6 weeks) by TCAs, MAOs, SSRIs, and SNRIs.
    ketamine
  52. ketamine mechanism
    blocking the NMDA receptor ion channel, inhibiting glutamate release, 

    enhancing glutamate reuptake transporter


    potentiate the AMPA receptor function, which includes enhanced AMPA-induced synaptic plasticity (both in functional and structural plastic changes) and increased BDNF
  53. A 30 amino acid neuropeptide implicated in mood disorders as well as in regulating feeding, cognitive performance, sleep, sexual activity, and stress responses.
    galanin
  54. which Galanin receptors cause depressive effects and which cause anti-depressive?
    Gal2- antidpressive (so give Gal2 agonist to treat depression)

    Gal 1 and Gal 3 - depressive (so give Gal 1 and Gal3 antagonist )
  55. _____ is the most effective medication and is the usual drug of choice for the majority of patients with bipolar disorder by the action of flattening the extremes.
    Lithium carbonate (enchance tryptophan which enchances serotonin)

     However, lithium reduces catecholamine activity: by enhancing reuptake and reducing release
  56. lithium no maintenance vs lithium maintenance mania and depressive episodes
    mania every 1.2 year to 9 years 

    depressive every 1.4 years to 4 years
  57. Lithium works on modulating _____

    Lithium has pronounced effects on 4 things
    2nd messenger functions

    adenylyl cyclase (PKA), phosphoinositide cycling (PKC), G protein coupling, and brain derived neurotrophic factors (BDNF).
  58. Lithium excretion is inversely proportional to ____
    sodium levels

    salt depletion = increased lithium at dose that could be toxic
  59. lithium therapeutic index is ____
    low

    therapeutic range = .07-1.2mM in blood

    toxic range = 2.0 mM in blood

    seizure coma death = 3.0mM
  60. Two anticonvulsant drugs used to treat mania of bipolar
    carbamazepine

    Valproate
  61. treat mania

    Carbamazepine (Tegretol) is a structurally atypical anticonvulsant because it resembles tricyclic antidepressants,and this similarity allows it to _____.


    Carbamazepine also acutely blocks ______ receptors;

    When use in a chronic manner, it up-regulates ______ receptors.

    Carbamazepine’s actions on intracellular signaling are similar to those of valproate and lithium – _______.
    inhibit NE reuptake

    adenosine

    adenosine

    acting on a few of 2nd messengers
  62. Several newer drugs such as topiramate (Topamax) and tiagabine (Gabitril) are similarly effective when compared with lithium but have a different toxicity profile.
    Several newer drugs such as topiramate (Topamax) and tiagabine (Gabitril) are similarly effective when compared with lithium but have a different toxicity profile.
  63. Researchers know that depressed individuals have an abnormal stress response involving the HPA axis because these individuals have all of the following except

    A) elevated levels of cortisol.
     
    B) enlarged pituitary and adrenal glands.

    C) higher CRF levels in cerebrospinal fluid (CSF).

    D) less CRF cells evident in postmortem hypothalamic tissue.
    D) less CRF cells evident in postmortem hypothalamic tissue.
  64. What is the major advantage of the second-generation antidepressants over the MAOIs and the TCAs?

    a- They are more effective in treating depression

    b- They work faster than the older classes of drugs

    c- They produce different and less harmful side effects than the older medications

    d- They are less selective in their action; hence they can be used for a number of conditions
    c- They produce different and less harmful side effects than the older medications

    • none are more effective
    • third generation work faster
    • they are more selective
Author
JAM41MAN
ID
340040
Card Set
the rest of neuropharmacology chapter 18 and 19 slides
Description
exam 3 neuro
Updated