the rest of neuropharmacology chapter 18 and 19 slides

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.

Neuropharmacologically, a specific BDZ receptor antagonist, ______, was developed. ______ prevents the effects of BDZ binding but has no effect on the GABA receptor.

pregnenolone, allopregnanolone, tetrahydrodeoxycorticosterone, and dehydroepiandrosterone (DHEA), are synthesized from cholesterol in both the CNS and PNS.

, 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.

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

What effects on dopamine?

Increase anxiety (β-carboline -> anxiogenic)

Diazepam (anxiolytic) blocks the anxiety responses to the stressors and to β-carboline treatment

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

_____ 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

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 _____.

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.

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.

children who have parents with PTSD have an increased risk for PTSD and also tend to have a ________

these two drugs bind to BDZ receptor and reduce anxiety at low concentrations indicating high therapeutic index

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

why barbiturates can be lethal while BDZs are not?

also why are BDZ safer? 3 reasons

3 differences in barbiturates side chains?

_______ was first BDZ. Within a few years diazepam (Valium), oxazepam (Serax), flurazepam (Dalmane), and at least a dozen other chemically related drugs were developed.

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)

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.

_________ is a way of inactivating drugs in the liver.

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

Buspirone advantages and disadvantages over BDZ

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.

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.

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

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.

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+.

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

Thoughts of suicide: _____% of depressed individuals commit suicide due to self-devaluation and loss of self-esteem.

Incidence of major depression _____ %

age of onset major depression _____

Incidence of bipolar ______%

age of onset bipolar _____

Mood disorder concordance rate for monozygotic twins _____

Mood disorder concordance rate for dizygotic twins ______

which has a higher genetic contribution, bipolar disorder or major depression?

Abnormal ______ is the most critical pathology for abnormal HPA axis

_______ 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.

abnormalities in sleep rhythm of depressed

_____ 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

norepinephrine metabolite ______

and serotonin metabolite ______

in the CSF, plasma, or urine of depressed patients may indicate depression

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 ____

antidepressants 

___ days and no change in serotonin autoreceptor sensitivity 

__ days and moderate change sensitivity 

___ days and significant change and sensitivity

brain region that excites and inhibits CRF in stress response

depression = high cortisol levels = what effect on hippocampus?

Cell loss including loss of hippocampal cells after stress can be due to deficits in neurotrophic factors such as ______

_____ 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.

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 _____.

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.

Tricyclic antidepressants (TCA) mechanism?

Tricyclic antidepressants:

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

amitriptyline

clomipramine 

imipramine 

nortriptyline

fluoxetine

sertraline 

maprotiline

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.

_______ 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.

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).

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 mechanism

A 30 amino acid neuropeptide implicated in mood disorders as well as in regulating feeding, cognitive performance, sleep, sexual activity, and stress responses.

which Galanin receptors cause depressive effects and which cause anti-depressive?

_____ 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 no maintenance vs lithium maintenance mania and depressive episodes

Lithium works on modulating _____

Lithium has pronounced effects on 4 things

Lithium excretion is inversely proportional to ____

lithium therapeutic index is ____

Two anticonvulsant drugs used to treat mania of bipolar

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 – _______.

Several newer drugs such as topiramate (Topamax) and tiagabine (Gabitril) are similarly effective when compared with lithium but have a different toxicity profile.

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.

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