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100 Cards in this Set

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what do central catecholamine-producing neurons that lack dopaine b-hydroxylase use as their NT?
dopamine, since they can't made NE from dopamine
what is the main role of catecholamines in the CNS?
- regulate mood, attentiveness, emotion
what is the main role of catecholamines in the peripheral NS?
- main NT by sympathetic postganglionic neurons
- secreted by the adrenal glands in response to stress
how do you get tyrosine, for synthesis of catecholamines?
- mainly from diet
- can also be synthesized in liver from phenylalanine
what does AADC do?
- aromatic L-amino acid decarboxylase
- conversion of L-DOPA to DA
- requires pyridoxal phosphate as a cofactor
what does the dopamine transporter also carry with it into the cell, along with DA?
- DA reuptake transporter couples DA reuptake with cotransport of Na
- DA reuptake is therefore indirectly dependent on a functioning Na/K pump, to maintain the Na concentration gradient
what is the difference between MAO-A and MAO-B?
MAO-A: found in the periphery
MAO-B: found in the CNS
where is COMT expressed?
- brain
- liver
- kidney
- heart
how does COMT work?
- inactivates catecholamines by adding a methyl group to the hydroxyl group at the 3 position on the benzene ring
what do MOA and COMT degrade DA into?
- homovanillic acid (HVA), which is excreted in the urine
what are the different DA receptor subtypes?
- each subtype is encoded by a separate gene
- there are 5, which are divided into 2 classes
- D1 (D1 and D5)
- D2 (D2_S, D2_L, D3, D4)
name similarities between DA receptors
- all are seven transmembrane domain, G-protein coupled receptors
- cAMP second messanger system
what does the D1 class of DA receptors do?
- D1 and D5
- mediate an increase in cAMP
what does the D2 class of DA receptors do?
- (D2_S, D2_L, D3, D4)
- mediate an decrease in cAMP
what are D2_S and D2_L
- D2_short and D2_long
- splice variants of the same gene
where are D1 and D2 receptors both highly expressed?
- in the striatum (caudate and putamen) -> motor control by the basal ganglia
- nucleus accumbans
- olfactory tubercle
where are D2 receptors highly expressed?
- ant. pituitary gland LACTOTROPHS, regulate prolactin secretion
- striatum
- substantia nigra
what are lactotrophs?
- glands in the ant. pituitary that regulate prolactin secretion
where are D3 receptors found?
- in the limbic system, including the nucleus accumbens and olfactory tubercle
where are D4 receptors found?
- frontal cortex, diencephalon, and brainstem
where are D5 receptors found?
- expressed generally at low levels, mainly in the hippocampus and hypothalamus
what happens when you stimulate DA autoreceptors?
- reduces DA tone by:
1. decreasing DA synthesis
2. reducing the rate of neurnal firing
- DA autoreceptors belong to the D2 class
what are the four areas of the brain that have particularly high concentrations of DA?
1. nigrostiatal system (80% of brain's DA!)
2. ventral tegmental area (VTA)
3. arcuate and periventricular nuclei of the hypothalamus
4. area postrema
tell me more about the DA nigrostriatal system
- the tract projects from cells in the pars compacta of the sub. nigra to terminals that innervate the striatum
- DA neurons in the nigrostriatal system are invovled in PURPOSEFUL MOVEMENT
- degeneration -> Parkinsons
why is the substantia nigra darkly colored?
- because of the decomposition of DA to melanin
where is the VTA found?
- medial to the substantia nigra
- in the midbrain
what does the VTA do?
- nnervates forebrain areas: cerebral cortex and limbic structures
- these structures play a role in motivation, goal-directed thinking, regulation of affect, and positive reinforcement (reward)
- derangement of these systems may cause schizophrenia
tell me more about the tubero-infundibular pathway
- DA cell bodies of the arcuate and periventricular nuclei of the hypothalamus project to the median eminence of the hypothalamus, and to the intermeiate lobe of the pit.
- release of DA from these neruons inhibits the release of prolactin by pituitary lactotrophs
where is the area postrema located?
- wall of the caudal end of the 4th ventricle
- contains a high concentration of DA receptors
- stimulation of DA receptors -> vomiting
what sorts of symptoms do parkinson's patients have?
- hypokinesia: lack of movement -> muscle rigidity and tremor
- have lost DA neurons in the substantia nigra pars compacta
what synthetic drugs can cause parkinson's like symptoms?
- opiod meperidine
- contaminant: MPTP which forms as an impurity in the synthesis of meperidine
what are some genetic leads on the etiology behind parkinson's disease?
- autorecessive mutation on the parkin gene
- autosomal dominant mutation on the a-synuclein gene
what are the classes of medication used for PD treatment?
- DA precursors
- DA receptor agonists
- inhibitors of DA degredation
DA precursors
- levodopa is still most effective treatment for PD
- L-dopa is carried past the BBB by a neutral aa transporter
- competes with other netural aas for transport. therefore, it's availability may be compromized by high protein meals
what are some mechanisms that cause L-dopa degredation before it can reach the brain?
- decarboxylases and MAO-A metabolize L-dopa in the GI tract
- DOPA decarboxylase in the periphery converts most of the L-DOPA into DA
- only 1-3% of the orally administered L-dopa actually makes it into the brain
how do you boost the levels of L-dopa that enters the brain?
- give carbidopa along with l-dopa
- carbidopa inhibits DOPA decarboxylase
- carbidopa itself does not cross the BBB, so it doesn't interfere with the ability of the brain to convert L-dopa to DA
- increases availability of L-dopa to 10% in the brain
what happens with continued use of levodopa?
- sensitization and tolerance
- patients develop fluctuations in motor fucntion: of periods interspersed with on periods
what is one major side effect of L-dopa?
dyskinesia: uncontrollable rhythmic movement of the head and trunk
why do PD patients develop dyskinesias and fluctuations?
1. continued destruction of DA neurons -> increased inability for striatum to store DA effectively
2. chronic L-dopa therapy causes adaptations in postsynaptic neurons in the striatum -> altered sensitivty to DA levles
what are some DA agonists used to treat parkinson's disease?
- bromocriptine (D2 agonist)
- pergolide (D1 and D2)
- pramipexole (D3? D2)
- ropinirole (D3 > D2)
- used as ajuvants to levodopa therapy
what are some advantages of using the DA agonist class of drugs for PD treatment?
- nonpetpid molecules- do not compete with L-dopa or other neutral aas for transport across the BBB
- do not require enzymatic conversion -> remain effective even late in the course of PD
selegiline
MAO inhibitor
- MAO B selective at low doses
- avoids toxic effects of dietary tyramine that is associated with nonselective MAO blockade
tolcapone and entacapone
- inhibit degradation of DA by inhibiting COMT
amantadine
- developed as an antiviral that reduces the severity of Influenza A infections
- in PD, used to treat l-dopa induced dyskinesias that develope late in the course of the disease
- mech: global blockade of excitatory NMDA receptors
trihexyphenidyl and benztropine
- muscarinic receptor antagonists that reduce cholinergic tone in the CNS
- reduce tremor
- used for PD treatment
name positive symptoms of schizophrenia
- delusions
- hallucinations
- disorganized speech
- catatonic behavior
name negative symptoms of schizophrenia
- affective flattening
- avolition (decrease in initiation of goal directed behavior)
how do you treat schizophrenia?
- with D2 antagonists
what is the dopamine hypothesis for schizophrenia?
- increased and dysregulated levels of DA neurotransmission in the brain
what do amphetamines, cocain, and apomorphine do?
- increase DA levels or activate DA receptors in the CNS
- can induce schizophrenia like symptoms
which anatomic location is suspect in schizophrenia?
1. the mesoLIMBIC system- a dopaminergic tract that originates in the VTA and other parts of the limbic system
- invovled in the development of emotions and memory
2. DA neurons of the mesoCORTICAL system originate in the VTA and project to the cerebral cortex (esp. prefrontal) -> problems with attention, planning, and motivated behavior
what are drugs that treat psychosis?
- neuroleptics: emphasis on drug's neurological actions that are manifested as side effects of treatment (i.e. extrapyramidals effects)
- antipsychotics: drugs abrogate psychosis and alleviate disordered thinking
where do extrapyramidal effects come from?
- DA receptor blockade in the basal ganglia
antipsychotics
- antagonize the mesolimbic and possibly the mesocortical D2 receptors
- able to control positive symptoms better than negative symptoms
side effects of antipsychotic drugs
1. caused by antagonist action at D2 receptors outside the mesolimbic and mesocortical systems (e.g. extrapyramidal effects)
2. caused by non-specific antagonsit action at other receptor types
- can induce parkinson like symptoms
what is the neuroleptic malignant syndrome?
- a sever side effect of antipsychotics
- catatonia, stupor, fever, autonomic instability, myoglobinemia, and death
what sort of effect do antipsychotics have on the hypothalamus
inhibit ability to regulate temperature
tardive dyskinesia
appears in 20% of patients after chronic antipsychotic use
- repetivie involuntary, sterotyped movements of the facial musculature, arms and trunk
- similar to Huntington's chorea
- can be axacerbated by the administration of antiparkinsonian drugs
what happens when you supress D2 receptor activation in the pituitary gland?
- you increase prolactin secretion (since DA inhibits prolactin)
- women: amenorrhea, galactorrhea, false pos preg test
- men: gynecomastia and decreased libido
haloperidol and fluphenazine
highly lipophilic
- provide week long acting formulation for antipsychotics
what are atypical antipsychoticss?
- have efficacy and side effect profiles that differ from typical antipsychotics
- better at treating the negative symptoms of schizophrenia
- have low affinity for D2 receptors
- affinity for D2 receptors does NOT correlate with efficacy
name some atypical antipsychotics
- clozapine
- olanzapine
- 1uetapine
- 1iprasidone
- resperidone
what is the 5-HT2 hypothesis for atypical antipsychotics?
- antagonist action at the 5-HT2 receptor or antagonist action at both 5-HT and D2 receptors is necessary for the antipsychotic effect
what is the D4 hypothesis for atypical antipsychotics?
- many of the atypical antipsychotics are also D4 receptor antagonists
where does Risperidone bind?
- combine antogaonistic properties at:
1. D2
2. 5-HT2
- also antagonizes a1, a2, and histamine receptors with relatively high affinity
where does Clozapine bind?
D1-D5 as well as 5-HT2
- also blocks a1, H1, and muscarinic receptors
who has bipolar disorder (BPD)?
- patients with one manic episode, with or without an addition history of depressive episodes
who has a major depressive disorder (MDD)?
- patients with major depressive episodes, and no history of mania
- life time prevalence is 17%
what is major depressive disorder linked to?
- dysfunction in serotonin or NE pathways
how do varicosities function?
- release large amounts of NT into the extracellular space- establishing concentration gradients
what is the primary mode of NT release from central serotonergic and adrenergic systems?
varicosities
where are 5-HT cells found?
raphe nuclei
- autoregulates own release
where are NE containing cells found?
locus ceruleus
- autoregulates own release
what are the rate limiting steps for NE and serotonin synthesis?
- always the first step:
- tyroside hydroxylase (TH)
- tryptophan hydroxylase (TPH)
- both enzymes are tightly regulated by inhibitory feedback
reserpine
- binds irreversibly to VMAT, and therefore prevents uptake of DA, NE, E, and 5-HT into vesicles
- also disintegrates vessles -> release of monoamines into cytoplasm
what are the different monoamine transporters?
- serotonin transporter (5HT)
- norepinephrine transporter (NET)
- dopamine transporter (DAT)
- can also transport the other monoamines, but less efficient
what do amphetamines do to the monoamine transporters?
- reverse the direction by dissipating the proton gradient across the membrane
what does MAO-A degrade?
- 5HT, NE, and DA
what does MAO-B degrade?
- DA more than 5HT or NE
what are the two classes of antidepressants?
- tricyclic antidepressants (TCA)
- monoamine oxidase inhibitors (MAO)
imipramine and desipramine
- imipramine blocks 5HT transporters
- the active metabolite of imipramine (desipramine) effectively blocks NE transporters
iproniazid
- inhibits MAO
- why does it take so long for antidepressants to have an effect?
- we don't know.
- could be caused by the need to first desensitize the physiologic inhibitory feedback mechanisms of autoreceptors to allow for increased neurotransmission
carbamazepine and valproic acid
- anticonvulsants for treating BPD
what are the four classes of drugs used to treat affective disorders?
1. TCA
2. SSRI
3. MAOI
4. atypical antidepressants
(also, lithium is used to treat mania)
imipramine
- the prototype TCA
- inhibit reuptake of 5HT and NE from synaptic cleft by blocking the transporters
what are the side effects of TCAs?
- can affect sodium channels in a quinidine like manner -> letha conduction delays (1st degree AV and BBB)
- can have anticholinergic effects -> drug mouth, nausea, vomiting, ect
- antihistaminergic effects: sedation, weight gain
- antiadrenergic effects: orthostatic HT, reflex tachycardia
anticholinergic effects
- nausea
- vomiting
- anorexia
- dry mouth
- blurred vision
- confusion
- constipation
- tachycardia
- urinary retention
antihistaminergic effects
- sedation
- weight gain
antiadrenergic effecs
- orthostatic hypotension
- reflex tachycardia
- drowsiness
- dizziness
name some SSRIs
- fluoxetine
- citalopram
- fluvoxamine
- paroxetine
- sertraline
what makes SSRIs preferable to TCAs?
- higher selectivity and reduced side effect profile
what is the mechanism of SSRIs?
same as for TCAs, but more selective for the serotonin transporters
- at high doses, also bind to NE transporters
what is serotonin syndrome?
- a serious adverse effect seen with SSRIs when given along with MAOIs. -
hyperthermia, muscle rigidity, myoclonus, and rapid fluctuation in memory
name some older non-selective MAOIs
- iproniazid
- phenelzine
- isocarboxazid
- irreversible inhibitors
name some newer MAO-A selective MAOIs
- moclobemide
- befloxatone
- brofaromine
- bind reversibly
name a MAO-B selective inhibotr
selegiline
- less effective in the treatment of depression
what is the most toxic side effect of MAOIs?
systemic tyramine toxicity
- eating redwime, aged cheese can lead to high levels of circulating tyramine
- tyramine is an indirect sympathomimetic -> hypertensive crisis
name the atypical antidepressants
- bupropion
- mirtazapine
- nefazodone
- trazodone
- velafaxine
how is lithium most commonly administered?
as lithium carbonate
- enters cells via sodium channels
- can mimic small monovalent cations