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362 Cards in this Set
- Front
- Back
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Monoamines affect what? |
Central Nervous System |
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Monoamines derive from what two single amino acids? |
1) Catecholamines - tyrosine 2) Indoleamines - tryptophan (in turkey)
(both digestible and derived from diet) |
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Where do their cell bodies begin and their axons extend to? (fairy localized set of neurons) |
Cell bodies in the brainstem and axons extend into variety of subcortical areas of the forebrain. |
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What percent or less of all neurons in the CNS are monoaminergic? |
Less than 5% |
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What kinds of neurons are these? |
Metabotropic and inhibitory neurotransmitters |
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Catecholaminergic neurons have high affinity transport system to what? |
Tyrosine |
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Tyrosine is incorporated into what neurons high affinity transport system? |
Catecholaminergic neurons |
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Where does the biosynthesis of catecholamines occur? |
Presynaptic terminal of the neuron |
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What is the anabolic Catecholine pathway? |
tyrosine (enzyme: tyrosine hydroxylase COCH) into L-dopa (dopa decarboxylase -OH group) into neurotransmitter Dopamine [DA] (dopamine beta hydroxylase [DBH] into extra step of Norepinephrine [NA, NE] |
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Special enzyme that turns on a special neuroandgeneric neuron..... |
Dopamine beta hydroxylase (DBH) |
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What is the major product of the catecholine anabolic pathway? (extra step very end) and Where does it occur? |
adrenaline; in the adrenal gland |
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Where is dopamine beta hydroxylase located? |
synaptic vesicles of noradrenergic neurons |
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Where does the conversion of dopamine to norepinephrine occur? |
Inside the vesicles (pre package) |
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What is the rate limiting step in the anabolic catecholine pathway? |
Conversion of tyrosine into L-dopa through the tyrosine hydroxyls enzyme [1st step] |
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What is the first step of the catecholine anabolic pathway? |
Converting tyrosine into L-dopa |
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What enzyme is used to preform the first step of the catecholine anabolic pathway? |
tyrosine hydroxylase enzyme |
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What is the tyrosine hydroxylase enzyme controlled by? (what process) |
end-product inhibition |
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What is end-product inhibition? |
the concentration of the end-prodcut neurotransmitter in the synapse control the saturabilty of the enzyme for its substrate |
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Usually the enzyme is fully saturated with what? |
Tyrosine |
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Tyrosine usually saturates what enzyme entirely? |
tyrosine hydroxylase enzyme |
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Why are presynaptic auto receptors important? |
They read the concentration of the neurotransmitter in the synapse. (too much or too little) |
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Who is responsible for reading the concentration of the neurotransmitter in the synapse? |
The presynaptic auto receptors |
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What inhibits tyrosine hydroxylase enzyme? |
Alpha methyl paratyrosine (AMPT) |
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What does Alpha methyl paratyrosine do? |
Inhibits tyrosine hydroxylase enzyme |
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What is an assembly line a metaphor for? |
The catecholine anabolic pathway. (workers down an assembly line) |
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Elimination of catecholamine NT from the synapse occurs in what disease? |
Parkinson's disease |
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What is the most common fate for catecholamine NT in the synapse? |
Reuptake, back into the presynaptic terminal and redepositing it into synaptic vesicle (similar to reuptake mechanism for glial cells) |
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What happens to catecholamines in the synapse? (those that are not reuptaken) |
Catecholamines are broken down in the synapse (or in nearby astrocytes surrounding the synapse) |
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What enzyme breaks down catecholamine NT in the synapse? |
Catechol-o-methyl transferase (COMT) |
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The catabolic enzyme (COMT) catechol-o-methyl breaks down what and where? |
Catecholamine NT's in the synapse |
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What does COMT catabolic enzyme do to dopamine (DA)? |
converts to homovanillic acid (HVA) |
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What does COMT catabolic enzyme do to norepinephrine (NE)? |
converts to 3-methoxy, 4-hydroxyphenethylene glycol (MHPG) |
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What is MAO? |
Monoamine oxidase a catabolic enzyme |
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Where is MAO located? |
membrane of mitochondria |
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What catabolic enzyme can be found bound to the membrane of mitochondria? |
Monoamine oxidase (MAO) |
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After begin reabsorbed back into the presynaptic terminal what happens to catecholamines? |
They are broken down in the cytoplasm by the catabolic enzyme MAO |
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What does the cytoplasm in the presynaptic terminal do to catecholamines that are reabsorbed? |
breaks them down with the catabolic enzyme MAO from the membrane of mitochondria |
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What does the catabolic enzyme MAO do to dopamine? |
converts it to homovanillic acid (HVA) by monoamine oxidase (similar to COMT) |
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What does MAO do to norepinphrine? |
converts it to 3,4 dihydroxymandelic acid (HMA) |
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What is HMA? |
dihydroxymandelic acid from norepinephrine and MAO |
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What are catabolites? |
waste products from catecholamine break down |
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Where are catabolites? |
blood, urine, and cerebrospinal fluid |
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Catecholaminergic activity happens where and why? |
Blood, urine, and cerebrospinal fluid due to indirect indices of catecholamine turnover from catabolites. |
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How many current Dopaminergic receptors are there? |
Five (D1, D2, D3, D4, and D5) |
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What is a dopamine agonist and what is it used to treat? |
bromocriptine (Parlodel) used to treat Parkinson's disease |
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Parkinson's disease uses what dopamine agonist for treatment? |
bromocriptine (Parlodel) |
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What is a dopamine antagonist and what is it used for? |
penathiazine, butyrophenomes used in traditional neuroleptics |
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Traditional neuroleptics that use dopamine antagonists are? (2) |
1) Phenathiazine 2) Butyrophenomes |
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What are the 4 Dopaminergic pathways? |
1) nigro-striatal pathway 2) meso-limbic pathway 3) meso- cortical pathway 4) tubero-infundibular pathway
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Dopaminergic pathway: Nigro-striatal pathway does what? |
contains 70% of all Dopamine neurons; originates in substantia nigra in the midbrain, most striatal dopamine receptors are D1 and D2 |
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Where does the nigro-striatal (dopaminergic) pathway originate? |
Midbrain, substantia nigra with stratal dopamine receptors D1 and D2 |
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What pathway contains the most dopamine neurons? |
Nigro-striatal pathway (midbrain) |
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Dopaminergic pathway: Meso-limbic pathway does what? |
runs from ventral tegmentaum area ( VTA) to the nucleus accumbens, amygdala, septum, and anterior cingulate gyrus |
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What pathway runs from the Ventral Tegmentaum Area (VTA) to the nucleus accumbens, amygdala, septum, and anterior cingulate gyrus? |
Meso-limbic pathway |
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Dopaminergic pathway: Meso-cortical pathway does what? |
runs from VTA (ventral tegmentaum area) to neocortex, specifically the prefrontal lobe |
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What dopaminergic pathway runs from the VTA to the neocortex (specifically the prefrontal lobe)? |
Meso-cortical pathway |
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Dopaminergic pathway: Tubero-infundibular pathway does what? |
has D2 receptors (probably auto receptors) involved in the inhibition of protactin by dopamine, neuroleptics can cause hyperprolactinemia |
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In what dopaminergic pathway can neuroleptics cause hyperprolactinemia? |
Tubero-infundibular pathway |
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In what two dopaminergic pathways are D2 receptors prominently found? |
Nigro-striatal and Tubero-infundibular pathways |
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In the Tubero-infundibular (dopaminergic) pathway dopamine is used as what? |
an inhibitory neuron |
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In the tuber-infundibular pathway protection is inhibited by what neuron? |
Dopamine with the help of D2 (auto receptors) |
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What are Adenoceptors? |
receptors for norepinephrine and epinephrine |
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What are the receptors for norepinephrine and epinephrine called? |
Adenoceptors |
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What are the two major Adenoceptors? |
1) Alpha receptors (2) 2) Beta receptors (2) |
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What do Alpha 1 receptors do? |
vasoconstriction of arterioles supplying blood to the skin; relaxation of gut |
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What do Alpha 2 receptors do? |
they are presynaptic receptors |
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Which alpha receptor is found in as the presynaptic receptor? |
Alpha 2 receptor |
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What are the Alpha 2 receptors agonist and antagonist? |
Agonist: Clonidine (Catapres) Antagonist: Mianserin |
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What does the Alpha 2 agonist Clonidine (Catapres) do? |
lowers NE release and reduces sympathetic output and blood pressure; sometimes useful in treatment of migraine |
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What Alpha 2 receptor is sometimes useful in treatment of migraines? |
Clonidine (Catapres) |
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What does the Alpha 2 antagonist Mianserin do? |
increases NE release and works as an antidepressant (not released in the US; but widely used in Europe) |
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What Alpha receptor is widely used in Europe and an antidepressant? |
Alpha 2 antagonist Mianserin |
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What does Alpha 2 receptors A (agonist) and B (antagonist) do? |
A) Clonidine (Catapres) decreases NE release, lowers blood pressure; treats migraines B) Mianserin increases NE release, works as antidepressant |
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What are some Nonspecific alpha blockers and what do they do? |
Phentolamine, Regetine used to treat hypertension, shock, peripheral vascular diseases such as Raynaud's disease |
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What is used to treat hypertension, shock, and peripheral vascular diseases such as Raynaud's disease? |
Nonspecific alpha blockers such as Phentolamine and Regetine |
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What do Beta 1 Adenoceptors do? |
accelerates heart and increases stroke volume |
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What Adenoceptors increase stroke probability? |
Beta 1 Adenoceptors |
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What do Beta 2 Adenoceptors do? |
relaxes the bronchial tubes and dilates the arterioles supplying the skeletal muscles |
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What is the major difference between Beta 1 and Beta 2 Adenoceptors? |
Beta 1: increases Beta 2: decreases |
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What are two nonspecific Beta Adenoceptors? |
1) Isoproteronol [agonist] 2) Propranolol (Indural) [blocker] |
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What does nonspecific Beta agonist Isoproteronol do? |
used as bronchial dilator and cardiac stimulant |
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What does nonspecific Beta blocker Propranolol (Indural) do? |
used to treat cardiac arythmias and dysrhythmias, angina, hypertension, and "somatic" anxiety |
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What are the dangerous side effects of Beta blocker Propranolol (Indural)? |
bronchial restriction dangerous side effect possibility in treating "somatic anxiety" |
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Why are Cocain and amphetamines examples of Adenoceptors? |
Because they allow NE to leak into synapse without benefit of an action potential and slows or blocks uptake of NE back into presynaptic terminal |
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What is another Adenoceptor other than Alpha receptors and Beta receptors? |
Cocaine and amphetamines |
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What are the 4 Noradrenergic pathways? |
1) Locus Cereuleus in the Pons 2) Descending tract to vital nuclei in the Medulla 3) Post-ganglionic neurons of the sympathetic nervous system 4) Chromaffin cells in Adrenal Medulla |
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Where is the Noradrenergic Locus Cereuleus pathway located? |
Pons |
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Where is the Noradrenergic Descending tract pathway to vital nuclei lead to? |
Medulla |
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Where are the Noradrenergic post-ganglionic neurons pathway located? |
Sympathetic Nervous System |
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Where are the Noradrenergic Chromaffin cells pathway located? |
Adrenal Medulla |
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In the Catecholine Anabolic pathway what are the two types of enzymes and in what order do they occur? |
1) Hydroxylase 2) Decarboxylase |
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What is the Indoleamine Neurotransmitter? |
Tryptophane |
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Tryptophan is incorporated into what transport system? |
Indoleaminergic neurons |
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Indoleaminergic neurons have a high affinity transport system for what? |
Tryptophan |
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Where does the biosynthesis of Indoleamines occur? |
Presynaptic terminals of indoleaminergic neurons (only) |
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Detail the anabolic pathway of Indoleamine NT's: |
Starts with tryptophane (enzyme tryptophane hydroxylast as pre-cursor) converts to 5 Hydroxytrytophan (enzyme aromatic amino acid decarboxylase) makes 5 Hydroxytrytamine [5HT] which is Serotonin which then can lead to make melatonin. |
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What is an important Indoleamine neurotransmitter produced through the anabolic pathway? |
Serotonin |
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What is an important neuromodulator/ hormone created by the Indoleamine anabolic pathway (after serotonin)? |
Melatonin; secreted by pineal gland, involved in regulation of seasonal behaviors (hibernation in bears) |
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Where is Melatonin, an indoleamine nueromodulator, secreted? |
Pineal gland |
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What is the Pineal glands function? |
to regulate seasonal behaviors (hibernation in bears) |
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What disorder can develop from a lack of Serotonin and Melatonin? |
Seasonal Affective Disorders (treated with light therapy) |
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Why are Serotonin and Melatonin affected by light? |
N-acetlytransferase is inhibited by light (by neuronal activity along optic tract) seasonal changes in ratio of daylight to night-time govern levels of serotonin and melatonin |
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What governs levels of Serotonin and Melatonin? |
Neuronal activity along the optic tract, light |
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What is the Rate-limiting step in the Indoleamine Anabolic Pathway? |
Conversion of trytophane to 5 hydroxytrytophan |
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What enzyme affects the rate-limiting step in the Indoleamine Anabolic Pathway? |
tryptophan hydroxylase enzyme |
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What inhibition limited this step, the conversion of tryptophan to 5 hydroxytryptophan? |
End-product inhibition (similar to catecholamine pathway) |
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Where does the end-product inhibition take place? |
Serotonergic synpase in the presynaptic auto receptors |
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What is the inhibitor of tryptophan hydroxylase? |
Parachlorophenylalanine (PCPA) |
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What is PCPA? |
specific inhibitor of tryptophan hydroxylase in the serotonergic synapse of the presynaptic auto receptors |
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What people have a low MHPG? |
Depressed individuals |
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What are the ways to eliminate serotonin from the synapse? |
1) Re-uptake and redepositing into synaptic vesicles (most common) 2) degraded by MAO |
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What is the most common way to eliminate serotonin from the synapse? |
Re-uptake and redepositing into synaptic vesicle |
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How is serotonin broken down in the synapse? |
MAO (monoamine oxydase) |
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What do MAO's convert serotonin into? |
Waste products: catabolites of 5 hydroxyindoleacetic acid (5 HIAA) |
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What is 5 HIAA? |
a catabolite waste product of serotonin after MAO |
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What does 5HT2(a) have an important connection to? |
Depression |
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What is 5HT3 involved in? |
Emesis |
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What are 5HT3 antagonists used for? |
Anti-emetic drugs, used in conjunction with cancer treatments |
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Indoleaminergic Serotonergic pathways (3): |
1) Raphe nuclei running from lower midbrain to Medulla 2) Ascending pathway (hypothalamus) 3) Descending pathway (Medulla) |
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What is the Ascending pathway of the Indoleaminergic Serotonergic pathway? |
extending to the suprachiasmatic nucleus (time; sleep and other biorhythms) and pre optic area (temperature regulation) of the hypothalamus |
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What two areas of the Hypothalamus are in the Ascending Indoleaminergic Serotonergic pathway? |
1) Suprachiasmatic nucleus (time; sleep and biorhythms) 2) Preoptic Area (temperature regulation) |
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What is the Descending pathway of the Indoleaminergic Serotonergic pathway? |
from Medulla (nucleus rap he magnus) to the spinal cord; dorsolateral funiculus - part of the top-down control system for pain reception |
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What two major areas does the Descending Indoleaminergic Serotonergic pathway use? |
Medulla to the Spinal cord |
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What area in the Medulla does the descending indoleaminergic serotonergic pathway use? |
the Nucleus Raphe Magnus |
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What area of the Spinal Cord does the descending idoleaminergic serotonergic pathway use? |
Dorsolateral Funiculus (pain reception) |
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What does the Dorsolateral Funiculus do for the spinal cord? |
It is part of the top-down control system for pain reception |
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What does LSD stand for? |
Lysergic Acid Diethylamide |
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What molecular structure is LSD similar to? |
Serotonin |
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What are the effects of LSD? |
decrease in sleep, decrease in pain sensitivity, marked enhancement in all other sensory experiences; synesthesia and visual hallucinations |
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What is the main symptom LSD users have? |
Hallucinations, it is a hallucinogenic (but perhaps not psychotomimetic) |
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What does MDMA stand for? |
Ecstacy |
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What is the difference between Ecstacy and amphetamines? |
Similar except for serotonergic neurons |
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How does ecstasy function? |
Allows serotonergic neurons to leak, without benefit of an action potential and slows or block reuptake of serotonergic neurons into presynaptic terminal |
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Who was the founder of Parkinson's and what did he call it? |
James Parkinson in 1817 "paralysis agitans" |
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What was the name of the essay describing James Parkinson's disease "Paralysis agitans"? |
"Essay on Shaky Palsy" |
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Who renamed Paralysis agitan or "Shaky Palsy"? |
Charcot in 1860-1870 |
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What is Parkinsonism? |
a cluster of symptoms constituting the Parkinsonian syndrome are caused by other, known factors |
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What are the 3 ways Parkinsonism can be induced? |
1) following post-encephalitic endemic, an encephalitic lethargic (followed Spanish flu) swelling of the brain 2) drug-induced MPTP 3) Common day effects |
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What causes a drug induced form of Parkinsons syndrome? |
Herion High gone wrong, creates MPTP |
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What are common everyday things that can cause Parkinsonianism? |
Coal gas poisoning Manganese poisoning (miners, welders) Vascular problems Tumors Syphilis Genetics (rare) |
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What is the second most common neurodegenerative disease? |
Idiopathic Parkinsonism (PD) |
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What is the most common degenerative disease affecting the motor system? |
Parkinsons (PD) |
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When does the typical onset of Parkinsons occur? |
Later in life disease (over the age of 50) as you get older the chance gets higher (80 years old 10% chance) |
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What kind of disease is Parkinsons? |
Progressive and neurodegenerative |
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What muscle group does Parkinsons affect? |
Reflexive muscles (fingers, back, all curved in and walks with a shuffle) |
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What are the 4 Major symptoms of Parkinsons? |
1) muscular rigidity 2) Hypokinesia, brady kinesia, akinesia (lack motor ability) 3) Tremor 4) Postural instability (ataxia) |
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What is Bradykinesia? |
general slowness in initiating voluntary movements like standing up from a chair or eating |
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What is Hypokinesia? |
an abnormally low amount of movement, mask-like expression and sits very still, blank stare with little eye-blinking |
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What is Akinesia? |
in advanced and sever cases: complete freezing |
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What is the first noticeable symptom of Parkinsons? |
Tremors: in early stages, prodromal symptom, can disappear as disease continues |
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What body system is affected by tremors? |
Unilateral motor system: fingers, hand, forearm, foot (not the head or neck) |
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What is Ataxia? |
Postural instability, balance problems |
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Akinesia and age also show correlation with what changes? |
Intellectual and personality changes |
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What is a prevalent secondary consequence of Parkinsons illness? |
Depression |
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What dopaminergic pathway is more prevalent in Parkinsons? |
Nigro-striatal pathway (melanin-containing dopaminergic neurons) axons extend to the corpus striatum |
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What does the Nigro-striatal pathway contain? |
80% dopaminergic axons in the brain (cell bodies of melanin) |
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Studies on Monkeys that result in Parkinsons symptoms are caused by what? |
Lesions of the substantial nigra (in the nitro-striatal pathway) |
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In large doses of a dopamine antagonist what drugs can induce Parkinsons symptoms (used on monkeys)? |
Chlorpromazine and Haloperidol |
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What kind of drugs are Chlorpromazine and Haloperidol? |
Dopamine antagonist |
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In post-mortem studies of PD patients what was relevant about their corpus striatum? |
Found reduced levels of dopamine and homovanillic acid (HVA) |
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What do the reduction in dopamine and HVA levels prove? |
cell loss in the pars compact which induce sever clinical symptoms of Parkinsons (akineasia) before patients death |
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How can we image the levels of dopamine in the corpus striatum of living patients? |
PET scans |
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PD patients have lover levels of what and proves what? |
lower levels of HVA in the cerebrospinal fluid which shows lower rates of dopamine turnover |
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Why is the dopamine turnover rate so low in PD patients? |
low levels of Homovanillic acid in the patients cerebrospinal fluid (cell death) |
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PD causes degeneration of cells in what pathway? |
degeneration of the cells composing the nitro-striatal pathway and lower the striatal levels of dopamine |
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To what degree does the cell loss of dopaminergic neurons have to be to induce Parkinsons symptoms? |
70-80% of cell loss in the substantial nigra pars compact of the corpus striatum in the mid bran |
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What pharmacologic intervention can inhibit the cell degeneration of the nigro-striatal pathway? |
there is none that have proven to be effective in providing symptom relief, continuous degeneration and we do not know what causes it or how to stop it. |
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What are Lewy bodies? |
Survival cells that have intracytoplasmic inclusions |
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What are the survival or care providing cells in the nitro-striatal pathway? |
Lewy bodies |
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What is used in PET scan to evaluate homovanillic acid levels in the body? |
Probinecin |
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What does Probinecin do? |
blocks the flow loss of cerebrospinal fluid to provide a steady rate in order to access the HVA levels and build up in the cerebrospinal fluid concentration |
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What was the second and more effective found treatment of Parkinsons? |
L-dopa (had to be in large doses) |
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What was the first successful drug treatment of the tremor symptom? |
Anticholinergic drugs (anti-muscarinic) ex. Scopolamine (have aggravate cognitive problem side effects) |
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What are some successful anticholinergic drugs? |
Benzotropin, Cogentin, Trihexylhenidyl, Artane |
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What did physicians research lead to in order to fix the pathology involved in PD? |
increase levels of dopamine in the brain |
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What effect does tyrosine have on dopamine levels? |
None, it is on the wrong side of the rate-limiting step (before) and cannot boost dopamine levels |
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Dopamine in reference to the Blood-brain barrier: |
Dopamine cannot pass through the blood brain barrier |
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L-dopa in reference to the Blood-brain barrier: |
L-dop can pass through the blood brain barrier and can readily be converted into dopamine on the other side of the barrier |
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What were some side effects of high doses of L-dopa? |
Adverse pheripheral side effects: nausea, vomitting, cardiac irregulartities, postural hypotension (can also cause hallucinations) |
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What was added to L-dopa in order to prevent adverse side effects and lower the direct dosage of L-dopa? |
a dopa decarboxylase inhibitor (unable to pass through blood brain barrier) combined L-dopa with Carbidopa (Synemed) cut dosages by 75-80% |
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What is Carbidopa and why was it added to L-dopa? |
a dopa decarboxylase inhibtor in order to reduce the high dosage levels of L-dopa and reduce peripheral side effects |
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What are the central side effects of L-dopa therapy? |
Psychotic and depressive symptoms, dyskinesias (nothing can be done to fix) |
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What is Dyskinesia? |
abnormally or impairment of voluntary movements |
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Where is dopa-decarboxylase (inhibitor) produced? |
Enzyme in the Liver |
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What is dopa-decarboxylase used to produce? |
Carbidopa (Synemed) |
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Why use L-dopa? |
patient responds quickly but lasts for brief moment (on-off phenomenon) |
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What is the on-off phenomenon of L-dopa treatment? |
effects quickly but last for brief time; quick relief (on), short lasting time (off) |
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Why add B MAO-inhibitor? |
allow dopamine to act longer |
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What B MAO-inhibitor (antidepressant) drugs are used in PD treatment? |
use of selegiline; Deprenyl and Eldepryl |
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What Dopamine Agonists are used in treatment of PD? |
bromocriptine (Parlodel) pramipexole (Mirapex) pergolide (Permax) ropinirole (Requip) |
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What side effects do Dopamine Agonists cause? |
nausea, sleep disturbances, psychotic symptoms, and hypotension (low blood pressure) |
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What COMT-inhibitors (degrader of NT) are used in treatment of PD? |
tolcapone (Tasmar) entacapone (Comtan) |
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What surgical interventions have reduced PD? |
1) Ablative procedures (thalamotomy, pallidotomy) 2) brain stimulation of the thalamus (tremor), globes pallid us, and sub thalamus |
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What tissue grafts have been used in treatment of PD? (grafted into corpus striatum) |
1) Chromaffin cells from adrenal gland 2) fetal tissue transplant from the ventral mesencephalon composed of dopamine-producing cells 3) embryonic stem cells |
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What problems are associated with Tissue graft interventions? |
low graft survival rate (may not work or last), limited re-establishment of neural connections, and ethical issues |
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Frozen Addict Case of William Langston: |
Parkinsons induced disease from drug addiction |
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What is the designer drug used in the frozen addict case of William Langston? |
MPPP (synthetic opiate) similar to Demerol |
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What happens when MPPP goes wrong? |
MPTP is created as by-product when trying to make MPPP |
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How is MPTP converted to MPP+? |
MAO (monoamine oxidase) in the neurons of the substantial nigra |
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What does MPP+ do? |
destroys cell bodies of melanin-contaning neurons in the substantia nigra |
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What role does neuromelanin play in PD? |
Neuromelanin increases with age (over time) which may account for the later onset of PD |
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What Type B MAO-ls are used? |
1) Selegeline (Deprenyl) prophylactic (prevention) treatment of PD 2) Rasagiline (developed for neuroprotection) |
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What is the most common B MAO-I drug used as prevention treatment of PD? |
Selegeline (Deprenyl) |
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What gene identifies the genetic onset of PD in families? |
Chromosome 6 (before age 40 early onset of PD) |
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What environmental toxin is created from MPP+? |
Paraquat |
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What does type A MAO-I do? |
inhibitor in only type A; CNS break down of neroepinphperine and serotonin |
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What does type B MAO-I do? |
effects PNS break down of dopamine (accompanies eating disorders) |
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What is the major difference in Parkinson's disease and Huntington's Disease? |
Both are movement disorders: PD is akinetic extrapyramidal disorder (voluntary movements) HD is dyskinetic extrapyramidal disorder (involuntary movements) |
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Where are PD and HD located? |
PD: degeneration of substantia nigra in the brain and the nigro-striatal pathway HD: degeneration of corpus striatum and the gabanergic stratal-nigral pathway |
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What causes akinetic symptoms (PD)? |
ACh greater than DA in corpus striatum |
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What causes dyskinetic symptoms (HD)? |
DA greater than ACh in corpus striatum (effects degeneration of gabanergic neurons) |
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How do antipsychotic drugs act with PD and HD? |
PD: will worsen symptoms HD: can be useful in treating (do not give L-dopa) |
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Who was the founder of Schizophrenic disorders? |
Emil Kraepelin |
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What were the two major forms of insanity Kraepelin found? |
1) Manic-depressive insanity 2) Dementia praecox |
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What is manic-depressive insanity? |
alteration in mood, episodic course |
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What is dementia praecox? |
alteration in thoughts; progressively deteriorating course into profound dementia |
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What does dementia praecox mean? |
emphasize the characteristic onset in adolescence or young adulthood |
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What is the end result of the progression of dementia praecox? |
inevitabel and unrelenting progress resulting in near vegetative existence |
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What are the three subtypes of dementia praecox? |
1) hebephrenic form 2) catatonic form 3) paranoid form |
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Who renamed dementia praecox to Schizophrenia? |
Eugen Bleuler |
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What are the gender differences of Schizophrenia? |
Men: early on set, puberty (makes more difficult to treat) and experience more sever symptoms
Women: later in life, more successfully treated until menopause |
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What is a common physical indicator of Schizophrenia? |
Ventricial Enlargement |
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What are common symptoms of Schizophrenia? |
Delusions, hallucinations, disorganized speech grossly disorganized or catatonic behavior, negative symptoms (affective flattening, alogia or avolition) |
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What is alogia? |
Inability to speak due to mental defect or mental confusion (aphasia), speech disturbancee and negative symptom of schizo. |
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What is avolition? |
characterized as general lack of drive or motivation to pursue meaningful goals; show littler participation in work and socializing, lack interest and may sit still for long periods of time |
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What determines diagnosis of schizophrenia? |
presence of two or more symptoms (i.e. delusions, hallucinations, disorganized speech, catatonic behavior, etc.) for a duration of 6 months |
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Who separated the categories of neurological symptoms? |
Hughlings Jackson into positive and negative symptoms |
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What are the positive symptoms of schizophrenia? |
Delusions, Hallucinations, Disordered thoughts and speech, Catatonic or grossly disorganized behavior |
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What are the negative symptoms of schizophrenia? |
Anhedonia, Austism, Avolition, and Alogia |
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What is the most common found form of Delusions? |
persecution (hostility or ill-treatment) |
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What is the most rare form of Delusions? |
Bizarre delusions (implausible and not understandable in context of person's ordinary life) |
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What is the most common form of Hallucinations? |
Auditory hallucinations (voices) and may last for continuous or long period of time, not always brief |
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What forms of catatonic behavior occur in schizophrenia? |
catatonic stupor, catatonic rigidity (posture), catatonic negativism (active resistance to instructions or attempts to be moved), catatonic posturing, catatonic excitement (purposeless and unstimulated excessive motor activity) |
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What is the range of disorganized behavior seen in schizophrenia? |
childlike silliness to unpredictable agitation (shouting/ swearing), or clearly inappropriate sexual behavior or an unusual manner of dressing |
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What do the negative symptoms directly relate to? |
emotions |
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What is the negative symptom anhedonia? |
emotional flatness; lack emotional responsiveness (diminished ability to be happy) |
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What characterizes the negative symptom Austism? |
withdrawal or avoidance of social connectedness; poverty of speech |
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What is avolition? |
amotivation, apathy, impairment in functional role as wage-earner, student, homemaker; marked lack of initiative, interest, or energy |
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What is alogia? |
absence of logical coherence in ones appraisal of events |
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Who also created categories for schizophrenia, after Jackson? |
Timothy Crow |
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What categories did Timothy Crow develop for schizophrenia? |
Type 1: good prognosis a) paranoia b) non paranoid
Type 2: poor prognosis a) ventricular enlargement b) hypofrontality decreased |
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What are the two subtypes of Type 1 Schizophrenia? |
A) paranoia B) non paranoia |
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What are the two subtypes of Type 2 Schizophrenia? |
A) venticular enlargement B) hypo-frontality decrease (state of decreased cerebral blood flow in the prefrontal cortex of the brain) |
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What is used to determine hypofrontality in schizophrenic patients? |
MRI - metabolic substance used to determine brain activity (low activity in frontal cortex) |
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What are the three cognitive symptoms of schizophrenia? |
1) executive function, abstraction, strategic problem solving: planning (prefrontal cortex) 2) spatial and verbal learning and memory (hippocampus) 3) complex and sustained attention (anterior cingulate gyrus) |
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What three neuro features are effected by cognitive symptoms of schizo? |
Prefrontal cortex, hippocampus, anterior cingulate gyrus |
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What are the three important categories of schizophrenia today? |
1) paranoid 2) disorganized (hebephrenic and catatonic) 3) negative (tim crow's type 2; ventricular enlargement and decreased cerebral blood flow, hypofrontality) |
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Why does age matter in onset of of disorder? |
More likely to be male, poorer premorbid adjustment, lower educational achievement, more structural brain abnormalities, more prominent negative symptoms, more cognitive impairment evident on neuropsychological testing and overall worse outcome! |
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What age is schizophrenia less likely to develop? |
before adolescence (rare) and after age 45. |
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What is the course of schizophrenia? |
some show continuous deterioration (Kraeplin) but more often show periodic relapses and remissions |
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Genetics of schizophrenia: |
both parents with schizo: 35% one sibling and one parent: 12.5% one parent: 9.7% general population: 0.8% Twin studies: 16-17% (much higher than general public) |
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Biological effects of schizo genes: |
candidate genes that affect dopamine and glutamate candidate genes that affect early development and maturation of nervous system |
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What neurodevelopment indicators prove schizophrenia? |
disruption in the development of the nervous system affecting cell proliferation, migration, synaptic connection, pruning and the establishment of neural networks |
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What neuro features are affected by the disruption of neurodevelopment? |
circuitry linking the limbic system with the prefrontal cortex |
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What are the 4 main contributing factors to schizophrenia development? |
1) viral infections 2) maternal health, diet, stress, exposure to terratogens 3) older paternal age (father is over 50) 4) birth complications |
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What birth complications can cause development of schizophrenia? |
a) prematurity b) low birth weight c) breech presentation, cord complications d) lower Apgar scores e) anoxia |
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What helps distinguish the effects of the schizo illness from the causes of the illness? |
Imaging Technology |
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What major physical features are measured in correlation to schizophrenia? |
1) ventricular enlargement 2) cortical gray matter volume (reduction) 3) subcortical volumes (reduction) |
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What three major subcortical volumes are measured? |
1) hippocampus 2) thalamus 3) cerebellum |
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Location of the cortical grey matter volume reductions? |
frontal lobes (prefrontal cortex) and temporal lobes |
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In measuring the grey matter volume in twin schizo studies where were the reductions found? |
prefrontal cortex, parietal lobe, and superior temporal gyrus (right larger than left in the planum temporal) |
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Why is the prefrontal cortex important in schizophrenic patients? |
special interest because this area of brain doesn't reach full maturity until late adolescence/ early adulthood (the typical time onset of schizophrenia) the prefrontal cortex also coordinates many of the functions that are impaired or aberrant in schizo |
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What important findings link the hippocampus to schizophrenia? |
neuron misalignment in hippocampus and parahippocampal gyrus: defects involving cell migration and pruning; hippocampus is smaller in schizo individuals |
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What drug correlates positively to hippocampal volume? |
Rispiridone |
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What is the importance of the thalamus to schizo patients? |
thalamus volume is smaller in schizo individuals and reduced metabolic activity in the thalamus of schizo patients |
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What have functional imaging studies found in schizo patients? |
best results obtained when comparing patients and controls as they perform some sort of task, not "resting" studies when subjects are inactive; attention/ working memory tests access hypofrontality in schizo |
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What was the average patient hospital stay for schizo patients in 1955? |
6 months |
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What was the average patient hospital stay for schizo patients 10 years later in 1965? |
2 months (significant reduction) |
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What caused this reduction in hospital stays? |
community mental health movement: emphasis on prevention, early detection, crisis intervention, brief hospitalization and early return to community
community-based support resources availability (receive psychological care outside) |
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What is Reserpine and where is it found? |
drug extracted from snake root (Rauwolfia Serpentina) it is a antihypertensive agent (lowers blood pressure) |
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What is Rauwolfia Serpentina? |
good for snake bite, ancient Hindu literature suggests it was used to combat the bite of a cobra; has antihypertensive agents that lower blood pressure; heavily sedated stupor |
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Who was the first to locate antipsychotic properties of Reserpine? |
Nathan Kline in 1954 |
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What was the first antipsychotic drug? |
organic drug; Reserpine to treat madness |
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What does reserpine directly induce in psychotic patients? |
Depressive side effects (about 25% of all psychotic patients develop it when treated with Reserpine) |
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What was then created to replace Resperine? |
A synthetic antipsychotic drug called Chlorpromazine |
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What does Resperine effect? |
the Central Nervous System |
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How does Resperine effect the CNS? |
interference with storage of catecholamine neurotransmitters (dopamine and norepinephrine) in synaptic vesicles |
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What two catecholamine NT's are affected by Resperine in the CNS? |
dopamine and norepinephrine storage and prevents dopamine release which reduces psychotic symptoms in schizo patients |
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Lack of storage and reuptake of catecholamine NT, what happens to them? |
increase degradation by MAO (monoamine oxydase) and lowering the level of catecholamines in the brain |
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What effect does Resperine have on psychotic symptoms? |
decrease in psychotic symptoms in CNS |
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Why do schizo patients avoid amphetamines? |
it increases their psychotic symptoms which they hate, releases catecholamine NT dopamine into the synapse at a high rate |
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Unlike amphetamines what will schizo addicts use? |
LSD and mushrooms |
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What happens when too much amphetamine is induced? |
Amphetamine psychosis: similar to acute paranoia schizophrenia |
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What else should schizo patients avoid to prevent increased psychotic symptoms? |
L-dopa and dopamine agonists used to treat PD and will also increase psychotic symptoms |
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What is and is not effective in reducing psychotic schizophrenia-like symptoms? |
Reduced by antipsychotic drugs but other general sedatives drugs are not effective |
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How does an amphetamine act in the CNS? |
referred to as an indirect agonist and inhibits re-uptake of catecholamines and thus permits these NT's to be released into synapse spontaneously without benefit of action potential |
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What is a traditional antipsychotic? |
chlorpromazine (Thyrazine) |
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Who discovered chlorpromazine? |
Henri Laborit |
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Why did Laborit discovery chlorpromazine? |
searching for antihistamine drug to diminish pre-surgical stress and allow for less anesthesia to be used during major surgeries (anesthesia prevention and surgically induced stress reduction) |
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What acts as a major tranquilizer? |
chlorpromazine (calming effects) |
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In 1951 who used chlorpromazine for calming effects on psychotic patients? |
Pierre Deniker and Jean Delay |
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What are the 3 main groups of traditional antipsychotic drugs? |
1) Phenothiazines 2) Thiozanthenes 3) Butyrophenones |
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What are antipsychotic drugs categorized as? |
catecholamine antagonists |
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What do Phenothiazine drugs do in the CNS? |
block dopamine and noradrenergic receptors as a post synaptic response |
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Phenothiazine at a lower potency does what? |
chlorpromazine (Thorazine) thioridazine (Mellaril) about 100 mg are anticholinergic and result in less Parkinsonian side effects |
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At a low potency what side effects can Phenothiazines like Thorazine and Mellaril cause? |
aggravate patients and cause cognitive problems and other side effects |
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At a high potency what do Phenothiazines cause? |
fluphenazine (Prolixin) and trifluperazine (Stelazine) 3 mg have less anticholinergic effects and cause extrapyramidal side effects and tardive dyskineasia |
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In a high potency Phenothiazines are usually paired with what to reduce side effects? |
Antipsychotics combined with Anticholinergic (benztropin, Cogentin and Artane) |
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What are Thioxanthene drugs? |
chlorprothixene (Taractan) thiothixene (Navane) |
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What do Thioxanthenes do? |
block both dopamine and noradrenergic receptors (similar to phenothiazines) |
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What are Butyrophenones and what do they do? |
haloperidol (Haldol) block dopamine receptors excessively |
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Due to research the catecholamine hypothesis of schizophrenia changes to what? |
the Dopamine hypothesis |
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What do all of the traditional antipsychotic drugs have in common? |
all are histamine (H1) antagonists and act as sedatives |
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What influences the clinical potency of these drugs? |
these drugs work by blocking dopamine receptor sites in the brain and potency is correlated with their binding affinity to these receptor sites |
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What kind of affect do these traditional antipsychotic drugs have on PD patients? |
increase or make Parkinsonian symptoms worse |
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With excessive doses of antipsychotic drugs how will this effect Schizo patients? |
they too will develop Parkinsonian symptoms due to the blocking of dopamine receptors in the striatum |
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What receptor does haloperidol bind to and what effect does this have? |
D2 receptors; better correlation with antipsychotic potency (Snyder) |
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What percent of D2 receptors need to be blocked in order to treat psychotic symptoms? |
60-65% of D2 receptors must be blocked |
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What is the Dopamine Theory of Schizophrenia? |
Post-synaptic problem; over production, more HVA w/ over production of dopamine |
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What are the reasons for thinking the dopamine theory of schizophrenia is a post-synaptic problem? |
HVA levels in schizo are normal (unlike PD); Prolactin secretion levels are normal in unmedicated acute and chronic schizos |
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Where does Prolactin secretion take place? |
Anterior Pituitary gland |
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What pathway plays a key role in Prolactin secretion and control dopamine release into the portal vessel system? |
Tubero-infundibular pathway |
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What NT is Prolactin secretion controlled by? |
Dopamine releasment into the portal vessel system by the neurons of the tuber-infundibular pathway |
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What are the major dopaminergic pathways in localizing schizophrenia and parkinsons? (which co-occur and are independent of each other) |
1) tubero-infundibular pathway (dopamine*) 2) nigro-striatal pathway 3) meso-limbic pathway (leading to subcortical nuclei such as the amygdala and the nucleus accumbens then to the meso-cortical pathway leading to the prefrontal cortex) |
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Which dopaminergic pathway is the most important in schizophrenic patients? |
Tubero-infundibular pathway (anterior pituitary gland) |
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Crow's research found what two major characteristics of the dopamine turnover rate in the mesolimbic-mesocortical pathway vs. the nigro-striatal pathway? |
Mesolimbic-mesocortical pathway correlates with dopamine binding potency as an antipsychotic
Nigro-striatal pathway dopamine binding correlates with tendency to elect extrapyramidal symptoms |
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Potency of an antipsychotic drug correlates with what dopamine binding tract? |
mesolimbic-mesocortical pathway |
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Tendency of extrapyramidal symptoms correlates with what dopamine binding tract? |
nigro-striatal pathway |
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Rat studies showed what due to sustained treatment with antipsychotics? |
increased production of DA receptors (all kinds of extra D2's) |
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In response to chronic DA blockade what is the result? |
production of more post-synaptic DA receptors |
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What is a time problem involving the delay in therapeutic effectiveness of antipsychotic drugs? |
receptor blockade occurs within about an hour but antipsychotics may take 3-6 weeks to reach full effectiveness |
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What is the rule of 3rd's concerning recovery from Schizophrenia? |
1/3 recover completely after single or few episodes and remain in remission without further antipsychotic medication 1/3 recover to a point where they are not obviously ill if they are adherent to medication but they will relapse 1/3 will have limited response to neuroleptic drugs and only partially recover, serious disability |
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What do traditional antipsychotic drugs manage? |
positive symptoms of schizophrenia but do not manage negative symptoms well |
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What are 2 categories of atypical antipsychotic drugs? |
1) Clozapine (Clozaril) 2) Rispiridone (Risperdal) planzapine (Zyprexa) quetiapine (Seroquel) ziprasidone (Geodon) |
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What is the difference between the two atypical antipsychotic drug categories? |
Clozapine has agranulocytosis problems unlike later developed drugs like Rispiridone, olanzapine, quetiapine, and ziprasidone |
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What amount of schizophrenia patients respond do atypical antipsychotic drugs? |
1/3 will respond (treatment-refractory patients) |
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Who are atypical antipsychotics successful in treating? |
refractory patients: who have failed 2 traditional antipsychotics |
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What kind of drugs are clozapine (Clozaril)? |
highly anticholinergic |
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What effects do anticholinergic drugs like clozapine (Clozaril) have on people? |
No extrapyramidal side effects and no tar dive dyskinesia (abnormally or impairment of voluntary movement) |
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What is the agranulocytosis problem with clozapine (Clozaril)? |
cell death of granulocytes (white blood cells; diminish the immune system cells) |
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What does cytosis of cell refer to? |
cell death |
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Where does the agranulocytosis problem occur? |
in the bone marrow, can result in death |
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What are other side effects of Clozapine (Clozaril) atypical antipsychotic drugs? |
sedation, fatigue, weight gain, restlessness, akathesia, and cognitive problems |
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What is akathisia? |
state of agitation, distress, and restlessness as a side-effect of antipsychotics and antidepressants |
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What defines a "dirty drug"? |
difficult to tell which NT systems are responsible for therapeutic improvement (binding affinity) |
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What atypical antipsychotics fixed the agranulocytosis problem? |
rispiridone (Risperdal), olanzapine (Zyprexa), quetiapine (Seroquel), and ziprasidone (Geodon) |
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What side effects do the later developed atypical antipsychotics have? |
gentler than the traditional atypical antipsychotic drugs and far less problems with the extrapyramidal symptoms (EPS), do not amplify negative symptoms (reduce PD symptoms) |
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What receptor is prominent in later developed atypical antipsychotic drugs? |
Less D2, more D4 receptor affinity |
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What pathway is effected by atypical antipsychotic drugs? |
meso-limbic and cortosil pathways (lower affinity for D2 receptors but affinities for broader set of dopamine receptors like D4) |
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What studies have been used to prove an increased number of D4 receptors in schizophrenic patients? |
PET scans |
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What percentages of blocking were found in study of "eye of the needle"? |
60-65% of DA receptors blocked to impact positive symptoms, 80% blockage of D1 and D2 receptors result in EPS (extrapyramidal symptoms) |
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What is a main defining features of atypical antipsychotic drugs? |
higher affinity for the 5HT2 receptor than for D2 receptors |
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What has been found more effective to add to the traditional antipsychotics? |
serotonin antagonsits + traditional antipsychotics |
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What is the third and newest category of atypical antipsychotics? |
Aripiprazole (Abilify) |
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What feature is specifically used in Aripiprazole (Abilify)? |
substantia nigra in the corpus striatum |
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What does this third generation of antipsychotic drugs do? |
agonist of D2 and 5HT1A (serotonin receptors) may block or stimulate receptors depending on the concentration of the NT being high or low (i.e. D4 blocked, D2 stimulated [balance]) |
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What area effects the positive symptoms of dopaminergic activity? |
subcortical areas such as the nucleus accumbens (when excessive) |
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Where does low dopaminergic activity effect the negative symptoms associated with hypofrontality located? |
corical areas such as the prefrontal cortex |
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Describe Crow's distinction of Type 1 (good prognosis) of schizophrenia: |
preponderance of positive symptoms good response to antipsychotic drugs (treatments) normal ventricular size over active DA systems (Paranoia) |
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Describe Crow's distinction of Type 2 (poor prognosis) of schizophrenia: |
preponderance of negative symptoms poor response to antipsychotics enlarged ventricular size "hypofrontality" normal or inactive DA systems (Disorganized) |
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What other problem does Crow's type 1 schizophrenia directly relate to? |
Amphetamine psychosis (paranoia) |
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What major NT located in the Thalamus effects disorganized (type 2) schizophrenia? |
Glutamate and NMDA receptors |
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What symptoms define disorganized schizophrenia? |
disorganized though processes, florid hallucinations, emotional flatness, social withdrawal, catatonic aberrations (diff. than paranoid schizo) |
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What is PCP? |
Phencyclidine psychosis; drug-induced model for disorganized schizophrenia (worsens psychotic symptoms in type 2 schizophrenic patients) |
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What does PCP block? |
glutamate receptors; it is a non-competitive antagonist for NMDA |
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What is NMDA? |
n-methyl-d-aspartate (excitatory ionotropic receptor) |
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Where is this excitatory ionotropic receptor NMDA found? |
frontal and temporal cortex of the brain, thalamus, amygdala, nucleus accumbens, and hippocampus |
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What is ketamine and who is it used on? |
heavy sedative for children (i.e. burn wards); antagonist for NMDA receptor [similar to PCP]) |
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What is ketamine similar to? |
PCP (sedative) |
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What other augmentations to antipsychotics reduce negative symptoms and are NMDA-receptor agonists? |
Glycine D-cycloserine |
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Are antipsychotics neuroprotective? |
They are becoming so |
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What is the importance of early diagnosis and early implementation of medication and treatment? |
Earlier treatment associated with better prognosis and lower rates of relapse |
