Unit 05: Physchosis and mood

Question 1

what is psychosis

Answer 1

• severe disturbances in brain function in which normal perceptions in environment are disrupted or dissociated (loss of contact with reality)
• auditory and visual hallucinations, suspicion, paranoia, attachment of excessive personal significance to daily events

*etiology (cause or origin) not known

Question 2

what causes drug induced psychosis

Answer 2

long term cocaine or amphetamine use

• affects dopamine neurotransmission and can lead to paranoia
• supports role of dopamine (DA) imbalance in psychosis
• hallucinogens such as PCP (NMDA receptor antagonist) and LSD (5-HT2A partial antagonist) can also induce hallucinations, paranoia and panic
• supports roles of glutamate and serotonin inbalance in psychosis

*glutamate and serotonin are linked with DA neurotramission in cortex and limbic system

Question 3

what is schizophrenia

Answer 3

• mental disorder charcaterized by breakdown of thought processes and lack of typical emotions
• symptoms are described in terms of positive (initial) and negative (later in the disease)
• positive = those that an individual does not normally experience but are present in those with schizophrenia (hallucinations and paranoia)
• negative = discrepancies of the thought process and emotional responses like apathy, social withdrawal and extreme inattentiveness

Question 4

how are intitial symptoms of schizophrenia treated

Answer 4

• antipsychotic drugs
• individuals diagnosed later in disease are not easily treatable
• many individuals with schizophrenia progress from more positive to more negative symptoms some will expereince both simultaneously
  ie: hear voices while being socially withdrawn

Question 5

what is the dopamine hypothesis

Answer 5

model that attributes psychosis to cahnges in dopamine function in the brain

• evidence for dopamine hypothesis comes from observations such as fact that anti-psychotic drugs block dopamine D2 receptors

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Question 6

drugs that increase dopamine activity _____

Answer 6

aggrevate or produce psychosis

• increase in dopamine receptor density has been reported in shcizophrenic patients and patients that were successfully treated for the disoder had dereased dopamine metabolits in their bodies

Question 7

what are the 3 main dopamine pathways

Answer 7

1. nigrostriatal - associated with movement
2. cortical
3. limbic - associated with behaviour

*high dopamine in limbic system has been linked with positive symptoms of psychosis while low dopamine in cortex has been linekd with negative symptoms

Question 8

what are antipsychotic drugs

Answer 8

also called neuroleptics

• believed to decrease psychotic symptoms by decreasing dopamine synpatic activity in the limbic pathway
• binding affintiy of drug with D2 receptors correlates with its clinical potency as an antipsychotic agent

Question 9

describe activation bc blocking D2 receptors

Answer 9

D2 receptors are G protein linked

• activation has inhibitory effects on cAMP
• blocking of D2 receptors in cortex would enhance negative symptoms of psychosis
• newer drugs have been designed to block both 5-HT2A and D2 receptors in order to normalize dopamine activity in limbin system

Question 10

what are the structural categories of commonly used first generation antipsychotics

Answer 10

• phenothiazines, thiozanthenes and hutyrophenones
• Haloperidol is one of the most widely used typical antipsychotics from the butyrophenone class of drugs

Olanzapine is an example of a second generation (atypical) drug which can be used for psychosis.

Question 11

receptor affinity Haloperidol

Answer 11

D2 > α1 > D4 > 5HT2A > D1 > H1

Question 12

receptor affinity of Olanzapine

Answer 12

5HT2A > H1 > D4 > D2 > α1 > D1 (note, H1 is histamine receptor). Olanzapine is also an antagonist at muscarinic receptors.

Question 13

what is believed to be the cause of difference in clincial effectiveness of antipsychotic drugs

Answer 13

• due to difference in affinity for D2 and 5-HT2A receptors
• antagonism at other receptors results in some adverse effects of antipsychotics

Question 14

why is there often a dely in clinical effects of antipsychotics

Answer 14

• few theories support the delat in clincial effects
• blockage of D2 receptor alone does not explain the antipsychotic action of the drugs
• second has to do with location of D2 receptors both pre- and post synpatically
• activation of D2 receptors results in inhibitiroy response (dec cAMP) so an initial presynpatic receptor blockade by drug like haloperidol would prevent this inhibitory effect and cause an inc in dopamine release

*would inc amount of dopamine available to compete with haloperidol at postsynpatic receptor

*Research studies have shown that tolerance to presynaptic blockade develops over time, making post-synaptic blockade more effective.

Question 15

treatment of negative symptoms

Answer 15

• negative symptoms are not efectively treated with classical antipsychotics - sometimes negative symptoms are a side effect of treatment
• hypothesis = negative symptoms are associated with dopamine hypofunction in cortex, newer drugs may be more effective due to differences in pharmacodynamic profile and the interaction between dopamine and serotonin in CNS

Question 16

haloperidol and effect on dopamine transmission

Answer 16

* haloperidol has a higher affinity for blocking the D2 receptor compared to 5HT2A receptor

• animal studies measured dopamine transmission in presence of haloperidol found to be normal in limbin system but low in cortex

Question 17

olanzapine effect on dopamine neurotransmission

Answer 17

Olanzapine preferentially blocks the 5HT2A receptor over the D2 receptor

• dopamine neurotransmission is found to be noral in both limbic and cortex

Question 18

what is PCP and what can it do

Answer 18

• NMDA receptor antagonist that can induce psychosis
• is based on the glutamate hypothesis of psychosis which states tha NMDA antagonists increase DA neurotransmission in the limbic system

*explains how drugs like PCP would induce psychosis

*there is an inc number of PCP bidnign sites in cortex of schizophrenics which suggets that glutamate hypofunction in cortex is associated with negative symptoms

Question 19

what types of drugs to treat psychosis are currently being investigated?

Answer 19

• newer drugs that increase NMDA receptor activation are under investigation as potential schizophrenia treatments
• drugs that increase glycine levels or bidn to glycine modulatory sites of NMDA receptor are also under investigation

Question 20

describe the structure of ionitropic glutamate receptors

Answer 20

* picture A

• all 3 ionotrpic glutamate receptors are tetrameric complexes composed of the same (termed homomeric) or different (termed heteromeric) subunits
• structure on right shows one ionotropic glutamate receptor subunit which spans membrane 3 times and has a partially spanning hairpin turn that when juxtaposed w/ homologous turns from the other 3 subunits forms the lining of the ion channels pore

Question 21

describe major binding sites on AMPA/kainate and NMDA classes of ionotropic glutamate receptors

Answer 21

picture B

• there is indirect evidence for the location of many of the drug binding sites that are schematically indicated in this diagram, the definitive localization of these sites remains to be determined.

Question 22

describe the adverse effects of antipsychotics

Answer 22

• assocaited with a wide range of adverse effects
• in CNS - parkinson-like symptoms can occur as a result of D2 receptor blockade and sedation from H1 receptor blockade
• autonomic efects can occur like hypotension from α1-receptor blockade

Question 24

adverse effect specific to olanzapine

Answer 24

Olanzapine also blocks muscarinic receptors; therefore atropine-like side-effects might result

• parkinson like extrapyramidal adverse effects

H1 blockade causing sedation

nonspecific blockage of muscarinic alpha receptors (lower bp)

Question 25

compare mainia and depression

Answer 25

* psychosis and depression often occur independently but for some individuals there is a cyclical relationship between manic episodes and depression

Question 26

what is bipolar disorder

Answer 26

• psychiatric diagnosis for mood disorder
• mood swings affiliated with bipolar disorder are not correlated to external environment - usually experience alternating episodes of mainia and depression

Question 27

what is the monoamine theory

Answer 27

suggests imbalances in norepinephrine, dopamine and/or serotonin are involved in what causes bipolar disorder

• most common theroy but exact reasion not known
• theory is supported by face that decreased monoamine activity is associted with depression and increased monoamine activity correlated with positive mood

Question 29

what does treatment for bipolar disorder usually involve?

Answer 29

• mono or combination therapy
• single drug treatment like lithium or antipsychotics can be administered alone or in various combinations ex: antipsychotic with antidepressant, lithium with antipsychotic, and lithium with antidepressant.

Question 30

describe lithium for treatment

Answer 30

• small monovalent cation effective against the mainic phase of bipolar disorder

*anti manic drug

• inc serotonin neutrotransmission and dec NE and dopamine neurotransmission

*mood stabilizer, paradoxical actions depend on the signalling cascade its affecting

• narrow margin of safety

Question 31

how does lithium wokr as a mood stabilizer

Answer 31

many intracellular effects

*inhibits inositol monophosphatase so free inositol cannot be generated form IP1 - results in dec PIP2 -> deg IP3 and DAG

• Lithium inhibits the phosphatase that conv IP2 to IP1 AND inhib IP1 to free inositol
  
  • free inositol is essential for regeneration of PIP2 so lithium blocks the phosphatidylinositol signalling casacde
• By blocking regeneration of PIP2 lithium affects central adrenergic, muscarinic and serotonergic neurotransmission

*causes decrease in precurors for IP3 and DAG synthesis - dec IP3 and DAG when receptors linked to these secondary messangers are activated like muscarinic, α1 and 5-HT2A receptors.