Schizophrenia

Question 1

Mesostriatal DA

Answer 1

Substantia nigra to Dorsal Striatum

Question 2

Mesocortical DA

Answer 2

VTA to neocortex

Question 3

Mesoaccumbens DA

Answer 3

VTA to Nacc (ventral striatum

Question 4

Kindling metaphor of mental illness

Answer 4

Graham Goddard, observed full tonic clonic seizures after many low intensity stimulations. In some brain regions, where you stuck an electrode and applied low intensity stimulation, the first time you do something nothing happens. After a few stimulations, you see full blown seizures.

Question 5

Typical Antipsychotics

Answer 5

Haloperidol is absorbed better; remains the gold standard for antipsychotic effectiveness

Metabolized very slowly; half-life of 48-96 hours w/ oral administration, weeks w/ IM administration;

stored in other tissues (lots of depot binding) such as liver, lungs, and spleen

ED50 = 2mg; LD50 = unknown; TI = estimated to be 100-500

Metabolized in liver by CYP, excreted in urine

Question 6

DA Hypothesis Problems

Answer 6

Dopamine levels not elevated in schizophrenics

Question 7

What results in hypofrontality?

Answer 7

Loss of DA release from VTA neurons projecting to prefrontal cortex (mesocortical pathway)

Question 8

What happens after hypofrontality?

Answer 8

Hypofrontality results in less glutamate stimulation from PFC back to VTA

Question 9

Glutamate-dopamine model

Answer 9

Impaired NMDA function makes this GLU stimulation of VTA even less effective… further reducing DA release in PFC -> leads to excessive DA release in limbic regions

Question 10

Major depression

Answer 10

recurring episodes of dysphoria and negative thinking

Question 11

Reactive depression

Answer 11

state of sadness in response to situations like loss of a loved one.

Question 12

Pathological depression

Answer 12

resembles an emotional state we have all experienced but differs significantly in intensity and duration

Question 13

Biological Bases for affective illness:

Answer 13

affective illnesses are due at least in part to an impairment in the function of two different monoamine neurotransmitters, norepinephrine and serotonin.

Question 14

Resperine

Answer 14

blocks vesicular transporter, can lead to depression… or can be used to treat mania.

Question 15

What do antidepressant drugs do?

Answer 15

Antidepressant drugs alter NE and 5-HT synapses in the nervous system… acute effects not clinically relevant, chronic effects are.

Question 16

Lithium

Answer 16

may be effective in manic-depressives, as it stabilizes 5HT synthesis

Question 17

5HT in bipolar disorder

Answer 17

; low 5HT levels may lead to NE levels determining mood. HI NE = mania; LO NE = depression.

Question 18

MAOIs

Answer 18

acutely block MAO and elevate levels of 5HT and NE, and ultimately produce long-term changes in the postsynaptic cell

Lots of side effects;

Question 19

MAOIs in use

Answer 19

currently 3 in regular use; best known is tranylcypromine (parnate), which irreversibly inhibits MAO; start-up; 5-10 TI

Question 20

Tricyclics

Answer 20

Replaced MAOis

May block 5HT reuptake, or NE reuptake, or both… and DA reuptake; D-2 antagonist; 5-HT2 antagonist; block Na+ and Ca2+ channels (dirty drugs)

Question 21

SSRI’s:

Answer 21

2nd golden age of psychopharm –

Prozac, 2nd generation of antidepressants; favored due to fewer side effects and higher TI, though therapeutic effects often no better.

Specifically block 5 HT reuptake carrier; a modified tricyclic

Question 22

BAR 5HT receptors in depressed individuals

Answer 22

BAR 5HT receptors – primary norepinephrine receptor…. Decrease in receptor number if patient is on antidepressants

Question 23

Why is lithium effective in treating bipolar disease?

Answer 23

Unknown mechanism of action – may stabilize proteins in neural membrane; reduced Ca2+ dependent release of catecholamines (but not 5-HT!); stabilize synthesis of 5-HT; alters many different aspects of 2nd messenger function.

Question 24

Dangers of lithium

Answer 24

Very low TI (~3); can kill if patient has heart of kidney problems; long half life, so several small doses taken each day; eliminated by kidneys without being metabolized (at Li+)

Question 25

NaCl and Lithium levels

Answer 25

Must watch NaCl intake as increased Na+ levels reduce amount of Li+ that can be excreted, NaCl levels too low cause toxic levels of Li+ to be retained.

Question 26

Drugs other than lithium for bipolar disease

Answer 26

Carbamazepine/oxacarbazapine and valproate also used as adjuncts or primary treatment; mechanism of action unclear; GABA indirect agonists; decrease neural excitability.