catecholamines 2

Question 1

Small amount of drug that stimulates D2 receptors do ——— but higher levels ———–

Answer 1

Small amount of drug that stimulates D2 receptors: much lower locomotion (activated autoreceptors - so reduction in dopamine levels)
Higher amount of the drug: much higher locomotion (activated receptors on postsynaptic neurons, despite low dopamine levels)

Question 2

Selective knockout of D2 autoreceptors (but not postsynaptic D2) in animals leads to

Answer 2

greater DA-mediated locomotion vs controls - confirming these receptors attenuate DA transmission

Question 3

DA originates from several cell groups, mostly in midbrain:

Answer 3

A few groups send out very distal broadcasts of dopamine, to their axons
Cell groups A1 to A7 are noradrenergic (a for amine probably)
Cell groups A8 to A16 are dopaminergic

Question 4

3 key dopamine pathways:

Answer 4

nigrostriatal (A9 axons): nigrostriatal for voluntary movement(can be damaged by neurotoxin 6-OHDA and MPTP), dorsal striatum DA for action selection
A10 (ventral tegmental) has 2 pathways: mesolimbic and mesocortical
mesolimbic: reward and motivational, linked to limbic system (NOT pleasure)
mesocortical: projects to frontal cortex, linked to cognitive functions

Question 5

DA receptor subtypes:

Answer 5

D1 to D5; all metabotropic; D1 and D5 are simliar, D2,D3 and D4 are similiar
D1 activation stimulates adenylyl cyclase and cAMP synthesis
D2 activation has opposite effect on cAMP

Question 6

D2 antagonists ——- DA release and ——– postsynaptic DA signaling

Answer 6

D2 antagonists increase DA release (by blocking autoreceptor) but also reduce postsynaptic DA signaling (so net effect is negative)

Question 7

–receptors have a higher (5x) affinity for dopamine compared to—–

Answer 7

D2 has 5x affinity than D1

Question 8

heteroreceptors

Answer 8

Some DA receptors are heteroreceptors, on glutamate/GABA terminals that modulate fast transmission presynaptically
E.g. Prefrontal cortical glutamate terminals in striatum contain D2 receptors - their activation attenuates glutamate release

Question 9

non-selective DA receptor agonist

Answer 9

apomorphine: Stimulates D1 and D2 receptors

Causes behavioural activation similar to that seen with cocaine, amphetamine (move a lot more)

Question 10

non-selective DA receptor antagonist

Answer 10

flupenthixol blocks both D1-D2 receptors (broad spectral drugs); reduces modivation and produces catalepsy at higher doses

Question 11

selective DA receptor antagonist

Answer 11

Haloperidol: Highly selective (>1000 times affinity) for D2-like vs D1-like - but - binds to D2, D3, and D4 with similar affinity
Easier to have antagonists that are selective

Question 12

behavioural supersensitivity experiment

Answer 12

Give D2 antagonist repeatedly over 12 days (e.g. haloperidol-HAL), rats develop behavioural supersensitivity
Initially, HAL blocks effects of DA agonist (like amphetamine - AMPH)
Locomotor actions are modulated by dopamine agonists like amphetamine
After chronic treatment, this dose HAL no longer effective at blocking AMPH effects (some kind of tolerance)
May underlie why some antipsychotics “stop working” over time
THEN - when antagonist treatment stopped - DA agonist (e.g. apomorphine, amphetamine) causes greater (locomotor) response vs. controls
May be caused to increase density of D2 receptors (receptor up-regulation)

Question 13

norepinepherine anatomy (central)

Answer 13

Central NE neurons cells bodies reside in pons and medulla in brain stem; locus coeruleus (LC) in the pones is a dense collection of NE neurons (A6 cell group)
- it looks blue; it is more spreadout than dopamine; axons extend to nearly all parts of forebrain, also reaches cerebellum and spinal cord

Question 14

norepinepherine anatomy (peripheral)

Answer 14

SNS uses NE that release from 1.sympathetic noradrenergic neurons at synapse-like contacts; 2. adrenal glands and travel in the bloodstream to target organs (but cannot cross BBB)

Question 15

adrenergic receptor families

Answer 15

2 main families, both metabotropic: alpha and beta; distributed widely across cortical and subcortical sites

Question 16

alpha 1 receptors

Answer 16

operate via phosphoinosite 2nd-messenger system (postsynaptic);

• agonist phenylepherin increases blood pressure
• antagonist prazosin reduces blood pressure

Question 17

alpha 2 receptors

Answer 17

reduce cAMP synthesis (like D2);
both pre and postsynaptic
- agonist = clonidine
- antagonist = yohimbine (increase NE but block postsynaptic receptors; increases anxiety like and stress response

Question 18

Beta 1 and beta 2 receptors

Answer 18

stimulate adenylyl cyclase and enhance synthesis of cAMP (like D1 receptors); beta 1 receptors are on cardiac cells in periphery;
non-selective agonist = isoproterenol
antagonist = propranolol

Question 19

firing during REM sleep

Answer 19

NE is key for arousal; LC neurons fire more rapidly during waking vs REM sleep

Question 20

NE and wakefulness

Answer 20

NE projections to medial septal and medial preoptic areas promote wakefulness
intracranial injections of a1 or b receptor agonists increase awake times

Question 21

NE regulates:

If people experience depletion of NE, you can activate —— to ameliorate those impairments

Answer 21

cognitive functions mediated by PFC: attention, working memory
PFC a2 receptors (guanfacine); which suggests that normally, NE activation of a2 facilitates PFC function

Question 22

resperine

Answer 22

lowers levels of catecholamines; worsens working memory (affected by both NE and DA, can be somewhat rescuted by NE agonist)

Question 23

too much stress causes —— in NE level in pfc which leads to —

Answer 23

increase / overflow, shuts down cognitive function

Question 24

PFC a1 receptors

Answer 24

when stimulated, imparis cognition like stress (so maybe stressed induced NE increase impairs cognitive impairment through this)
when antagonised, can ignore the above line
has lower affinity for NE compapred to a2

Question 25

strong emotional states can enhance memory consolidation which may be mediated by

Answer 25

NE, through beta adrenergic receptors that help with enhancement of memory for emotional content

emotional / stressful events increase NE release in amygdala and enhances consolidation of memories (may underly PTSD so first responders may give beta blockers to people at traumatic events to prevent this)