Lecture 8- Stimulants II Flashcards
Proccess of L DOPA to Epinephrine
-L dopa is the product of L tyrosine
-From L-dopa to Dopa decarboxylase
-Creates dopamine
-Become norephedrine
-Becomes Epinephrine
What is the rate-limiting step (slowest) in catecholamine synthesis
Tyrosine hydroxylase (TH)
Dopamine was originally only believed to be
A precursor for NE and E, not it’s own NT
How did Arvid Carlsson demonstrate that dopamine was a NT
-Removed dopamine from rabbits and gave it back
-Rabbits start to move again
-When they remove dopamine, they’re more catatonic
Dopamine transporter also does what
Reuptakes dopamine
In the brain all monoamines are packaged into vesicles by
VMAT2
All monamines are degraded by
Monoamine oxidase
In the striatum, what are the dopamine classes
-D1 class (D1,D5)
-D2 class (D2-4)
D2 class features
-Receptors couple to inhibitory G protein
-Presynaptic Autoreceptors are usually D2
D1 class features
-Receptors are usually coupled to stimulatory G proteins
All dopamine classes can be
Postsynatic
D1 and D2 class receptors are usually on different
Neurons
Hundreds of thousands of DA, NE and 5-HT cells in the midbrain nuclei send
Broad, diffuse projections to large areas of the forebrain, suggesting these signals are global
Striatum is divided into 2 main parts
-Nucleus accumbens
—Important for reward
-Dorsal striatum/ caudate putamen
—Involved in movement
The striatum is a key site of
-Dopamine action
-Dopamine is important for striatal function
A9, Substania nigra
-Project their axons to the dorsal striatum
-Nigrostriatal pathway
A10, Ventral tegmental area (VTA)
-Projects their axons to the nucleus accumbens
-Mesolimbic pathway
Dopamine terminals can be identified via
Tyrosine hydroxylase (TH staining)
Amphetamines dopamine increase measured by microdialysis
-In the nucleus accumbens, 1000%
-In the dorsal striatum, 500%
Cocaine dopamine increase measured by microdialysis
-In the nucleus accumbens, 300%
-In the dorsal striatum, 200%
What’s the primary site of action of amphetamines and cocaine
Monamine transporters
Distribution of cocaine matches that of
DAT
Effects of cocaine blocking DAT
-High doses of cocaine can produce 2-4 times increase in striatal dopamine release
-Dopamine accumulates in the synaptic cleft
Which produces a greater effect on momamines
Amphetamines more than cocaine
Amphetamines effect on DAT
-Entry via DAT
-Inhibits dopamine storage in vesicles through VMAT blockade
-DAT works in reverse to remove dopamine from terminal to cleft
Why when dopamine blockers are added do rats increase pressing a lever
Panic, want more drug, eventually drops when nothing is received
What do DA and NE antagonists show about amphetamine reward
-DA blockers cause spike and drop in lever presses
-NE is unchanged
What blockers are not commonly abused by people
-NET
-SERT
Repeated treatment which procedures sensitisation of psychomotor also
Increases DA transmission
Subjective high requires
40-60% DAT occupancy
Cocaine has frequent administration due to
Fast uptake and clearance from the brain
Dopamine terminals destroyed using
Toxin 6-OHDA
What are stereotyped behaviours
Meaningless repetitive movement
Psychostimulant microinjections into the nucleus accumbens cause
Increased locomotor behaviour
Psychostimulant microinjections into the dorsal striatum causes
Increased stereotyped behaviours
6-OHDA lesions to the nucleus accumbens causes
-Decreased locomotor response following systemic administration of low dose psychostimulants
-Decreasing reinforcing effectiveness
6-OHDA lesions to the dorsal striatum causes
Decreased stereotyped behaviours following systemic administration of high dose psychostimulants
Amphetamine microinjection to the nucleus accumbens causes
Reinforcing to the animal
Cocaine microinjection to the nucleus accumbens causes
Reinforcing to the animal
Dopamine blockade in the dorsal striatum causes
Normal Acquisition of cocaine self administration
Dopamine blockade in the nucleus accumbens causes
Disrupted acquisition of cocaine self administration
Stimulant ‘bath salts’ contain
Cathinones such as MDVP
How does bath salts differ to cocaine
-More DA release per mg of product
-Increased heart rate
