Neurobiology of Addition Medicine

Question 1

mesolimbic DA pathway

Answer 1

projection from ventral segmental area (VTA, area A10) –> nucleus accumbens

Question 2

corticolimbic pathway

Answer 2

projections from VTA –> prefrontal cortex

Question 3

nigrostriatal pathway

Answer 3

projections from SN (area A9) –> dorsal striatum

Question 4

How GABAergic projections to the mesolimbic DA system modulate DA release in addiction

Answer 4

GABA projections from NA go to ventral palladium and inhibit GABA cells, creates “inhibition of inhibition = excitation” effect

those VP GABAs usually inhibit DA in VTA,
so if inhibiting those ultimately releasing more DA –> excitation

Question 5

How glutamatergic projections to the mesolimbic DA system modulate DA release in addiction

Answer 5

DA release from VTA to prefrontal cortex –> glutamate release from prefrontal cortex to VTA –> release more DA, EXCITATION

or

glutamate release from prefrontal cortex to NA –> GABA release from NA to VTA –> INHIBITION of DA release

Question 6

nicotine

Answer 6

acts at ligand-gated ion channels that comprise VTA nicotinic ACh receptors

gate Na+ and allow selective permeation of Ca++

dominantly PRESYNAPTIC

Question 7

cocaine

Answer 7

DA reuptake blocker from synapse by blockade of DAT

*cocaine reward is intact in DAT KO mice, poss due to reuptake blockade of DA at NEPI/5HT transporters

Question 8

amphetamines

Answer 8

targets monoamine storage

competitive ligand to DAT and VMAT2 transporters (amphetamine builds up in vesicle, displaces DA to cytosol and extracellular space)

DAT starts to work in reverse and pump DA out of the cell and into synaptic cleft

• amphetamine also partial blocks normal DAT reuptake

Question 9

opioids

Answer 9

• Activate metabotropic μ-opioid receptors on VTA cells. (G protein-linked receptor)
• Normal endogenous ligands: Endomorphin, Enkephalin, Dynorphin.

Question 10

cannabinoids

Answer 10

• Activate metabotropic G protein-linked CB1 receptors on VTA cells primarily in CNS
• Also activate peripheral CB2 receptors
• Endogenous ligand: Anandamide

Question 11

Barbiturates/Benzodiazepines

Answer 11

CNS depressants, sedatives, anxiolytics

• work at allosteric sites on GABA-gated chloride ion channels (Increase length of channel opening or frequency of firing)
• Increases inhibition of feedback from NA to VTA
• also blocks AMPA glutamate receptors –> CNS depression and relaxation, not euphoria (does not inc DA release).

Question 12

EtOH effects on GABA receptors

Answer 12

• Positive allosteric modulator of GABA-A –> inhibition of GABAergic VTA neurons –> disinhibiting dopaminergic neurons in the VTA (euphoria)
• XS activity causes downregulation of GABA-A receptors

Question 13

EtOH effects on NMDA receptors

Answer 13

• Negative modulator of NMDA receptors –> increased neuronal excitability (EtOH w/d symptoms)
• XS activity causes upregulation of NMDA receptors

Question 14

EtOH w/d

Answer 14

aroused and hyper-aggressive

• downregulated GABA-A receptors
• upregulated of NMDA receptors
• increased neuronal excitability during acute w/d
• decreased DA release

Question 15

Phencyclidine (PCP)

Answer 15

hallucinogen-dissociative anesthetic

blocks NMDA glutamate-gated ion channels and nAChr

Question 16

Lysergic acid diethyl amide (LSD)

Answer 16

hallucinogen-dissociative anesthetic

partial agonist of 5-HT2A receptor in CNS, binds almost all monoaminergic receptors