Neurobiology of Addiction Exam 3

AM404

Blocks anandamide uptake to prolong endocannabinoid signaling

AM374

FAAH inhibitor to prevent breakdown of anandamide → increases levels and enhances CB1R activation

Anandamide

Endogenous cannabinoid, activates CB1Rs leading to decreased NT release

Amphetamine

Indirect sympathomimetic; enters DA and NE terminals through transporters → disrupts vesicular storage via VMAT2 and reverses DAT/NET → massive release of DA/NE into synapse

Arachidonic Acid

Breakdown product of anandamide and 2-AG after FAAH or MAGL activity in endocannabinoid metabolism pathway

β-Endorphin

Endogenous opioid peptide, activates MORs for analgesia and reward

Buprenorphrine

Partial agonist at MORs, high affinity, limited euphoria and RD, used as treatment for OUD due to ceiling effect

Cocaine

Inhibits DAT, NET, and SERT → increased DA in NAc; strongly reinforcing

Cotinine

Primary metabolite of nicotine; long-half life → biomarker for tobacco exposure

CREB

Transcription factor upregulated by chronic stimulant use, → increased dynorphin production → dysphoria and negative affect during withdrawal

2-AG

Endocannabinoid synthesized from DAG by DAGL; full agonist at CB1Rs; broken down by MAGL

DAGL

Synthesizes 2-AG from DAG

Dynorphin

Endogenous opioid peptide; activates KOR → inhibits DA realease → dysphoria and negative affective state during stimulant withdrawal

Endorphins

Endogenous opioid peptides; act at MORs and DORs → analgesia and reward

Epinephrine

Acts at adrenergic receptors to increase arousal

FAAH

Hydrolyzes anandamide → terminates signaling at CB1

GIRK

G-protein-activated inwardly rectifying potassium channels; CB1 activation → GIRK opens → hyperpolarization of presynaptic terminal + decreased NT release

Heroin

Opioid prodrug converted to morphine in brain; increases DA release via MORs

K2/Spice

Synthetic cannabinoids, full agonist at CB1Rs; higher efficacy than THC and associated with severe toxicity

MAGL

Enzyme that degrades 2-AG → reduced CB1R signaling

Methamphetamine

More potent form of amphetamine; increased ability to release dopamine and norepinephrine

Morphine

MOR agonist; analgesia, reward, tolerance, physical dependence

MDMA

Amphetamine-like stimulant that releases serotonin, DA, and NE

Naloxone/Naltrexone

Opioid antagonists

Nicotine

Agonist at nAChRs; increases VTA dopamine neuron firing → highly reinforcing

TRV130

G-protein-dependent-biased MOR agonist; produces analgesia with reduced respiratory depression (minimizes beta-arrestin recruitment)

Rimonabant

CB1 inverse agonist; cause cannabinoid withdrawal and blocks THC effects

Δ9 THC

Partial agonist at CB1Rs, primary psychoactive part of cannabis, reinforcement via VTA GABA disinhibition

WIN55

High-efficacy synthetic CB1 agonist

VMAT2

Transports and concentrates dopamine into vesicles

CB1 Receptor Activation

Activates G_i/o protein → inhibits AC → decreased cAMP production → decreased PKA activation → decreased phosphorylation → increased K⁺ release

Net: presynaptic hyperpolarization → decreased NT release

CB2 Receptor Activation

Inhibits dopamine neuron → decreased dopamine release → aversive

Synthesis, Release, and Metabolism of Endocannabinoids

PC + PE = NAPE (NAT) → anandamide (PLD) → CB receptor → g-protein activation → response → anandamide → cell membrane → transported by AT → arachidonic acid and ethanolamine (AAH)

Ptdlns → DAG (PLC) → 2-AG → arachidonic acid (MAGL)

Glutamate Negative Feedback Loop

Glutamate release → activates mGluR → stimulates 2-AG production (PLC and DAGL) → activates CB1 receptor → decreases glutamate release → 2-AG action terminated by MAGL (conversion to arachidonic acid)

GABA Positive Feedback Loop

Activation of post synaptic cell → Ca²⁺ influx → anandamide production → CB1 on GABA → inhibits GABA release → disinhibition of posysynaptic cell

G-Protein-Dependent Signaling

Opioid → receptor → g-protein activation →

→ inhibits AC → decreased cAMP → decreased PKA → more inhibition of Ca²⁺ and Na⁺ influx → cell inhibited

→ activates GIRK → enhanced K⁺ outflux

G-Protein-Independent Signaling

GRK phosphorylates receptor → internalization → beta-arrestin binds receptor → binds clathrin → tightness of binding determines if return to membrane or breakdown by lysosomes