What regulates cannabinoids

• 1. Dopaminergic drugs influence endocannabinoid synthesis
• 2. Activated receptors cause endocannabinoid synthesis
  • 2.1. Dopamine D2 receptors, D2R
  • 2.2. Metabotropic glutamatergic GPCRs, mGluR
  • 2.2. Coactivation of ionotropic AMPAR and NMDAR as well as muscarinic M1R
  • 2.3. Muscarinic acetylcholine receptors, mAChR
  • 2.4. Serotonin receptors
  • 2.5. Angiotensin AT1 receptors
• 3. Sports increase endocannabinoids
• 4. Sugar consumption
• 5. Stress reduces AEA

1. Dopaminergic drugs influence endocannabinoid synthesis¶

Chronic drug use changes the CB1R density in various brain regions.
Chronic cocaine use causes:¹

• small but significant decrease in 2-AG in the limbic forebrain

Chronic exposure to alcohol causes:¹

• AEA decreases in the midbrain
• 2-AG decreases in the midbrain
• AEA increased in the limbic forebrain

Chronic nicotine exposure causes:¹

• AEA increased in the limbic forebrain and brainstem
• 2-AG increased in the brain stem
• AEA and 2-AG reduced in hippocampus, striatum and PFC
• CB1R unchanged

2. Activated receptors cause endocannabinoid synthesis¶

2.1. Dopamine D2 receptors, D2R¶

Stimulation of D2R increases endocannabinoids in the striatum^{23 4 5} and sensitizes the CB1R.⁶

D2R expressed on cholinergic interneurons inhibited 2-AG release by inhibiting the release of acetylcholine⁷

2.2. Metabotropic glutamatergic GPCRs, mGluR¶

mGluRs (metabotropic glutamatergic GPCRs) trigger the release of endocannabinoids.⁸ This endocannabinoid release caused by mGluR activation is found in many areas of the brain.⁹
Coupling postsynaptic depolarization with the activation of Gq-like G proteins (such as the group I metabotropic glutamate receptors, mGluR1, mGluR5) or the M1 and M3 subtypes of muscarinic acetylcholine receptors (mAChR1, mAChR3, which activate phospholipase C) increases endocannabinoid synthesis and release.¹⁰

2.2. Coactivation of ionotropic AMPAR and NMDAR as well as muscarinic M1R¶

Efficient 2-AG mobilization required the co-activation of ionotropic AMPA and NMDA glutamate receptors and muscarinic M1 receptors⁷
D2R expressed on cholinergic interneurons inhibited the mobilization of 2-AG by inhibiting the release of acetylcholine⁷

2.3. Muscarinic acetylcholine receptors, mAChR¶

mAChR (muscarinic acetylcholine receptors) cause the release of endocannabinoids in the hippocampus.¹¹

2.4. Serotonin receptors¶

5HT2A and 5HT2C receptors release endocannabinoids and activate the endocannabinoid system.¹² In CB1R-KO mice, serotonergic function via 5HT2A and 5HT2C receptors is impaired.
Systemic administration of serotonin exacerbated abdominal pain and colitis, which correlated with decreased AEA levels via 5-HT3 and 5-HT4 receptors. Serotonin administration significantly reduced the AEA precursor NAPE-PLD. 5-HT3 and 5-HT4 receptor antagonists remedied this.¹³

2.5. Angiotensin AT1 receptors¶

Activation of G-coupled AT1 receptors by angiotensin can stimulate CB1R, which regulates blood pressure in the hypothalamus.¹²

3. Sports increase endocannabinoids¶

Sports increased CB1R-mediated presynaptic control of inhibitory postsynaptic striatal currents in rodents, while the sensitivity of glutamate synapses to CB1R stimulation remained unchanged, as did that of GABA synapses to stimulation of presynaptic GABA-B receptors. Sensitization of CB1R mediated sports-induced protection against stress damage.⁶
One round of aerobic exercise, especially at moderate intensity, increased blood levels of the endocannabinoids AEA and 2-AG¹⁴
This contributes significantly to mood enhancement and stress reduction in healthy individuals. Moderate and high-intensity aerobic exercise modulates stress through a negative feedback loop on the HPA axis as well as the sympathetic nervous system, which facilitates stress regulation that plays a crucial role in endocannabinoid synthesis.¹⁴

4. Sugar consumption¶

Sugar consumption increased CB1R-mediated presynaptic control of inhibitory postsynaptic striatal currents in rodents, while the sensitivity of glutamate synapses to CB1R stimulation remained unchanged, as did that of GABA synapses to stimulation of presynaptic GABA-B receptors.⁶

5. Stress reduces AEA¶

See under Cannabinoids for ADHD and stress