Lecture 13 Flashcards
What are the central effects of THC?
- impaired short-term memory and motor coordination
- altered sense of time
- changes in mood (euphoria/dysphoria)
- catalepsy (trance-like state)
- hypothermia (read out of THC action)
- analgesia
- antiemetic
- increase in appetite
What are the peripheral effects of THC?
- tachycardia (risk of myocardial infarction)
- vasodilation (bloodshot eyes)
- fall in intraocular eye pressure
- bronchodilation
What are the pharmacokinetics of THC?
- smoked or taken orally
- smoking > oral (due to quicker onset)
- metabolised by conjugation and enterohepatic circulation (prolongs duration)
- lipophilic (sequestered in body fat, detectable after several weeks of admin)
How was the CB1 cannabinoid receptor discovered?
- ligand-binding assay
- tritiated form of a cannabinoid
- specific binding occurred and analogue was displaced by delta 9 THC and was saturable
- if binding was non-specific= no saturation
- decreased binding of a non-hydrolysable GTP analog suggests it is a GPCR which acts through allosteric regulation
How was the CB2 cannabinoid receptor discovered?
- identified among cDNAs based on similarity in sequence to CB1 receptor
- molecular explanation of cannabinoid effects on the immune system
- inhibits adenylyl cyclase activity
What is the distribution of the cannabinoid receptors?
- CB1= widespread brain distribution e.g. cortex. hypothalamus, amygdala
- CB2= more defined pattern in cells and tissues of the immune system e.g. glial cells
What are the mechanisms of cannabinoid GPCR activation?
- couples with G protein
- inhibits Ca2+ channels
- activates K+ channels
- inhibits cAMP and PKA
- inhibition of synaptic transmission
What are the effects of knocked out CB1 receptors (in mice)?
- increased mortality
- leanness, resistance to diet induced obesity, enhanced leptin sensitivity
- loss of THC-induced hypothermia
- less pain sensitive in tests of supraspinal pain responses
What were the first identified endogenous ligands for CB receptors?
- anandamide
- 2-arachidonoyl glycerol (2-AG)
- all are lipids
- both activate CB1 + CB2
What are the properties of the endogenous ligands?
- produced on demand and not stored in vesicle
- produced following elevation of intracellular Ca2+ by Ca2+ sensitive enzymes
How is anandamide synthesised?
- enzymatic hydrolysis of a family of membrane phospholipids (NArPE)
- NAPE-PLD is Ca2+ sensitive and catalyses the hydrolysis of NArPE to anandamide
How is 2-AG synthesised?
DAGs converted into 2-AG via two Ca2+-sensitive DAG lipases (DAG-α and DAGL-β)
How are cannabinoids synthesised and released?
- produced from phospholipids present in the cell membrane
- released in a regular and retrograde direction
- CB receptors present on both the pre and post synapse
- also receptors present on glial cells
What enzymes terminate cannabinoid activation?
- MAGL (monoacylglycerol lipase)
- FAAH (fatty acid amide hydrolase)
What is the function of FAAH?
Main metabolising enzyme for the fatty acid amides (e.g. anandamide)
