Marijuana & Cannabinoids

Describe the cannabinoid receptors, including receptor subtypes, receptor distribution, and functional consequences of agonist activation.

-Cannabinoids acts on cannabinoid receptors. These are Gi/o protein-coupled (metabotropic) receptors. -Receptor distribution: CB1 receptors are found in the basal ganglia, cerebellum, hippocampus, and cerebral cortex. CB2 receptors are found in the immune system, bone and fat, and some areas of the brain. -Receptor subtypes: CB1, which is a CNS cannabinoid receptor. These are found on presynaptic structures such as the nerve terminal or axon segments near the nerve terminals. CB2, expressed in neurons in some areas of the brain, but at lower levels than CB1 receptors. -Agonist activation: activation of cannabinoid receptors results in the inhibition of adenylyl cyclase, inhibit Ca2+ channels, and activating K+ channels. This inhibits the release of many NT such as ACh, DA, NE, serotonin, GABA, and glutamate. However, it also activates a MAP kinase system that plays a role in synaptic plasticity, memory, and learning, as well as epigenetic changes. THC=a PARTIAL agonist on CB1 and CB2. Rimonabant=first selective CB1 antagonist CB1 agonist effects-Administration of THC leads to reduced locomotor, reduced body temp, catalepsy, reduced cognitive function and reduced pain sensitivity. There is also memory deficits because of the inhibition of LTPs in the hippocampus. CB1 KO mice do not experience these effects. CB2 agonist effects-inhibition of cytokine release, suppression of immune system.

Describe the pharmacokinetics of cannabis.

-Smoked THC is quickly absorbed in the lungs and result in rapidly rising levels in the blood plasma. IV injections are equally as fast. -Oral administration leads to a prolonged but poor absorption of THC. This is because of its degradation in the stomach and first-pass metabolism. Absorbed by gastrointestinal tract. -Metabolites: 11-hydroxy-THC and THC-COOH. 2/3 of administered dose is excreted in the feces and 1/3 is excreted in the urine. -Elimination of marijuana is slow because it is stored in the fat tissue. Has a half life of about 20-30 hours.

Describe the behavioral effects of endocannabinoid signaling as well as cannabis intoxication.

Endocannabinoid signaling consists of 3 different signaling mechanisms: 1) Retrograde signaling-most common. Endocannabinoid is released from its site of synthesis ion a dendritic spine on the post synaptic cell and binds to a CB1 receptor on the presynaptic terminal. This inhibits Ca2+ mediated NT release. 2) Non-retrograde signaling-Endocannabinoid activates either postsynaptic CB1 receptors or TRPV1 cation channels (involved in pain processing, mood, motor function, learning and memory) 3) Neuron-astrocyte signaling: Endocannabinoid activates CB1 receptors on the astrocyte, which releases glutamate. Behavioral effects: the endocannabinoid system helps to alleviate fear, anxiety, and stress. It produces feelings of relaxation. Activation of this system also affects the gut and leads to motivation to eat and to seek food-mediated reward. Elevated cannabinoid activity=antidepressant effect vs. reduced cannabinoid activity=depressive like behavior. CB1 KO mice show increased anxiety. Inhibition of FAAH prevented anxiety. CB1 and CB2 KO mice/ mice treated with rimonabant exhibited increased pain sensitivity. Cannabis intoxication: Intoxication is dose-dependent. It can lead to personality changes, perceptual distortion, hallucinations. It can also evoke psychotic symptoms like depersonalization (separated from self) and derealization (feeling that the external world is unreal). Deficits in thought processes, verbal behavior, memory loss.

What are phytocannabinoids and endocannabinoids? Give an example of each.

Phytocannabinoids-Compounds with a cannabinoid structure that are found in the cannabis plant. Ex. THC-the compound that gives weed its psychoactive properties, CBD. Endocannabinoids-endogenous cannabinoids (cannabinoids made "within"), an NT-like substance that is naturally made in our brain. Ex. anandamide, 2-AG

Describe endocannabinoid synthesis, reuptake, degradation, and signaling.

Synthesis-Endocannabinoids are lipids that contain the fatty acid arachidonic acid in their structure. Not stored in vesicles. Synthesis is triggered by a rise in intracellular Ca2+ levels. Reuptake-Endocannabinoid membrane transporters bind to endocannabinoid and transports it across the membrane of the cell. Degradation-anandamide is broken down by fatty acid amide hydrolase (FAAH) while 2-AG is broken down by monoacyl-glycerol lipase (MAGL). Both can be metabolized by COX-2. NSAIDs=COX-2 inhibitors. 2-AG=FULL CB1 and CB2 agonist, said to be the more important synaptic signaling molecule out of the two. Anandamide=PARTIAL CB1 and CB2 agonist.

Describe the evidence for cannabinoid-mediated reward and reinforcement.

The reinforcing effect of cannabinoids are dependent on CB1 activation. Cannabinoids activate the mesolimbic dopaminergic pathway indirectly; CB1 receptors are not found on dopaminergic neurons. Instead, the CB1 receptors on GABAergic neurons are activated, and the reduction in GABA release, resulting in increased DA cell firing.