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History• 1964: structure of δ-9-tetrahydrocannabinol (THC)• 1990: CB1• 1993: CB2• 1994: Rimonabant (Acomplia), a CB1 receptor blocker is developed• Chinese Emperor Shen Nung- recommended its use for a variety of ailments 2400 BC
• THC acid is the predominant form of the plant THC, and this is readily converted to THC upon heating, such as when cannabis is smoked.• Estimates suggest that 20 to 80 µg of THC reach the brain after one smokes a marijuana cigarette
Endocannabinoids• Anandamide• 2-arachidonylglycerol (2-AG)• N-arachidonyldopamine (NADA)• 2-arachidonoyl glycerol ether (noladin ether),• Virodhamine• Anandamide -mimic THC• Inhibition of spontaneous movement• Promotion of freezing spells• Reducing pain sensitivity• Decreasing body temperature.
• CB1 receptor selectivity : Anandamide > NADA > noladin ether.• virodhamine prefers CB2 receptors ,partial agonist activity at CB1.• 2-AG appears not to discriminate between CB1 and CB2.
Biosynthesis• Arachidonic acid -building block• Endocannabinoids are not stored in synaptic vesicles for later use, but are synthesized on demand• Endocannabinoids are highly lipophilic and thus poorly soluble in cerebrospinal fluid (CSF)
Fatty acid amide hydrolase (FAAH)• Converts anandamide to arachidonic acid and ethanolamine• Found in regions of the brain where CB1 receptors are predominant• Localizes to postsynaptic neurons where anandamide is made.• Inhibitors of FAAH -analgesic effects and reduce anxiety in animal models,• Do not have the undesirable effects of THC
Cannabinoid Receptors• CB1 receptors -axons and nerve termini, with little present on neuronal dendrites and the cell body.• presynaptic rather than postsynaptic side of the neuronal cleft, suggesting a role in regulation of neurotransmission.• CB2 - expressed on the surface of white blood cells of the immune system, small in brainstem.• B cells> NK cells > monocyte > T8 >T4.• the most abundant G-protein coupled receptors in the brain
• Highest density in the basal ganglia, cerebellum, hippocampus, hypothalamus, anteri or cingulate cortex, and cerebral cortex, particularly the frontal cortex• Large doses of THC develop catalepsy, a reduction of spontaneous movement, and freeze in bizarre and unnatural postures.• The action of cannabinoids in the basal ganglia and cerebellum may be associated with these behaviors, which may prove relevant in understanding catatonic symptoms in schizophrenia
Neurotransmission• G proteins intracellular signaling inhibition of adenylyl cyclase decrease in cyclic adenosine monophosphate.• Activation of potassium channels• Inhibition of N-type calcium channels• Block the release of a variety of neurotransmitters- GABA, nor epinephrine, and acetylcholine.• Increase the release of brain endorphin neurotransmitters• Increase dopamine release in the nucleus accumbens• Synaptic plasticity, including LTP and long-term depression (LTD).
• Endocannabinoids may be the best candidate to date as the retrograde messenger that diffuses from a postsynaptic neuron to act upon a presynaptic neuron
• Endocannabinoid-mediated inhibition of neurotransmission comes in two forms:Transient and longlasting.• Transient,also termed DSI(depolarization-induced Suppression of inhibition) or DSE(depolarization- induced suppression of excitation), relies on generation of endocannabinoids following increases in intracellular Calcium• Short duration, lasting tens of seconds,localized• Endocannabinoid LTD(eLTD) only requires CB1 receptor activation for its initiation; once established eLTD is independent of CB1 receptor activation
Anxiety and Mood• Tranquillizing effect• Loss of signaling by the endocannabinoid system appears to promote anxiety-like states.• CB1 receptor-deficient animals exhibit more pronounced anxiety behavior when exposed to stress• Anandamide and 2-AG were found to increase in the amygdala immediately following exposure of mice to stress
• Enhancing levels of endocannabinoids may represent a therapeutic target for anxiety• Novel FAAH inhibitors reduce the breakdown of anandamide and reduce anxiety-like behaviors• FAAH inhibitors improved the ability of the animals to cope with these stresses, a benefit also observed by treatment with antidepressant drugs.• The endocannabinoid pathway may represent an attractive target in understanding posttraumatic stress responses and phobias
• The anxiolytic properties of CBD do not seem to be mediated by benzodiazepine receptor• cannabinoid interacts with 5HT1A receptors and this interaction seems to be involved in its anxiolytic-like effects
• The effects of CBD (300mg) on the SPS test• The SAD group that received CBD presented lower levels of anxiety in the anticipatory and performance phases of the test, fewer somatic symptoms, and less negative self-evaluation as compared with the SAD group that received placebo• SPECT-pattern of brain activity induced by CBD is compatible with anxiolytic-like activity
CB1 Antagonist-Rimonabant• Primary indication - obesity• Secondary indications - disorders that have a prominent craving component• Rimonabant - SR141716 or acomplia, was the ﬁrst cb1antagonist reported.• Diarylpyrazole with nanomolar afﬁnity for CB1 receptors and little afﬁnity for the CB 2 receptor.• A frequent adverse reaction to the drug is increased anxiety and depression.• Long term use increase suicidal ideation
Addiction• Mice deficient in CB1 receptors - resistant to the behavioral effects of cannabinoids• Have reduced addiction to and withdrawal from opiates• Increase the release of dopamine in the nucleus accumbens,• Rats with a preference to alcohol have decreased FAAH activity
• CB1 receptor blockade may decrease the strength of speciﬁc environmental cues associated with receiving nicotine• CB1 receptor activation enhance alcohol consumption while blocking these receptors decreases consumption• The usefulness of CB1 antagonism in smoking cessation has been investigated in the STRATUS-US trial
Psychosis• Cannabis use -worsens psychosis in schizophrenia,• Heavy use - associated with developing schizophrenia• Increase the release of dopamine• Elevated levels of anandamide in cerebrospinal fluid• Normalized with clinical improvement• Elevated CB1 receptor levels in postmortem brain - dorsolateral prefrontal cortex and cingulate cortex• Polymorphisms in the CB1 receptors
Feeding• Increased appetite – “munchies”• Depend on CB1 receptors present in the hypothalamus• CB1 receptor antagonist, rimonabant, appears to facilitate weight loss by blocking cannabinoid signaling
Brain Injury and Pain• 2-AG appears neuroprotective, reducing brain edema, infarct size, and cell death, while improving functional outcomes.• Anandamide also protected against brain injury in a model of multiple sclerosis• FAAH inhibitors improved motor symptoms in a mouse model of Parkinsons disease
• Neurotransmission via the endocannabinoid pathway is increasingly appreciated to regulate pain perception• CB1 receptor plays an important role in these effects as the analgesic effects of cannabinoid drugs are lost when CB1 antagonist rimonabant is given• Mediate stress-induced analgesia• Both anandamide and NADA activate a calcium channel known as the vanilloid receptor (TRPV-1) that is found on sensory nerves• Promoting analgesia through the CB1 and CB2 receptors, but potentially increasing pain via TRP channels
Alzheimer’s disease• The immunohistochemical analysis of postmortem brains from patients with AD revealed an upregulation of both CB2 receptors and the endocannabinoid-degrading enzyme, fatty acid amide hydrolase (FAAH) in glial cells associated with senile Plaques• Administration of Dronabinol (a pharmaceutical preparation based on THC) for six weeks has been recently reported as very useful for the treatment of both the severity of disturbed behaviour and anorexia in food- refusing patients with AD and other dementias
• Direct relaxation of vascular smooth muscle by local CB1 receptors.• Conjunctiva of the eyes - “bloodshot” appearance in some cannabis users.• Relaxation of ocular arteries - treatment for glaucoma
• Synthetic 9 THC Dronabinol is approved in the US for treatment of nausea and vomiting associated with chemotherapy as well as an appetite stimulate in AIDS.
References• CTP-Kaplan & Sadok’s• Essential psychopharmacology-Stephen stahl• cannabinoid receptors as therapeutic targets-by Kenmackie• Therapeutical use of the cannabinoids in psychiatry-José Alexandre S. Crippa, Antonio Waldo Zuardi, Jaime E. C. Hallak