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Greatest slectivity to CB1 receptor. anand-, folowed by NADA and noladin ether. Virodhamine prefers CB2 receptors and has only partial agonist activity at CB1. 2- AG no discrimination between CB1 and 2.
Anandamide- mechoulam discovered-lipid produced endogenously in the brain that could activate cannabinoid receptors and function as neurotransmitter. Derived from sanskrit word ananda- translates as BLISS!
Anandamide synth- 2 step process. The enzyme NAT transfers arachidonic acid chain from phospholipid (APL) to phosphatidylethanolamine, producing NAPE(N-arachidonyl phosphatidyl ethanolamine) a 2nd enzyme, NAPe-PLD generates anandamide., 2 Ag synthesized similarly in 2 steps by enzymes PLC and DAGL. Dag(sn-1 acyl 2 arachidonyl glycerol Phospho lipase C. And dagl(diacyl glycerol lipases)
Used as building block. Endocannabinoids cross the synaptic cleft to to act on cannabinoid receptors, a transporter is belived to help in this.
Enzyme-Do not have the undesirable effects of THC
CB 1- the most abundant G-protein coupled receptors in the brain Presyn-suggesting a role in regulation of neurotransmission. CB2- small amounts in the brain stem.
Humans or animals who recive large doses of THC develop catalepsy, reduction of spontanos movt, unnatual postues,believed to be due to action of cannabinoids in basal ganglia. Cerebellum.
Cb1 associated with G protiens, activation of cb1 also causes activation of potassium channels. And
Implicated in , endogenous morphine") are endogenous opioid inhibitory neuropeptidesnucleus accumbens - - reward center relevant to addiction and learningIn neuroscience, synaptic plasticity is the ability of synapses to strengthen or weaken over time, in response to increases or decreases in their activity. Plastic change also results from the alteration of the number of neurotransmitter receptors located on asynapse. Long-term potentiation Long-term potentiation, commonly referred to as LTP, is an increase in synaptic response following potentiating pulses of electrical stimuli that sustains at a level above the baseline response for hours or longer. Brief activation of an excitatory pathway can produce what is known as long-term depression (LTD) of synaptic transmission in many areas of the brain. LTD is induced by a minimum level of postsynaptic depolarization and simultaneous increase in the intracellular calcium concentration at the postsynaptic neuron
A typical presynaptic neuron containing dopamine or glutamate releases its nT, leading to depolarization of the post synaptic neuron. The second neuron can release endocannabinoid which diffuses across the synaptic cleft and inhibits further neurotransmitter release from presynaptic neuron.
relies on generation of endocannabinoids following increases in intracellular Calcium, Short duration, lasting tens of seconds,localized
Endocannabinoid ntmission regulator of anxiety?, in animals, CB1 receptor-deficient animals exhibit more pronounced anxiety behavior when expose D, tone shock- amouse model employed when tone coupled with shock, exp to tone, froze in anticipation of shock. Nolonger paired- extinction.Animals without cb1 – did not have this extinction- exp endocan nt mediate ability to forget anxiety associated wth painful memory.
2. reduce the breakdown of anandamide and
Cann recept blocker. Freq side effect- anxiety and depressiob
CB1 receptor blockade may decrease the strength of speciﬁc environmental cues associated with receiving nicotine
Have reduced addiction to and withdrawal from opiates Cb1 deficient animals decreased alcohol intake,
Heavy use lead to development of, psychotic symptoms,or due to vulnerability? , accelerated development of schizophrenia.,?Signaling increase dopamine- which normalized with clinical improvement
Foll drug ingestion- appetite stimulant ,endo cannob levels increase in hypothalamus and limbic system when animals deprived of food. Studies have shown that.
Mouse models of traumatic brain injury. Chronic pain,. Neurotransmission via the endocannabinoid pathway is
Stress assoc with decreased pain perception eg in military.
The immunohistochemical 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
Vasodialattaion extends to conjunctivaof eyes leading to blood shot appearance .
Raphael Mechoulam and Yeheel
Cannabis acting on a neural pathway involving
cannabinoids endogenous to the human brain
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
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)
Converts anandamide to arachidonic acid and
Found in regions of the brain where CB1 receptors are
Inhibitors of FAAH -analgesic effects and reduce anxiety in
axons and nerve termini, with little present on neuronal
dendrites and the cell body.
presynaptic rather than postsynaptic side of the neuronal
CB2 - expressed on the surface of white blood cells of the
G proteins intracellular signaling inhibition
of adenylyl cyclase decrease in cyclic
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
Endocannabinoids may be
the best retrograde
messenger that diffuses from
a postsynaptic neuron to act
upon a presynaptic neuron
Endocannabinoid-mediated inhibition of
neurotransmission Transient and long lasting.
Transient,also termed DSI(depolarization-induced
Suppression of inhibition) or DSE(depolarization-
induced suppression of excitation),
Anxiety and Mood
Loss of signaling by the
endocannabinoid system appears
to promote anxiety-like states.
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 anxiety-like behaviors
Cannabinoid interacts with 5HT1A receptors and this
interaction seems to be involved in its anxiolytic-like
Rimonabant - SR141716 or
acomplia, ﬁrst cb1antagonist
Primary indication - Obesity
Secondary indications -improves
dyslipidemia and improves
Long term use increase suicidal
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
Mice deficient in CB1 receptors - resistant
to the behavioral effects of cannabinoids
Increase the release of dopamine in the
Rats with a preference to alcohol have
decreased FAAH activity
Cannabis use -worsens psychosis in schizophrenia,
Heavy use –schizophrenia
Increase the release of dopamine
Elevated levels of anandamide in CSF.
Elevated CB1 receptor levels in postmortem brain -
dorsolateral prefrontal cortex and cingulate cortex
Increased appetite – “munchies”
Depend on CB1 receptors
present in the hypothalamus
CB1 receptor antagonist,
rimonabant, appears to
facilitate weight loss by blocking
Brain Injury and Pain
2-AG appears neuroprotective, reducing
brain edema, infarct size, and cell
death, while improving functional
Regulate pain perception
FAAH inhibitors improved motor
symptoms in a mouse model of
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
Analysis of postmortem brains
from patients with AD-
Upregulation of CB2
fatty acid amide hydrolase
(FAAH) in glial cells
associated with senile Plaques.
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
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.
108-115:James Sadock,Viginia Alcott Sadock.
Comprehensive text book of psychiatrty.
10.1192/bjp.178.2.116 Published 1 February 2001
Pharmacol Rev. 2006 Sep; 58(3): 389–462.
Br J Pharmacol. 2012 Apr;165(8):2485-96. doi:
Alexandre S. Crippa, Antonio Waldo Zuardi, Jaime E. C.
Hallak:Therapeutical use of the cannabinoids in psychiatry
Kenmackie;cannabinoid receptors as therapeutic targets