This document discusses the endocannabinoid system. It outlines the history of discoveries related to endocannabinoids including the identification of cannabinoid receptors CB1 and CB2 in the 1990s. It describes the endogenous cannabinoids anandamide and 2-AG and their roles in neurotransmission, analgesia, anxiety, mood, addiction, psychosis, and other processes. The document also discusses the CB1 antagonist Rimonabant and the potential therapeutic applications of targeting the endocannabinoid system for conditions like obesity, anxiety, addiction, brain injury, pain, and Alzheimer's disease.

1. ENDOCANNABINOIDS
Dr.A.Godson

2. 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

3. • 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

4. 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.

5. • 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.

6. 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)

7. 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

8. 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

9. • 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

10. 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).

11. • Endocannabinoids may be the best candidate to
date as the retrograde messenger that diffuses
from a postsynaptic neuron to act upon a
presynaptic neuron

12. • 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

14. 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

15. • 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

16. • 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

17. • 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

18. 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

19. 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

20. • 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

21. 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

22. 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

23. 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 Parkinson's disease

24. • 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

25. 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

26. • 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

27. • 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.

28. 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