Systems

pharmacology

CNS pharmacology

Aoife Gowran
gowrana@tcd.ie
 Introduc4on
Challenging problem

Most administered without prescrip=on

CNS is the most complicated system in the body -

structure & func=on provides a means to modify CNS

func=on (inhibi=on/excita=on)

Many drugs act within the CNS

Special signicance, therapeu=c importance

We will Cover:

Anti-depressants

Anxiolytics and hypnotics

Anti-psychotics (neuroleptics)

Special focus on:

Cannabinoid pharmacology
 Review:
Central neurotransmi<ers

Biogenic amines: dopamine, nor-adrenaline, adrenaline,

serotonin, histamine

Acetylcholine; mainly excitatory (e) in CNS vs., inhibitory (i)

effects in the PNS

Amino acids: GABA (i), glycine (i), glutamate (e), aspartate (e)

Neuropeptides: vasopressin, oxytocin, endorphins, enkephalines

Purine nucleotides: adenosine, ATP

Neurolipids: anandamide, 2-arachidonoyl glycerol, ceramide

 An4-depressants - heterogenous disorder
- 10% life =me risk

Symptoms
Impaired concentra=on
Inability to experience pleasure
Increased fa=gue
Missed deadlines or drop in standards
Signicant change in personality/behaviour
Increased alcohol/drug use
Thoughts of suicide
3 Major Types of Depression
- Diagnostic & Statistical manual of Mental Disorders(DSM-IV)
- Based on the cause/origin (simiplified)

Reactive or Secondary (~60%)

Related to some loss, physical illness (MI, Cancer), Drugs, Other
psychiatric disorders (senility)

Major or Endogenous (~25%)

No clear/adequate precipitating event, re-current, inability to exp.
ordinary pleasure/cope with everyday life

Bipolar affective/ manic-depression (10-15%)

Episodes of mania associated with depression
Depression alone - occasional; Mania alone - rare
Depression - Causes
Most focus on neurochemical processes

- abnormal amounts of NTs

- decreased post-synaptic sensitivity

NB serotonin, nor-adrenaline and dopamine

- all effected by anti-depressants

Anti-depressants therapeutic effect:

increasing NT levels
or
decreasing re-uptake
The Amine Hypothesis - provides pharmacological
evidence for a bio-genic disorder
1950s - Reserpine
Alkaloid from root of Indian snake root plant (Rauwola serpen.na).
Primi=ve Hindu medicine for hypertension, insomnia & insanity.
Inves=gated for hypertension (s=ll available)
Found to interact with storage vesicles & deplete NA & 5-HT in CNS & PNS
Induced severe depression
Suicide was common with early use of high dose

X
NA

1 vasoconstriction

Blood vessel
X Increased TPR
Single biologic abnormality is not supported

Underlying role for several brain circuits with the

poten=al for dysfunc=on

Amine hypothesis has provided experimental models

used for the discovery of new an=depressant drugs.
 An=-depressant drugs
1. Tricyclic an4depressants
desipramine (Nor-pramin), imipramine (Tofranil), nor-
triptyline (Pamelor), pro-triptyline (Vivactil)

2. Selec4ve serotonin reuptake inhibitors
citalopram (Celexa), fluoxetine (Prozac), fluvoxamine
(Luvox), paroxetine (Paxil), sertraline, (Zoloft)

3. Monoamine oxidase inhibitors

phenelzine (Nardil), isocarboxazid (Marplan)
TCAs R2
R1

imipramine inves=gated for schizophrenia

Found to be ineec=ve an=psycho=c
But elevated mood in depressed pa=ents
Seda=ve eects in non-depressed pa=ents

Conclusion: imipramine selec.vely reverses

depression (vs, producing a
general ac=va=ng eect)
 Mechanism of ac4on

inhibits the reuptake of NA

& 5-HT by blocking their
membrane transporters
 Side Effects
R R
2
1
- anti-muscarinic: dry mouth, constipation, urinary
retention, aggravation of glaucoma
- anti-histamine: sedation (tolerance can develop)
- Na channel block: arrhythmias
- alpha-1 blockade: orthostatic hypotension,
tachycardia, erectile dysfunction

Now used for severe depression refractory to other treatments

(e.g. SSRIs)
Selective serotonin reuptake inhibitors (SSRIs)

Paroxetine
Sertraline
(Paxil)
Fluoxetine (Zoloft)
(Prozac)

- 2nd generation anti-depressants

- First line therapy
- Also used to manage other disorders (panic, OCD)
- Inhibit the re-uptake of serotonin (indefinately)
Side Effects: SSRIs

Fewer side eects vs. TCAs (be\er tolerated),

lack an=-cholinergic eects, no cardiac eects
no postural hypotension

Safer than TCAs (less poten=al for overdose)

Equally eec=ve as TCAs in depression, eect reached

in 3-4 weeks
MONOAMINE OXIDASE (MAO)
Enzyme present on:

1. Mitochondria
Inactivation of endogenous
and ingested amines 1
(oxidative de-amination)
Food and endogenous
sources

2. Synaptic cleft
Regulates free intraneuronal
[ ] of NA, A, D and 5-HT 2
2 subtypes MAO-A (NTs) &
MAO-B (dietry amines)
MONOAMINE OXIDASE INHIBITORS (MAOI)

Form an irreversible
complex with MAO
PHENELZINE

Increase 5-HT, NA, dopamine

content of brain

cheese reac=on due to

exogenous tyramine
(hypertensive crisis due to SELEGILINE*
release of endogenous
amines)
tyramine free diet * MAO-B not targetted
 Anxioly=c and hypno=c drugs
ANXIETY:
- Verbal complaint
- Somatic and autonomic symptoms (anticipatatory)
restless, tachycardia, sweating
- pathological state of anxiety not clear

DRUG GROUPS:
1. Benzodiazepines (valium, anxiolytic and hypnotic)
2. Barbiturates
 Pharmacological eects
Reduc=on in anxiety and aggression
Seda=on and induc=on of sleep
Reduced muscle tone and coordina=on
an=convulsant
GABA receptor
A

- Bezodiazepines (Bz/BDZ) act specically

- enhance response to GABA
- allosteric binding site receptor anity for GABA

Enahnced excitatory transmission

 Adverse eects Benzodiazepine

Overdose risk low

Drowsiness, confusion, impaired co-ordina=on
Dependence
Treatment withdrawal
increased anxiety
Tremor
nervousness
 Barbiturate
Overdose risk high

Tolerance
- pharmacokine=c (upregula=on of liver enzymes)
- =ssue tolerance (downregula=on of receptors)
 Anti-psychotic (neuroleptic) drugs

Drugs used to manage psychosis

Psychosis definition:
impaired capacity to - recognise reality
- communicate
- relate to others
- deal with ordinary life

Psychosis is associated with schizophrenia

- disturbances in multiple psychological processes

 Schizophrenia
It is a disease that aects 1% of the worlds popula=on (1/100)

It is a disease that aects men and women equally

It is a disease of the brain (disturbed thinking)

Has a gene=c component

Exact pathogenesis is unknown

It is now recognised as a biological illness

 Symptoms

Excesses, exaggera4ons or distor4ons

- Unchanging facial expression (a<ening)

- Disorganized thinking/speech
- Inappropriate aect (emo4on)
- Hallucina4ons
sensory experiences without external s=mula=on
commonly auditory
- Delusions
beliefs that are contrary to reality
commonly persecutory in nature
some=mes delusions of grandeur
 Subtypes

Paranoid delusions, hallucina=ons, anxiety (present)

- disorganised thought/behavior & a\ening (absent)

Disorganised thought disorder & a\ening (both present)

Catatonic disturbed movement (immobile/agitated)

Undieren4ated - symptoms of > 1 type of schizophrenia

Residual some of the symptoms above, not many/all

Causes of Schizophrenia

1. Familial incidence

2. Anatomical changes
- ventricular enlargement
- underdevelopment of neurons in parahippocampal region
- abnormalities cause circuitry abnormalities

3. Dopamine hypothesis - dopamine hyperactivity

- receptor hypersensitivity

4. Drugs/Environmental- cannabis induced psychosis

 Dopamine Hypothesis
Increased dopamine receptors & metabolites in brains of
schizophrenics

Drugs that increase dopaminergic ac=vity aggravate

schizophrenia

Eec=ve an=-psycho=c drugs block dopamine receptors in

CNS

BUT! Only par=ally eec=ve in many pa=ents

 Side eects of neurolep=cs
Autonomic nervous system:

Dry mouth, cons=pa=on, diculty urina=ng - block mAch receptors

Orthosta=c hypotension, failure to ejaculate - block -AR

CNS:
Parkinsons syndrome - block DA receptors in substan=a nigra
Toxic confusional state - muscarinic block

Endocrine system:

Amenorrhea-galactorrhea, infer=lity -
DA block resul=ng in hyperprolacinemia
Therapeutic sites of action
 Dopamine receptor Antagonists

Chlorpromazine (Thorazine)
Deriva=ve of phenothiazine (an=-eme=c)
Very seda=ng at rst but tolerance builds
Some an= cholinergic ac=vity (dry mouth, blurred vision)
Ac=vely metabolized (Half life of 30hrs)

Side eects: Tardive Dyskinesia

Haloperidol (Haldol)

Potent dopamine antagonist

Uses - non drug-compliant patients
- acute psychotic episodes

Long time in the body 3 week half life.

Only 60% excreted in the first week.

Side effects: dry mouth, dystonia, sedation,

depression, tardive Dyskinesia
Clozapine (Clozaril)
Ac=ve at DA and 5-HT receptors
Treats posi=ve and nega=ve symptoms
Half Life of 12 hrs
Limited to treatment resistant pa=ents
Strong risk of seizures
Side eects: An=cholinergic, adrenoly=c,
an=histaminic and an=serotonergic ac=vity.
 Cannabinoids
& CNS Func=on
 CANNABIS HISTORY
In use since 2,800 BC

Knowledge in
Europe

First ban
in Europe
CANNABIS HISTORY
First scientific research

Medicinal use
Cannabis sativa is STILL a
plant of medicinal and
economic value

Most used recreational drug

prevalent in young males (NACD, 2004)

9-Tetrahydrocannabinol 9- THC

(9- THC)
main psychoactive component
9- THC
Psychoactive effects are mediated
through the CB1 receptor CB1
G protein-coupled
G
* THC can be obtained from :
a) Leaves
b) Stem
c) Resin from flower head
 THE CANNABIS HIGH

Cannabis Vapour

9-Tetrahydrocannabinol
(9-THC)

Vapour

Heart/Brain
 THE CANNABIS HIGH

* THC is highly lipophilic

* THC half-life is 7 days
* THC metabolised in liver (11-OH-THC) **psychoactive metabolite
 Numerous preparations
of cannabis
9
Preparation Approx. -THC
Source
type content

Cigarette of dried leaves/flowers etc., 9

1 - 3% -THC
from plants cultivated in the 1960s and
(10 mg/cigarette)
1970s
Cannabis
(herbal)
Modern cannabis cigarette using more 9
6 - 20% -THC
potent material or plant strains
(60 - 150 mg/cigarette)
(sinsemilla, skunk, white widow et al.)
9-THC
concentrations in Cannabis resin
Resin secreted in the flower heads 10 - 20% 9
-THC
(Hashish)
different preparations
9
Product of extraction by organic 15 - 30% -THC
Hashish oil
solvents (sometimes up to 65%)

Adapted from Ashton, 1999.

 Behavioural effects
* Euphoria followed by sedation

* Altered time perception

* Dissociations of ideas

* Impaired cognitive performance

- Slow reaction time

- Motor disturbances
- Short-term memory deficits
 CANNABIS USE TODAY
Table 2.2.2 Lifetime, last-year and last-month prevalence of cannabis in Ireland,
2002/2003
Ever used cannabis Adults Males Female Young adults
1564 yrs 15-64 yrs 15-64 Yrs 15-34 Yrs
% % % %
Lifetime 17.4 22.4 12.3 24
Last year 5 7.2 2.9 8.6
Last month 2.6 3.4 1.7 4.3

Adapted from: National Advisory Committee on Drugs and Drug and

Alcohol Information and Research Unit, 2005.

* Tolerance with moderate cannabis doses

* Dependence?
 Other
phyto-Cannabinoids
Guzman et al., 2003, Nature Reviews Cancer 3, 745-755

The cannabis plant contains a family of approximately

60 related compounds, which are termed
cannabinoids.

Cannabidiol, (CBD) Cannabinol, (CBN)

No psychoactivty
 Cannabinoid receptors - CBRs

* The psychoactive effects of 9-THC were

believed to be as a consequence of its
interaction with the plasma membrane

9- THC

Membrane disturbance

passive diffusion
 Cannabinoid receptors

NH2 C SD
C V I
N K S N K
W K Q
F KM L extracellular
P N R K D G
L P
FG I
L QQ S V F H N P SV L L Y D V T K
A I A V D F H F L F L P L E D I I M V A F V
L S L V Y S F G L K I A V L Y T L L A S C F
T V V G F M P M
G L V I F A T
S A I V I W CWG L C L
F T G S F I T V G L
V T L
L
T
S A MW T
S L I I T S N
N E L A D G V L L L V V
V
L S
F C I L V V P N
L V L L S L A L F T V V A I F L
T L V L A Y I
I
C H F I G A Y A Y V L
I V I
R D PK A M R L A K SR
S H L R P S Y I Y T R I Y
MD I K
R C H I S V L I I Q A R DA intracellular
SL R R KW PO4 I D L F FM
C
I A H
P R H M S P R R P E
K H A I T H S S G
L A Y R
SV QT S A T
E T
R R Q V
G K D Q
G V
K
7 transmembrane domains
COOH

CB1 CB2 homology

-68% sequence homology in transmembrane
-44% throughout entire protein
 Cannabinoid receptor 1 distribution in
the rat brain

CB1R

Ross et al

CB1 is one of the most abundantly expressed

neuronal receptors
a) Cerebellum
b) Hippocampus
c) Cortex

CB1 expression in periphery

 Cannabinoid receptors

- Gi &Go
- inhibit voltage-dependent Na+ channels
- inhibition of adenylyl cyclase
- inhibition of Ca channels
- activation of K channels

- activation of MAP kinases (context dep.)

- expression consistent with psy. Effects
- pre-synaptic localisation (axon terminals)
- Neurotransmission
(inhibits cholinergic, glutamatergic, dopaminergic,
adrenergic)
Periphery
CB2R Almost exclusively restricited to cells
and organs of the immune system

CB1 and CB2 (existence of other isoforms)

 CB2 expression is almost exclusively restricited to cells
and organs of the immune system

Science. 2005 Oct 14;310(5746):329-32.

Ann N Y Acad Sci. 2006 Aug;1074:514-36.

CB2 receptors in the brain: role in central immune function

G A Cabral, E S Raborn, L Griffin, J Dennis & F Marciano-Cabral
Br J Pharmacol. 2008 Jan;153(2):240-51. Epub 2007 Nov 26.
 The Bodys Own cannabis - Endocannabinoids
(eCBs)
? why should we have receptors for a plant derived substance such as 9-
THC ?

The presence of CBRs suggested the presence of an

endogenous ligand
eCBs exist as precursors in the cell membrane

Unsaturated fatty acid derivatives

Produced in response to specific stimuli

depolarization

Differ in pharmacology
Guzman et al., 2003, Nature Reviews Cancer 3, 745-755
(2-AG more efficacious)
 Role of endogenous cannabinoids

* Precise physiological role unknown

* Inhibit memory consolidation

* Inhibit neurotransmission

* Regulation of JNK, ERK, p38, PKB, adenylate cyclase

 ECB biosynthesis

Derived from unsatura\ed FA arachidonic acid

(FA found in phospholipids in cell membranes)

Not stored in vesicles but are produced on demand

Biosynthesis increases upon nerve cell ac=va=on

Guirida et al (1999) dopamine

 ECB degradation
2-AG

Monoacyl glycerol lipase

(MAGL)

Glycerol + arachidonic acid

AEA

Fatty acid amide Hydrolase

(FAAH)

Ethanolamine + arachidonic acid

Vincenzo Di Marzo et al., 2004, Nature Reviews Drug Discovery 3, 771-784

 Retrograde signalling Activation of pre-synaptic CB1
decreases neurotransmitter
release

Since ECBs are synthesised

during
neuronal activity - presCB1
forms a
sort of feedback inhibition

Serves to attenuate or
enhance
excitability, depending on the
type
of transmitter released

The Brain's Own Marijuana" in the December 2004 issue of Scientific American.
 Man-made synthetic cannabinoids
Synthetic analogues of THC

O
N
10 1
O
N 3 Cesamet
8O

5
W I N 5 5 2 1 2 -2
 Man-made synthetic cannabinoids

Specific CB2 agonist

JWH 133

Receptor antagonists

CB2

CB1
 Endocannabinoid system

Novel
2-arachidonoyl
Anandamide ligands
FAAH (AEA)
Glycerol MAGL
(2-AG)

CNS Endogenous Ligands

Periphery
CB1R CB2R
Metabolic enzymes

Interaction with other Novel

receptor types receptors
 Endocannabinoid system

Fear & Pain

CNS development and plasticity
Cell Fate
Appetite control & metabolism
Immune system
Reproduction
Bone metabolism
 Cannabinoids and Cell Fate

Toxic Protective
Glioma cells, Sanchez et al., 1998
Hp neurones, Chan et al., 1998
? Ischaemia, Louw et al., 2000
Excitotoxicity, Gilbert et al., 2007

Neurodengeneration

THC apoptosis
Lysosomal
Cyt-c JNK1 THC leakeage
P
Caspase-3 Campbell, 2000 p53
Downer et al., 2003, 2007
Downer et al., 2001 Gowran and Campbell, 2008
Con

Neonate
THC
 eCB signalling in CNS development

Tunes neuronal specification programs

CB1R activation on neural progenitors promotes gliosis

Interacts with other signalling pathways e.g., Neurotrophins

Induces the migration of late-gestational GABAergic interneurones

Shapes neuronal connectivity

growth cone navigation
axonal elongation
synaptogenesis
Harkany T, Guzmn M, Galve-Roperh I, Berghuis P, Devi LA, Mackie K.
Trends Pharmacol Sci. 2007 Feb;28(2):83-92. Epub 2007 Jan 10
 IS CANNABIS TOXIC?
Cannabis exposure
Cigarrette smoking
during pregnancy

Low birth weight

Small head size
Prenatal study
Fried et al.
 Cannabis exposure during
pregnancy
Deficits in executive function & Visuospatial working
memory

Persists into adulthood

Animal studies - CB receptor agonists decreases glutamatergic

Transmission

Abnormal activation of these pathways by exogenous CBs may

lead to cognitive impairments in later life
 CANNABIS AS MEDICINE

Cannabinol, CBN

Cannabidiol, CBD

Ryan N. Philippe The science creative quarterly

2007, Issue 3 Downregulation of inflammation etc.

Reverses Tau hyperphosphorylation

CB1 independent signalling

no psychoactive activity
 Cannabinoid system and
Neurodegeneration

Chronic recreational use of cannabis is linked with morphological

changes in brain structures
- frontal white matter volume decreased
- reduced grey matter

Could be related to alterations in the control of neurogenesis,

synaptogenesis and wiring.
 Cannabinoid system and AD

Drobinol (solution of THC) improves disturbed behaviour and

stimulates appetite in AD patients

Increased expression of CB receptors on microglia within

plaques

FAAH is upregulated in plaques - increased AEA metabolites

increases PGs & increases pro-inflammatory molecules
2-AG is increased during A exposure - local
neuroprotection

Drugs that augment eCB tone - potential treatment of AD

THC reduces A aggregation

Cannabinoid system and AD

Gowran et al., 2010.

 Cannabinoids and MS

Clifford, 1983, Ann. Neurol 13:669-671.

The endocannabinoid system and multiple sclerosis.

Baker D, Pryce G.
Curr Pharm Des. 2008;14(23):2326-36.
 Cannabinoid system modulating drugs

Marinol Sativex
(dronabinol)
Acomplia Pain relief in
THC MS
Anti-nausea (rimonabant) Cesamet
Appetite stimulant Anti-obesity (nabilone)
THC
analogue
anti-emetic
in cancer
therapy