Transcript Schizophrenia II - Psychiatry Training

Amino Acid Neurotransmitters
Paul Glue
Objectives
• Review:
– Relative abundance of AAs vs monoamines
– Pharmacology of glutamate, GABA
– Postulated role of glutamate, GABA
dysfunction in neuropsych disorders
Relative abundance of neurotransmitters
• Glutamate ~60% of synapses
• GABA ~30% of synapses
• Monoamines, peptides, other AAs (e.g.
glycine) <5%
COOH
Glutamate Pharmacology
COOH
H2N
• Glutamate is one of the most common transmitters in
the CNS
– Fast, excitatory transmitter; receptors on almost all neurons.
Transmitter in ~60% of neurons, esp cortex, limbic
structures.
• Glutamate binds to 4 classes of receptor
– three "ionotropic" receptor classes - ligand-gated ion
channels which are characterized by the different ligands that
bind to them:
• AMPA
• kainic acid
• N-methyl-D-aspartate or NMDA
– one G-protein coupled or "metabotropic" receptor class.
The Glutamate Synapse
Interconversion of
glutamate to
glutamine
Note – significant
Glu uptake (mainly
astrocytes)
COOH
Glutamate Function
COOH
H2N
• Under physiological conditions, activation of ionotropic
receptors in neurons initiates transient depolarization and
excitation.
• AMPA-Rs mediate the fast component of excitatory
postsynaptic currents
• NMDA-Rs underlie a slower component.
• AMPA-Rs modulate Ca++ influx thru NMDA-Rs.
– Depolarization of the postsynaptic neuronal membrane via
AMPA-Rs relieves the Mg++ block of the NMDA-R ion
channel (this occurs in NMDA-R under resting conditions).
This allows controlled Ca++ influx through the NMDA-R.
This voltage-dependent modulation of the NMDA-R results
in activity-driven synaptic modulation.
• Glutamate overactivity can lead to neuronal death due to Ca++
toxicity, other associated mechanisms.
NMDA-Receptors
Structure - tetramers of two NR1 subunits and two NR2
subunits (some brain areas have NR3 subunits).
Binding sites on the extracellular domain: NR1: coagonist glycine; NR2: glutamate. For efficient ion
channel opening, the NMDA receptor requires both
glutamate and the co-agonist glycine.
Binding sites in the ion channel: Mg2+; PCP/ketamine site
NMDA antagonists: Synthetic antagonists include:
MK-801 (dizocilpine)
Phencyclidine
Ketamine
Dextromethorphan
Memantine, Amantadine
Procyclidine
Ketamine
and
NMDA modulators: Mg2+ blocks the NMDA channel in a
voltage-dependent manner.
- Na+, K+ and Ca2+ not only pass through the NMDA
receptor channel but also modulate the activity of
NMDA receptors.
- Zn2+ blocks the NMDA current in a non-competitive and voltage-independent manner.
- The activity of NMDA receptors is also sensitive to the changes in H+ concentration, and is
partially inhibited by the ambient concentration of H+ under physiological conditions.
Metabotropic glutamate receptors
• Metabotropic receptors are coupled to their associated ion channel
through a second messenger pathway.
– May be located pre-, post- or extra-synaptically
• Glutamate binding activates a G-protein and initiates an intracellular
cascade
• There are 8 cloned mGluRs (mGluR1-mGluR8)
– classified into three groups (I, II, and III) based on structural homology,
agonist selectivity, and associated second messenger cascade
• Group I mGluRs (mGluR1 and mGluR5) are coupled to the hydrolysis
of fatty acids and the release of calcium from internal stores.
Quisqualate and trans-ACPD are Group I agonists.
• Group II (mGluR2 and mGluR3) and Group III (mGluRs 4, 6, 7, and
8) receptors are considered inhibitory because they are coupled to the
downregulation of cyclic nucleotide synthesis
– Appear to have neuroprotective effects in animal models
mGluR1
mGluR2
mGluR3
mGluR4
mGluR5
mGluR subtype
mRNA distribution
in rat brain
Glutamate hypothesis of schizophrenia (1)
• Is DA antagonism alone enough for an
effective antipsychotic agent?
– DA antagonism has limited effects on negative
symptoms
– DA antagonists take several weeks to show
clinical antipsychotic activity; other
pharmacological effects (PRL, EPSE) much
more rapid.
• NMDA receptor antagonists (ketamine,
PCP) are psychotogenic in normal
individuals and schizophrenic patients;
positive in animal models indicative of
psychotogenic potential.
• Potency of antagonism correlates with
ability to produce behavioral/
psychotogenic effects
Glutamate hypothesis of schizophrenia (2)
• Glutamate may have a significant role in the control of dopamine transmission in
the striatum.
– Dopamine transmission occurs in two different temporal modes, phasic and tonic.
• Phasic DA release is transient and rapidly terminated, and selectively affects only receptors
within or near the synapse. Phasic transmission is primarily dopamine dependent.
• Tonic release of dopamine results in a constant level of dopamine in the extracellular,
extrasynaptic space and is regulated mainly by glutamate.
• Not all GluRs are realistic targets –
– Ionotropic GluRs mediate most fast synaptic transmission in the CNS - too ubiquitous
– Excess Glu is neurotoxic; NMDA antagonism is psychotogenic
• Metabotropic glutamate receptors may be better targets
– These modulate synaptic neurotransmission
– mGluR2 and 3 are primarily distributed in forebrain regions.
– Stimulation of these mediates presynaptic depression and decreases evoked release
of glutamate.
– PCP and other NMDA antagonists increase glutamate efflux; this may increase DA
activity (amongst others)
– Reduction of presynaptic glutamatergic activity by targeting group II mGluRs may be a
novel approach to treating schizophrenia
Clinical
Trial:
LY2140023:
(mGluR 2/3
agonist in
acute SCZ)
(Nat Med 2007)
LY=OLZ, >pbo for:
PANSS, CGI
LY=pbo, >OLZ for:
Weight, PRL
Dopamine
Glutamate Antagonists in Major Depression
• Rationale:
– NMDA-antagonists are effective in animal models of depression
– Elevated glutamate levels in occipital cortex of depressed patients
– Chronic antidepressants may work indirectly on NMDA systems
(altered subunit transcription, binding density)
– Inhibitors of glutamate release (lamotrigine, riluzole) have
antidepressant properties
• Clinical studies using single dose ketamine infusions
– Placebo-controlled, crossover, double-blind
– May work through effects on mTOR (promotes synapse
development) (Science 2010)
40
Single Dose Ketamine
Infusion Studies (1)
MADRS score
•Diazgranados; Arch Gen
Psych 2010
30
20
10
•Treatment refractory bipolar
depression, unmedicated
Ketamine
Placebo
0
40
•Randomized, double blind, 2
period crossover
•Assessments to 14 days
110
230
1
Minutes
2
3
7
10
14
Days
Time after infusion
80
MADRS Responders (%)
•Ketamine (0.5mg/kg) or
placebo via 40 minute IV
infusions
80
60
Ketamine
Placebo
40
20
0
40
80
110
Minutes
230
1
2
3
7
Days
Time after infusion
10
14
Single Dose Ketamine Infusion Studies (2)
• Zarate, Arch Gen Psych 2006
• Treatment resistant MDD, unmedicated
• Single 0.5mg/kg IV infusion; placebo controlled, crossover design
100
90
100
Percent of responders (>50% ↓HAMD)
90
80
80
70
70
Percent in remission (HAMD <7)
Ketamine
Placebo
60
60
(%)
(%)
50
50
40
40
30
30
20
20
10
10
0
0
40 80 110 230 24 48 72 168
- - - - -mins- - - - - - - - - - - - - -hours- - - - - (time)
40 80 110 230 24 48 72 168
- - - - -mins- - - - - - - - - - - - - -hours- - - - - - (time)
•Main side effects of ketamine: Perceptual disturbances and dizziness;
confusion; elevated blood pressure; euphoria; increased libido
•Generally occurred in 1st 20min of infusion.
Glutamate and other disorders
• All effective mood stabilizers influence
glutamate signalling (generally )
– Li  Glu transport; LTG  Glu release, etc
• Excess Glu signalling in alcohol
withdrawal, epilepsy, ? anxiety
GABA
• Inhibitory amino acid neurotransmitter; both pre- and postsynaptic receptors
• 2 receptors – GABA-A – ion channel
• GABA-B – G-protein coupled receptor
(heterodimer)
Besides CNS, GABA
also found in liver, GI
tract, uterus, ovary,
testis, lung, etc
BDZs bind to the GABA-A Receptor
-Ligand-gated receptor complex
-Made up of 5 helical columns
surrounding a chloride channel
-Separate binding sites for
•GABA, GABA agonists/
antagonists
•benzodiazepines
•barbiturates
•ethanol
•neurosteroids (pregnanolone)
•convulsants (picrotoxin, PTZ)
Resting state
outside
video
plus GABA
GABA
plus GABA and BDZ
GABA
BDZ
Cell membrane
inside
ClCl- Cl- Cl-
Cl- ClCl- Cl-
Cl-
Cl- Cl-
Benzodiazepine pharmacology
Agonists
Partial
Agonists
Anxiolytic
Anticonvulsant
Amnestic
Sedating
Diazepam
Lorazepam
Antagonists
Neutral/
no effect
Abecarnil
Bretazenil
Flumazenil
Partial Inverse
Agonists
Inverse
Agonists
Anxiogenic
Convulsant
Promnestic
Arousing
FG7142
DMCM
Clonazepam
(all BDZs and
Z-drugs in
clinical use)
Pharmacological theories of Anxiety (1) - GABA theories
• Observations:
• positive modulators of GABA-A receptor are anxiolytic (BDZs;
barbiturates; ethanol)
• negative modulators are anxiogenic (FG7142; metrazol) in normals
• flumazenil (BDZ antagonist) is anxiogenic in panic disorder but not in
healthy controls; BDZs are less sedating/impairing in anxious patients
than in controls
Agonists
-anxiolytic
-diazepam, etc
Antagonists
-neutral/no effect
-flumazenil
Inverse
Agonists
-anxiogenic
Normal
Panic
Disorder
Agonists are
less sedating
Antagonists
are anxiogenic
Pharmacological theories of Anxiety (1) - GABA theories
• Observations (cont’d):
• Altered GABA-A PET binding in panic disorder
•15-BDZ naïve, drug free patients with panic disorder and 18 controls
•Statistical parametric map illustrating an area where benzodiazepine receptor binding
(11C-flumazenil) was decreased in subjects with panic disorder vs control subjects (R
dorsal anterolateral prefrontal cortex). Arch Gen Psych 2008:1166