PS 3010 Behavioural Pharmacology lecture 3a, semester 2: 20042005

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PS 3010 Behavioural Pharmacology lecture 3a,
semester 2 2004-2005

• Epilepsy and anticonvulsants Parkinsons disease
  and Huntingtons chorea.
• Prof. Michael H. Joseph
• School of Psychology

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Epilepsy

• The group of epilepsies are relatively common
  neurological disorders (overall incidence 0.5-
  1).
• They are neurological because there is a clear
  physical cause in the brain.
• Generalised seizures - what is usually thought of
  as an epileptic fit - are observed as clonic
  movements of the limbs
• may also be tonic, or sometimes only tonic.
• (this is Grand mal epilepsy)
• Patient falls to ground, loss of consciousness,
  followed by period of confusion.

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What is epilepsy ?

• End 19th C. Hughlings Jackson - British
  neurologist - insightful definition
• -- an episodic disorder arising from excessively
  synchronous and sustained discharge of a group of
  neurones.
• (importance in development of neuroscience).
• Development of EEG recording (1930's) allowed
  this to be visualised (OHD)
• 1 - normal 2 - seizure 3 - inter-ictal 4 -
  recovery
• Seizure episodes are classically thought of as
  motor (convulsions), but depends on brain area.

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Brain areas and epilepsy

• If motor areas are involved as the fit spreads
  through the brain, convulsions are seen.
• Seizure activity in other areas results in
  experiences reflecting the functions of those
  areas, e.g. sensory, autonomic or psychic in
  nature.
• Each attack may develop from focal seizures
  (which could be focal motor attacks, or focal
  somatosensory, or psychic).
• Site of origin, and direction and extent of
  spread, determine form.
• Alternatively, generalised convulsions may have
  no clear focal origin.

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Partial (focal) seizures

• a) myoclonic seizures (localised muscle groups)
• b) absence seizures (petit mal) - very brief
  - can be very frequent
• c) atonic seizures
• Complex partial seizures, include temporal lobe,
  psychomotor seizure with impairment of
  consciousness - behavioural automatisms,
  may include psychotic symptoms

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Causes of epilepsy

• Epilepsy can be idiopathic (no obvious direct
  cause) its form is then most commonly
  generalised seizures.
• One common cause is peri-natal hypoxia.
• Epilepsy can be a result of CNS damage (trauma,
  infection, tumour) its form is then most
  commonly focal or partial.

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Animal models I - natural

• Audiogenic - many single-locus genetic mutations
  in mice are associated with spontaneous seizures,
  and/or noise induced seizures.
• Photic stimulation can precipitate epileptic
  attack in one breed of baboons
• (from one area of Senegal).
• Idiopathic genetic epileptic disorder found in
  some Beagle dogs very similar to human
  idiopathic epilepsy.

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Animal models II epileptic foci

• Chronic epileptic focus can be induced by topical
  application of cobalt, aluminium or iron to the
  cortex. Penicillin also used topically to
  produce acute experimental focus.
• Also alumina paste to monkey motor cortex leads
  to seizures that generalise over time.  
• These models are useful to explore the
  neurobiology of epilepsy, but impractical for
  routine prediction of anticonvulsant activity of
  drugs, for use in humans.

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Animal models 3 - induced seizures

• Antagonism of chemically or electrically induced
  seizures in animals is an accurate and widely
  used effect for prediction of anticonvulsant
  activity in humans.
• Pentylenetetrazole (PTZ leptazol) - induced
  seizures antagonism predicts drugs effective
  against absence seizures
• Electrically induced seizures
• - reduced duration and spread, predict drugs
  against Grand Mal
• - increased threshold predicts drugs effective
  against absence seizures.

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Animal models IV - kindling

• Another interesting animal model for epilepsy is
  kindling, to which the amygdala and hippocampus
  are particularly vulnerable.
• Repeated stimulation in this area, sufficient to
  cause an after-discharge, but not enough for a
  direct seizure, leads over several days to full
  seizures following this sub-threshold stimulation
  (i.e. threshold is reduced).
• Maybe related to changes in glutamate receptors
  similar to those occurring in LTP.

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Animal models IV - kindling and cellular
mechanisms

• Like LTP, the kindling response is blocked by
  antagonists at the NMDA-glutamate receptor.
• Hence the mechanism by which repeated
  subthreshold stim gt seizures, and repeated
  seizures gt neuronal damage, may be similar to
  glutamate excitotoxicity see next.
• Kindling can be induced by repeated application
  of glutamate (in place of electrical
  stimulation), and these approaches show
  cross-sensitisation. Could be analogous to drug
  sensitisation, and even to learning.

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Excitatory amino acid neurotoxicity

• Subcutaneous glutamate in mice is retinotoxic.
  (Lucas Newhouse, 1957)
• Systemic glutamate causes brain damage in
  neonatal mice - especially arcuate nucleus of
  hypothalamus. (Olney 1969)
• Damage was limited to post-synaptic sites.
  Thus hypothesised that damage was due to
  glutamate stimulation of receptors.
• Glutamate directly into brain, or kainate, an
  analogue, result in neurotoxic damage to cells in
  that area, but not to fibres of passage.

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Excitatory amino acid neurotoxicity and epilepsy

• This became a useful experimental lesioning tool.
• This exptl phenomenon led to speculation that
  EAAs might play a role in the genesis of
  neurological disorders, especially epilepsy.
• Cerebral ischaemia - heart attack, stroke. gt
  haemorrhage. Results after several minutes in
  massive glutamate release, which can cause
  excitotoxic damage, over the next few hours.
  Hippocampus is especially vulnerable to this

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Excitatory amino acid neurotoxicity and epilepsy
II

• 1880 Sommer discovered an area of the
  hippo-campus injured in patients suffering
  recurrent or prolonged seizures (status
  epilepticus).
• Principal damage in pyramidal (glu) cells of CA1,
  also subiculum (due to their vulnerability to
  reduced oxygen). This area contains the highest
  concentration of NMDA receptors in the brain.
• Hence NMDA receptors implicated in both
  seizure-induced and ischaemic brain damage, and
  also in kindling (Meldrum, 1991).

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GABA links with epilepsy

• Focal epilepsy is characterised by spike-and-wave
  in inter-ictal period.
• Spike is due to excitatory inputs, and wave is
  hyperpolarisation due to inhibitory actions.
• Since GABA is a principal inhibitory transmitter,
  reduced GABA function might be associated with
  the transition from spike and wave to full blown
  seizure.
• 3 strategies have been used to look at this
  a) differences in GABA function in brains
  of epileptics b) ability of GABA drugs to
  suppress or promote seizures c) involvement of
  GABA in animal models of epilepsy.

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GABA links with epilepsy (a)

• GABA reported to be reduced in CSF from epileptic
  patients (Wood et al).
• However all patients were receiving drugs, and
  reduction was seen in many neurological
  conditions, only some of which (e.g.
  Huntington's) are plausibly associated with
  reduced GABA function in brain.
• Post mortem analysis (of focal tissue after
  surgical removal). GABA rises rapidly in tissue
  after excision, so direct measures probably not
  valid. Reductions were reported in synthetic
  enzyme (GAD), and GABA receptors. Results on
  reduction in degradat. enzyme (GABA-T) mixed.
  
• Some reports of increased Glutamate in focus
• Hence these results do not clearly support the
  hypothesis of reduced GABA in brain  

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GABA links with epilepsy (b c)

• Kindling in rats is associated with persistently
  reduced GABA levels, as well as increased
  glutamate, at time of seizure.
• Seizures are induced experimentally
  (in animals) by inhibition of GAD, which
  synthesises GABA, by drugs which interfere with
  the co-factor pyridoxyl-P.
• They are also induced by blocking GABA receptors
  directly (bicuculline), or indirectly
  (allosterically) by acting on the nearby
  picrotoxin site (PTZ also acts here).

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GABA links with epilepsy, anticonvulsants

• Of the widely used human anticonvulsants, BDZs
  and phenobarbitone clearly act at least partly
  through GABA mechanisms.
• They potentiate GABA action at its chloride
  channel, via distinct sites on the receptor
  complex (converse of PTZ above).
• Phenobarbitone Effective, but sedative, and has
  abuse potential Increases GABA action at GABA-A
  receptors. Phenobarbitone is preferred among
  barbiturates because it has an unusually high
  anticonvulsant to sedative ratio. Also effective
  against focus, while BDZ effects limited to
  spread.

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Anticonvulsant drugs and GABA II

• Phenobarbitone cont. Hence it may well have an
  effect on the excitatory responses, as well as
  enhancing gaba-mediated inhibition
• Benzodiazepines Effective against spread. Drug
  of choice (given i.v.) for status epilepticus.
  Increases GABA action by binding at distinct site
  on receptors
• Valproate chemically distinct. An inhibitor of
  GABA-transaminase increases GABA levels
• Ethosuximide used for absence seizures petit
  mal. Structurally related to barbiturates.
  Mechanism unknown possibly via GABA

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Anticonvulsant drugs and GABA III

• Vigabatrin is an example of rational drug design
  - aim to produce an inhibitor of GABA-T - an
  analogue with double bonds - in fact it
  covalently binds to the enzyme.
• has been used to identify brain areas where
  increased GABA may be most effective it also
  protects rats from hippocampal cell loss, in an
  animal model of epilepsy.
• Found to increase brain GABA in animals, and
  increases stimulation-induced release. Also
  found to increase CSF GABA in man.
• Tiagabine inhibits GABA reuptake.

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GABA and glutamate in epilepsy

• Thus there is good evidence from drug actions,
  that reduced GABA function might be involved in
  the triggering of convulsions, and that increased
  GABA function might have the opposite effect.
• However, beware the treatment/cause fallacy
  that the endogenous pathology must be the
  opposite of the drug action.
• Also, quite a lot of evidence for Glutamate
  involvement in in pathology of epilepsy.
  Lamotrigine is an example of an NMDA-glutamate
  antagonist which is an effective anticonvulsant.

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Other major anticonvulsant drugs

• Phenytoin (and other hydantoins)
• Widely effective, but not against absence
  seizures.
• Needs plasma monitoring.
• Acts on voltage-dependent sodium channels
  preventing the propagation of action potentials.
  They display use dependence, i.e. they block
  preferentially on axons/cells that are firing
  repetitively. This is done by holding the
  channels in their inactivated state (reached
  after strong firing) for longer.
• Carbamazepine Similar effectiveness, plus good
  for temporal lobe / psychomotor epilepsy.
  Structurally related to tricyclic
  antidepressants. Action as phenytoin also
  possible actions on monoamines.

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Epilepsy and anticonvulsants conclusions

• Complex topic because there are many types of
  epilepsy and of anticonvulsant drug.
• Anticonvulsants may work against excessive
  (glutamate) excitation, or on insufficient (GABA)
  inhibition, or directly on axonal conduction.
• Strangely enough, intermittent convulsions appear
  to do relatively little harm to the brain
  (cf. use of ECT in Psychiatry).

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Parkinsons disease

• Common neurodegenerative disorder usual age of
  onset over 50.
• Principal symptoms
• Bradykinesia - slowness and poverty of movement
• Muscular rigidity
• Resting tremor (not during movement)
• Abnormalities in posture and gait
• Progresses to complete akinesia, and often a
  degree of cognitive rigidity, depression and
  dementia.

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Causes of Parkinsons disease

• Idiopathic
• Viral (post encephalitic)
• Toxin induced (Manganese,
• MPTP - heroin impurity, ? others)
• neuroleptic drug induced

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Brain changes in Parkinsons

• Loss of pigmentation in substantia nigra (SN)
• This reflects degeneration of the dopaminergic
  (DA) system projecting from SN to the striatum
  (caudate-putamen) and, to a lesser extent, of
  projections to the rest of the basal ganglia,
  including the putamen, and the n. accumbens
• Of secondary importance, is damage to
  noradrenergic and serotonergic systems and damage
  to cholinergic projections to the cortex.

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Models of Parkinsons, and drugs

• 6-hydroxydopamine lesions of nigrostriatal DA
  projections (bilateral vs unilateral)
• MPTP lesions in primates, or mice, but not rats
• Drugs used to treat Parkinsons (I)
• Anticholinergics not a primary ACh disorder,
  but these restore balance, and hence function,
  between (depleted) DA, and ACh, in striatum
• - effective against tremor and rigidity

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Drugs used to treat Parkinsons (II)

• L-DOPA - precursor of dopamine which can cross
  the blood brain barrier
• - effective especially against akinesia
• Concurrent use of a dopa-decarboxylase inhibitor
  (carbidopa, benserazide), not penetrating to the
  brain, - reduces dose of DOPA required, and
  peripheral side effects
• Direct DA agonists apomorphine, bromocriptine,
  pergolide, lisuride
• DA releasing agent - Amantadine
• Blocker of DA metabolism (MAO-B inhibitor)
  - Selegiline (deprenyl)

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Treatment of Parkinsons (cont)

• Limitations on treatment
• Progresssive degeneration
• On-off phenomena (receptor changes ?)
• Other approaches
• Pallidotomy circumscribed lesions in globus
  pallidus interna. Also stimulation.
• Results encouraging
• Transplantation of new cells (Adrenal cells vs
  Foetal cells vs immortalised stem cells, which
  will become DA specific). Results equivocal.
• Ethical and anatomical problems

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Huntingtons disease (chorea)

• Rare inherited neurodegenerative disorder - usual
  onset over 50.
•  Principal symptoms
• Involuntary and irregular limb movements
  (chorea dance in Greek).
• These progress, and are accompanied by
  cognitive disorder and dementia
• Massive neuronal loss of GABA output cells from
  the corpus striatum (can progress to 90 loss)
  (contrast Parkinsons - loss of DA input).

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Genetic basis for Huntingtons

• Inherited as autosomal dominant the child of an
  affected parent has a 50 chance of inheriting
  it.
• Gene has now been identified on Chromosome 4, and
  the defect identified as multiple repetitions of
  the base triad that codes for the amino acid
  glutamine.
• Hence the protein product, known as huntingtin,
  has an extra stretch of glutamines. The longer
  this is, the younger the age of onset, suggesting
  a causal role.

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Genetic basis for Huntingtons II

• Also targeted mutations for this gene are fatal
  in utero in the mouse.
• However the role of the protein, and how it
  damages the striatum selectively, is not known.
• Suggestions focus on interference with glucose
  metabolism.

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Models of Huntingtons

• Since the mechanism is not yet understood, models
  focus on the consequences at cellular level,
  rather than the cellular cause.
• Coyle and Schwarcz (1976) pointed out that
  excitotoxic lesions of striatum (initially using
  kainate) could mimic the neurochemical and
  histopathological features of the disorder.
• Some investigators have suggested that quinolinic
  acid, an excitatory amino acid analogue formed
  endogenously from tryptophan, produces an even
  better model, and have suggested that it might
  contribute as an endogenous neurotoxin (this
  pathway is known to be active in brain).

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Models of Huntingtons (cont.)

• Striatum is vulnerable because it has massive
  glutamatergic input from cortex, and hence many
  glutamate receptor sites, both NMDA and non-NMDA.
  
• They are principally on Gaba medium spiny output
  cells projecting to the pallidum, substantia
  nigra (pars reticulata), thalamus and
  sub-thalamic n.
• Relevant neurochemical observations Glucose
  metabolic rate in striatum is reduced
  (2-deoxy-glucose technique - Kuhl et al, 1985).
  Could enable possible early detection. Also CSF
  GABA concn. is reduced (Manyam et al, 1980)

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Brain mechanisms in Parkinsons and Huntingtons

• Diagram of the striatum.
• Essentially there are cortico-striatal-pallidal-t
  halamo-cortical loops.
• There is a direct pathway, and an indirect
  pathway.
• In addition, the DA input from the substantia
  nigra (SN) is excitatory in association with the
  direct pathway, and inhibitory in association
  with the indirect pathway.

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Brain mechanisms in (II) Parkinsons and
Huntingtons

• In PD, loss of the DA input to the striatum
  results in increased activity of the indirect
  output (via globus pallidus external (GPe) and
  subthalamic nucleus (STN), and reduced activity
  of the direct output, to the globus pallidus
  internal (GPi). Both of these effects increase
  inhibition of the thalamus and reduce motor
  output from the cortex.
• In HD, loss of the inhibitory output from the
  striatum to the GPe (indirect pathway) results in
  excessive inhibition of the STN, and thus the
  GPi. This results in reduced inhibition of the
  thalamus by the GPi, and hence increased
  excitation of the motor cortex, and motor output
  (opposite effect to PD)