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PS 3010 Behavioural Pharmacology

lecture 3a, semester 2: 2004-2005

Epilepsy and anticonvulsants; Parkinson’s disease and

Huntington’s 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 => seizures, and repeated seizures => 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. => 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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Parkinson’s disease• Common neurodegenerative disorder – usual age

of onset: over 50.• Principal symptoms:

Bradykinesia - slowness and poverty of movementMuscular rigidityResting 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 Parkinson’s disease

• Idiopathic

• Viral (post encephalitic)

• Toxin induced (Manganese,

MPTP - heroin impurity, ? others)

• [neuroleptic drug induced]

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Brain changes in Parkinson’s

• 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 Parkinson’s, 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 Parkinson’s (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 Parkinson’s (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 Parkinson’s (cont)

• Limitations on treatmentProgresssive 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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Huntington’s disease (chorea)

• Rare inherited neurodegenerative disorder - usual onset: over 50.

•  Principal symptomsInvoluntary 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 Parkinson’s - loss of DA input).

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Genetic basis for Huntington’s

• 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 Huntington’s 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 Huntington’s• 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 Huntington’s (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 Parkinson’s and Huntington’s

• Diagram of the striatum. Essentially there are cortico-striatal-pallidal-thalamo-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) Parkinson’s and Huntington’s • 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)