Transmitters and Disorders Handout
Transmitters and Disorders Handout
Transmitters and Disorders Handout
LEARNING OBJECTIVES
1) They increase receptor signalling by either: a) increasing the availability of a transmitter (e.g.
Parkinsons disease where more precursor is supplied or depression where metabolism or uptake is
blocked) or b) through direct receptor activation (e.g in anxiety and epilepsy with the
benzodiazepines).
Issues: This may appear straightforward, but therapy aimed at the CNS is very different from, say
cardiovascular therapies, since the CNS has several billion neurones, which form hundreds of
contacts with each other. It is also a lot harder to quantify symptoms of schizophrenia than it is to
measure blood pressure or heart rate.
There are some other considerations that need to be taken into account:
Multiple receptors - for example 5HT has a number of receptors, some of which are excitatory and
some are inhibitory - thus tactic 1a may lead to multiple effects.
The CNS is complex, so too are the synaptic connections, and transmitters can have actions at
many sites in the brain.
As a result there can be problematic side-effects although if different effects of transmitters are
mediated by different receptors then drugs selective for receptors may be useful for therapy.
Drug effects can initiate feedback responses (excitatory or inhibitory ) and prolonged stimulation or
blockade of receptors can lead to receptor down or up regulation. This latter point is important in
the therapy for Parkinsons, depression and schizophrenia.
Drugs acting on the CNS have to cross the blood brain barrier and this presents particular
problems for drugs based on peptides that penetrate poorly into the CNS. Non-peptide drugs acting
at the receptors for peptide transmitters indicate that these recently characterized systems may be
very important therapeutic targets.
Some disorders will result from excess neuronal activity (chronic pain, epilepsy), others are
associated with a selective decrease in function (e.g. Parkinson’s). Some disorders result from
external events (depression or anxiety as a result of life events or pain from trauma or surgery)
whereas epilepsy, Parkinson’s disease and schizoprenia result from changes in the CNS (though
these changes too may result from external events).
Parkinson’s disease and Alzheimer’s disease result from the death of neuronal systems, in the case
of the former, a very well-defined pathway, whereas stroke is due to generalized death of neurones.
The aim of therapy is to restore normal function.
Epilepsy:
A motor disorder where uncontrolled neuronal activity drives motor systems and hence the fits and
convulsions. Epilepsy is categorized into several types and it is thought to generally be due to
overactive glutamatergic transmission or reduced GABA function. The balance thus shifts to excess
firing of neurones. The treatments are either drugs that block Na + channels and so reduce repetitive
firing of cells or drugs that enhance GABA function. Barbiturates open Cl channels and so cause
major inhibition – they are used for severe cases whereas benzodiazepines enhance GABA
transmission and so are gentler in their effects.
Anxiety:
A mood disorder that can be triggered by external events (exams, debts, hot dates) and which
ranges from mild (which can improve performance) to debilitating. Typically treated either with
benzodiazepines or drugs that increase 5-HT receptor function.
Schizophrenia:
A disorder of mood and thought processes that involves increased dopamine function (but in
pathways separate to those that fail in Parkinson’s disease). Patients have hallucinations, become
withdrawn and the altered thought patterns can result in paranoia and suspicions. Treatment is
typically through drugs that block the DA 2 receptor. Too much DA 2 receptor antagonist will lead to
patients acquiring motor problems.
Parkinson’s disease:
James Parkinson first described “Shaking Palsy” in 1817. This disease, now named after him, is
unique in that the symptoms result largely from a single transmitter deficit due to the loss of
dopamine neurones in the substantia nigra. The degeneration of these neurones means that
dopamine is depleted from the nigrostriatal projection zones in the striatum, around 70-80% of the
nigrostriatal neurones have to die before the symptoms appear. The cause of the neuronal death is
unclear, however, flawed designer drugs (MPTP – a toxic opioid metabolite that triggered PD in
several young Americans) and environmental chemical factors have been implicated in the aetiology
of PD, there is little evidence to suggest that the disorder is anything other than an ongoing loss of
vulnerable neurons as part of the ageing process. Life events may speed the process. Symptoms
include muscle rigidity, akinesia (poverty of movement) and tremor at rest. Treatment is L-DOPA,
the precursor for dopamine, given together with drugs that reduce metabolism of both L-DOPA and
dopamine.
Alzheimer’s disease:
A disease of mood and cognition where memory and communication become disrupted. Thought to
be due to neuronal degeneration, in particular of acetylcholine pathways. The major roles of this
transmitter in the autonomic and motor systems makes the approaches used in Parkinson’s almost
impossible to apply. As such, anticholinesterases are used which have very limited therapeutic
efficacy.
Depression:
Like anxiety, depression can be triggered by external events (bad hair, bereavement etc. and so can
be mild and acute or severe and chronic) and is part of the mood changes that life brings. Depression
can also arise out of the blue when there are neurochemical changes independent of the outside
world. If prolonged, severe and untreated, depression can result in major social and other
impairments of function and lead to self-harm and suicide. The monoamine transmitters, NA and 5-
HT are critical for mood regulation and treatments are based on the block of their reuptake or
metabolism – this results in increased synaptic levels of these transmitters.
Pain:
A disorder of excess activity that results from peripheral and central events. Large numbers of
patients suffer from acute and chronic pains. There is now much evidence to suggest that the
pharmacology of both pain transmission and analgesia exhibits considerable plasticity - the
mechanisms of pain and the ability to control it may adapt in different pain states. Understanding
this plasticity is critical for a rational basis for the treatment of neuropathic and inflammatory pain,
the two major types of pain. Acute pain involves activation of sensory receptors on peripheral C-
fibres, the nociceptors. However, once tissue damage and inflammation occurs, the peripheral
actions of prostanoids, bradykinin, 5-HT etc plays a major role in sensitization and activation of C-
fibres. NSAIDs (aspirin and ibuprofen) act to block the actions of the prostanoids at the site of injury
and local anaesthetics blocks Na+ channels and so reduces the firing of pain fibres. Very brief acute
pains are transmitted via the AMPA receptors. The situation within the spinal cord changes if the
peripheral stimulus continues. Peptides are released from C-fibres that allow spinal N-Methyl-D-
aspartate (NMDA) receptor activation which in turn gives rise to central states of hyperexcitability
which are of major importance to many pain states. Morphine is one of the oldest drugs known to
mankind is found in the juice of the opium poppy. Morphine acts on the mu opioid receptor, and so
do most of the clinically used opioid drugs. This mu receptor is the receptor for endogenous opioid
peptides.