Neuropharmacology (8.3) Flashcards
Outline the metabolism of monoamines
*Draw diagram*
Dopamine: Receptor
*G-protein coupled receptors - D1 - D5*
Dopamine: Functional associations
- Control of movement (nigrostriatal dopamine)
- Emotional (mesocorticolimbic dopamine)
- Reward pathways (mesocorticolimbic dopamine) - link to addiction
Noradrenaline/adrenaline: Receptor
NA and Adr act through α- and β-adrenoreceptors - linked to G-proteins, effects via second messengers
The most prominent adrenoreceptor in the forebrain are β-adrenoreceptors (may be targetted by anti-depressants).
Noradrenaline: Functional associations
- Arousal and attention
- Related to mood and behaviour
- Role in facilitating the responsiveness of the brain to other neurotransmitters (released simultaneously)
Serotonin: Receptor
At least 14 different 5-HT subtypes which are all G-protein linked, apart from 5-HT3
5-HT1 can function as an autoreceptor (pre-synaptic), mediating the effects of serotonergic transmission.
Serotonin: Functional associations
-
Mood and pain
- Diminished transmission has been implicated in depression
- Released from platelets following activation
- Released from enterochromaffin cells - stimulates feelings of nausea
Raphe nuclei contains the serotonergic nuclei.
- Descending fibres: Travel to the spinal cord, inhibit nociceptive pathways
- Ascending fibres: Travel to the forebrain and cerebral blood vessels
Monoamines: Endogenous regulation of activity
Monoamine: Enzymatic degradation pathways
*therapeutic targets*
Parkinson’s disease: Definition, symptoms
Definition: Characterised by the degeneration of dopaminergic neurones of the substantia nigra. This loss of dopaminergic neurones leads to dopamine depletion
Symptoms:
- Bradykinesia
- Resting tremor
- Muscular rigidity
Parkinson’s disease: Treatment
Aim: Restore dopaminergic transmission through increasing dopamine levels
- Dopamine precursor: L-DOPA (alongside inhibitors of enzymes which convert L-DOPA to its active form (dopa decarboxylase) in the periphery. Acts to increase the concentration available to cross the BBB)
- Dopamine receptor agonist: Act mainly at D2 (Gi, decrease cAMP) but also at D3
- Muscarinic receptor antagonist: As Cholinergic overactivity is seen in Parkinson’s disease.
- MAO-B and COMT inhibitors: Prevent the breakdown of dopamine, increasing availabilty at the synaptic cleft
Parkinson’s disease: Treatment ADRs
L-DOPA (dopamine precursor):
- Motor complications: Dyskinesias, on-off phenomenon
- GI: Peripheral dopamine antagonists
- Behavioural: Resultant of the increased levels of dopamine - antipsychotics may be used to combat this
Dopamine receptor agonists:
- Mental disturbances
- GI disturbances
- Fatigue and somnolence
Inhibitors of MAO (MAO-B)
- Less likely to cause hypertension HOWEVER MAO-A may also be inhibited at high doses which may preciptate a hypertensive crisis(due to peripheral accumulation of noradrenaline - see metabolic pathways)
- Fatal hyperthermia if + meperidine, cocaine or fluoxetine
L-DOPA + COMT
- Hyperdopaminergic symptoms
Parkinson’s disease: Therapy of non-motor symptoms
Schizophrenia: Definition, symptoms
Definition: A type of psychosis (individuals are unable to distinguish their own thoughts and ideas from reality) which changes the way individuals think and behave.
Acute schizophrenia: Patients experience periods when symptoms are particularly severe followed by periods with few or no symptoms.
Symptoms:
Usually classified into positive and negative symptoms.
Positive symptoms: Changes in thought and behaviour, such as hallucinations and delusions
Negative symptoms: Withdrawal or lack of function unexpected of a ‘healthy’ person. Often seen many years prior to the acute schizophrenic episode, referred to as the prodromal period.
- Hallucinations: Hearing, smelling, tasting seeing or feeling things that are do not exist beyond their own mind. Most commonly voices
- Delusions: A belief held with complete conviction despite often being based on a mistaken, strange or unrealistic view
- Thought disorder: Trouble keeping track of thoughts and conversations
- Changes in behaviour and thoughts
Schizophrenia: Treatment
Aim: Decrease signal transmission through dopamine receptors (antagonise). For some patients medications which also act at other receptors types, such as serotonin (5-HT) are required
Depression: Definition, symptoms
Definition: Persistent sadness/hopelessness for weeks or months
Symptoms:
- Loss of interest in activities (anhedonia)
- Anxiety
- Loss of appetite
- Decreased energy/fatiguability
- Vacillation
- Psychomotor agitation/psychomotor depression
- Loss of confidence
Depression: Treatment
Aim: Depression has been linked to monoamine deficiency. Subsequently, treatment focuses on increasing serotonin and noradrenaline levels
Reuptake inhibitors
- TCA: Inhibit reuptake of serotonin and noradrenaline, through inhibition of SERT and NET of the pre-synpatic membrane
- SSRI: Inhibit the reuptake of serotonin, through inhibition of SERT
- SNRI: Inhibit reuptake of serotonin and noradrenaline, through inhibition of SERT and NET of the pre-synpatic membrane
- NRI: Block the reuptake of noradrenaline (NET)
Atypical antidepressants:
- MOA-A inhibitors: Prevent metabolism of noradrenaline and serotonin
- Increasing release of neurotransmitters
- Ketamine/LSD: Act on NMDA
Depression: Treatment ADRs
Glutamate: Sources and synthesis
Sources: Glutamate can be obtained from the diet but may also be synthesised from α-ketoglutarate or glutamine.
Synthesis: Synthesised from α-ketoglutarate or glutamine and then packaged into synaptic vesicles ready for release following an action potential.
Glutamate: Action
99 % of transmission is excitatory. Mainly acts through inotropic receptors, AMPA and NMDA.
The receptors are composed of 4 subunits, with an integral ion channel.
Permeabilty:
AMPA: Na+ and K+
NMDA: Ca2+, Na+ and K+
NMDA receptors have a Mg2+ blockade, preventing their activation. The receptors can only be activated following cell depolarisation through the repeated activation of AMPA receptors. The depolarisation of the neuron ‘drives’ Mg2+ out of the channel, allowing for the entry of Ca2+. This provides the basis for long-term potentiation - which allows for learning and memory (creates reinforcement), as the Ca2+ influx allows for the generation of secondary messengers implicated in this process.
Glutamate: Reuptake
2 possible mechanisms:
Glutamate → reuptake into glutaminergic neurones via pre-synaptic transporters → repackaged into vesicles and used again
Glutamate → reuptake by glial cells → converted to glutamine (inactive) → travels to glutaminergic neurone → converted to glutamate → repackaged
Glutamate: Functional assoications
Involved in fast excitatory neurotransmission in the CNS
Extremely important for learning and memory, via LTP. Acetylcholine is also implicated.
CAUTION: Tonic excitation may result in some cases, leading to the death of neuronal cells.
Mechanism: Excessive excitation of AMPA and NMDA leads to a large influx of Ca2+. Reuptake of glutamate is impaired, due to the vast quantity released. As glutamate remains within the synpatic cleft there is excessive stimulation of the receptors, leading to excitotoxic neuronal cell death. Antagonists may be used to avoid this.
GABA: Souces and synthesis
Sources: Synthesised from glutamate
Synthesis: Synthesised from glutamate in GABAergic neurones. GABA is then packaged into synaptic vesicles and released following action potential propagation.
GABA: Action
Role in arousal/attention, memory formation, anxiety, sleep and muscle tone.
GABA activation is inhibitory, causing neuronal cells to become less excitatory (resting membrane potential is decreased and so are less likely to reach the activation threshold).
Main action is through GABAA iontropic receptors, which have a central Cl- channel.
