Chemical signalling 2: other neurotransmitters Flashcards
What is neuromodulation?
Modulates and fine-tunes activity of neurotransmitter. Neuromodulators do not carry primary information - all they do is fine-tune things.
How do modulatory systems diffuse?
Specific populations of neurons that project diffusely and modulate the activity of Glutamate and GABA neurons in their target areas. Have widespread projections. Primarily in the midbrain, and projects to other areas.
What is dopamine?
Involved in motivation and reward. Dopamine system originates in the midbrain (VTA). Projects to areas like the striatum (involved in motor control) and to the prefrontal cortex.
What is the dopaminergic system?
Different dopamine systems that have different functions and project to different areas:
- Nigrostriatal system - substantia nigra projections to neostriatum. Plays important role in movement. Dysfunction results in Parkinson’s disease and Huntington’s disease.
- Mesolimbic system - VTA projections to NAcc. Plays important role in reward. Dysfunction results in addiction.
- Mesocortical system - VTA projections to the prefrontal cortex. Role in functions such as working memory and planning. Dysfunction results in schizophrenia and addiction.
What is involved in dopamine synthesis?
Tyrosine (essential amino acid, obtained in diet) is catalysed by tyrosine hydroxylase (TH), which holds things up. L-Dopa is then catalysed by dopa decarboxylase, which results in dopamine. One synthesised, dopamine is stored in vesicles.
How is tyrosine hydroxylase activity regulated?
Provides a means of controlling the size of the pool of dopamine available for release and thus regulated its transmission. This is done in one of three ways:
A) Feedback inhibition by endproducts – Dopamine competes for binding with an essential cofactor – too much Dopamine lowers TH activity. DOWN-REGULATION of synthesis
B) Presynaptic activity (DA release) leads to phosphorylation of TH (via autoreceptor) which increases its activity. UP-REGULATION of synthesis (replenishing pool)
C) Prolonged activity in the presynaptic neuron leads to an increase in transcription of the TH gene leading to more enzyme synthesised. UP-REGULATION of synthesis (increasing size of pool).
What drugs affect dopamine synthesis and storage modulate behaviour?
- Reserpine impairs storage of monoamines in synaptic vesicles. (The vesicles remain empty resulting in no transmitter release upon activation).
- L-Dopa - used as a treatment for Parkinson’s disease, results in a dramatic improvement. However as disease progresses, L-Dopa stops working, and plays a role in reward (can result in addiction).
- AMPT - inactivates TH, meaning dopamine levels go down. Used experimentally, not in treatment. Role and importance of neurotransmitter systems in behaviour revealed by drugs. (e.g. Reserpine was used to treat high blood pressure but caused depression).
How is dopamine released?
Released when there is a depolarisation in the presynaptic membrane. Influx of Ca2+ through voltage gated channels. Ca2+ dependent vesicle docking and release.
What is involved in dopamine reuptake?
Signal terminated by reuptake into the axon terminal by transporters powered by electrochemical gradient (Dopamine transporters (DATs))
in the cytoplasm dopamine is:
- reloaded back into vesicles
- enzymatically degraded by Monoamine oxidases (MAOs) or
Catechol-O-methyl-transferase (COMT).
What drugs affect dopamine release and reuptake module behaviour?
- Cocaine, Amphetamine and Methnyphenidate (Ritalin). All block the reuptake of monoamines into terminals. This means there is more dopamine in the synaptic cleft. There is also an extended action of dopamine on the postsynaptic neuron. Amphetamine’s reverse the transporter, so pumps out transmitter - this creates an uncontrolled release, and the effect of the drug therefore lasts hours.
- Selegiline and Entacapone - both are inhibitors of MAO (what breaks down dopamine). These drugs can have antidepressant activity and can be used for treating Parkinson’s.
What is the Noradrenergic System?
Projections form the Locus Coeruleus (LC) throughout the brain. Role in arousal and attention. Dysfunction results in:
Anxiety
Heroin withdrawal
Depression.
What is the Serotonergic system?
Nine raphe nuclei (in brain stem). Projects serotonin across the brain. Raphe neurons fire tonically during wakefulness (even at rest, they fire), and are quiet during sleep. Have function in mood, sleep, pain, emotion, and appetite.
What is involved in serotonin synthesis?
Tryptophan (essential amino acid obtained in diet) leads to 5-hydroxytryptophan, which leads to serotonin. Serotonin is then loaded into vesicles, and released when calcium comes in. Signal is terminated by reuptake by Serotonin transporters (SERTs) on the presynaptic membrane, and degraded by MAOs in the cytoplasm.
Serotonin really important for mood regulation.
What are drugs that affect serotonin release and reuptake module behaviour?
- Fluoxetine (Prozac) blocks reuptake of serotonin (SSRI – selective serotonin reuptake inhibitor) – antidepressant / anti-anxiety. Prozac targets serotonin – serotonin levels go up, reduces depressant symtpoms and reduces anxiety.
- Fenfluramine causes the release of serotonin and inhibits its reuptake (has been used as an appetite suppressant in the treatment of obesity). Related to heart problems, so was banned.
- MDMA (ecstasy). causes noradrenaline and serotonin transporters to run backwards releasing neurotransmitter into synapse/ extracellular space. Has sensory-altering effects, makes you happy.
All of these drugs cause an increase in serotonin levels.
What is the cholinergic system?
Widespread in the brain, terminals everywhere. Projections to the hippocampus and cortex.
Pontomesencephalotegmental complex = cholinergic link between the brain stem and basal forebrain complex.
