Brain substrates - Catecholamines Flashcards
What are catecholamines?
A group of biogenic amines that are derivatives of catechol and contain an amine group.
What common neurotransmitters are catecholamines?
Dopamine, adrenaline and noradrenaline.
How are catecholamines synthesised?
In a multi-step pathway (tyrosine, DOPA, dopamine, noradrenaline).
What enzymes are used to synthesise noradrenaline?
Tyrosine hydroxylase (TH), aromatic amino acid decarboxylase (AADC) and dopmaine beta-hydroxylase (DBH).
What enzymes are used to synthesise dopamine?
Tyrosine hydroxylase (TH) and aromatic amino acid decarboxylase (AADC).
Which enzyme is the rate-limiting enzyme in the pathway to synthesise catecholamines?
Tyrosine hydroxylase (TH). It's slower and therefore determines the overall rate of catecholamine production.
What do high catecholamine levels do?
Inhibit TH production = negative feedback mechanism.
What enzyme does neuronal activity stimulate?
TH. Helpful during stress, for example - can accelerate production.
What does catecholamine depletion cause in rabbits?
Behavioural sedation, which is reversed by treatment with DOPA.
(As shown by injecting rabbits with reserpine).
What is the role of autoreceptors in neurons?
Self-regulation - inhibits catecholamine release by reducing the amount of Ca2+ that enters the terminal in response to an impulse.
What are the three ascending dopamine pathways?
Nigrostriatal, mesolimbic and mesocortical.
What exactly does reserpine do?
Blocks both VMAT1 and VMAT2, meaning that catecholamines are no longer protected from breakdown in the nerve terminal.
What does VMAT stand for?
Vesicular monoamine transporter.
What does catecholamine depletion cause in humans?
Depressive symptoms.
Which drugs cause a release of catecholamines independent of nerve cell firing?
Psychostimulants - amphetamine and methamphetamine.
What does catecholamine release in animals cause?
Behavioural activation - at low doses, increased locomotor activity, and at high doses stereotyped behaviours.
What does catecholamine release in humans cause?
Increased alertness, heightened energy, euphoria and insomnia.
What structures are involved in the nigrostriatial tract/pathway?
The substantia nigra (A9), the globus pallidus and the striatum/caudate-putamen.
In what condition is the nigrostriatal pathway damaged?
Parkinson’s disease - there is a striking loss of nerve cells in the substantia nigra.
What ascending dopamine pathway is associated in the control of movement?
The nigrostriatal pathway.
What structures are involved in the mesolimbic dopamine pathway?
The VTA and various structures of the limbic system (nucleus accumbens, septum, amygdala and hippocampus).
Which dopamine pathway is implicated in natural reward and drug abuse?
Mesolimbic pathway.
What is the role of the nucleus accumbens?
It’s sort of the reinforcement centre of the brain.
What structures are involved in the mesocortical dopamine pathway?
The VTA and the cerebral cortex - hippocampus, lateral septum and anterior olfactory nucleus.
In what condition is the mesocortical dopamine pathway implicated?
Schizophrenia.
What does unilateral damage to the nigrostriatal pathway cause?
Degeneration of dopaminergic fibres in the striatum. Affects motor ability.
What is the typical effect of administering a DA receptor antagonist?
Suppression of spontaneous exploratory and locomotor behaviour, at a higher level cataplexy.
Define cataplexy.
A lack of spontaneous movement.
What happens to rat pups when they’re injected with haloperidol?
They show cataplexy and do not change position even when uncomfortable. Similar to effect seen in severe catatonic schizophrenia.
What does current theory state is the cause of Parkinson’s Disease?
Dopamine neuron damage and eventual death from oxyradical-induced oxidative stress.
What does loss of dopaminergic innervation of the striatum correlate with?
Symptom severity in Parkinson’s (Fischmann et al., 1998).
What, according to Giros et al (1996), is the most obvious characteristic of DA transporter knockout mice?
They are hyperactive - DA neurons can’t remove DA from the synaptic cleft so postsynaptic cells are exposed to excessive amounts.
What did M.Xu et al (2000) find about D1 receptor knockout mice?
They are unaffected by psychostimulants (cocaine).
What did Stine et al (2002) find?
That when opioid-dependent patients were infused with either yohimbine (NA a2 receptor antagonist) or a saline solution, yohimbine caused a rapid increase in experimenter-rated withdrawal symptoms over the next hour.
Where does the ascending noradrenergic system originate?
In the locus coeruleus (A6), a small area of the pons. It contains a dense collection of noradrenergic neurons which provide nearly all the NA in the cortex, limbic system, thalamus and hypothalamus.
Where does the locus coeruleus project to?
Almost all regions of the forebrain as well as the cerebellum and spinal cord. It’s the only NA pathway.
What are the two families of adrenergic receptors?
Alpha and beta.
What did Berridge et al (2003) find about the effect of noradrenergic agonists?
After either alpha or beta agonists (phenylephrine and isoproteronol) (or both - strongest effect), rats stayed awake longer.
According to Aston-Jones (1985), what is the role of the locus coeruleus in vigilance?
LC firing is activated by arousing sensory stimuli and inhibited during maintenance behaviours such as sleeping, grooming and eating. Therefore it may be important in vigilance, i.e. attentiveness to important external stimuli.
