Lec 15- Dopamine Flashcards
DA (dopamine brief history)
- Pre-1960 DA and DOPA intermediates in the biosynthesis of NA from tyrosine
- 1959 Horykiwicz reduction in DA in Parkinson’s disease. 1961- replenishment of stores with DL-DOPA
- 1972 Kebabian and Calne- Biochemical studies second messenger assays
- 1976 Snyder- DA hypothesis of schizophrenia
- 1979- D1 and D2 receptor subtypes
- The late 1980s- five receptor subtypes
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Anatomy of central dopaminergic pathways
- Originate in the midbrain
- A8-A15 cell groups
- Nigro-striatal system
- Mesolimbic/Mesocortical pathways
- Tubero-hypophyseal system
Nigro-striatal system
- Substantia nigra pars compacta- where cell bodies sit
- sends projections through medial forebrain bundle to striatum

Mesolimbinc/ Mesocortical Pathways
- Mesolimbic pathways
- Cells sit in VTA project through medial forebrain bundle into the nucleus accumbens
- Mesocorticalpathway
- VTA => Hippocampus, pre-frontal cortex, motor cortex
Tubero-hypophyseal system
- Pituitary => hypothalamic nucleus

Consequences of DA release
- DA has 3 functional consequences in the brain
- Motor control (A9, nigrostriatal system 75%)
- Behavioural effects (A10, mesolimbic and mesocortical system to accumben, amygdala and cortex)
- Endocrine control (A12, tubero-hypophyseal system arcuate nucleus of hypothalamus to medial eminence and pituitary gland)
Nigro-striatal system
- A9, Substantia nigra pars compacta to corpus striatum
-
Motor control, motor planning
- Loss of DA results in Akinesia- parkinson like symptoms
- Unilateral 6-OH DA lesions- circling towards the lesioned side. DA agonist injection induce turning toward injection site
- Parkinson’s disease is associated with a deficiency of nigrostriatal dopaminergic neurones
Mesolimbic/Mesocortical pathways
- A10- Ventral tegmental area to nucleus accumbens, amygdala and cortex
- Motivation, behavioural reward, cognition
- Implicated in drug self-administration as shown by animal models using amphetamine (DA releasing agent) or apomorphine (DA agonist)
- Rewarding properties blocked by DA antagonist
- Large doses give rise to stereotyped repetitive inappropriate behaviour patterns such as licking, rearing, gnawing etc- psychosis response
- Side effect of L-DOPA= psychosis and shizophrenia (excess DA)
Tubero-hypophyseal system
- A12, arcuate nucleus of the hypothalamus to medial eminence and pituitary gland
- Hormone release from the anterior pituitary is regulated by DA. DA inhibits prolactin release and increases growth hormone release.
- Anti-psychotic D2 antagonists cause breast development and lactation
Other sites of action
- Chemo-receptor trigger zone, DA agonist all cause nausea and vomitting by action at
- Vascular smooth muscle- dilation of blood vessels
Major function divisions of DAergic pathways
- Nigrostriatal
- Motor
- Internal modulation of basal ganglia
- Parkinson’s disease
- Mesolimbic
- Motivation, emotion
- Reward system
- Addiction
- Mesocortical
- Cognition, arousal
- Schizophrenia
DA neurones
- All contain Tyrosine hydroxylase
- Identified easily electrophysiologically- Tonic/burst firing- 6Hz
- controlled by inputs from the cortex (GLU), SNr (GABA), Raphe (5-HT) Locus coeruleus (NADR)
- Release at classical synapses by calcium dependent exocytosis. Also a non-exocytotic release from dendrites and fibre varicosities
- Neuromodulatory- Regulate and enable function
Biosynthesis of DA
- DA cells dont have dopamine-B-hydroxylase (so we dont make NA)

Signal termination
- Re-uptake in synaptic terminals by DA transport
- The main mechanism of termination- blocked by cocaine (also 5-HT and NADR)
- Mice have been produced in which the DA transporter gene has been disrupted
- It has been shown that in these animals the DA released remains in the synaptic cleft for about 100 times longer than in normal animals
- The animals display the hyper-locomotion that one normally sees in animals that are treated with cocaine
Signal termination
- Enzymic degradation
- To dihydroxyphenyl acetic acid (DOPAC) by MAO and aldehyde dehydrogenase
- To Homovanillic acid (HVA) by COMT, MAO and (aldehyde dehydrogenase)
- DOPAC and HVA excreted in urine, provide an index of DA release. HVA used as the index of DA turnover
Dopamine receptors
- G-protein coupled receptor
- D1-like and D2-like families
-
Major subdivision through positive or negative coupling to adenylate cyclase
- D1 = Increase adenylate cyclase and cAMP
Dopamine receptors
-
D1 like receptors activate adenylate cyclase to increase cAMP levels
- Consist of two subtypes D1 and D5
-
D2 like receptors inhibit adenylate cyclase to decrease cAMP levels
- Consist of 3 subtypes: D2, D3 and D4
A G-protein Coupled DA receptor
- 7 membrane spanning helices
- Bundling forms ligand binding site
- D1 short 3rd intracell Loop
- D2 Long 3rd intracell Loop
DA receptors
- D1 family= D1 +D5
- Gs (+) adenylate cyclase
- D2 family= D2 (short and long); D3; D4
- Gi/o (-) adenylate cyclase
- Increase K+ (inward rectifier)- more negative membrane potential
- Decrease Ca2+ (VDCC)- Ca dependent exocytosis
Agonist pharmacology of DA receptor

Antagonist pharmacology of DA receptors
- Because clozapine only acts on D4 we reduce side effect profile of the drug

General characteristics - D1 family
- D1,5
- No discriminating agents
- Low affinity for DA
- Post-synaptic transmission
General characteristics- D2 family
- D2,3,4
- Selective agents becoming available
- High affinity
- Post-synaptic transmission
- Pre-synaptic heteroreceptor
- Autoreceptor role
Autoreceptor functions
- If DA is released on post-synaptic D2 like receptors
- K+ increase = reduced firing = reduced AP = reduced Ca dependent exocytosis = reduced DA release
- NB- Receptors can give pre-synaptically, different location gives the same result

Tissue distribution-highlights
- mRNA used for distribution studies
- Distinct but overlapping distributions
- D1 and D2 (most abundant)- found in all terminal fields (often co-localised)
- D3 and D4 more selectively found in limbic areas (emotional, hypothalamus, amygdala) (i.e. input from VTA, cognition/emotion)
- D5 only in hippocampus, hypothalamus and thalamus
Location and function of DA receptor
- Clozapine = can cause agranulocytosis

Targets for pharmacological therapy
- Schizophrenia
- Attention deficit disorder
- Drug dependence
- Endocrine functions
- Movement disorders
- Parkinson’s disease