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Dopamine
Uni of Notts, Neurobiology of disease, second year, topic 1
| Term | Definition |
|---|---|
| Dopamine biosynthesis | Tyrosine 6-hydroxylated using tyrosine hydroxylase (TH) & BH4 (tetrahydrobiopterin) to DOPA. DOPA is carboxylated to dopamine by aromatic L-amino acid decarboxylase (AADC) |
| VMAT-2 | Vesicular MonoAmine Transporter 2. Protons are pumped into monoamine vesicles by symport creating a gradient & VMAT2 is an antiporter channel which exchanges 2 H+ for every monoamine transported in |
| How reserpine induces depressive symptoms | Has high affinity for VMAT2 & binds irreversibly, cytosolic monoamines are quickly degraded by MAO so vesicles stay empty |
| DAT (& how they're effected by drugs) | Dopamine transporter, DA reuptake antiport with Na+ ions (maintained by Na+/K+ pump). Cocaine & methylphenidate blocks it, amphetamines reverse it & cause DA efflux |
| Historic dopaminergic tissue imaging & modern techniques | Falck (1960) used Hillarp Fluorescence: Freeze-drying to remove water then exposing tissue to formaldehyde vapours to convert DA to fluorescent isoquinoline. Now we use TH antibody immunohistochemistry |
| Effects of DAT knockout in mice | Elevated synaptic DA concentrations with up to 40-fold lifespans, hyperactivity & stereotyped behaviours, partial downregulation of post-synaptic DA receptors, compensatory TH upregulation to combat intracellular depletion & poor DA recycling |
| Dopamine synthesis regulation | Tyrosine Hydroxylase (TH) catalyses the rate-limiting step of dopamine (& other monoamine) production & can be inhibited by high catecholamine concentration |
| 6-hydroxydopamine + uses | Synthetic DA neurotoxin, generates ROS by auto-oxidation (usually H2O2) in the mitochondria leading to death of dopaminergic neurones allowing for replication of diseased phenotypes in animals |
| Dopamine metabolism | MOA hydrolyses amine on DA to a carboxyl to form DOPAC which is C3 etherified by COMT to homovanillic acid which can be excreted |
| Synthesis of noradrenaline and adrenaline | Dopamine hydroxylated (alkyl chain) to noradrenaline by dopamine β-hydroxylase then the amine is methylated to adrenaline by phenylethanolamine N-methyltransferase (PNMT) |
| How neurones are regulated to only produce 1 type of catecholamine (remember enzyme names) | dopaminergic: Only expresses TH & AADC Noradrenergic: Expresses TH, AADC, & DAβH Adrenergic: Expresses TH, AADC, DAβH, & PNMT |
| Dopaminergic pathways: Mesocortical (What it regulates, where it originates, & where it projects to) | Cognition, decision making, emotion & social behaviour. Originates in the VTA, projects to prefrontal cortex |
| Dopaminergic pathways: Mesolimbic (What it regulates, where it originates, & where it projects to) | Reward, pleasure, & motivation. Originates in the VTA, projects to nucleus accumbens, amygdala, hippocampus etc. |
| Mesolimbic hyperdopaminergia | Hyperactivity, mania, psychosis, & hallucinations. Behaviours consistent with positive symptoms of Schizophrenia & addiction |
| Mesolimbic hypodopaminergia (neuroleptic induced deficiency syndrome) | Negative amotivation symptoms like lethargy, social withdrawal, & anhedonia. Behaviours consistent with negative symptoms of Schizophrenia & drug withdrawal |
| Dopaminergic pathways: Nigrostriatal (What it regulates, where it originates, & where it projects to) | Voluntary movement & motor planning of skeletal muscles. Starts in substantia nigra & projects to striatum |
| Nigrostriatal hyperdopaminergia | Uncontrolled 'stereotypes' movements |
| Dopaminergic pathways: Tuberoinfundibular (What it regulates, where it originates, & where it projects to) | Antagonises prolactin secretion. Originates in the hypothalamus & projects to the pituitary glands |
| Tuberoinfundibular hyper & hypodopaminergia | Hyper: Too little prolactin - Low libido, irregular or no menstruation, little to no lactation, reduced muscle mass Hypo: Too much prolactin - low libido, infertility, male lactation |
| D1-like DA receptors | D1 & D5. Purely post-synaptic, excitatory using Gs subunits, have a longer C-terminal section |
| D2-like receptors | D2, D3 & D4. Can be both pre & post-synaptic. Inhibitory using Gi subunits, have a longer intracellular loop |
| Difficulty in drug targeting DA receptors | Structurally very similar with similar affinities, signal through multiple pathways by dimerizing with other GCPRs, widely distributed throughout the brain, & the neurones can undergo adaptive regulation to oppose the drugs |
Created by:
Denny12
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