Lecture 7 - Pharmacology of reward pathways Flashcards
What structures in the brain do dependendence producing drugs act upon to alter synaptic transmission?
- transporters involved in NT uptake
- enxymes involved NT synthesis/degradation
- GPCRs
- NT receptors
What is the process of synaptic transmission at the dopaminergic synapses?
- dopamine is synthesised locally in the persynaptic nerve terminal from L-Tyrosine to L-Dopa (by Tyrosine Hydroxylase)
- L-dopa is then converted to dopamine by Dopa Decarboxylase
- VMAT (Vesicular monoamine transporter) then loads the neurotransmitter into vesicles to be released
- Dopamine bind to the Dopamine Receptor D1 (GPCR) and the αs/olf subunit turns on acteycylase which converts ATP to cAMP
- Dopamine is taken back up in the presynaptic terminal via the dopamine transporter DAT and recyled into transport vesicles or degraded by Monoamine oxidase (MAO)
What is the result of drugs of abuse interacting with dopamine transporters in the reward pathway?
increases synaptic dopamine
What is the mechanism by which cocaine acts?
blocks DAT
- acutely increasing dopamine in the syapse
- activates VTA Nuc Acc in excessively
How was it shown that cocaine and amphetamines act by blocking the DAT transporter?
DAT knockout mice shown no behavioural activation after cocain or amphetamines
- WT mice given repeated injections of cocaine showed a behavioural phenotype (due to the action of the drug on other parts of the brain), involveing increased motor activity, sniffing, raring, grooming
- No behaviour detected in DATA knockout mice
What brain regions are involved in the motor functions shown in cocaine response in mice?
Dopaminergic projections from substantia nigra to the dorsal striatum (caudate and putamen)
Which affected region(s) of the brain accounts for motor symptoms of individuals with Huntington’s disease?
Basal ganglia
What is the region of the brain damaged in Parkinsons disease?
Substnatia nigra
How do amphetamines function?
- amphetamines enter post synaptic nerve terminal via DAT (as similar structure to dopamine) and then vesicles via VMAT forcing dopamine into the presynaptic terminal
- this makes DAT work in reverse
- leading to monoamine release
- and an increase in synaptic dopamine
What do high concentration of amphetamies do?
inhibit MAO
What is the reward circuitry?
- VTA sends dopaminergic projections to the Nuc Acc and Amygdala (via the mesolimbic pathway) and to the prefrontal cortext (mesocortical pathway)
- VTA and Nuc Acc recieve glutamatergic inputs from the Amygdala and prefrontal corext
- local GABAergic interneurons and NAc projections inhibit the VTA
How do opiates function?
- opiates inhibit GABAergic neurons projecting onto VTA
- this disinhibits VTA neurons causing them to release more dopamine
- works as there are natural receptors for opiates in the body e.g. for endorphins
How do opiates inhibit GABAergic enurons?
-act via a G protein coupled receptor
-reduce the excitability of presynaptic membrane so inhibit GABA release
Via either
1- The Gi/o protein inhibits AC I, acting on the α subunit
-this reduces VGCC Ca2+ currents consequentially inhibiting adenylcyclase levels and decreasing cAMP levels
2- βγ subunits directly open G protein gated inwardly rectifying (GIRK) K+ channels, hyperpolarising the neuron
How was addictive behaviour assessed experimentally?
use ‘conditioned place placement’
1- mouse given drug or saline injections in one of two compartments
2-the measure how long the mouse spends in each compartment
SHOW - seek out the place they were originally given the drug, and spend more time there, indicative of addictive behaviour
What is ‘conditioned place preference’?
The development of a preference for an environment associated with a repeated administration of a drug of abuse
What were the results shown from the conditioned place preference test on mice for response to morphine?
- Dopamine D2 receptor knocked out in mice
- SHOW knockout mice don’t show a morphine induced place preference
- CONCLUSION - morphine utilises the dopemine D2 receptor to induce addictive behaviour
What are the features of nicotine as a drug of abuse?
- indirectly modulates the reward circuitry
- acts via the Nicotinic Acetylcholine receptor (nAChR) as an agonist
- causes depolarisation and dopamine release by VTA neurons
- through direct and indirect actions
How does Nicotine act?
Direct
-Nicotine attached to the nAChR causing an influx of Na+ and K+ efflux leading to a polarisation of the presynaptic membrane and the induction on an AP
-dopamine is released from the presynaptic terminal
Indirect
-Acts on the presynaptic channels on the glutamatergic axons from the amygdala and cortex that project to the VTA and Nac neurons
-this increases its excitability so that more glutamate is released onto the VTA and NucAcc
Why are no side effects experienced from natural cannabanoids?
e.g. Anandamide
-their synthesis is regulated and restricted
-localised so that there are no side effects
-only naturally released when have high circuitry firing to modulate excitability
However, exogenous molecules have access to all brain circuitry
What region of the brain is associated with insomia?
The neurons in pons arousal nuclei in the brain stem
What region of the brain is associated with poor balance and coordingation in response to abusive drugs?
Cerebellum
-phenotypic behaviour of drug abuse similar to that of patients with lesions in the cerebellum
What is defined as tolerance to an addictive substance?
Homeostatic adaptation/changes in cells and circuitry (lowered sensitivity)
What is defined as a dependence on an addictive substance?
Drug induced changed that when unmasked by drug cessation lead to withdrawal
What is the mechanism of addiction?
All addictive stimuli activate the nucleus accumbens neurons leading to homeostatic changes due to routine exposure
- this leads to a compensatory change because of increased levels of dopamine
- post synaptic neurons adapt and express less dopamine receptors showing a lowered sensitivity
- more is needed for the same effects
- occurs via signalling induced changes in gene expression
