Pharmacology Dopaminergic Pathways Flashcards
What does the effect of dopamine depend on?
The receptor subtype expressed on the postsynaptic neuron
What dopamine receptors are excitatory?
D1/D5
Increase cAMP levels
What dopamine receptors are inhibitory?
D2/D3/D4
Decreases cAMP
Increase potassium currents and decrease number of voltage gated calcium channels
Nigrostriatal pathway
Begins in the substantia Nigra pars compacta and projects to the striatum basal nuclei
Modulates excitatory input from motor cortex for direct movement
* this is the pathway that when it degenerates in Parkinson’s, causes the tremors
Mesolimbic pathway
Starts in the Ventral tegmental area (VTA) projects to the ventral striatum
Assocaited with reward and learned behaviors
- dysfunctions of this pathway result in
- addictive behavior
- schizophrenia
- psychoses
- bipolar depression
- learning deficits (only in extreme cases)
Mesocortical pathway
Begins in the VTA and projects to all of the following:
- amygdala
- hippocampus
- orbital and medial prefrontal cortex
- cingulate gyrus
Is associated with development and maintenance of high cognitive functions (especially learning and conditioning)
*sometimes looped together with the mesolimbic pathway as the “mesocorticalmesolimbic” pathway
Tuberoinfundibular pathway
Begins in the arcuate nucleus of the the hypothalamus and projects to the anterior pituitary
Functions to modulate endocrine functions:
- tonically inhibits prolactin secretion
- tonically helps modulate immune system activity
Area posterema and dopamine
There are large amounts of D2 dopamine receptors in this region
- also known as the vomiting center in the 4th ventricle.
Is a circymventricular organ and acts as a blood chemosensor for the CNS
- D2 antagonists can be used as antiemetic drugs because of this
What is the general broad mechanism of the basal ganglia as a whole?
To tonically inhibit the thalamus excitatory signals
- dopamine medications can either increase or decrease tonic inhibition on the thalamus
The striatums effect in the CNS
Regulates the basal nuclei by dopamine released from the substantia Nigra pars compacta
- either stimulates or inhibits
- also integrates signals from other brain inputs
Contains the putamen and caudate nucleus
How can the striatum have such a widespread control over various different brain inputs?
Uses medium spiny neurons (MSNs) and large cholinergic interneurons
MSNs are GABA neurons that make a plethora of connections.
- inhibit signals via a Cholinergic + GABA neuron connection (net negative)
- excites signals via a GABA + GABA neuron connection (net positive)
- also can heavily excite various pathways via cholinergic interneurons that are not inhibited due to degradation of GABA neurons (seen in Parkinson’s)
Direct vs indirect pathways in the basal nuclei
both exist and function simultaneously to control focused movement
Direct: cortex -> putamen -> GPi -> thalamus
- enable direct/focused movements
- expresses D1 receptors
Indirect: cortex -> putamen-> GPe -> sub thalamic nucleus -> GPi -> thalamus
- reduces irrelevant/unfocused movements
- expresses D2 receptors
- this pathway is affected in Parkinson’s
How does the substantia Nigra affect both the direct and indirect pathways of the basal nuclei
Activates the direct pathway
Inhibits the indirect pathway
*all done via dopamine signaling
Direct pathway in detail
1) Motor cortex projects to the putamen via the corticostriatal fibers (glutamate)
2) in addition, nigrostriatal fibers also project to the putamen via nigrostriatal fibers (dopamine)
3) both 1 and 2 excite D1 neurons in the putamen and result in a GABA release in the globus pallidus
4) this results in reduced activity of GABAergic pallidothalmis neurons (net positive)
5) overall results in less GABA -> thalamus and disinhibition of the thalamus. Leads to excitatory input to motor cortex and peripheral
(+/-/-)
Indirect pathway in detail
1) corticostriatl fibers (glutamate) and nigrostriatal fibers (dopamine) project to the putamen via the cortex and substantia Nigra respectively
2) results in excitation of glutamate striatopallidal neurons and inhibition of cholinergic interneurons and GABA striatopallidal neurons
3) striatopallidal neurons release glutamate to the GPe neurons which release GABA
4) GABA from GPe limits activity of BAGA pallidosubthalamic nucleus
5) less GABA in the STN fibers allows for GPi outputs to be uninhibited
6) GPi outputs go to the thalamus and stimulates release of GABA in the thalamus
7) overall results in a net inhibition of the thalamus and excitatory input to the cortex
(+/-/-/+/-)
