Step I Pharm ?

[TheEleventhReel]

Alright, so I'm trying to re-learn these neuroleptic drugs. FA says the MOA is to block the D2 receptor (b/c schizophrenia is associated w/excess dopamine). I know the D2 receptor is coupled to a Gi protein. Does anyone know what the Gi inhibits? I can't find an answer to this. Thanks

 

[Friendly]

Alright, so I'm trying to re-learn these neuroleptic drugs. FA says the MOA is to block the D2 receptor (b/c schizophrenia is associated w/excess dopamine). I know the D2 receptor is coupled to a Gi protein. Does anyone know what the Gi inhibits? I can't find an answer to this. Thanks

adenylate cyclase and, ultimately, cAMP production.

 

[TheEleventhReel]

Right, I know it inhibits cAMP. So, it inhibits a second messenger. What I don't know is what are the effects of that second messenger? What ultimately happens?

 

[Fuzuli]

Since cAMP activates cAMP-dependent protein kinases (CDPK), a decreased level of cAMP means decreased activation of CDPKs. For example, cAMP binds to regulatory regions of a type of CDPK called protein kinase A, allowing ATP to be hydrolyzed and promote phosphorylation of protein kinase A. Phosphorylated protein kinase A may modify ion channels, promote transcription from specific regions of DNA, etc. Thus, a decreased level of cAMP would mean a decreased phosphorylation of protein kinase A and decreased transcription.
Note that not all types of protein kinases are activated by cAMP. Another type that comes to my mind is protein kinase C, which is activated by Ca++ and diacylglycerol.
Hope this helps.

 

[TheEleventhReel]

I guess I really need to be more clear. What is the effect outside of the target cell? Is prolactin synthesis increased? Is dopamine synthesis decreased? What is the net effect of blocking a D2 receptor?

 

[Fuzuli]

"Dopaminergic Systems
Five important dopaminergic systems or pathways are now recognized in the brain. The first pathway—the one most closely related to behavior—is the mesolimbic-mesocortical pathway, which projects from cell bodies near the substantia nigra to the limbic system and neocortex. The second system—the nigrostriatal pathway—consists of neurons that project from the substantia nigra to the caudate and putamen; it is involved in the coordination of voluntary movement. The third pathway—the tuberoinfundibular system—connects arcuate nuclei and periventricular neurons to the hypothalamus and posterior pituitary. Dopamine released by these neurons physiologically inhibits prolactin secretion. The fourth dopaminergic system—the medullary-periventricular pathway—consists of neurons in the motor nucleus of the vagus whose projections are not well defined. This system may be involved in eating behavior. The fifth pathway—the incertohypothalamic pathway—forms connections from the medial zona incerta to the hypothalamus and the amygdala. It appears to regulate the anticipatory motivational phase of copulatory behavior in rats.

The Dopamine Hypothesis of Schizophrenia
The dopamine hypothesis for schizophrenia is the most fully developed of several hypotheses and is the basis for much of the rationale for drug therapy. Several lines of circumstantial evidence suggest that excessive dopaminergic activity plays a role in the disorder: (1) many antipsychotic drugs strongly block postsynaptic D2 receptors in the central nervous system, especially in the mesolimbic-frontal system...

The D2 receptor is coded on chromosome 11, decreases cAMP (by Gi-coupled inhibition of adenylyl cyclase), and inhibits calcium channels but opens potassium channels. It is found both pre- and post-synaptically on neurons in the caudate-putamen, nucleus accumbens, and olfactory tubercle."

(From Katzung's Basic and Clinical Pharmacology 10th edition, Antipsychotic Agents Chapter)

Since mesolimbic pathway and nucleus accumbens is involved in pleasure sensation, excess dopamine levels in these structures is thought to be linked with psychosis. So it basically works like this:

Note: It shows Na+ channel instead of Ca++ channel in the image

a. Pathological Condition
Excess dopamine binds to post-synaptic D2 receptors on neurons located within the limbic system and nucleus accumbens > D2 receptors are over-stimulated > Ca++ channels are closed whereas K+ channels are opened > Decreased flow Ca++ into the neuron and increased flow of K+ out of the neuron prevents depolarization > Activity of neuron is inhibited > Pleasure sensation is decreased, psychosis occurs > 🙁

b. With pharmacotherapy
Neuroleptic drug blocks D2 receptor, preventing its activation by dopamine > Ca++ channels remain open / K+ channels remain closed > Depolarization occurs normally > Pleasure sensation is maintained > 🙂

 

[TheEleventhReel]

"Dopaminergic Systems
Five important dopaminergic systems or pathways are now recognized in the brain. The first pathway—the one most closely related to behavior—is the mesolimbic-mesocortical pathway, which projects from cell bodies near the substantia nigra to the limbic system and neocortex. The second system—the nigrostriatal pathway—consists of neurons that project from the substantia nigra to the caudate and putamen; it is involved in the coordination of voluntary movement. The third pathway—the tuberoinfundibular system—connects arcuate nuclei and periventricular neurons to the hypothalamus and posterior pituitary. Dopamine released by these neurons physiologically inhibits prolactin secretion. The fourth dopaminergic system—the medullary-periventricular pathway—consists of neurons in the motor nucleus of the vagus whose projections are not well defined. This system may be involved in eating behavior. The fifth pathway—the incertohypothalamic pathway—forms connections from the medial zona incerta to the hypothalamus and the amygdala. It appears to regulate the anticipatory motivational phase of copulatory behavior in rats.

The Dopamine Hypothesis of Schizophrenia
The dopamine hypothesis for schizophrenia is the most fully developed of several hypotheses and is the basis for much of the rationale for drug therapy. Several lines of circumstantial evidence suggest that excessive dopaminergic activity plays a role in the disorder: (1) many antipsychotic drugs strongly block postsynaptic D2 receptors in the central nervous system, especially in the mesolimbic-frontal system...

The D2 receptor is coded on chromosome 11, decreases cAMP (by Gi-coupled inhibition of adenylyl cyclase), and inhibits calcium channels but opens potassium channels. It is found both pre- and post-synaptically on neurons in the caudate-putamen, nucleus accumbens, and olfactory tubercle."

(From Katzung's Basic and Clinical Pharmacology 10th edition, Antipsychotic Agents Chapter)

Since mesolimbic pathway and nucleus accumbens is involved in pleasure sensation, excess dopamine levels in these structures is thought to be linked with psychosis. So it basically works like this:

Note: It shows Na+ channel instead of Ca++ channel in the image

a. Pathological Condition
Excess dopamine binds to post-synaptic D2 receptors on neurons located within the limbic system and nucleus accumbens > D2 receptors are over-stimulated > Ca++ channels are closed whereas K+ channels are opened > Decreased flow Ca++ into the neuron and increased flow of K+ out of the neuron prevents depolarization > Activity of neuron is inhibited > Pleasure sensation is decreased, psychosis occurs > 🙁

b. With pharmacotherapy
Neuroleptic drug blocks D2 receptor, preventing its activation by dopamine > Ca++ channels remain open / K+ channels remain closed > Depolarization occurs normally > Pleasure sensation is maintained > 🙂

Thanks!