Medical Pharmacology: Adrenergic, Autonomic pharmacology

**Dopamine Pathways, Antipsychotics and Extrapyramidal Syndromes**

Attribution: Dirty Medicine Dopamine Pathways, Antipsychotics, and EPS https://www.youtube.com/watch?v=wCtC3LN2Vfc Dirty Medicine Youtube Channel https://www.youtube.com/channel/UCZaDAUF7UEcRXIFvGZu3O9Q

Dopamine Overview
Dopamine
Dopamine β-hydroxylase catalyzes the conversion of dopamine to norepinephrine.⁴
Dopamine is an important CNS neurotransmitter and loss of dopaminergic projections in the basal ganglia is considered causative in Parkinson's disease.⁴

**Basal Ganglia**⁸⁹

"The basal ganglia comprises the caudate nucleus, the putamen and the globus pallidus, and forms part of the ‘extrapyramidal motor system’. The basal ganglia is involved in the control of movement. Abnormalities in this area of the brain can result in a variety of diseases, including Parkinson’s disease and Huntington’s disease."⁸²

Over 50% of CNS catecholamine content is due to dopamine.⁸¹
- Highest amounts are localized in the caudate nucleus (basal ganglia), central nucleus of the amygdala, the median eminence, and restricted frontal cortex fields.
Concerning dopaminergic pathways, emphasis has been placed on projections between dopamine containing substantia nigra nuclei and ventral tegmentum and their terminations in the stratum, limbic zones of the cerebral cortex and in other non-hippocampal limbic areas.



"Dopamine is transmitted via three major pathways: The first pathway extends from the substantia nigra to the caudate nucleus-putamen (neostratum) and is concerned with sensory stimuli and movement. The second pathway projects from the ventral tegmentum to the mesolimbic forebrain and is thought to be associated with cognitive, reward and emotional behavior. The third pathway, known as the tubero-infundibular system, is concerned with neuronal control of the hypothalamic-pituitary endocrine system."⁸²

Dopamine actions at the level of the cell depend both on dopamine receptor subtype expression and interactions of dopamine with other narrow transmitters at the same neural target cell.
- Outside the CNS, dopamine is synthesized in renal proximal tubule epithelial cells where dopamine promotes both natriuretic and diuretic actions.
  - Because dopamine is a substrate for catecholamine-O-methyltransferase (COMT) as well as for monoamine oxidase (MAO), oral administration is not effective.

Dopamine Receptors⁸¹

Initially two subtypes of dopamine receptors were identified: D₁ and D₂.

These receptors are G protein coupled.

D₁ receptors were found to couple to G_s and act to increase adenylyl cyclase catalytic activity.

D₂ receptors act via G_i and reduce adenylyl cyclase activity.

Molecular cloning studies later identified additional dopamine receptor subtypes.

One, D₅ appear similar to the D₁ dopamine receptor; whereas, D₃ and D₄ more closely resemble the D₂ form.

There appear to be two D₂ receptor isoforms, D₂ short (D_2s) and D2 long (D_2L), reflecting differing lengths of the third intracellular loop.

Proposed Structure of D₁-like Dopamine Receptor⁸⁴

G-protein generalized structure illustrating 7 transmembrane loops and dopamine extracellular and G-protein intracellular binding domains⁹²

Dopamine receptors are a member of one of four receptor superfamilies.

The superfamilies are described as follows:

(1) ion channel linked (ionotropic) receptors;

(2) G-protein coupled (metabotropic) receptors;

(3) kinase-linked receptors; and

(4) gene transcription regulators.

Dopamine receptors belong to the second type, G-protein coupled receptors.

These receptors exhibit seven transmembrane spanning loops that are α-helical structures.

Dopamine association with its extracellular binding domain induces structural changes in the G-protein complex.

Inhibitory or stimulatory effects depend on the type of dopamine receptor activated.

For example, dopamine D₁ and D₅ receptors are associated with inhibitory G-proteins; however, dopamine D₂, D₃, and D₄ receptors are associated with stimulatory G-proteins.⁸⁵

G-Protein Cycle: note agonist binding (), dissociation-reassociation of α-β-δ G-protein subunits, and GDP-GTP cycling⁹³

Second messenger effects of dopamine receptor activation⁸⁶

Activation of D₁ receptors results in increased cAMP, increased Ca^{2 +} mobilization (via IP₃) and activation of protein kinase C (via diacylglycerol (DAG)).

Activation of D₂receptors decreases cAMP (G_i), increases K⁺, and decreases voltage-gated Ca^{2 +} currents.

α-adrenergic receptors are expressed both postsynaptically and presynaptically.

In that case, α₁ receptors populate mainly the postsynaptic membrane; whereas, α₂-adrenergic receptors are localized presynaptically and regulate norepinephrine release.

By analogy, some dopamine receptors are also localized presynaptically. These presynaptic dopamine receptors are of the D₂variety.⁸⁶

Following dopamine release, some dopamine molecules, by diffusion, will interact with presynaptic D₂ receptors, a consequence of which is a decrease in dopaminergic release.

Additionally, D₂ receptor activation reduces presynaptic dopamine synthesis and the reduction in dopamine release may be accounted for by decrease in neuronal firing frequency.

Reduced dopamine synthesis itself is a cAMP-dependent process which downregulates (reduces) tyrosine hydroxylase activity.

The reduction in dopamine release and firing frequency are associated with changes in activity of Ca²⁺ and K⁺ channels.

Enhanced K⁺ channel conductance results in an increased hyperpolarizing current, which displaces membrane potential away from the threshold potential.

Reduced Ca²⁺ channel conductance decreases intracellular Ca²⁺ concentration which in turn decreases Ca²⁺-dependent dopamine release.

The association of a dopamine D₂ receptor antagonist at the binding domain prevents dissociation of the G protein complex and release of inhibitory G protein, G_i.

Therefore, subsequent effects on adenylyl cyclase activity, protein kinase C activity and ionic channel activity do not occur.⁸⁸

Various roles have been suggested for the five different dopamine receptor types; however, the common thread is either stimulation or inhibition of adenylyl cyclase.⁹⁴

A D₁-like brain receptor coupled to G_q/11 (a.k.a. G_q protein) when activated, may stimulate phospholipase C and promoting intracellular calcium release.⁹⁴

Unique pharmacological responses to dopamine agonists indicate that this D1-like receptor differs from the Gs/olf system.

However, a heterotrimeric D₁-D₂dopamine receptor signaling complex and brain has been discovered.

This heterotrimeric structure is coupled to Gq/11 and necessitates agonist binding to both receptors for G protein activation with subsequent intracellular Ca²⁺ release.

Dopamine Receptor Complexes and Differing Cell Signalling^94a

Dopamine receptor distribution: D₁, D₅ versus D₂-D₄ differences with respect to localization and relative presence^86,87

The receptor subtypes are present in overlapping areas which is expectable given that D₁ receptors are found in the stratum, limbic system, thalamus and hypothalamus and that D₂ receptors are present not only at those sites but also in the pituitary gland. D₃ and D₄ receptors are also present in the limbic system.

The D₁ and D₂ receptors are notably present in the stratum as well as in the nucleus accumbens and olfactory tubercle.

D₂ receptors are notably expressed on anterior pituitary gland lactotrophs, regulating prolactin secretion.

D₂ receptors may play a role in schizophrenia given that many antipsychotic drugs exhibit affinity for this receptor type. D₃ and D₄ receptors which appear related to D₂ may also be involved in schizophrenia pathogenesis.

Elevated levels of D₃ are noted in the limbic system including the nucleus accumbens and olfactory tubercle; moreover, D₄ receptors are localized in frontal cortices, diencephalon and brainstem.

D₅ receptor types are expressed to a reduced extent, localized mainly in olfactory tubercle, hippocampus and hypothalamus.

Schizophrenia may be associated with dopaminergic hyperactivity and dopamine antagonists which are used as antipsychotic agents, including haloperidol, risperidone, and chlorpromazine, exhibit pharmacological antagonism at D₅-like receptors.

D₂ receptors may play a role in schizophrenia given that many antipsychotic drugs exhibit affinity for this receptor type.

Bromocriptine is an example of an agent clinically used to decrease prolactin secretion from pituitary tumors.

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