Dopaminergic system

The term "dopaminergic system" refers to all neurons that use the neurotransmitter dopamine (DA) for release. Dopamine belongs to the monoamines or biogenic amines and forms the group of catecholamines together with adrenaline and noradrenaline.

The starting point for the biosynthesis of dopamine is L-tyrosine. L-tyrosine is ingested with food. L-tyrosine can also be produced by conversion of the essential amino acid L-phenylalanine. Through hydroxylation (enzyme tyrosine hydroxylase), the dopamine precursor L-dopa is formed in a first step. Subsequent decarboxylation (enzyme aromatic L-amino acid decarboxylase) produces dopamine, which is no longer liquid-permeable due to the lack of a carboxyl group. After biosynthesis, dopamine is now transported axonally into the synaptic terminal nodules, where it is taken up by the vesicular monamine transporter type 2 (VMAT-2) in storage vesicles.

Dopamine release occurs by exocytosis and is controlled by presynaptic D2 receptors in a negative feedback loop fashion.

Dopamine inactivation occurs via 2 processes:

• By reuptake of DA into the presynaptic cell (neuronal reuptake and uptake into postsynaptic cells = reuptake) by means of carrier proteins. These bind the transmitter molecules and channel them back into the cell.
• Degradation of DA: In the presynaptic terminal as well as in the postsynaptic cell, the enzyme monoamine oxidase (MAO-A) deaminates excess amounts of dopamine to dihydroxyphenylacetic acid (DOPAC). DOPAC is the major presynaptic dopamine metabolite. In postsynaptic cells, catechol-O-methyltransferase(COMT) is another inactivating enzyme. COMT catalyzes dopamine to methoxytyramine (MT) by transferring a metyhl group.

Finally, DOPAC and methoxytyramine can be metabolized to homovanillic acid (HVA) by COMT and MAO, respectively. This metabolite can be detected in CSF and, to some extent, in blood and urine, so its concentration can be considered a (not uncontroversial) measure of synaptic degradation and the amounts of transmitter available at synapses.

Dopamine receptors

The effect of DA on a downstream cell depends on the receptor in the postsynaptic membrane. In general, 5 different G protein-coupled receptor types are known: D1-D5 receptors. They can be assigned to 2 receptor families:

• The_GS-coupled D1 family (D1/D5).
• The_Gi -coupled D2 family (D2/D3/D4)

Receptors of the D1 family act excitatory and are almost exclusively localized at the postsynaptic membrane. Upon binding of the transmitter to such a receptor, a second-messenger cascade is triggered. Via a G protein, the enzyme adenylate cyclase is activated, which converts ATP into cAMP. cAMP-dependent protein kinases phosphorylate ion channels, leading to activation changes of these channels. It can also trigger chemical reactions within the cell or even in the genetic material in the nucleus.

D2-like receptors act inhibitory and are found in both the pre- and postsynaptic membranes. The inhibitory effect of this type of receptor consists, on the one hand, in the inhibition of cAMP formation and, on the other hand, in the opening of potassium channels in the postsynaptic membrane via second-messenger cascades. The increased potassium influx into the cell leads to a hyperpolarization, which increases the threshold for excitation transmission by an action potential.

D2 receptors in the presynaptic membrane are found only in the nigrostriatal and mesolimbic DA systems and are referred to as autoreceptors. They regulate DA release via a negative feedback loop by inhibiting the enzyme tyrosine hydroxylase whenever DA molecules bind to these receptors.

Receptor blockers: Substances that can occupy a receptor but do not cause ion channels to open are called receptor blockers because they block the receptor from competing transmitter molecules. Thus, DA receptors can be blocked by neuroleptics (antipsychotics), which act in the opposite way or abolish the effect of DA. In contrast, substances that bind to a receptor and exert a similar effect behave like other ligands and are called agonists (Köhler, 2001). Agonists and antagonists bind with different strength to the different receptor types.

Influencing processes at the dopaminergic synapse

Stimulation of DA production by precursors that are accessible to liquids (e.g. DA precursor LDopa in Parkinson's disease)

Inhibition of DA production by diet (low-tyrosine diet) or blockade of tyrosine hydroxylase by α-methyltyrosine or reduced DA synthesis by chronic amphetamine administration (negative feedback via autoreceptors)

Influence of reserpine on DA uptake and storage, which dissolves vesicles in presynaptic terminal nodules

Stimulation of DA release by amphetamines (acceleration of vesicle emptying into the synaptic cleft) or autoreceptor blockade (turns off negative feedback)

Inhibition of DA release, e.g., by γ-hydroxybutyric acid, which inhibits action potentials in the presynaptic cell, or autoreceptor stimulation (negative feedback)

Enhancement of transmitter effects at the receptor by a second ligand (e.g., apomorphine, bromocriptine, or pergolide as DA agonists that bind mainly to D1 but also to D2 receptors) or increase in receptor sensitivity (sensitization)

Weakening of transmitter action at the receptor by neuroleptic blockade, such as by phenothiazines (e.g., chlorpromazine), butyrophenone derivatives (e.g., haloperidol), and some atypical neuroleptics as D2 receptor antagonists and atypical neuroleptics (e.g., clozapine) as D4 receptor antagonists

Enhancement of downstream signal induction, e.g., by blockade of phosphodiesterase, which terminates the second-messenger effect (e.g., by caffeine or sildenafil as phosphodiesterase inhibitors)

In the periphery, D2 receptors are responsible for inhibition of prolactin secretion, inhibition of aldosterone secretion, and presynaptic inhibition of norepinephrine release from noradrenergic neurons. D1 receptors on smooth muscle of renal and mesenteric blood vessels mediate vasodilatory effects of dopamine. In the kidneys, D1 and D2 receptors mediate the diuretic and vasodilatory effects of dopamine.

Inhibition of downstream signal induction by inhibition of secondmessenger formation.

Prevention of inactivation by inhibition of degradation in the presynaptic neuron or blockade of the degradative enzyme (e.g., pargyline and iproniazid are MAO inhibitors and tropolone inhibits COMT) or reuptake inhibition (amphetamine and cocaine block DA carrier proteins)

Acceleration of inactivation, e.g. by reserpine and degradation enzymes The use of substances that interfere with the dopaminergic system provides information about certain functions that are modulated by DA. The far-reaching influence of the neurotransmitter will become clear in the next section.