Dopaminergic system

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

The starting point for the biosynthesis of dopamine is L-tyrosine. L-tyrosine is ingested with food. It can also be produced by converting the essential amino acid L-phenylalanine. Hydroxylation (by the enzyme tyrosine hydroxylase) produces the dopamine precursor L-dopa in a first step. Subsequent decarboxylation (by means of the enzyme aromatic L-amino acid decarboxylase) produces dopamine, which is no longer soluble due to the missing carboxyl group. After its biosynthesis, dopamine is axonally transported to the synaptic terminal buttons, where it is taken up into salivary vesicles via the vesicular monoamine transporter type 2 (VMAT-2).

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

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 transport 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 most important presynaptic dopamine metabolite. In the postsynaptic cells, catechol-O-methyltransferase (COMT) is another inactivating enzyme. COMT catalyzes dopamine to methoxytyramine (MT) by transferring a methyl group.

Finally, DOPAC and methoxytyramine can be metabolized to homovanillic acid (HVA) by COMT and MAO, respectively. This metabolite can be detected in the cerebrospinal fluid and partly also in blood and urine, so that its concentration can be regarded as a (not uncontroversial) measure of synaptic degradation and the amount of transmitter available at the 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. After the transmitter binds to such a receptor, a second-messenger cascade is triggered. The enzyme adenylate cyclase is activated via a G protein, which converts ATP into cAMP. cAMP-dependent protein kinases phosphorylate the ion channels, which leads to a change in the activation of these channels. In addition, chemical reactions can also be triggered within the cell or even in the genetic material in the cell nucleus.

D2-type receptors have an inhibitory effect and are found in both the pre- and postsynaptic membrane. 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 the potassium channels in the postsynaptic membrane via second-messenger cascades. The increased potassium influx into the cell leads to hyperpolarization, which increases the threshold for excitation transmission by an action potential.

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

Receptor blockers: Substances that can occupy a receptor but do not cause the opening of ion channels are called receptor blockers because they block the receptor from competing transmitter molecules. For example, DA receptors can be blocked by neuroleptics (antipsychotics), which have the opposite effect or cancel out the effect of DA. In contrast, substances that bind to a receptor and exert a similar effect behave like other ligands and are referred to as agonists (Köhler, 2001). Agonists and antagonists bind to the different receptor types with different strengths.

Influencing the processes at the dopaminergic synapse

Stimulation of DA production by precursors that are accessible to the liquor (e.g. DA precursor L-dopa 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 with chronic amphetamine administration (negative feedback via autoreceptors)

Influencing the uptake and storage of DA by reserpine, which dissolves the vesicles in the presynaptic terminal buttons

Stimulation of DA release by amphetamines (acceleration of vesicle emptying into the synaptic cleft) or autoreceptor blockade (switches 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 the transmitter effects at the receptor by a second ligand (e.g. apomorphine, bromocriptine or pergolide as DA agonists, which mainly bind to D1 but also to D2 receptors) or increase in receptor sensitivity (sensitization)

Weakening of the transmitter effect at the receptor by neuroleptic blockade, e.g. by phenothiazines (such as 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 blocking phosphodiesterase, which terminates the second-messenger effect (e.g. by caffeine or sildenafil as phosphodiesterase inhibitors)

In the periphery, D2 receptors are responsible for the inhibition of prolactin secretion, the inhibition of aldosterone secretion and the presynaptic inhibition of noradrenaline release from noradrenergic neurons. D1 receptors on the smooth muscle of renal and mesenteric blood vessels mediate the 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 second-messenger formation

Prevention of inactivation by inhibiting degradation in the presynaptic neuron or blocking the degradation 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 becomes clear in the next section.