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6. Dopamine action: DA receptors

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6. Dopamine action: DA receptors

Dopamine receptors are predominantly (and in vertebrates are exclusively) coupled to G-proteins. They are orders of magnitude slower than ionotropic receptors.1
Activation of dopamine receptors causes changes in intracellular cAMP levels and triggers gene transcription via a signaling cascade. There are 2 classes of dopamine receptors, differentiated by G-protein partners and intracellular signaling mechanisms:2
The D1-like receptors (D1 and D5) are Gs/olf-coupled. Their activation increases intracellular cAMP and has an excitatory effect.
The D2-like receptors (D2, D3 and D4) are Gi/o coupled. Their activation reduces intracellular cAMP and has an inhibitory effect.

The D1-like dopamine receptors (D1 and D5) are activated postsynaptically by dopamine released from the presynaptic neuron into the synaptic cleft. When activated, they enhance neuronal activity. This is a phasic response.
The D2-like dopamine receptors are partly postsynaptic but can also be presynaptic. Presynaptic dopamine receptors are activated by extracellular dopamine exiting the synapse. This action serves as an inhibitory feedback mechanism when dopamine levels exceed reuptake capacity.3 Postsynaptically, D2-like receptors have an inhibitory effect on neuronal activity.

Rats with low dopamine receptor density in the striatum, thus with lower dopaminergic binding capacity, are more susceptible to rewarding/reinforcing substances.4

In addition to signal transduction via the adenylyl cyclase-cAMP system (the main mechanism of action), dopamine receptors also activate phospho-lipase C via the Gq/11 system and increase intracellular calcium levels. Dopamine receptors besides interact with glutamate receptors and mobilize intracellular Ca2+ stores.5

Dopamine receptors can occur as monomers, as dimeric and/or as oligomeric complexes. This can occur by association of different subtypes, either alone or with other GPCRs and ligand-gated channels. As homodimers occur:

  • D1R-D2R
  • D2R-D4R
  • D1R-D3R
  • D2R-D3R
  • D2R-D5R

Dimer/oligomeric complexes exhibit pharmacological and functional properties that differ from those of the receptors that form them. Oligomeric complexes with dopamine receptors may be associated with adenosine A1 and A2, serotonergic 5-HT2A, histaminergic H3, glutamatergic mGlu5, and NMDA receptors.6

6.1. Frequency distribution of dopamine receptors

The distribution of receptors (in the rat) is (from frequent to rare):

  1. D1 (approx. 3 to 5 times as frequent as D2)
  2. D2
  3. D3 (D3 to D5 are considerably less frequent than D1 and D2)
  4. D5
  5. D4

Within brain regions, the frequency of dopamine receptors differs:7

PFC:

  • Frequent
    • D1
    • D4
  • Rare
    • D2
    • D3
    • D5

Striatum:

  • D1 (dorsal and ventral)
  • D2 (dorsal and ventral)
  • D3 (ventral) (dorsal?)
  • Hardly D4
  • Hardly D5
  • D1 and D2 are found separately on D1 and D2 MSNs, respectively
    • D1-MSN
      • predominantly express D2
      • approx. 50 %
      • direct way
        • projects GABAerg from striatum into inner pallidum and substantia nigra pars reticulata
        • from inner pallidum and substantia nigra pars reticulata further GABAerg into thalamus
        • Result: Increase in thalamic activity (disinhibition: two inhibitory neurons connected in series).
      • enables movement and reinforcement learning
    • D2-MSN
      • predominantly express D2
      • approx. 50 %
      • indirect way
        • projects GABAerg from striatum into outer pallidum
        • from outer pallidum further GABAerg into nucleus subthalamicus
        • from nucleus subthalamicus further glutamatergic to the GABAergic neurons of the inner pallidum and the pars reticulata of the nucleus niger
      • inhibits, inhibits movement and reinforcement learning
    • Both MSN types
      • respond to dopamine release from non-synaptic varicosities
      • can receive synapse-like inputs of dopamine axons with connections between dopamine varicosities and GABAergic postsynaptic assemblies
  • D2 are also expressed on dopamine axons

Nucleus accumbens:

  • D3 frequent
  • D1
  • D2

Nucleus caudatus:

  • D1
  • D2

Putamen ventral:

  • D3 moderate

Blockade of dopamine receptors increases the release of acetylcholine. Acetylcholine is partly responsible for the development of extrapyramidal symptoms.8

6.2. Dopamine affinity of dopamine receptors

Dopamine has different affinities for different receptors and within them depending on the gene variant. From affinity to less affinity:9

  • D4 receptors
    • DRD4-2R
    • DRD4-4R
    • DRD4-7R
  • D2 receptors
    • D2 short
    • D2 long
    • D2-D4 receptor heteromers

D3 and D5 receptors are high-affinity, D1 and D2 receptors low-affinity on dopamine.10 The earlier model that D1 is low-affinity and D2 is high-affinity is outdated.

6.3. Dopamine receptors mostly extrasynaptic

Like DAT, which is critical for dopamine reuptake, most dopamine receptors-including the D2 autoreceptor-are located extrasynaptically rather than within synapses.11

6.4. D1-like dopamine receptors: activating

D1R-like receptors (D1R and D5R) generally couple to the Gs/olf proteins that stimulate adenylate cyclase (AC). Adenylate cyclase is an enzyme that converts adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP). cAMP activates protein kinase A (PKA), which in turn phosphorylates cAMP response element-binding protein (CREB). CREB translocates to the nucleus and activates CREB-dependent transcription of genes involved in synaptic plasticity. D1R modulate several ion channels, including voltage-activated Na+, K+, and Ca2+ channels, as well as the G-protein gated inwardly rectifying K+ channel (GIRK).212 [15,16,17,18].

6.4.1. D1 receptor

  • Low affinity10
  • Anti-inflammatory (neuroinflammation)10
  • Postsynaptic
  • Activating
    when dopamine binds to receptors D1 or D5, the respective downstream synapse is activated = depolarized (excitatory postsynaptic potential)
    • Promotes the production of cAMP13
    • Increases intracellular calcium (Ca2+)13
    • Stimulates PI hydrolysis13
  • Appearance:
    • Nucleus accumbens (ventral striatum) (together with D3 receptors)141314
    • Olfactory bulb14
    • Basal Ganglia14
      • Caudate nucleus15
      • Putamen15
    • Hypothalamus
    • Thalamus
    • (only) in projections (without mRNA) from striatal GABAergic cells that simultaneously produce substance P,
      in
      • Entopeduncular nucleus
      • Globus pallidus
      • Substantia nigra pars reticulata
    • Lower also in the PFC14
  • Agonists:
    • Bromocriptine
    • Fenoldopam13
    • SKF-3839313
    • SKF-8252613
  • Antagonists:
    • SCH-2339013
    • (+)Butaclamol13
    • Cis-fluopenthixol13

Involved in the formation of aversive memories.
In mPFC pyramidal neurons, D1 receptors on dendritic spines and D5 receptors on dendritic shafts are more prominent. Simultaneous pharmacological activation of D1 and D5 receptors in mPFC by the D1 and D5 agonist SKF-38393 promoted the development of aversive memories.16

After birth, the density of D1 and D2 receptors in the striatum initially increases. In adolescence, the number of these receptors decreases to 40% of the initial level.17 This decrease is again significantly greater in males than in females.

High expression of dopamine transporters could potentially result in increased expression of D1, D2, and VMAT2 receptors.18

Glucocorticoids cause sensitization of D1 receptors in GABAergic cells of the striatum in rats,1920 as well as stress.2122

6.4.2. D5 receptor

Involved in the formation of aversive memories.
In mPFC pyramidal neurons, D1 receptors on dendritic spines and D5 receptor on dendritic shafts are more prominent. Simultaneous pharmacological activation of D1 and D5 receptors in mPFC by the D1 and D5 agonist SKF-38393 promotes the generation of aversive memories.16

  • High affinity10
  • Pro-inflammatory (neuroinflammation)10
  • Postsynaptic
  • Activating: if dopamine binds to the receptors D1 or D5, the respective following synapse is activated = depolarized (excitatory postsynaptic potential)
    • Promotes the production of cAMP13
    • Promotes the production of adenylyl cyclase13
  • Appearance:
    • Much rarer than D1 receptor
    • Hippocampus14
    • Hypothalamus14
    • Lateral mammilar body
    • Parafascicular nucleus of the thalamus
  • Agonists:
    • Fenoldopam13
    • SKF-3839313
    • Dopamine13
  • Antagonists:
    • SCH-2339013
    • Cis-fluopenthixol13
    • (+)Butaclamol13

6.5. D2-like dopamine receptors: inhibitory

D2R-like receptors (D2R, D3R, and D4R) induce by coupling to Gi/o proteins:223

  • The inhibition of AC- and PKA-dependent signaling pathways
  • The activation of GIRK
  • The closure of voltage-activated Ca2+ channels.

For activation or deactivation of the subsequent synapse, a certain percentage of the activating or inhibiting (here: dopamine) receptors must be initiated by means of dopamine binding. If there is too little dopamine in the synaptic cleft due to the overactivity of the dopamine reuptake transporters, not enough receptors are initiated. As a result, the activation / deactivation of the subsequent synapse, which is actually due, fails to occur.

It is interesting to note that the brain makes the decision to act up to 7 seconds before the person becomes aware of the decision itself. These 7 seconds are available to the person to still suppress an already “made” decision - by means of inhibitory deactivation of the synapses that pass on the decision. Still 200 milliseconds before the execution, the person can cancel the already made decision.24
Figuratively, one brain area puts intended decisions “up for discussion” and gives other brain regions the opportunity to evaluate and allow or disallow them.
This testing and aborting mechanism is controlled to a large extent by dopamine. If the dopamine control circuit is disturbed, the mechanism that leads to the termination of adverse decisions is inhibited.

6.5.1. D2 receptor

  • Low affinity,10 at least in vivo as low affinity as D11
    • No activation by basal dopamine levels (2 to 20 nM)
    • Activation at 100 μM by phasic dopamine release
  • Anti-inflammatory (neuroinflammation)10
  • Presynaptic and postsynaptic
  • 2 Isoforms25
    • D2 short
      • Presynaptic26
    • D2 long
      • Postsynaptic26
  • D2 short receptors can function as autoreceptors
    • Inhibitory feedback mechanism by modifying26
      • DA synthesis
      • DA release
      • DA recovery
        in response to increasing amounts of extracellular synaptic dopamine.
    • Presynaptic D2 autoreceptors are 6 times more affine to dopamine than postsynaptic D2 receptors
    • D2 autoreceptors on dopamine axons respond to tonic and phasic dopamine2728
      • Your activation
        • Inhibits dopamine synthesis
        • Increases dopamine uptake
        • Regulates VMAT2 expression29
    • D2 autoreceptors in the soma
      • Activation inhibits firing of dopamine neurons30
  • Inhibiting:
    when dopamine binds to receptors D2, D3 or D4, the respective following synapse is inhibited = polarized (inhibitory postsynaptic potential)
    • Inhibits adenylyl cyclase13
    • Inhibits cAMP production
      • D2 short inhibits cAMP more effectively and requires fewer agonists for this purpose than D2 long13
    • Enhances ATP- or calcium ionophore-induced arachidonic acid release in CHO cells13
    • Increases the intracellular calcium level in13
      • Ltk cells
        • Due to increased PI hydrolysis
      • CCL1.3 cells
        • Due to increased PI hydrolysis
      • CHO cells
        • But not by increased PI hydrolysis
  • The more dopamine receptors present, the greater the acetylcholinergic excess that occurs if these receptors are blocked.
  • The administration of typical antipsychotics (= typical neuroleptics, e.g. haloperidol), which block the postsynaptic dopamine D2 receptors as D2 antagonists, causes pronounced acetylcholinergic side effects such as extrapyramidal symptoms or akathisia (taskinesia, restlessness) in patients with a high number of dopamine receptors. The acetylcholinergic excess in sufferers with a high number of dopamine receptors explains the frequent use of anticholinergic and sedating substances as well as the frequent use of cocaine.
  • Appearance:
    • Striatum (together with D1 receptors)14
      • Expressed by GABAergic neurons, which at the same time express enkephalins13
      • D2 are also expressed on dopamine axons
    • Olfactory bulb14
      • Expressed by GABAergic neurons, which at the same time express enkephalins13
    • Nucleus accumbens 14
      • Expressed by GABAergic neurons, which at the same time express enkephalins13
    • Substantia nigra pars compacta
      • Expressed by dopaminergic neurons13
    • Ventral tegmentum
      • Expressed by dopaminergic neurons13
    • Adrenal gland
      • Here the D2 receptor regulates the production and release of PRL
  • Agonists
    • Bromocriptine13
    • Dopamine13
    • Apomorphine13
    • N043731
    • Norepinephrine25
      • Norepinephrine has differential affinity on D2-type receptors: D3R > D4R ≥ D2SR ≥ D2L.
  • Antagonists:
    • Spiperon1331
    • Racloprid1331
    • Sulpiride13
    • Haliperidol
    • Paliperidon, (RS)-3-{2-[4-(6-Fluor-1,2-benzisoxazol-3-yl)piperidino]ethyl}-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-on; 9-Hydroxy-Risperidon
    • L74162631
    • Clozapine32
      stronger D4 than D2 antagonist
  • Antagonist and agonist
    • Aripiprazole33
      • D2 receptor partial agonism
        • Acts as an antagonist in the case of dopamine excess and as an agonist in the case of dopamine deficiency.
          Has an inhibitory effect against dopaminergic hyperfunction in the mesolimbic system and an activating effect against dopaminergic hypofunction in the mesocortical system. Thus low risk of excessive D2 receptor blockade in striatum or pituitary gland
      • Serotonin 5-HT1A receptor partial agonism
      • 5-HT2A receptor antagonism
      • Only very weak prolactin agonist
      • Outreach. Schizophrenia
    • D2-, D3- and D4- receptors act
      • Prolactin activating
      • Acetylcholine inhibiting
  • Poisons
    • Reduction of D2 receptors by34
      • Pesticides
      • Mercury
      • Formaldehyde

Blockade of D2 receptors leads to an increase in dopamine levels.35

After birth, the density of D1 and D2 receptors in the striatum initially increases. The increase in D2 receptors after birth is more pronounced in males than in females.36
In adolescence, the number of these receptors drops to 40% of the initial level.17 This decrease is again significantly greater in males than in females.
With age, the density of D2 receptors in the striatum decreases.37

High expression of dopamine transporters could possibly result in increased expression of D1 receptors, D2 receptors, and VMAT2 receptors.18

A rather small study of children with ADHD (quite a few of whom experience prematurity or were born with low weight) found evidence of lower D2/D3 receptor binding/number in ADHD-C sufferers than in ADHD-I subtype sufferers: ADHD-C: 2.9 (2.6 - 3.5); ADHD-I: 4.0 (3.3 - 4.5).38

D2 and D3 agonists increase cataplexy (narcolepsy symptom), D2 and D3 antagonists decrease it.39

D2 and D3 agonists do not appear to affect REM sleep.39

6.5.3. D3 receptor

  • High affinity10
  • Pro-inflammatory (neuroinflammation)10
  • Presynaptic and postsynaptic
  • Inhibiting:
    when dopamine binds to receptors D2, D3 or D4, the respective following synapse is inhibited = polarized (inhibitory postsynaptic potential)
    • Inhibits adenylyl cyclases
      • Lower than D2 receptors in13
        • CHO 10001 cells
        • 293 cells
        • NG108-15 cells
      • And not at all in
        • GH4C1 cells
        • MN9D cells
        • SK-N-MC cells
        • CHO cl cells
        • NG108-15 cells
        • CCL1.3 Cells
    • At least in CHO cells or GH4CI cells, no enhancement of ATP- or calcium ionophore-induced arachidonic acid release was observed13
    • No stimulation of PI hydrolysis13
  • Appearance
    • Predominantly in the limbic system4014
    • Nucleus accumbens
    • Olfactory bulb
    • Cerebellum
      • Since the cerebellum is not connected to other brain areas via dopaminergic projections (communication pathways), D3 receptors are thought to exert nonsynaptic dopaminergic functions here
    • Islands of Calleja (a group of densely packed small cells in the cortex of the hippocampal gyrus)
    • Low in the nucleus accumbens (ventral striatum)32
  • D3 receptor agonists
    • Quinpirole13
    • 7-OH-DPAT13
    • Apormophine13
    • Pramipexole, (S)-2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole; (S)-2-amino-6-(propylamino)-4,5,6,7-tetrahydrobenzothiazole
    • Ropinirole, 4-[2-(dipropylamino)ethyl]indolin-2-one
    • (+)-PD12890731
    • Norepinephrine25
      • Norepinephrine has different affinity on D2-type receptors: D3R > D4R ≥ D2SR ≥ D2L
  • Antagonists:

D2 and D3 agonists increase cataplexy (narcolepsy symptom), D2 and D3 antagonists decrease it.39

D2 and D3 agonists do not appear to affect REM sleep.39

6.5.4. D4 receptor

D4 receptors are involved in encoding the memory of fear, but not in encoding the memory of reward.16

  • Rather high affinity
  • Presynaptic and postsynaptic
  • Inhibiting:
    when dopamine binds to receptors D2, D3 or D4, the respective following synapse is inhibited = polarized (inhibitory postsynaptic potential)
    • Inhibits adenylyl cyclases, but only in some cell lines13
    • Enhances ATP- or calcium ionophore-induced arachidonic acid release in CHO cells13
    • No stimulation of PI hydrolysis13
  • Appearance:
    • Less frequently than other dopamine receptors
    • PFC
      • DRD4 also binds (at least in the PFC) norepinephrine41
    • Medulla
    • Limbic regions14
      • Amygdala
      • Hypothalamus
    • Midbrain (Mesencelaphone)
    • Heart
    • Low occurrence in the striatum32 and the remaining basal ganglia
  • Agonists
    • Apormophine13
    • Quinpirole13
    • Dopamine13
    • FAUC 17942
    • (-)-(R)-N-propylnorapomorphine31
    • L-745,87031
    • Norepinephrine25
      • Norepinephrine has different affinity on D2-type receptors: D3R > D4R ≥ D2SR ≥ D2L
  • Antagonists:
    • Spiperon1331
    • Clozapine3213
      • Stronger D4 than D2 antagonist
      • Serotonin receptor 5-HT2A antagonist40
      • Antagonist of other catecholamine receptors40
    • Sulpiride13
    • NGD 94-131
      selective D4 antagonist
      Selective D4 antagonists proved ineffective for antipsychotic treatment. Apparently, a combined treatment of the dopaminergic and serotonergic systems is needed.43

6.6. Heteromeric

Dopamine receptors form pure dopaminergic heteromers as well as heteromers with other receptor families, e.g.:

  • D1 / D2 - Heterodimers44
  • D1 / D3 - Heterodimers45
  • Adenosine A2A / D2 - heterodimers appear to be partially responsible for the psychomotor and reinforcing effects of psychostimulants such as cocaine and amphetamine.46
  • Cannabinoid CB1 / D2 - Heterodimers in the striatum47
  • Cannabinoid-CB1 / Adenosine-2A / D2 - Heretotrimers4849
  • Adenosine-2A / D2 / glutamate Metabotropic mGlu(5) - Heterotrimers in the striatum50

6.7. G protein-independent dopamine receptor activation

DA receptors can also be activated by mechanisms independent of G proteins. This may be mediated by the multifunctional adaptor protein arrestin, which binds DA receptors phosphorylated by GPCR kinases (GRKs) and recruits several proteins, including Akt, GSK-3, MAPK, c-Src, Mdm2, and N-ethylmaleimide-sensing factor. Binding of arrestin to active phosphorylated receptors halts further activation of G proteins and promotes endocytosis of the receptor. In mammals, there are seven GRKs: GRK2, GRK3, GRK4, GRK5, and GRK6 regulate D1R and D2R, while GRK4 controls D3R. In the striatum, GRKs 2, 3, 5, and 6 are expressed with different expression levels and different cellular and subcellular distribution.251

6.8. Dopamine agonists and antagonists

6.8.1. Dopamine agonists

  • Apomorphine31
  • FAUC 17931
  • Budipin, 1-tert-butyl-4,4-diphenylpiperidine
    • Dopamine receptor agonist
    • NMDA receptor antagonist
    • MAO inhibitor antagonist
    • Weak anticholinergic effect
  • Cabergoline, 1-[(6-allyl-8beta-yl)carbonyl]-1-[3-(dimethylamino)propyl]-3-ethylurea; 1[(6-allyl-8-beta-ergolinyl)carbonyl]-1-[3-(dimethylamino)propyl]-3-ethylurea, N-[3-(dimethylamino)propyl]-N-[(ethylamino)carbonyl]-6-(prop-2-enyl)-8beta-ergoline-8-carboxamide
    • Dopamine receptor agonist
    • Prolactin antagonist
  • Dihydroergocryptine, 9,10-dihydro-12-hydroxy-2-isopropyl-5 alpha-(2-methylpropyl)ergotaman-3,6,18-trione
    • Dopamine receptor agonist
  • Levodopa
    • Dopamine / norepinephrine / epinephrine - prodrug
  • Carbidopa
  • Lisuride, 1,1-diethyl-3-(6-methyl-9,10-didehydroergolin-8alpha-yl)urea
    • Dopamine receptor agonist
    • Prolactin antagonist
    • Influence on growth hormone
  • Pergolide, 8beta-(methylthiomethyl)-6-propylergoline
    • Dopamine receptor agonist
  • Piribedil, 2-[4-(1,3-benzodioxol-5-ylmethyl)piperazin-1-yl]pyrimidine. Piperazidine. Piprazidine
    • Dopamine receptor agonist
    • Acetylcholine receptor antagonist
  • Pramipexole, (S)-2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole. (S)-2-amino-6-(propylamino)-4,5,6,7-tetrahydrobenzothiazole
    • D3 dopamine receptor agonist31
  • Ropinirole, 4-[2-(dipropylamino)ethyl]indolin-2-one
    • D3 dopamine receptor agonist31
  • 5,6,7,8-Tetrahydro-6-(2-propen-1-yl)-4H-thiazolo[4,5-d]azepin-2-amin Dihydrochlorid (BHT-920)
    • D2 agonist52

6.8.2. Indirect dopamine receptor agonists

Indirect dopamine receptor agonists increase (via different mechanisms) the activity of the mesolimbic dopaminergic system:

  • Cocaine32
  • Amphetamine32
  • Opioids32
  • Ethanol32
  • Nicotine32
  • Adenosine antagonists
    • Caffeine
    • Theobromine

6.8.3. Dopamine antagonists

  • Paliperidon, (RS)-3-{2-[4-(6-Fluor-1,2-benzisoxazol-3-yl)piperidino]ethyl}-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-on; 9-Hydroxy-Risperidon
    • Dopamine antagonist
    • Norepinephrine antagonist
    • Adrenaline antagonist
    • Serotonin antagonist
    • Histamine antagonist
  • Adenosine
    • Dopamine Inhibitors

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