6. Dopamine action at receptors and transporters.

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

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. Dopamine binds to many receptors and transporters
• 6.2. Frequency distribution of dopamine receptors
• 6.3. Dopamine affinity of dopamine receptors
• 6.4. Dopamine receptors mostly extrasynaptic
• 6.5. D1-like dopamine receptors: activating
  • 6.5.1. D1 receptor
  • 6.5.2. D5 receptor
• 6.6. D2-like dopamine receptors: inhibitory
  • 6.6.1. D2 receptor
  • 6.6.3. D3 receptor
  • 6.6.4. D4 receptor
• 6.7. Heteromeric
• 6.8. G protein-independent dopamine receptor activation
• 6.9. Dopamine agonists and antagonists
  • 6.8.1. Dopamine agonists
  • 6.9.2. Indirect dopamine receptor agonists
  • 6.9.3. Dopamine antagonists
  • 6.9.4. Receptor binding of dopamine agonists and antagonists

6.1. Dopamine binds to many receptors and transporters¶

Dopamine binds not only to dopamine receptors but, even with similar affinity, to others:⁷

• Dopamine
  • Receptors:
    • D1: Ki 4.3 - 5.6
    • D2: Ki 5.3 - 6.4
    • D3: Ki 6.3 - 7.4
    • D4: Ki 7.6
    • D5: Ki 6.6
  • Dopamine transporter (DAT): Ki 5.3
• Norepinephrine
  • Norepinephrine transporter (NET): Ki 4.55
  • Α1-AR receptors: Ki 5,6
  • Α2-AR: Ki 6.01
  • Β1-ARs: Ki 5.0
  • β2-ARs: Ki 4.3

• Serotonin transporter (SERT): Ki 4.53
• Melatonin receptor MT1A: Ki 5.15
• Melatonin receptor MT1B: Ki 5.04

6.2. 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:⁸

PFC:

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

Striatum:

• D1 (dorsal and ventral)
• D2 (dorsal and ventral)
• D3 (ventral) (dorsal?)
• Hardly D4
• Hardly D5

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.⁹

6.3. 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:¹⁰

• 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.¹¹ The earlier model that D1 is low-affinity and D2 is high-affinity is outdated.

6.4. 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.¹²

6.5. D1-like dopamine receptors: activating¶

D1R-like receptors (D1R and D5R)¹³

• increase adenylate cyclase
  • especially D1R
• increase phosphoinositide metabolism
  • especially D5R
    D1R and D5R generally couple to the Gs/olf proteins that stimulate adenylate cyclase (AC). The enzyme adenylate cyclase 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, and the G-protein gated inwardly rectifying K+ channel (GIRK).²¹⁴
    D1R-like receptors do not contain introns, unlike D2R-like receptors, which therefore know “long” and “short” D2 receptor isoforms.⁷

6.5.1. D1 receptor¶

• Low affinity¹¹
• Anti-inflammatory (neuroinflammation)¹¹
• Postsynaptic
• Activating
  when dopamine binds to receptors D1 or D5, the respective downstream synapse is activated = depolarized (excitatory postsynaptic potential)
  • Promotes the production of cAMP¹⁵
  • Increases intracellular calcium (Ca2+)¹⁵
  • Stimulates PI hydrolysis¹⁵
• Appearance:
  • Nucleus accumbens (ventral striatum) (together with D3 receptors)¹⁶¹⁵¹⁶
  • Olfactory bulb¹⁶
  • Basal Ganglia¹⁶
    • Caudate nucleus¹⁷
    • Putamen¹⁷
  • 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 PFC¹⁶
• Agonists:
  • Bromocriptine
  • Fenoldopam¹⁵
  • SKF-38393¹⁵
  • SKF-82526¹⁵
  • A77636⁷
  • SKF-81297⁷
  • SKF-83959⁷
• Antagonists:
  • SCH-23390¹⁵⁷
  • (+)Butaclamol¹⁵
  • Cis-fluopenthixol¹⁵
  • SKF-83566⁷
  • Ecopipam⁷
  • [125I]SCH23982⁷

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.¹⁸
Blockade of D1 receptors disrupted corticostriatal long-term potentiation (LTP, “learning”), whereas blockade of D5 receptors prevented LTD (long-term depression, “forgetting”).¹⁹
Blockade of D1 receptors increased motor activity, whereas blockade of D1 and D5 receptors decreased motor activity.¹⁹

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.²⁰ 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.²¹

Glucocorticoids cause sensitization of D1 receptors in GABAergic cells of the striatum in rats,²²²³ as well as stress.²⁴²⁵

6.5.2. 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.¹⁸

• High affinity¹¹
  • D5 is up to 10 times more dopamine affine than D1⁷
• Pro-inflammatory (neuroinflammation)¹¹
• 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 cAMP¹⁵
  • Promotes the production of adenylyl cyclase¹⁵
• Appearance:
  • Much rarer than D1 receptor
  • Hippocampus¹⁶
  • Hypothalamus¹⁶
  • Lateral mammilar body
  • Parafascicular nucleus of the thalamus
• Agonists:
  • Fenoldopam¹⁵
  • SKF-38393¹⁵
  • Dopamine¹⁵
• Antagonists:
  • SCH-23390¹⁵(Myslivecek (2022): Dopamine and Dopamine-Related Ligands Can Bind Not Only to Dopamine Receptors. Life (Basel). 2022 Apr 19;12(5):606. doi: 10.3390/life12050606. PMID: 35629274; PMCID: PMC9147915. REVIEW))
  • Cis-fluopenthixol¹⁵
  • (+)Butaclamol¹⁵
  • SKF-83566⁷
  • Ecopipam⁷
  • [125I]SCH23982⁷

6.6. D2-like dopamine receptors: inhibitory¶

D2R-like receptors (D2R, D3R, and D4R) induce by coupling to Gi/o proteins:²²⁶

• The inhibition of AC- and PKA-dependent signaling pathways
• The activation of GIRK
• The closure of voltage-activated Ca2+ channels.
• The activation of phospholipase C⁷

D2R-like receptors contain introns and therefore know “long” and “short” D2 receptor isoforms, unlike D1R-like receptors.⁷

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.

6.6.1. D2 receptor¶

• Low affinity,¹¹ 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)¹¹
• Presynaptic (short) and postsynaptic (long)²⁸
• 2 Isoforms²⁹
  • D2 short
    • Presynaptic³⁰
  • D2 long
    • Postsynaptic³⁰
• D2 short receptors can function as autoreceptors
  • Inhibitory feedback mechanism by modifying³⁰
    • 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 dopamine³¹³²
    • Your activation
      • Inhibits dopamine synthesis
      • Increases dopamine uptake
      • Regulates VMAT2 expression³³
  • D2 autoreceptors in the soma
    • Activation inhibits firing of dopamine neurons³⁴
• Inhibiting:
  when dopamine binds to receptors D2, D3 or D4, the respective following synapse is inhibited = polarized (inhibitory postsynaptic potential)
  • Inhibits adenylyl cyclase¹⁵
  • Inhibits cAMP production
    • D2 short inhibits cAMP more effectively and requires fewer agonists for this purpose than D2 long¹⁵
  • Enhances ATP- or calcium ionophore-induced arachidonic acid release in CHO cells¹⁵
  • Increases the intracellular calcium level in¹⁵
    • Ltk cells
      • Due to increased PI hydrolysis
    • CCL1.3 cells
      • Due to increased PI hydrolysis
    • CHO cells
      • Here, however, not through 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)¹⁶
    • Expressed by GABAergic neurons, which at the same time express enkephalins¹⁵
    • D2 are also expressed on dopamine axons
  • Olfactory bulb¹⁶
    • Expressed by GABAergic neurons, which at the same time express enkephalins¹⁵
  • Nucleus accumbens ¹⁶
    • Expressed by GABAergic neurons, which at the same time express enkephalins¹⁵
  • Substantia nigra pars compacta
    • Expressed by dopaminergic neurons¹⁵
  • Ventral tegmentum
    • Expressed by dopaminergic neurons¹⁵
  • Adrenal gland
    • Here the D2 receptor regulates the production and release of PRL
• Agonists
  • Bromocriptine¹⁵
  • Dopamine¹⁵
  • Apomorphine¹⁵
  • N0437³⁵
  • Norepinephrine²⁹
    • Norepinephrine has different affinities on D2-type receptors: D3R > D4R ≥ D2SR ≥ D2L
  • MLS1547⁷
  • Rotigotine⁷
  • Ropinirole⁷
  • Pramipexole⁷
  • PD 128907⁷
  • PD168,077⁷
  • A412997⁷
• Antagonists:
  • Spiperon¹⁵³⁵
  • Racloprid¹⁵³⁵⁷
  • Sulpiride¹⁵⁷
  • 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
  • L741626³⁵
  • Clozapine³⁶
    • Stronger D4 than D2 antagonist
  • Pipotiazine⁷
  • Perospiron⁷
  • ML321⁷
  • Prochlorperazine⁷
  • NGB 2904⁷
• Antagonist and agonist
  • Aripiprazole³⁷
    • 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 by³⁸
    • Pesticides
    • Mercury
    • Formaldehyde

Blockade of D2 autoreceptors leads to an increase in dopamine levels.³⁹

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.⁴⁰
In adolescence, the number of these receptors decreases to 40% of the initial level.²⁰ This decrease is again significantly greater in males than in females.
With age, the density of D2 receptors in the striatum decreases.⁴¹

High expression of dopamine transporters could possibly result in increased expression of D1 receptors, D2 receptors, and VMAT2 receptors.²¹

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 affected individuals than in ADHD-I subtype affected individuals: ADHD-C: 2.9 (2.6 - 3.5); ADHD-I: 4.0 (3.3 - 4.5).⁴²

D2 and D3 agonists increase cataplexy (narcolepsy symptom), D2 and D3 antagonists decrease it.⁴³

D2 and D3 agonists do not appear to affect REM sleep.⁴³

D2R regulates positive emotionality and extraversion.⁴⁴

6.6.3. D3 receptor¶

• High affinity¹¹
• Pro-inflammatory (neuroinflammation)¹¹
• 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 in¹⁵
      • 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 observed¹⁵
  • No stimulation of PI hydrolysis¹⁵
• Appearance
  • Predominantly in the limbic system⁴⁵¹⁶
  • 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)³⁶
• D3 receptor agonists
  • Quinpirole¹⁵
  • 7-OH-DPAT¹⁵
  • Apormophine¹⁵
  • Pramipexole, (S)-2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole; (S)-2-amino-6-(propylamino)-4,5,6,7-tetrahydrobenzothiazole⁷
  • Ropinirole, 4-[2-(dipropylamino)ethyl]indolin-2-one⁷
  • (+)-PD128907³⁵
  • Norepinephrine²⁹
    • Norepinephrine has different affinities on D2-type receptors: D3R > D4R ≥ D2SR ≥ D2L
  • Rotigotine⁷
  • PD 128907⁷
  • A412997⁷
  • [3H]PD128907⁷
• Antagonists:
  • Spiperon¹⁵³⁵
  • Racloprid¹⁵³⁵⁷
  • Sulpiride¹⁵⁷
  • SB-277011³⁵
  • Perospiron⁷
  • Prochlorperazine⁷
  • S33084⁷
  • NGB 2904⁷
  • SB 277011-A⁷
  • (+)-S-14297⁷

D2 and D3 agonists increase cataplexy (narcolepsy symptom), D2 and D3 antagonists decrease it.⁴³

D2 and D3 agonists do not appear to affect REM sleep.⁴³

6.6.4. D4 receptor¶

D4 receptors are involved in encoding the memory of fear, but not in encoding the memory of rewards.¹⁸ D4R are involved in the regulation of action impulsivity (inhibition problems) and choice impulsivity (devaluation of distant rewards).⁴⁴
D4R is found in humans, primates, and rodents primarily in the PFC, particularly in deep layer neurons. In contrast, DRD4 mRNA expression is much lower in the striatum.⁴⁴

• 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 lines¹⁵
  • Enhances ATP- or calcium ionophore-induced arachidonic acid release in CHO cells¹⁵
  • No stimulation of PI hydrolysis¹⁵
  • Activating D4R in the PFC keeps the output signal of the PFC network low⁴⁴
  • D4R-KO mice show hyperexcitability of frontal cortical P neurons⁴⁴⁴⁶
    • In contrast, the gain of function by D4.7R shows a decrease in cortico-striatal glutamatergic transmission⁴⁷
  • D4R in frontal cortico-striatal terminals mediate significant inhibition of striatal glutamate release⁴⁴
  • Rodents with neonatal 6-OH dopamine lesions show typical ADHD symptoms, including locomotor hyperactivity, with concomitant increased striatal D4R density⁴⁸
• D4Rs can indirectly modulate the function of adrenoceptors and other dopamine receptor subtypes through heteromerization⁴⁴
• Appearance:
  • Less frequently than other dopamine receptors
  • PFC
    • DRD4 also binds (at least in the PFC) norepinephrine⁴⁹⁴⁴
  • Medulla
  • Limbic regions¹⁶
    • Amygdala
    • Hypothalamus
  • Midbrain (Mesencelaphone)
  • Heart
  • Retina⁵⁰
  • Pinealocytes of the pineal gland⁵¹
    • These are involved in the circadian system through the release of melatonin
  • Low occurrence in the striatum³⁶⁵² and the remaining basal ganglia
• Variants⁵³
  • DRD4.2R: 2 repeats (8%)
  • DRD4.4R: 4 repeats (60 %)
  • DRD4.7R: 7 repeats (20 %)
    • Compared to DRD4.4R:⁴⁴
      • Higher suppression of network bursts and NMDA receptor-mediated excitatory postsynaptic currents of P neurons in vitro
      • Stronger downregulation of NR1 NMDA receptor surface expression in frontal cortical cells in vitro
      • Attenuated methamphetamine-induced cortical activation
      • Attenuated ontogenetic and methamphetamine-induced glutamate release frontal cortico-striatal
      • Greater inhibition of frontal cortico-striatal neurotransmission by:
        • Specifically higher dopamine potency in the D2R-D4.7R heteromer than in the D2R-D4.4R heteromer, compared to the D2R homomer
        • Differential decrease or increase in constitutive activity of D2R when it forms D2R-D4.4R or D2R-D4.7R heteromers, respectively
        • More frequent formation of D4.7R homomers instead of heteromers than in D4.4R
          • D4.7R forms heteromers with D2R less frequently than does D4.4R
          • D4.7R forms homomers more frequently than D4.4.R
          • Significantly higher dopamine action for D4.4R-D4.4R and D4.7R-D4.7R homers than for D2R-D4.4R and D2R-D4.7R heteromers also leads to functional enhancement of D4.7R compared with D4.4R
      • Less frequent formation of D4.7R-α2AR heteromers than of D4.4R-α2AR in brain
        • D4.7R-α2AR increases the efficacy of norepinephrine in activating α2AR, but not D4.4R-α2AR
        • D4.7R does not allosterically inhibit α2AR-mediated signaling in the heteromer, compared to D4.4R
        • Therefore, dopamine does not inhibit α2AR signaling in α2AR-D4.7R, but does in α2AR-D4.4R heteromers
          • D4R can also be activated by endogenous norepinephrine in the cerebral cortex
          • High dopamine should cause significant inhibition of α2AR signaling by the α2AR-D4.4R but not by the α2AR-D4.7R heteromer
          • Α2AR-D4R heteromers appear to primarily decrease the excitability of P neurons
          • Therefore higher frontal-cortical inhibition by D4.7R
  • No significant differences between D4.2R, D4.4R, and D4.7R with respect to dopamine-induced activation of the five Gi/o protein subtypes⁴⁴
• Agonists
  • Apormophine¹⁵
  • Quinpirole¹⁵
  • Dopamine¹⁵
  • FAUC 179⁵⁴
  • (-)-(R)-N-propylnorapomorphine³⁵
  • L-745,870³⁵
  • Norepinephrine²⁹
    • Norepinephrine has different affinities on D2-type receptors: D3R > D4R ≥ D2SR ≥ D2L
    • Norepinephrine binds and activates D4Rs at submicromolar concentrations up to ten times higher than the concentration that can activate β1R or α1BR in pineal preparations or pineal tissue.⁴⁴
  • Rotigotine⁷
  • PD168,077⁷
  • A412997⁷
• Antagonists:
  • Spiperon¹⁵³⁵
  • Clozapine³⁶¹⁵
    • Stronger D4 than D2 antagonist
    • Serotonin receptor 5-HT2A antagonist⁴⁵
    • Antagonist of other catecholamine receptors⁴⁵
  • Sulpiride¹⁵⁷
  • NGD 94-1³⁵
    • Selective D4 antagonist
  • Perospiron⁷
  • Sonepiprazole⁷
  • L745870⁷
  • A-381393⁷
  • L741742⁷
  • ML398⁷
  • [125I]L750667⁷
  • [3H]NGD941⁷

Selective D4 antagonists proved ineffective for antipsychotic treatment. Apparently, a combined treatment of the dopaminergic and serotonergic systems is needed.⁵⁵

Injections of the selective D4R agonist A-412997 (5 and 10 mg/kg) and the antagonist L-745870 (5 and 10 mg/kg) significantly altered hippocampal and PFC activity.
The D4R agonist A-412997 enhanced the slow rhythm of the PFC (delta, 2-4 Hz) and suppressed the theta rhythm of the hippocampus.
The D4R antagonist L-745870 had the opposite effect. Analogous changes in both slow rhythms were also found in the nucleus reuniens of the thalamus, which has connections to both forebrain structures. Slow oscillations play a key role in interregional cortical coupling; in particular, delta and theta oscillations have been shown to entrain neuronal firing and modulate gamma activity in interconnected forebrain structures, with the hippocampal theta relatively dominant over the PFC. D4R activation thus appears to be able to induce an abnormal bias in bidirectional PFC-hippocampal coupling that can be reversed by D4R antagonists.⁵⁶

D4R moderate action impulsivity and choice impulsivity (along with DAT, COMT, and α2AR).⁴⁴

6.7. Heteromeric¶

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

• D1 / D2 - Heterodimers⁵⁷
• D1 / D3 - Heterodimers⁵⁸
• D2 / D4 heteromers⁴⁴
  • in striatal terminals
  • possibly in the perisomatic region of P neurons in the striatum
• Adenosine A2A / D2 - heterodimers appear to be partially responsible for the psychomotor and reinforcing effects of psychostimulants such as cocaine and amphetamine.⁵⁹
• Cannabinoid CB1 / D2 - Heterodimers in the striatum⁶⁰
• Cannabinoid-CB1 / Adenosine-2A / D2 - Heretotrimers⁶¹⁶²
• Adenosine-2A / D2 / glutamate Metabotropic mGlu(5) - Heterotrimers in the striatum⁶³

6.8. 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.²⁶⁴

6.9. Dopamine agonists and antagonists¶

6.8.1. Dopamine agonists¶

• Apomorphine³⁵
• FAUC 179³⁵
• 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 agonist³⁵
• Ropinirole, 4-[2-(dipropylamino)ethyl]indolin-2-one
  • D3 dopamine receptor agonist³⁵
• 5,6,7,8-Tetrahydro-6-(2-propen-1-yl)-4H-thiazolo[4,5-d]azepin-2-amin Dihydrochlorid (BHT-920)
  • D2 agonist⁶⁵

6.9.2. Indirect dopamine receptor agonists¶

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

• Cocaine³⁶
• Amphetamine³⁶
• Opioids³⁶
• Ethanol³⁶
• Nicotine³⁶
• Adenosine antagonists
  • Caffeine
  • Theobromine

6.9.3. 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

6.9.4. Receptor binding of dopamine agonists and antagonists¶

The values are in Ki in nM. The lower the value, the higher the receptor binding.
>10,000 was also given for “no binding”,
Based on Melis et al.⁶⁶

Agonist	D1	D2	D3	D4	D5
Dopamine	?	?	?	11.6 (D4-2) 56.2 (D4-4) 9.8 (D4-7)	?
Apomorphine	?	32	26	2.6 / 1.1 (D4-2) 4.0 (D4-4) 1.2 (D4-7)	?
Quinpirole		1.8	0.96	3
Pramipexole		3.9	0.5	5.1
PD 128,907		931	9.7	2430
ABT-724	>10,000	>10,000	>10,000	57.5 (D4-2) 63.6 (D4-4) 46.8 (D4-7)	>10,000
PIP-3EA		990	3900	2.8
FAUC 3019		33	82	0.4
A-412997		2848	2095	7.9
CP 226269		1760		6.0
SKF 38393	?

The values are in Ki in nM. The lower the value, the higher the receptor binding.

Antagonist	D1	D2	D3	D4	D5
L-741,626		2.4	100	200
SB277011A		1000	10
FAUC 365		3600	0.5	340
L-745,870		960	2300	0.43
Haloperidol		6.3	6.1	10
Racloprid		1	1.3	5070