7. Dopamine effect on receptors

Dopamine receptors are predominantly (and in vertebrates exclusively) coupled to G proteins. They are metabotropic receptors and therefore orders of magnitude slower than ionotropic receptors,¹ and therefore longer lasting.
While ionotropic receptors directly open an ion channel, excitatory dopamine receptors activate an excitatory G protein,
which is located on the inside of the cell membrane near the receptor. This G protein activates an enzyme, which in turn produces a second messenger. This second messenger diffuses to nearby ion channels, attaches to them and opens them. Stimulation of an inhibitory dopamine receptor, on the other hand, activates inhibitory G-proteins, which inhibit the production of second messengers.²

An important second messenger addressed by dopamine receptors is cyclic adenosine monophosphate, cAMP. in addition to opening ion channels, cAMP can also trigger gene transcription and alter the expression of specific genes.
There are 2 classes of dopamine receptors that differ according to G-protein partners and intracellular signaling mechanisms:³
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, which is released from the presynaptic neuron into the synaptic cleft. When activated, they increase neuronal activity. This is a phasic response.
The D2-like dopamine receptors are partly postsynaptic, but can also occur presynaptically. Presynaptic dopamine receptors are activated by extracellular dopamine leaking from the synapse. This action serves as an inhibitory feedback mechanism when the dopamine level exceeds the reuptake capacity.⁴ Postsynaptically, D2-like receptors have an inhibitory effect on the activity of the nerve cell

It is unclear whether dopamine transmission is mediated by a synaptic or a volume-dependent mechanism. Dopamine-dependent transmission works differently than a purely synaptic mechanism. While glutamate is present in the synaptic cleft for less than 1 ms, and the time course of NMDA-dependent transmission depends on the rate of deactivation of glutamate from the receptor (tau = 250-400 ms, dopamine must be present for about 100 ms to reach the full amplitude of the IPSC⁵

In addition to signal transmission via the adenylyl cyclase-cAMP system (the most important mechanism of action), dopamine receptors also activate phospho-lipase C via the Gq/11 system and increase intracellular calcium levels. Dopamine receptors also interact with glutamate receptors and mobilize intracellular Ca2+ stores.⁷

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

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

Dimer/oligomeric complexes have 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.⁸

• 7.1. Dopamine binds to many receptors and transporters; dopamine affinity
• 7.2. Frequency distribution of the dopamine receptors
• 7.3. Dopamine release from dopamine receptors
• 7.4. Dopamine receptors and DAT mostly extrasynaptic
• 7.5. Heteroreceptors (postsynaptic receptors)
  • 7.5.1. D1-like dopamine receptors: activating
    • 7.5.1.1. D1 receptor
    • 7.5.1.2. D5 receptor
  • 7.5.2. D2-like dopamine receptors: inhibitory
    • 7.5.2.1. D2 receptor
      • 7.5.2.1.1. 2 Isoforms
      • 7.5.2.1.2. Occurrence of D2R:
      • 7.5.2.1.3. D2 agonists
      • 7.5.2.1.4. D2 antagonists:
      • 7.5.2.1.5. Antagonist and agonist
      • 7.5.2.1.6. Poisons
      • 7.5.2.1.7. Effect
    • 7.5.2.3. D3 receptor
    • 7.5.2.4. D4 receptor
• 7.6. Autoreceptors (D2, D3, D4)
  • 7.6.1. Effect of dopaminergic autoreceptors
  • 7.6.2. Up-/Downregulation of dopaminergic autoreceptors
  • 7.6.3. Agonists and antagonists
  • 7.6.4. Dopamine regulation through postsynaptic dopamine receptors
• 7.7. Heterodimers and homodimers
• 7.8. High-affinity and low-affinity receptor status
• 7.9. Dopamine - Spare receptors / receptor reserve?
• 7.10. G-protein-independent dopamine receptor activation
• 7.11. Dopamine agonists and antagonists
  • 7.11.1. Dopamine agonists
  • 7.11.2. Indirect dopamine receptor agonists
  • 7.11.3. Dopamine antagonists
  • 7.11.4. Receptor binding of dopamine agonists and antagonists

7.1. Dopamine binds to many receptors and transporters; dopamine affinity¶

Dopamine binds not only to dopamine receptors, but also - even with similar affinity - to noradrenaline receptors, serotonin receptors and melatonin receptors as well as to dopamine transporters and noradrenaline transporters.⁹¹⁰ (Sorting from affine to less affine). Within the receptors, there are again differences in affinity depending on the gene variant (sorting from affine to less affine).¹¹

• Dopamine receptors:
  • D4: pKi 7.6; Kd 450 [nM]a
    • DRD4-2R
    • DRD4-4R
    • DRD4-7R
  • D5: pKi 6.6; Kd 228 [nM]a
  • D3: pKi 6.3 - 7.4; Kd 27 [nM]a
  • D2: pKi 5.3 - 6.4; Kd 1705 [nM]a
    • D2 short (autoreceptors)
    • D2 long (heteroreceptors)
    • D2-D4 receptor heteromers
  • D1: pKi 4.3 - 5.6; Kd 2340 [nM]a
• Dopamine transporter (DAT): pKi 5.3
• Noradrenaline transporter (NET): pKi 4.55
• Noradrenaline receptors:
  • Α2-AR: pKi 6.01
  • Α1-AR receptors: pKi 5.6
  • Β1-ARs: pKi 5.0
  • Β2-ARs: pKi 4.3

• Serotonin transporter (SERT): pKi 4.53
• Melatonin receptors:
  • MT1A: pKi 5.15
  • MT1B: pKi 5.04

(Ki, Kd: dissociation constant, the lower, the more affine)¹²
(pKi: negative logarithmic dissociation constant (negative logarithm of Ki), the higher the more affine)

D3 and D5 receptors have a high affinity, D1 and D2 receptors have a low affinity for dopamine.¹³ The earlier model that D1 has a low affinity and D2 a high affinity¹⁴ is outdated. The preference of D2 receptors for tonic dopamine and of D1R for phasic dopamine derived from this outdated view has also not been confirmed. Both D1R and D2R respond to tonic and phasic dopamine.¹⁵ Of the D2Rs, only postsynaptic D2Rs are thought to respond to tonic dopamine.¹⁶

7.2. Frequency distribution of the dopamine receptors¶

The frequency of dopamine receptors differs within the brain regions:¹⁷¹⁸

Brain region	D1	D2	D3	D4	D5
Striatum	+++1917	+++19 17	+1719	-17	-17 / Nucleus caudatus: o19
Nucleus accumbens (ventral striatum)	+++1917	+++19 17	+++17 Shell: +++l19	+17	-17 / o19
Substantia nigra	+++19	++19	+19	SN pars reticulata: +19	+19
VTA		++19	+19
Septum	+17	+17 / ++19	+1719	-17	-17
Tuberculum olfactorium	+++17	+++19 17	+17 / +++19	-17	-17
Amygdala	+++17	+17 / ++19	+17	+1917	-17
Hippocampus	+1719	+17 / ++19	+1719	+1917	+17
Cortex	+17 / ++18 / PFC: +++19	+17 / -18 / ++19	+1719 / -18	+17 / ++18	-17 /+19 / +19
Entorhinal cortex					+19
Premotor cortex					+19
ACC					+19
Dentate gyrus					+19
Hypothalamus	+1719	+17	+17	+1917	-17 / +19
Thalamus	+1719	+17 / ++19	+17	+1917	+17
Cerebellum	+1719	+17	+17	-17	-17
Islands of Calleja			+++19
Globus pallidus				+19
Retina	++19	++19		++19
Pituitary gland		+++19
Smelling flask	+++19

+++: frequent; ++ moderate; + low; o very low; - none observed; blank: no information

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

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

Nucleus accumbens:

• D3 frequent
• D1
• D2

Caudate nucleus:

• D1
• D2

Putamen ventral:

• D3 moderate

Blocking dopamine receptors increases the release of acetylcholine. Acetylcholine is partly responsible for the development of extrapyramidal symptoms.²⁰

7.3. Dopamine release from dopamine receptors¶

DRD1 and DRD2 release dopamine very slowly (“unbinding”). The half-life of the dopamine release of DRD1 and DRD2 is 80 seconds²¹ and is therefore much longer than bursts, which last only fractions of a second to a few seconds.

7.4. Dopamine receptors and DAT mostly extrasynaptic¶

Receptors are mostly, but not exclusively, located within synapses.
Dopamine receptors are predominantly located outside of synapses (extrasynaptic). This also applies to the D2 autoreceptor and the DAT, which is responsible for dopamine reuptake ^{22 2324}

In the striatum, dopaminergic fibers form en passant synapses every 4 mm.²⁵
Due to diffusion and reuptake (not degradation), the half-life of extracellular dopamine in the caudate nucleus is less than 50 ms, while it is slightly longer in the nucleus accumbens.²⁶²⁷ Thus, D1 receptors can be stimulated by DA that diffuses into the extrasynaptic extracellular space up to 12 micrometers away from the release sites²⁸

Dopamine uptake in the mPFC, nucleus accumbens and caudate nucleus/putamen correlates with the number of dopamine receptors present. In the amygdala, on the other hand, dopamine uptake is lower and slower and corresponds to that of the neuroendocrine tuberoinfundibular dopamine system.²⁷

7.5. Heteroreceptors (postsynaptic receptors)¶

Released catecholamines act on postsynaptic heteroreceptors (here on inhibitory as well as activating ones), as well as on presynaptic autoreceptors (here only inhibitory ones).²⁹

7.5.1. D1-like dopamine receptors: activating¶

D1R-like receptors (D1R and D5R)³⁰

• increase adenylate cyclase
  • especially D1R
• increase the phosphoinositide metabolism
  • especially D5R
• are located on non-dopamine neurons³¹
• stimulate neuronal signaling by binding to Gαs/olf to activate adenylyl cyclase. The enzyme adenylyl cyclase (AC) converts adenosine triphosphate (ATP) into cyclic adenosine monophosphate (cAMP). cAMP activates protein kinase A (PKA), which in turn phosphorylates the cAMP response element binding protein (CREB). CREB is translocated to the nucleus and activates CREB-dependent transcription of genes involved in synaptic plasticity. D1R increases excitability in axonal terminals by modulating various ion channels, including voltage-activated Na+, K+ and Ca2+ channels and the G-protein gated inwardly rectifying K+ channel (GIRK).³³²³¹
• D1R-like receptors do not contain introns, unlike D2R-like receptors, which therefore recognize “long” and “short” D2 receptor isoforms.⁹

7.5.1.1. D1 receptor¶

Most common dopamine receptor in the dlPFC of primates. Mediates most cellular dopamine effects in the dlPFC.³³

• Low affinity¹³
• Anti-inflammatory (neuroinflammation)¹³
• Postsynaptic
• Activating
  when dopamine binds to the D1 or D5 receptors, the subsequent synapse is activated = depolarized (excitatory postsynaptic potential)
  • Promotes the production of cAMP³⁴
    • Stimulation of cAMP by dopamine in the striatum requires a dopamine concentration of at least 0.3 μM³⁵
  • Increases intracellular calcium (Ca2+)³⁴
  • Stimulates PI hydrolysis³⁴
• Appearance:
  • Nucleus accumbens (ventral striatum) (together with D3 receptors)³⁶³⁴³⁶
  • Olfactory bulb³⁶
  • Basal ganglia³⁶
    • Caudate nucleus³⁷
    • Putamen³⁷
  • Hypothalamus
  • Thalamus
  • (only) in projections (without mRNA) from striatal GABAergic cells, which also produce substance P, in
    • Entopeduncular nucleus
    • Globus pallidus
    • Substantia nigra pars reticulata
  • Lower also in the PFC³⁶
• Agonists:
  • (R)-SKF82526; Kd: 28 nM at DRD1; KL: 21 nM at DRD1 striatal³⁸
  • SKF38393³⁴; Kd: 150 nM at DRD1; KL: 381 nM at DRD1 striatal³⁸
  • (R)-(+)-6-Br-APB; Kd: 384 nM³⁸
  • (R)-apomorphins; Kd: 680 nM; KL: 206 nM at DRD1 striatal³⁸
  • (S)-SKF82526³⁴; Kd: 1818 nM at DRD1; KL: 1.1335 nM at DRD1 striatal³⁸
  • (R)-NPA; Kd: 1816 nM at DRD1; KL: 625 nM at DRD1 striatal³⁸
  • (+)-6,7-ADTN; Kd: 4600 nM at DRD1; KL: 734 nM at DRD1 striatal³⁸
  • Dopamine; Kd: 2,500 nM (2.5 μM) at DRD1; KL: 580 nM at DRD1 striatal³⁸
  • Serotonin; Kd: 9690 nM at DRD1; KL: 6,543 nM at DRD1 striatal³⁸
  • Noradrenaline; Kd: 50,000 nM (50 μM) at DRD1; KL: 4,141 nM at DRD1 striatal³⁸
  • Adrenaline; Kd: 55 000 nM at DRD1; KL: 980 nM at DRD1 striatal³⁸
  • Bromocriptine
  • Fenoldopam³⁴
  • A77636⁹
  • SKF-81297⁹
  • SKF-83959⁹
• Antagonists:
  • SCH-23390³⁴⁹
  • (+)Butaclamol³⁴
  • Cis-Fluopenthixol³⁴
  • SKF-83566⁹
  • Ecopipam⁹
  • [125I]SCH23982⁹

Involved in the formation of aversive memories.
Regulates the sustained firing of dlPFC neurons during the delay phase of delayed-response tasks that require working memory.³³
Blockade of D1 receptors interfered with corticostriatal long term potentiation (LTP, “learning”), while blockade of D5 receptors prevented LTD (long term depression, “forgetting”).³⁹
Blockade of D1 receptors increased motor activity, while blockade of D1 and D5 receptors decreased motor activity.³⁹
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 the mPFC by the D1 and D5 agonist SKF-38393 promoted the formation of aversive memories.⁴⁰

After birth, the density of D1 and D2 receptors in the striatum initially increases. In adolescence, the number of these receptors drops to 40 % of the initial level.⁴¹ This decrease is again significantly greater in men than in women.
A high expression of dopamine transporters could possibly cause an increased expression of D1, D2 and VMAT2 receptors.⁴²

Glucocorticoids cause a sensitization of D1 receptors in GABAergic cells of the striatum in rats,⁴³⁴⁴ as well as stress.⁴⁵⁴⁶

7.5.1.2. D5 receptor¶

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 the mPFC by the D1 and D5 agonist SKF-38393 promotes the formation of aversive memories.⁴⁰

• High affinity¹³
  • D5 has up to 10 times the dopamine affinity of D1⁹
• Pro-inflammatory (neuroinflammation)¹³
• Postsynaptic
• Activating: when dopamine binds to the D1 or D5 receptors, the subsequent synapse is activated = depolarized (excitatory postsynaptic potential)
  • Promotes the production of cAMP³⁴
  • Promotes the production of adenylyl cyclase³⁴
• Appearance:
  • Much rarer than D1 receptor
  • Hippocampus³⁶
  • Hypothalamus³⁶
  • Lateral mammary body
  • Parafascicular nucleus of the thalamus
• Agonists:
  • Fenoldopam³⁴
  • SKF-38393³⁴
  • Dopamine³⁴
• Antagonists:
  • SCH-23390³⁴⁹
  • Cis-Fluopenthixol³⁴
  • (+)Butaclamol³⁴
  • SKF-83566⁹
  • Ecopipam⁹
  • [125I]SCH23982⁹

7.5.2. D2-like dopamine receptors: inhibitory¶

D2R-like receptors (D2R, D3R and D4R) are inhibitory. They induce by coupling to Gi/o proteins:³⁴⁷

• The inhibition of AC- and PKA-dependent signaling pathways
• The activation of inhibitory G-protein-activated inwardly rectifying potassium channels (GIRK)
• The closing of voltage-activated Ca2+ channels.
• The activation of phospholipase C⁹

The majority of D2 receptors are located on non-dopamine neurons (postsynaptic).³¹ For presynaptic autoreceptors, see below.

D2R-like receptors contain introns and therefore know “long” and “short” D2 receptor isoforms, unlike D1R-like receptors.⁹

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 that is actually due does not take place.

7.5.2.1. D2 receptor¶

• Low affinity,¹³ at least in vivo just as low affinity as D1¹
  • No activation by basal dopamine levels (2 to 20 nM)
  • Activation at 100 μM through phasic dopamine release
• Anti-inflammatory (neuroinflammation)¹³

7.5.2.1.1. 2 Isoforms¶

presynaptic (short) and postsynaptic (long)^{49 50} in substantia nigra, VTA and striatum⁵¹

• D2 long
  • Postsynaptic⁵²
  • Lower dopamine affinity than presynaptic D2 receptors
    • 5 to 100 times lower sensitivity⁵¹
    • 6 times lower dopamine affinity⁵²
• D2 short
  • Presynaptic⁵²
  • Are found on dopaminergic neurons (autoreceptors)⁵¹
    • On cell bodies
    • On dendrites
    • On endings in the nigrostriatal and midbrain-limbic system
• Autoreceptors = inhibitory feedback mechanism through changes in⁵²
  • DA synthesis
  • DA release
  • DA recovery
    in response to increasing amounts of extracellular synaptic dopamine.
• D2 autoreceptors on dopamine axons respond to tonic and phasic dopamine⁵³⁵⁴
  • Your activation
    • Inhibits the synthesis of dopamine
    • Increases dopamine uptake
    • Regulates VMAT2 expression⁵⁵
• D2 autoreceptors in the soma
  • Activation inhibits the firing of dopamine neurons⁵⁶
• No selective D2 autoreceptor agonists or antagonists are known to date⁵⁷
• Inhibiting:
  when dopamine binds to the receptors D2, D3 or D4, the subsequent synapse is inhibited = polarized (inhibitory postsynaptic potential)
• Inhibits adenylyl cyclase³⁴
• Inhibits cAMP production
  • D2 short inhibits cAMP more effectively and requires fewer agonists to do so than D2 long³⁴
• Enhances ATP- or calcium ionophore-induced arachidonic acid release in CHO cells³⁴
• Increases the intracellular calcium level in³⁴
  • 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 are present, the greater the acetylcholinergic excess that occurs when 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 people with ADHD with a high number of dopamine receptors. The acetylcholinergic excess in persons with ADHD with a high number of dopamine receptors explains the frequent consumption of anticholinergic and sedative substances as well as the frequent use of cocaine.

7.5.2.1.2. Occurrence of D2R:¶

• Striatum (together with D1 receptors)³⁶
  • Expressed by GABAergic neurons that also express enkephalins³⁴
  • D2 are also expressed on dopamine axons
• Olfactory bulb³⁶
  • Expressed by GABAergic neurons that also express enkephalins³⁴
• Nucleus accumbens ³⁶
  • Expressed by GABAergic neurons that also express enkephalins³⁴
• Substantia nigra pars compacta
  • Expressed by dopaminergic neurons³⁴
• Ventral tegmentum
  • Expressed by dopaminergic neurons³⁴
• Adrenal gland
  • Here the D2 receptor regulates the production and release of PRL

7.5.2.1.3. D2 agonists¶

• (R)-apomorphine; Kd: 24 nM at DRD2; KL: 127 nM at DRD2 striatal³⁸
• (R)-SKF82526h; Kd: 28 nM; KL: 23 nM at DRD2 striatal³⁸
• (R)-(+)-6-Br-APB; Kd: 384 nM³⁸
• (S)-SKF82526; KL: 1,000 nM at DRD2 striatal³⁸
• (R)-NPA; Kd: 20 nM at DRD2³⁸
• (+)-6,7-ADTN; KL: 463 nM at DRD2 striatal³⁸
• Dopamine; Kd: 1,705 to 17,000 nM (2.5 μM) at DRD2; KL: 4,300 nM at DRD2 striatal³⁸
• SKF38393; Kd: 9,500 nM to DRD2³⁸
• Noradrenaline; KL: 126,000 nM at DRD2 striatal³⁸
• Adrenaline; KL: 128,000 nM at DRD2 striatal³⁸
• Serotonin; KL: 183,000 at DRD2 striatal³⁸
• Bromocriptine³⁴
• Apomorphine³⁴
• N0437⁵⁸
• Noradrenaline⁴⁹
  • Noradrenaline has different affinities on D2-type receptors: D3R > D4R ≥ D2SR ≥ D2L
• MLS1547⁹
• Rotigotine⁹
• Ropinirole⁹
• Pramipexole⁹
• PD 128907⁹
• PD168,077⁹
• A412997⁹

7.5.2.1.4. D2 antagonists:¶

• Spiperon³⁴⁵⁸
• Racloprid³⁴⁵⁸⁹
• Sulpiride³⁴⁹
• 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
• L741626⁵⁸
• Clozapine⁵⁹
  • Stronger D4 than D2 antagonist
• Pipotiazine⁹
• Perospirone⁹
• ML321⁹
• Prochlorperazine⁹
• NGB 2904⁹

7.5.2.1.5. Antagonist and agonist¶

• Aripiprazole⁶⁰
  • D2 receptor partial agonism
    • Acts as an antagonist when there is an excess of dopamine and as an agonist when there is a lack of dopamine.
    • Has an inhibitory effect against dopaminergic hyperfunction in the mesolimbic system and an activating effect against dopaminergic hypofunction in the mesocortical system. This reduces the risk of excessive D2 receptor blockade in the striatum or pituitary gland
  • Serotonin 5-HT1A receptor partial agonism
  • 5-HT2A receptor antagonism
  • Only a very weak prolactin agonist
  • Use. Schizophrenia
• D2, D3 and D4 receptors work
  • Prolactin activating
  • Acetylcholine inhibiting

7.5.2.1.6. Poisons¶

Reduction of D2 receptors through⁶¹

• Pesticides
• Mercury
• Formaldehyde

7.5.2.1.7. Effect¶

Blocking D2 auto-receptors leads to an increase in dopamine levels.⁶²

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 men than in women.⁶³
In adolescence, the number of these receptors falls to 40% of the initial level.⁴¹ This decrease is again significantly greater in men than in women.
With increasing age, the density of D2 receptors in the striatum decreases.⁶⁴

A high expression of dopamine transporters could possibly cause an increased expression of D1 receptors, D2 receptors and VMAT2 receptors.⁴²

A fairly small study of children with ADHD (many of whom were born prematurely or at low weight) found evidence of lower D2/D3 receptor binding/number in persons with ADHD-C than in persons with ADHD-I subtype: ADHD-C: 2.9 (2.6 - 3.5); ADHD-I: 4.0 (3.3 - 4.5).⁶⁵

D2 and D3 agonists increase cataplexy (narcolepsy symptom), D2 and D3 antagonists reduce it.⁶⁶

D2 and D3 agonists do not appear to affect REM sleep.⁶⁶

D2R regulates positive emotionality and extraversion.⁶⁷

7.5.2.3. D3 receptor¶

DRD3 may be the only dopamine receptor not associated with ADHD.⁶⁸⁶⁹⁷⁰

• High affinity¹³
• Pro-inflammatory (neuroinflammation)¹³
• Presynaptic and postsynaptic
• Inhibiting:
  when dopamine binds to the receptors D2, D3 or D4, the subsequent synapse is inhibited = polarized (inhibitory postsynaptic potential)
  • Inhibits adenylyl cyclases
    • Less than D2 receptors in³⁴
      • 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
  • No enhancement of ATP- or calcium ionophore-induced arachidonic acid release was observed, at least in CHO cells or GH4CI cells³⁴
  • No stimulation of PI hydrolysis³⁴
• Appearance
  • Predominantly in the limbic system⁷¹³⁶
  • Nucleus accumbens
  • Olfactory bulb
  • Cerebellum
    • Since the cerebellum is not connected to other areas of the brain via dopaminergic projections (communication pathways), it is assumed that D3 receptors perform non-synaptic 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)⁵⁹
• D3 receptor agonists
  • Quinpirole³⁴
  • 7-OH-DPAT³⁴
  • Apormophine³⁴
  • Pramipexole, (S)-2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole; (S)-2-amino-6-(propylamino)-4,5,6,7-tetrahydrobenzothiazole⁹
  • Ropinirole, 4-[2-(dipropylamino)ethyl]indolin-2-one⁹
  • (+)-PD128907⁵⁸
  • Noradrenaline⁴⁹
    • Noradrenaline has different affinities on D2-type receptors: D3R > D4R ≥ D2SR ≥ D2L
  • Rotigotine⁹
  • PD 128907⁹
  • A412997⁹
  • [3H]PD128907⁹
• Antagonists:
  • Spiperon³⁴⁵⁸
  • Racloprid³⁴⁵⁸⁹
  • Sulpiride³⁴⁹
  • SB-277011⁵⁸
  • Perospirone⁹
  • Prochlorperazine⁹
  • S33084⁹
  • NGB 2904⁹
  • SB 277011-A⁹
  • (+)-S-14297⁹

D2 and D3 agonists increase cataplexy (narcolepsy symptom), D2 and D3 antagonists reduce it.⁶⁶

D2 and D3 agonists do not appear to affect REM sleep.⁶⁶

7.5.2.4. D4 receptor¶

D4 receptors are involved in the encoding of the memory of fear, but not in the encoding of the memory of rewards.⁴⁰ D4Rs are involved in the regulation of action impulsivity (inhibition problems) and choice impulsivity (devaluation of distant rewards).⁶⁷
In humans, primates and rodents, D4R is mainly found in the PFC, especially in neurons of the deep layer. In contrast, DRD4 mRNA expression is much lower in the striatum.⁶⁷

• Rather high affinity
• Presynaptic and postsynaptic
• Inhibiting:
  when dopamine binds to the receptors D2, D3 or D4, the subsequent synapse is inhibited = polarized (inhibitory postsynaptic potential)
  • Inhibits adenylyl cyclases, but only in some cell lines³⁴
  • Enhances ATP- or calcium ionophore-induced arachidonic acid release in CHO cells³⁴
  • No stimulation of PI hydrolysis³⁴
  • Activating D4R in the PFC keeps the output signal of the PFC network low⁶⁷
  • D4R-KO mice show hyperexcitability of frontal cortical P neurons⁶⁷⁷²
    • In contrast, the functional gain by D4.7R shows a decrease in cortico-striatal glutamatergic transmission⁷³
  • D4R in frontal cortico-striatal terminals mediate significant inhibition of striatal glutamate release⁶⁷
  • Rodents with neonatal 6-OH dopamine lesions show typical ADHD symptoms, including locomotor hyperactivity, with increased striatal D4R density⁷⁴
• D4Rs can indirectly modulate the function of adrenoceptors and other dopamine receptor subtypes through heteromerization⁶⁷
• Appearance:
  • Less frequently than other dopamine receptors
  • PFC
    • DRD4 also binds noradrenaline (at least in the PFC)⁷⁵⁶⁷ , unlike other dopamine receptors⁷⁶
  • Medulla
  • Limbic regions³⁶
    • Amygdala
    • Hypothalamus
  • Midbrain (mesencelaphon)
  • Heart
  • Retina⁷⁷
  • Pinealocytes of the pineal gland⁷⁸
    • These are involved in the circadian system through the release of melatonin
  • Low occurrence in the striatum⁵⁹⁷⁹ and the other basal ganglia
  • Frequency distribution PFC > midbrain > amygdala > striatum⁷⁶
• Variants⁸⁰
  • DRD4.2R: 2 repeats (8 %)
  • DRD4.4R: 4 repeats (60 %)
  • DRD4.7R: 7 repeats (20 %)
    • Compared to DRD4.4R:⁶⁷
      • 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
      • Stronger inhibition of frontal cortico-striatal neurotransmission:
        • Specifically higher dopamine potency with the D2R-D4.7R heteromer than with the D2R-D4.4R heteromer, compared to the D2R homomer
        • Differential decrease or increase in the 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 with D4.4R
          • D4.7R forms heteromers with D2R less frequently than D4.4R
          • D4.7R forms homomers more frequently than D4.4.R
          • Significantly higher dopamine effect for D4.4R-D4.4R and D4.7R-D4.7R homomers than for D2R-D4.4R and D2R-D4.7R heteromers also leads to functional enhancement of D4.7R compared to D4.4R
      • Less frequent formation of D4.7R-α2AR heteromers than of D4.4R-α2AR in the brain
        • D4.7R-α2AR increases the effectiveness of noradrenaline 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 noradrenaline 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 reduce 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 regard to dopamine-induced activation of the five Gi/o protein subtypes⁶⁷
• Agonists
  • Apormophine³⁴
  • Quinpirole³⁴
  • Dopamine³⁴
  • FAUC 179⁸¹
  • (-)-(R)-N-propylnorapomorphine⁵⁸
  • L-745,870⁵⁸
  • Noradrenaline⁴⁹
    • Noradrenaline has different affinities on D2-type receptors: D3R > D4R ≥ D2SR ≥ D2L
    • Noradrenaline binds and activates D4Rs at submicromolar concentrations up to ten times higher than the concentration that can activate β1R or α1BR in pineal gland preparations or pineal gland tissue.⁶⁷
  • Rotigotine⁹
  • PD168,077⁹
  • A412997⁹
• Antagonists:
  • Spiperon³⁴⁵⁸
  • Clozapine⁵⁹³⁴⁷⁶
    • Stronger D4 than D2 antagonist
    • Serotonin receptor 5-HT2A antagonist⁷¹
    • Antagonist of other catecholamine receptors⁷¹
  • Sulpiride³⁴⁹
  • NGD 94-1⁵⁸
    • Selective D4 antagonist
  • Perospirone⁹
  • Sonepiprazole⁹
  • L745870⁹
  • A-381393⁹
  • L741742⁹
  • ML398⁹
  • [125I]L750667⁹
  • [3H]NGD941⁹

Selective D4 antagonists proved to be ineffective for antipsychotic treatment. Apparently, a combined treatment of the dopaminergic and serotonergic systems is required.⁸²

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 the activity of the hippocampus and PFC.
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 the two 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 were shown to entrain neuronal firing and modulate gamma activity in interconnected forebrain structures, with relative dominance of the hippocampal theta over the PFC. D4R activation thus appears to be able to induce an abnormal bias in the bidirectional PFC-hippocampal coupling, which can be reversed by D4R antagonists.⁸³

D4R moderate action impulsivity and choice impulsivity (together with DAT, COMT and α2AR).⁶⁷

7.6. Autoreceptors (D2, D3, D4)¶

The presentation of this paragraph is based on Ruskin et al.²⁹ and Cooper et al.⁸⁴

Released catecholamines act not only on postsynaptic heteroreceptors (here on inhibitory as well as activating ones), but also on presynaptic autoreceptors. Autoreceptors are always inhibitory (D2, rarely also D3 and D4).

7.6.1. Effect of dopaminergic autoreceptors¶

Dopaminergic autoreceptors control three things:

• The dopaminergic firing rate
• the synthesis of dopamine
• the release of dopamine.

Autoreceptors are found presynaptically on many areas of dopaminergic neurons, including:

• Soma (D2)

  • Autoreceptor stimulation is reduced:
    • dopaminergic firing rate⁸⁴
    • Dopamine release⁸⁵

• Dendrites (D2)

  • Autoreceptor stimulation is reduced:
    • dopaminergic firing rate⁸⁴
    • Dopamine release⁸⁵

• Terminals (D2)

  • Autoreceptor stimulation is reduced:⁸⁴
    • Dopamine synthesis
    • Dopamine release

• There are no terminal autoreceptors in PFC and ACC that influence dopamine synthesis⁸⁴

• there are terminal but no somatodendritic autoreceptors in the PFC⁸⁶

The activation of D2 autoreceptors by

• exogenous administration of agonists
  • causes a potassium conductance-mediated inhibition of neurons in the substantia nigra and the VTA⁸⁷
• electrical stimulation
  • causes endogenous dopamine release, which triggers an inhibitory postsynaptic current (IPSC).⁸⁸⁸⁹

The effect of autoreceptors depends on their temporal activation in relation to the action potential.
If D2 autoreceptors are activated immediately before the action potential from the nerve cell, they completely suppress the release of dopamine. The later they were activated after the action potential, the weaker the inhibition became. D2 activation 90 ms after the action potential only inhibited by just under 20 %, and from around 200 ms after the action potential it no longer inhibited at all. The inhibition was fully maintained for 10 minutes and then decreased over 30 minutes⁵

7.6.2. Up-/Downregulation of dopaminergic autoreceptors¶

Autoreceptors are 5 to 10 times more sensitive to agonists (e.g. dopamine or apomorphine) than postsynaptic dopamine receptors.⁸⁶ Therefore, autoreceptors respond faster to agonists with downregulation than postsynaptic receptors ^{90 91 9293}

Autoreceptors are subject to significant up- and downregulation.⁸⁴⁸⁶
Chronic administration of D2 antagonists or prolonged dopamine depletion cause their increased sensitization (upregulation).
Chronic administration of D2 agonists causes their reduced sensitization (downregulation).

Consequently, low doses of direct-acting agonists should preferentially activate autoreceptors, resulting in reduced tonic spike formation and transmitter release and thus reduced activation of postsynaptic dopamine receptors, which then mediate motor activation.

• Low doses of direct dopamine agonists
  • reduce spontaneous motor behavior
• Higher doses of direct dopamine agonists
  • can also activate postsynaptic receptors directly
  • increase motor activity

From this model, it was hypothesized that low doses of stimulants have a calming effect in ADHD by reducing dopamine transmission.⁹⁴
However, stimulants such as MPH and AMP are not direct-acting dopamine receptor agonists, but have an indirect effect. In addition, D-AMP acts equally strongly on postsynaptic and presynaptic receptors in the basal ganglia.⁹³

7.6.3. Agonists and antagonists¶

D2 autoreceptors are only very slightly activated by tonically released extracellular dopamine. The activation appears to be mainly due to phasically released dopamine that diffuses from the synaptic cleft into the extracellular space.⁵ A high concentration (30-100 μM) of synaptically released dopamine binds to the D2 autoreceptor within less than 30 ms⁹⁵ for around 90 ms⁵ and triggers its effect.

The D2 autoreceptor is also activated by noradrenaline, although its affinity for noradrenaline is weaker than for dopamine.⁵

There are some relatively selective autoreceptor agonists and antagonists:⁹⁰

• Selective autoreceptor agonists:
  • 3-PPP
  • EMD 23-448
• Selective autoreceptor antagonists:
  • (+)-UH232
  • (+)-AJ76

7.6.4. Dopamine regulation through postsynaptic dopamine receptors¶

The regulation of dopaminergic activity is not controlled by autoreceptors in all brain regions. While the firing rate of the dopamine neurons of the substantia nigra pars compacta is regulated by somatodendritic autoreceptors, the firing rate of the globus pallidus is regulated by postsynaptic dopamine receptors of the striatum and the globus pallidus itself.
In peripheral motor neurons, presynaptic inhibition can be mediated by signals from interneurons.⁸⁵

7.7. Heterodimers and homodimers¶

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

• D1 / D2 - Heterodimers⁹⁶
  • relevant for addiction, schizophrenia⁹⁷
  • DRD1 activation is selectively inhibited at micromolar dopamine concentrations⁹⁸
  • DRD2 is only inhibited at nanomolar dopamine concentrations⁹⁸
• D1 / D3 - Heterodimers⁹⁹
  • relevant for addiction⁹⁷
• D2 / D2 homodimers¹⁰⁰
• D2 / D3 heteromers⁹⁷
  • relevant for schizophrenia⁹⁷
• D2 / D4 heteromers⁶⁷
  • in striatal terminals
  • possibly in the perisomatic region of P neurons in the striatum
  • relevant for ADHD⁹⁷- -
• D2 / D5 heteromers⁹⁷
• D4 / Alpha1A adrenoceptor - heteromers¹⁰¹
  • relevant for ADHD: -D4.7 / Alpha1A adrenoceptor - heteromers
  • relevant for PTSD: -D4.4 / Alpha1A adrenoceptor - heteromers
• D1 / Adenosine A1 - Heteromers⁹⁷
  • relevant for addiction⁹⁷
• D2 / adenosine A2A heterodimers appear to be partly responsible for the psychomotor and reinforcing effects of psychostimulants such as cocaine and amphetamine.¹⁰²
  • Addiction, schizophrenia, Parkinson’s disease⁹⁷
• D2 / Adenosine-2A / Glutamate Metabotropic mGlu(5) - Heterotrimers in the striatum¹⁰³
  • relevant for schizophrenia⁹⁷
• D2 / Cannabinoid-CB1 - Heterodimers in the striatum¹⁰⁴
• D2 / Cannabinoid-CB1 / Adenosine-2A - Heretotrimers¹⁰⁵¹⁰⁶
• D1 / NMDA heteromer⁹⁷
  • relevant for schizophrenia⁹⁷
• D2 / NMDA heteromer⁹⁷
  • relevant for addiction⁹⁷
• D2 / 5HT2A heteromer⁹⁷
  • relevant for schizophrenia⁹⁷
• D1 / Histamine H3 heteromer⁹⁷
  • relevant for ADHD, addiction, schizophrenia⁹⁷
• D2 / Histamine H3 heteromer⁹⁷
  • relevant for ADHD, addiction, schizophrenia⁹⁷

7.8. High-affinity and low-affinity receptor status¶

A high affinity state and a low affinity state are reported for dopamine receptors (high affinity state / low affinity state).¹⁰⁰¹⁰⁷

The high affinity state is the functional state for both D1 and D2 receptors. Stimulants can alter the balance between the high and low affinity state by increasing the extracellular level of dopamine.¹⁰⁸

In the high state, the D2 receptor is 50% occupied by around 10 nM dopamine.¹⁰⁹

The D2-high receptor state in the anterior pituitary can be completely converted to the D2-low state. The conversion in brain tissue seems to depend on the presence of serotonin receptors, as in the rat striatum or in the human nucleus accumbens, where very few serotonin receptors are found.¹¹⁰

7.9. Dopamine - Spare receptors / receptor reserve?¶

Receptor reserve (spare receptors) refers to the phenomenon that an agonist elicits the maximum response by activating only a fraction of the receptor population present in the system¹¹¹
Little information is available on dopamine spare receptors.¹⁰⁷

7.10. G-protein-independent dopamine receptor activation¶

Dopamine receptors can also be activated by mechanisms that are independent of G proteins:³
The multifunctional adaptor protein arrestin can bind DA receptors phosphorylated by GPCR kinases (GRKs) and recruit several proteins, including

• Act
• GSK-3
• MAPK
• c-Src
• Mdm2
• N-ethylmaleimide-sensitive factor.
  If arrestin binds to active phosphorylated receptors, further activation of G proteins is stopped and endocytosis of the receptor is promoted.

Dopamine receptors continue to be regulated by G protein-coupled receptor kinases (GRKs).
There are seven GRKs for mammals:
D1R and D2R regulate GRK2, 3, 4, 5, 6
D3R is controlled by GRK4.

In the striatum, GRKs 2, 3, 5 and 6 are expressed with different expression levels and different cellular and subcellular distribution.¹¹²

A DA lesion with 6-hydroxydopamine led to multiple protein- and brain region-specific changes in the expression of GRKs. Reduced were¹¹³

• in the globus pallidus:
  • reduced: GRK2, 3, 5, 6
• caudal caudate-putamen:
  • reduced: GRK2, 3, 6
• rostral caudate putamen:
  • reduced: GRK3
  • increased: GRK6
  • increased by subsequent L-dopa: GRK2
• Nucleus accumbens
  • increased: GRK6
    These changes remained unchanged by subsequent L-DOPA and were reversed by the D2/D3 agonist pergolide. L-dopa downregulated GRK5.
    Subsequent L-DOPA influenced the expression of arrestin3.

7.11. Dopamine agonists and antagonists¶

7.11.1. Dopamine agonists¶

• ADTN (2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide)¹¹⁴
• Apomorphine⁵⁸
• FAUC 179⁵⁸
• Budipin, 1-tert-butyl-4,4-diphenylpiperidine
  • Dopamine receptor agonist
  • NMDA receptor antagonist
  • MAO inhibitor antagonist
  • Weak anticholinergic effect
• Cabergoline, 1-[(6-allylergolin-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-ergolin-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 / Noradrenaline / Adrenaline - 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 agonist⁵⁸
• Ropinirole, 4-[2-(dipropylamino)ethyl]indolin-2-one
  • D3 dopamine receptor agonist⁵⁸
• 5,6,7,8-Tetrahydro-6-(2-propen-1-yl)-4H-thiazolo[4,5-d]azepin-2-amin Dihydrochlorid (BHT-920)
  • D2 agonist¹¹⁵

7.11.2. Indirect dopamine receptor agonists¶

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

• Cocaine⁵⁹
• Amphetamine⁵⁹
• Opioids⁵⁹
• Ethanol⁵⁹
• Nicotine⁵⁹
• Adenosine antagonists
  • Caffeine
  • Theobromine

7.11.3. 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
  • Noradrenaline antagonist
  • Adrenaline antagonist
  • Serotonin antagonist
  • Histamine antagonist
• Adenosine
  • Dopamine inhibitors

7.11.4. Receptor binding of dopamine agonists and antagonists¶

The values are in Ki in nM. The lower the value, the higher the receptor binding.
Greater than 10,000 was also specified for “no commitment”.
Based on Melis et al.¹¹⁶ and Zhou et al.¹¹⁷
Differing values from different sources are separated by “;”.

Agonist	D1	D2	D3	D4	D5
Dopamine	0.9 - 2,340	2.8 - 474	4 - 27	28 - 450; 11.6 (D4-2); 56.2 (D4-4); 9.8 (D4-7)	< 0.9 - 261
Apomorphine	0.7 - 680	32; 0.7 - 24	26; 20 - 32	2.6; 4; 1.1 (D4-2); 4.0 (D4-4); 1.2 (D4-7)	122 - 168
ADTN	2.9 - >10,000	1 - 1,370		393
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	3,900	2.8
FAUC 3019		33	82	0.4
A-412997		2,848	2,095	7.9
CP 226269		1,760		6.0
SKF 38393	1 - 150	150 - 9,560	5,000	1,000 - 1,300	0.5 - 100
PD 168077	>10,000	2,820 - 3,740	2,810	8.7 - 25

The values are in Ki in nM. The lower the value, the higher the receptor binding.
Differing values from different sources are separated by “;”.

Antagonist	D1	D2	D3	D4	D5
L-741,626		2.4	100	200
SB277011A		1000	10
FAUC 365		3600	0.5	340
L-745870		960	2,300	0.43
Haloperidol	27 - 203	0.6 - 1.2; 6.3	2.74 - 7.8; 6.1	2.3 - 5.1; 10	33 - 151
Racloprid		1	1.3	5070
Spiperon	99 - 350	0.06 - 0.37	0.43 - 0.71	0.05 - 4	135 - 4,500
SCH 23390	0.11 - 0.35	270 - 1,100	314 - 800	3,000 - 3,560	0.11 - 0.54
Sulpiride	20,400 - 45,000	2.5 - 7.1	8 - 206	21 - 1,000	11,000 - 77,270