Canonical and Non-Canonical Antipsychotics’ Dopamine-Related Mechanisms of Present and Next Generation Molecules: A Systematic Review on Translational Highlights for Treatment Response and Treatment-Resistant Schizophrenia
Abstract
:1. Introduction
- (1)
- Is there space for more dopaminergic strategy beyond dopamine D2R occupancy in psychosis treatment?
- (2)
- If antipsychotics tune the dopaminergic system by mechanisms other than the non-direct D2R-mediated one, what are the other non-canonical dopaminergic targets?
- (3)
- How do antipsychotics acting at D2R impact trans-synaptically other neurotransmitter systems, as well as synaptic and meta-synaptic plasticity?
- (4)
- Finally, how the next generation of antipsychotics now appearing on the landscape of schizophrenia treatment may regulate the dopaminergic system?
2. Materials and Methods
3. Results
3.1. Dopamine Receptors and Transporters: Canonical and Non-Canonical Mechanism of Action Relevant for Schizophrenia and Treatment-Resistant Schizophrenia
3.1.1. Dopamine D2 Receptors: Relevance for Treatment-Resistant Schizophrenia and Putative Link with Dopamine Supersensitivity Psychosis
3.1.2. The “Other” Dopamine D2-like Receptors, Dopamine Non-D2 Receptors and Their Non-Canonical Position in Antipsychotics’ Mechanism of Action
The Dopamine D3R
The Dopamine D4R
The Dopamine D1R
3.1.3. The Role of Presynaptic Dopaminergic Terminals and Dopamine Transporter
3.2. Dopaminergic Mechanisms and Correlations with Antipsychotics Receptor Profile: Insights from Present and Next Molecules
3.2.1. Dopamine and Serotonin Receptors
3.2.2. GABA Receptors
3.2.3. Noradrenergic Receptors
3.2.4. Muscarinic Receptors
3.2.5. Histamine Receptors
3.2.6. TAAR1
3.2.7. Dopamine-Antagonism and Glutamate-Based Augmentation of Antipsychotics
3.3. Dopamine Antagonism and Trans-Synaptic Effects at the Postsynaptic Density
3.4. Antipsychotics and PSD Modulation: A Relevant Non-Canonical Antipsychotic-Induced Effect?
3.4.1. Homer Proteins and Splicing Variants
Gene | Drug | D2/5HT2A Affinity Ratio | Dose | Duration | Effects on Gene Expression/Rat Brain Region | Brain Region of Interest | Reference |
---|---|---|---|---|---|---|---|
Homer 1a | Haloperidol | 0.00087 | 0.8 mg/kg | Acute treatment | ↑ in striatum | DMCP, DLCP, VMCP, VLCP, CAb, SAb | [283,284,286,287,288,289,291,292,293,294,295,296,297,298,299] |
↓ in cortex | ACC, MAC, MC, SS, IC | [286,289,292,296] | |||||
Chronic treatment (sacrifice after 90′ from last injection) | ↑ in striatum and cortex | DMCP, DLCP, VMCP, VLCP, CAb SAb, ACC, MAC, MC, SS, IC | [283,284,286,287,300] | ||||
↓ in cortex | MAC, MC, IC | [300] | |||||
Chronic treatment (sacrifice after 24 h from last injection) | ↑ in cortex | ACC, MAC, MC, SS, IC | [284] | ||||
0.25 mg/kg | Acute treatment | ↑ in striatum | DMCP, DLCP, VLCP | [288] | |||
Chronic treatment (sacrifice after 90′ from last injection) | ↑ in striatum | DLCP, VLCP, DMCP, SAb | [300] | ||||
0.5 mg/kg | Acute treatment | ↑ in striatum | DMCP, DLCP, VMCP, VLCP | [288] | |||
Chronic treatment (sacrifice after 90′ from last injection) | ↓ in cortex | MC | [300] | ||||
Haloperidol + Valproate | 0.8 mg/kg + 500 mg/kg | Acute treatment | ↑ in striatum | DMCP, DLCP, VMCP, VLCP, CAb | [289] | ||
Ziprasidone | 2.57 | 4 mg/kg | Acute treatment | ↑ in striatum | DMCP, DLCP, VMCP, VLCP | [284] | |
10 mg/kg | Acute treatment | ↑ in cortex and striatum | DMCP, DLCP, VMCP, VLCP, CAb, SAb, ACC, MC, SS, IC | ||||
Chronic treatment (sacrifice after 90′ from last injection) | ↑ in striatum | DLCP, VLCP, CAb SAb | |||||
Asenapine | 3.39 | 0.05 mg/kg | Acute treatment | ↑ in striatum and cortex | AC, M2, M1, SS, DMCP, DLCP, VMCP, VLCP, CAb | [288] | |
Chronic treatment (sacrifice after 90′ from last injection) | ↑ in striatum | DLCP | [300] | ||||
0.1 mg/kg | Acute treatment | ↑ in striatum and cortex | AC, M2, M1, SS, IC, DMCP, DLCP, VMCP, VLCP, CAb, SAb | [288] | |||
Chronic treatment (sacrifice after 90′ from last injection) | ↓ in cortex | IC | [300] | ||||
0.3 mg/kg | Acute treatment | ↑ in striatum | DMCP, DLCP, VMCP, VLCP, CAb, SAb | [288] | |||
Olanzapine | 1.00 | 2.5 mg/kg | Acute treatment | ↑ in striatum and cortex | AC, M2, M1, I, DMCP, DLCP, VMCP, VLCP, CAb, SAb | [288,290] | |
Chronic treatment (sacrifice after 90′ from last injection) | ↑ in striatum | DLCP, SAb | [286,300] | ||||
Sertindole | 5.37 | 2 mg/kg | Acute treatment | ↓ in striatum | SS, IC | ||
GBR 12909 | - | 15 mg/kg | Acute treatment | ↑ in cortex | SS | [283] | |
↑ in striatum and cortex | FC outer, FC inner, Cingulate cortex, DLCP, VMCP, VLCP, CAb, Sab | [287] | |||||
Chronic treatment (sacrifice after 90′ from last injection) | ↑ in cortex | SS | [283] | ||||
Aripiprazole | 0.0093 | 12 mg/kg | Acute treatment | ↑ in striatum | DMCP, DLCP, VMCP, VLCP | [287] | |
Chronic treatment (sacrifice after 90′ from last injection) | ↑ in striatum and cortex | FC inner, Cingulate cortex, DLCP, | |||||
30 mg/kg | Acute treatment | ↑ in cortex | FC outer, FC inner, Cingulate cortex, SAb | [287] | |||
Clozapine | 2.63 | 15 mg/kg | Acute treatment | ↑ in cortex | ACC, MAC, SS, IC | [284] | |
↑ in striatum | SAb | [287] | |||||
Chronic treatment (sacrifice after 90′ from last injection) | ↑ in cortex | FC inner, PC inner | |||||
Risperidone | 1.62 | 3 mg/kg | Acute treatment | ↑ in striatum | DLCP, VLCP | [290] | |
Sulpiride | - | 50 mg/kg | Acute treatment | ↑ in striatum | VLCP, CAb | [290] | |
Ketamine | - | 25 mg/kg | Acute treatment | ↑ in cortex | IC | [314] | |
GBR-12909 | - | 30 mg/kg | Acute treatment | ↑ in striatum | VMCP, SAb | [292] | |
Caffeine | - | 40 mg/kg | Acute treatment | ↑ in striatum | DMCP, SAb | [292] | |
Caffeine +. Haloperidol | - | 40 mg/kg + 0.8 mg/kg | Acute treatment | ↓ in striatum | DMCP, VMCP | [292] | |
Nicotine + Haloperidol | - | 1.5 mg/kg+ 0.8 mg/kg | Acute treatment | ↑ in striatum | DMCP, CAb, SAb | [292] | |
Escitalopram | - | 12 mg/kg | Acute treatment | ↑ in cortex | outer parietal cortex | [293] | |
Citalopram | - | 14 mg/kg | Acute treatment | ↓ in cortex | M1, SS, IC | [289] | |
Haloperidol + Escitalopram | - | 0.8 mg/kg + 12 mg/kg | Acute treatment | ↑ in striatum and cortex | outer parietal cortex, DLCP, VLCP, CAb | [293] | |
Haloperidol + Citalopram | - | 0.8 mg/kg + 14 mg/kg | Acute treatment | ↑ in striatum and cortex | outer parietal cortex, DLCP, VLCP, DMCP, VMCP, CAb | [293] | |
Amisulpride | 0.00078 | 35 mg/kg | Chronic treatment (sacrifice after 90′ from last injection) | ↑ in striatum and cortex | VMCP, DMCP, ACC, MAC, MC, SS, IC | [295] | |
Acute treatment | ↑ in striatum | VMCP, DMCP | [298] | ||||
Ketamine | - | 50 mg/kg | Acute treatment | ↑ in striatum | VMCP, VLCP | [315] | |
Ketamine | - | 12 mg/kg | Acute treatment | ↑ in striatum | CAb, SAb | [315] | |
SCH-23390 | - | 0.5 mg/kg | Acute treatment | ↑ in striatum and cortex | VLCP, CAb, SAb, MAC, MC | [296] | |
L-741,626 | - | 2 mg/kg | Acute treatment | ↑ in striatum and cortex | VMCP, DMCP, VLCP, DLCP, CAb, SAb, MAC, MC | [296] | |
U-99194 | - | 5 mg/kg | Acute treatment | ↑ in cortex | MAC, MC | [296] | |
Terguride | - | 0.5 mg/kg | Acute treatment | ↑ in striatum | VLCP, DLCP | [296] | |
↓ in cortex | MC | ||||||
Quetiapine | 0.35 | 30 mg/kg | Acute treatment | ↑ in cortex | ACC, M2, M1 | [289] | |
Chronic treatment (sacrifice after 90′ from last injection) | ↓ in cortex | M2, M1, SS | |||||
15 mg/kg | Chronic treatment (sacrifice after 90′ from last injection) | ↓ in cortex | M2, M1, SS | ||||
Haloperidol + Mynocycline | - | 0.8 mg/kg + 45 mg/kg | Acute treatment | ↑ in striatum | VMCP, DMCP, DLCP | [299] | |
Homer 1b/c | Ziprasidone | 2.57 | 10 mg/kg | Chronic treatment (sacrifice after 24 h from last injection) | ↑ in striatum | DLCP | [284] |
Haloperidol | 0.00087 | 0.25 mg/kg | Acute treatment | ↑ in striatum | CAb | [288] | |
0.5 mg/kg | ↑ in striatum and cortex | M1, CAb | |||||
0.8 mg/kg | ↑ in striatum and cortex | AC, M2, M1, CAb | |||||
0.8 mg/kg | Chronic treatment (sacrifice after 90′ from last injection) | ↑ in striatum and cortex | DLCP, VMCP, VLCP, CAb, Sab, ACC, MAC, SS, IC | [286] | |||
↓ in striatum and cortex | VMCP, DMCP, MAC | [300] | |||||
Asenapine | 3.39 | 0.1 mg/kg | Acute treatment | ↑ in striatum and cortex | AC, M2, M1, CAb | [288] | |
0.3 mg/kg | |||||||
Olanzapine | 1.00 | 2.5 mg/kg | Acute treatment | ↑ in striatum and cortex | AC, M2, M1, CAb | ||
Sertindole | 5.37 | 2 mg/kg | Chronic treatment (sacrifice after 90′ from last injection) | ↑ in cortex | ACC, MAC, SS, IC | [286] | |
Ketamine | - | 25 mg/kg | Acute treatment | ↓ in cortex | MC | ||
Ketamine | - | 50 mg/kg | Acute treatment | ↓ in striatum and cortex | MAC, MC, DLCP | [314] | |
GBR-12909 | - | 30 mg/kg | Acute treatment | ↑ in striatum and cortex | ACC, MAC, MC, SS, IC, VMCP, DMCP, DLCP | [292] | |
Nicotine | - | 1.5 mg/kg | Acute treatment | ↑ in striatum and cortex | MAC, SS, DMCP, VMCP, CAb, SAb | [292] | |
Caffeine +. Haloperidol | - | 40 mg/kg + 0.8 mg/kg | Acute treatment | ↑ in striatum | MAC, SS | [292] | |
Nicotine + Haloperidol | - | 1.5 mg/kg + 0.8 mg/kg | Acute treatment | ↑ in striatum | ACC, MAC, MC, SS, IC, VMCP, DMCP, DLCP, CAb, SAb | [292] | |
SCH-23390 | - | 0.5 mg/kg | Acute treatment | ↑ in striatum | CAb | [296] | |
↓ in cortex | MC | ||||||
L-741,626 | - | 2 mg/kg | Acute treatment | ↓ in striatum and cortex | VLCP, SAb, MC, SS, IC | [296] | |
L-745,870 | - | 3 mg/kg | Acute treatment | ↓ in striatum and cortex | VMCP, VLCP, SAb, MC, SS | [296] | |
Terguride | - | 0.5 mg/kg | Acute treatment | ↓ in striatum and cortex | VMCP, VLCP, CAb, SAb, MC, SS, IC | [296] | |
PSD-95 | Ziprasidone | 2.57 | 10 mg/kg | Chronic treatment (sacrifice after 90′ from last injection) | ↑ in striatum | DMCP, DLCP, VMCP, VLCP, CAb, SAb | [284] |
Chronic treatment (sacrifice after 24 h from last injection) | ↑ in striatum and cortex | VMCP, ACC, MAC, MC | |||||
Haloperidol | 0.00087 | 0.25 mg/kg | Chronic treatment (sacrifice after 90′ from last injection) | ↓ in cortex | ACC, MAC, MC, SS, IC | [300] | |
0.5 mg/kg | Acute treatment | ↑ in cortex | AC, M1 | [288] | |||
0.8 mg/kg | ↑ in striatum and cortex | ACC, M2, M1, I, DMCP, DLCP, VMCP, CAb, SAb | |||||
Chronic treatment (sacrifice after 90′ from last injection) | ↑ in striatum and cortex | DMCP, DLCP, VMCP, VLCP, CAb, SAb, ACC, MC, SS | [284,286] | ||||
↓ in cortex | ACC, MAC, MC, SS | [300] | |||||
Chronic treatment (sacrifice after 24 h from last injection) | ↑ in cortex | ACC, MAC, MC | [284] | ||||
Asenapine | 3.39 | 0.05 mg/kg | Acute treatment | ↑ in striatum and cortex | AC, M2, M1, SS, I, DMCP, DLCP, VMCP, VLCP, CAb, SAb | [288] | |
0.1 mg/kg | Acute treatment | ↑ in striatum and cortex | AC, M2, M1, SS, I, DMCP, DLCP, VMCP, VLCP, CAb, SAb | [288] | |||
Chronic treatment (sacrifice after 90′ from last injection) | ↓ in cortex | ACC, MAC, MC, SS, IC | [300] | ||||
0.3 mg/kg | Acute treatment | ↑ in striatum and cortex | ACC, M2, M1, SS, I, DMCP, DLCP, VMCP, VLCP, CAb, SAb | [288] | |||
Olanzapine | 1.00 | 2.5 mg/kg | Acute treatment | ↑ in striatum and cortex | ACC, M2, M1, SS, I, DMCP, DLCP, VMCP, VLCP, CAb, SAb | [288] | |
Ketamine | - | 25 mg/kg | Acute treatment | ↓ in striatum | VMCP | [314] | |
Ketamine | - | 50 mg/kg | Acute treatment | ↓ in striatum | VMCP | [314] | |
MK-801 | - | 0.8 mg/kg | Acute treatment | ↓ in striatum | VMCP, VLCP | [314] | |
Haloperidol + Valproate | - | 0.8 mg/kg + 500 mg/kg | Acute treatment | ↑ in striatum and cortex | ACC, SS, DMCP | [289] | |
Quetiapine | 0.35 | 15 mg/kg | Acute treatment | ↓ in cortex | M2, M1 | [289] | |
Citalopram | - | 14 mg/kg | Acute treatment | ↑ in striatum and cortex | ACC, M2, SS, IC, DMCP, DLCP, VMCP, VLCP, CAb, SAb | [289] | |
IP3R | Haloperidol | 0.00087 | 0.8 mg/kg | Chronic treatment (sacrifice after 24 h from last injection) | ↑ in cortex | MAC | [284] |
Ziprasidone | 2.57 | 10 mg/kg | |||||
Arc | Haloperidol | 0.00087 | 0.25 mg/kg | Acute treatment | ↓ in cortex | M2, M1, SS, I | [288] |
Chronic treatment (sacrifice after 90′ from last injection) | ↓ in cortex | ACC, MAC, MC, SS, IC | [300] | ||||
0.5 mg/kg | Acute treatment | ↑ in striatum | DLCP, VLCP, CAb, SAb | [286] | |||
Chronic treatment (sacrifice after 90′ from last injection) | ↓ in cortex | ACC; MAC, MC, SS | [300] | ||||
0.8 mg/kg | Acute treatment | ↑ in striatum | DMCP, VMCP, DLCP, VLCP, CAb, SAb | [286,298,299] | |||
↓ in cortex | AC, M2, SS | [286] | |||||
Chronic treatment (sacrifice after 90′ from last injection) | ↓ in cortex | ACC; MAC, MC, SS | [300] | ||||
Asenapine | 3.39 | 0.1 mg/kg | Acute treatment | ↓ in cortex | AC, M2, M1 | [288] | |
Chronic treatment (sacrifice after 90′ from last injection) | ↓ in cortex | MC, SS, IC | [300] | ||||
0.3 mg/kg | Acute treatment | ↑ in striatum | DLCP, VLCP, CAb | [288] | |||
Chronic treatment (sacrifice after 90′ from last injection) | ↓ in cortex and stritum | MAC, MC, SS, IC, VMCP | [300] | ||||
0.05 mg/kg | Chronic treatment (sacrifice after 90′ from last injection) | ↑ in striatum | DLCP | [300] | |||
Ketamine | - | 25 mg/kg | Acute treatment | ↑ in cortex | MAC, MC, SS, IC | [314] | |
Ketamine | - | 50 mg/kg | Acute treatment | ↑ in cortex | ACC, MAC, MC, SS, IC, CAb, SAb | [314] | |
Memantine | - | 5 mg/kg | Acute treatment | ↑ in cortex | MAC | [314] | |
MK-801 | - | 0.8 mg/kg | Acute treatment | ↑ in cortex | ACC, SS, CAb, SAb | [314] | |
Caffeine | - | 40 mg/kg | Acute treatment | ↓ in cortex and striatum | IC, DMCP, VMCP, VLCP, CAb | [292] | |
Nicotine | - | 1.5 mg/kg | Acute treatment | ↓ in cortex and striatum | MC, IC, VMCP | [292] | |
GBR-12909 | - | 30 mg/kg | Acute treatment | ↑ in striatum | CAb | [292] | |
Caffeine | - | 40 mg/kg | Acute treatment | ↓ in striatum | IC, DMCP, VMCP, VLCP, CAb | [292] | |
Caffeine +. Haloperidol | - | 40 mg/kg + 0.8 mg/kg | Acute treatment | ↓ in cortex and striatum | MC, SS, IC, VMCP, CAb | [292] | |
Nicotine + Haloperidol | - | 1.5 mg/kg + 0.8 mg/kg | Acute treatment | ↑ in striatum | DMCP, CAb | [292] | |
Olanzapine | 1.00 | 2.5 mg/kg | Chronic treatment (sacrifice after 90′ from last injection) | ↓ in cortex and striatum | ACC, MAC, MC, SS, IC, DMCP, VMCP | [300] | |
Mynocycline | - | 45 mg/kg | Acute treatment | ↑ in striatum | DMCP, DLCP, VMCP, VLCP, SAb | [300] | |
Haloperidol + Mynocycline | - | 0.8 mg/kg + 45 mg/kg | Acute treatment | ↑ in striatum | ACC, MAC, MC, SS, IC, DMCP, DLCP, VLCP | [300] | |
c-Fos | Haloperidol | 0.00087 | 0.25 mg/kg | Acute treatment | ↑ in striatum | VMCP, DLCP, SAb | [288] |
0.5 mg/kg | VMCP, DLCP, VLCP, SAb | ||||||
0.8 mg/kg | DMCP, DLCP, VMCP, VLCP, CAb, SAb | [283,288,297] | |||||
Haloperidol + D-cycloserine | - | 0.8 mg/kg + 20 mg/kg | Acute treatment | ↑ in striatum | DLCP, CAb, SAb | [297] | |
Clozapine+ D-cycloserine | - | 15 mg/kg + 20 mg/kg | Acute treatment | ↑ in striatum | DLCP, CAb, SAb | [297] | |
Clozapine | 2.63 | 15 mg/kg | Acute treatment | ↑ Nucleus accumbens | CAb, SAb | [297] | |
Asenapine | 3.39 | 0.3 mg/kg | Acute treatment | ↑ in striatum | DMCP, DLCP, VMCP, VLCP, CAb, SAb | [288] | |
Olanzapine | 1.00 | 2.5 mg/kg | Acute treatment | ↑ in striatum | VMCP, VLCP | [288] | |
MK-801 | - | 0.8 mg/kg | Acute treatment | ↑ in cortex | ACC, SS, IC | [314] | |
Ketamine | - | 25 mg/kg | Acute treatment | ↑ in cortex | IC | [314] | |
Ketamine | - | 50 mg/kg | Acute treatment | ↑ in cortex | MAC, IC | [314] | |
Memantine | - | 5 mg/kg | Acute treatment | ↑ in cortex | MAC, SS | [314] | |
Amisulpride | 0.00078 | 10 mg/kg | Acute treatment | ↑ in striatum | DMCP, VMCP | [298] | |
35 mg/kg | Acute treatment | ↑ in striatum | DMCP, VMCP | [298] | |||
Zif-268 | Haloperidol | 0.00087 | 0.25 mg/kg | Acute treatment | ↑ in striatum | DMCP, DLCP, VMCP, VLCP, SAb | [288] |
0.5 mg/kg | ↑ in striatum | DMCP, DLCP, VMCP, VLCP, CAb, SAb | [288] | ||||
0.8 mg/kg | ↑ in striatum and cortex | DMCP, DLCP, VMCP, VLCP, CAb, SAb, M1, SS, IC | [288,298] | ||||
Asenapine | 3.39 | 0.05 mg/kg | Acute treatment | ↑ in striatum | DMCP, DLCP, VMCP, VLCP, SAb | [288] | |
0.1 mg/kg | |||||||
0.3 mg/kg | |||||||
Olanzapine | 1.00 | 2.5 mg/kg | Acute treatment | ↑ in striatum | DLCP, VLCP, SAb | [288] | |
Amisulpride | 0.00078 | 10 mg/kg | Acute treatment | ↑ in striatum | DMCP, VMCP | [272] | |
35 mg/kg | Acute treatment | ↑ in striatum and cortex | DMCP, VMCP, ACC, M1 | [298] | |||
Ania-3 | Haloperidol | 0.00087 | 0.8 mg/kg | Acute treatment | ↑ in striatum and cortex | DMCP, DLCP, VMCP, VLCP, SAb, ACC, MAC | [288] |
↑ in striatum | DMCP, DLCP, VMCP, VLCP, SAb, CAb | [257,260,261,267] | |||||
Chronic treatment (sacrifice after 90′ from last injection) | ↑ in striatum | DMCP, DLCP, VMCP, VLCP, CAb | [283,287] | ||||
GBR 12909 | - | 15 mg/kg | Acute treatment | ↑ in cortex and striatum | M2, M1, DMCP, VMCP, VLCP, SAb, PC outer, PC inner, DLCP | [283,287] | |
Chronic treatment (sacrifice after 90′ from last injection) | ↑ cortex | SS | |||||
Quetiapine | 0.35 | 30 mg/kg | Chronic treatment (sacrifice after 90′ from last injection) | ↑ in striatum | SAb | [283] | |
Aripiprazole | 0.0093 | 12 mg/kg | Acute treatment | ↑ in striatum | DMCP, DLCP, VMCP, VLCP | [287] | |
Chronic treatment (sacrifice after 90′ from last injection) | ↑ in striatum | DLCP, VLCP | |||||
Haloperidol + Escitalopram | - | 0.8 mg/kg + 12 mg/kg | Acute treatment | ↑ in striatum and cortex | Inner frontal cortex, DLCP, VLCP | [293] | |
Haloperidol + Citalopram | - | 0.8 mg/kg + 14 mg/kg | Acute treatment | ↑ in striatum | DLCP, VLCP, | [293] | |
Amisulpride | 0.00078 | 10 mg/kg | Acute treatment | ↓ in cortex | M1 | [298] | |
35 mg/kg | Acute treatment | ↑ in striatum | DMCP, VMCP | [298] | |||
mGluR5 | Haloperidol | 0.00087 | 0.8 mg/kg | Chronic treatment (sacrifice after 90′ from last injection) | ↑ in striatum and cortex | DMCP, DLCP, VMCP, ACC, MC | [286] |
Sertindole | 5.37 | 2 mg/kg | Chronic treatment (sacrifice after 90′ from last injection) | ↑ in striatum and cortex | DMCP, DLCP, VMCP, ACC, MC | [286] | |
SCH-23390 | - | 0.5 mg/kg | Acute treatment | ↑ in striatum and hippocampus | DMCP, CAb, CA3, DG | [296] | |
αCaMKII | Haloperidol | 0.00087 | 0.8 mg/kg | Chronic treatment (sacrifice after 90′ from last injection) | ↓ in cortex | MC | [286] |
Ketamine | - | 12 mg/kg | Acute treatment | ↑ in striatum and brainstem | DMCP, DLCP, VMCP, VLCP, CAb, SAb, SNc and VTA | [315] | |
Homer 2 | Haloperidol | 0.00087 | 0.8 mg/kg | Chronic treatment (sacrifice after 90′ from last injection) | ↑ in lateral Septum | Intermediate and ventral septum | [287] |
Clozapine | 2.63 | 15 mg/kg | Chronic treatment (sacrifice after 90′ from last injection) | ↑ in lateral Septum | Intermediate septum | [287] | |
DAT | Ketamine Ketamine | - | 12 mg/kg | Acute treatment | ↑ in brainstem | SNc and VTA | [315] |
50 mg/kg | |||||||
Shank1 | Haloperidol | 0.00087 | 0.25 mg/kg | Chronic treatment (sacrifice after 90′ from last injection) | ↓ in cortex | ACC, IC | |
0.5 mg/kg | ↓ in cortex | ACC, IC | [300] | ||||
Asenapine | 3.39 | 0.05 mg/kg | Chronic treatment (sacrifice after 90′ from last injection) | ↓ in cortex and striatum | ACC, IC, VMCP, VLCP, DMCP, DLCP, CAb, SAb | [300] | |
0.1 mg/kg | ↓ in cortex | ACC, IC | [300] | ||||
0.3 mg/kg | ↓ in cortex | IC | [300] | ||||
ERK | Valproate | - | 500 mg/kg | Acute treatment | ↑ in striatum and cortex | ACC, M2, M1, SS, VMCP, VLCP, DMCP, DLCP, SAb | [289] |
Haloperidol + Valproate | - | 0.8 mg/kg + 500 mg/kg | Acute treatment | ↑ in striatum and cortex | ACC, M2, M1, SS, IC, VMCP, VLCP, DMCP, DLCP | [289] | |
Quetiapine + Valproate | - | 30 mg/kg + 500 mg/kg | Acute treatment | ↑ in striatum and cortex | ACC, M2, M1, SS, DMCP, DLCP, VMCP, SAb | [289] | |
Norbin | Haloperidol | 0.00087 | 0.8 mg/kg | Acute treatment | ↑ in striatum and cortex | VLCP, DLCP, IC | [298] |
3.4.2. PSD-95
3.4.3. Shank Proteins
3.4.4. Dopamine Regulation of Key Early Genes
Activity-Regulated Cytoskeleton-Associated Protein
The Immediate Early Genes c-Fos and Zif-268
3.5. Intracellular Mechanisms and Antipsychotics Signaling: Non-Canonical D2R Druggable Targets in Schizophrenia
3.5.1. Modulation of Neuroprotective Molecules as Targets in Schizophrenia
Antipsychotic Modulation of Neuroprotective Processes
Antipsychotic Treatment | Molecular Targets | Dopaminergic Modulation | Molecular Mechanism | Biological Role | References |
---|---|---|---|---|---|
Aripiprazole | Akt Thr308 and Ser473 and GSK-3β Ser9 phosphorylation | D2R-signaling | AKT-GSK-3β cascade | Neuroprotective action | [273,390] |
Aripiprazole, haloperidol | decrease D2R-DISC1 complexes | D2R-signaling | DISC1 | Neuroprotective action | [387] |
Clozapine | BDNF-CREB | D2R-signaling | decreased Akt activity and phosphorylation of GSK3 | Neuronal survival and regulation of synaptic plasticity | [390,412,413] |
NMDAR | DAT | Akt-GSK3 | Neuroprotective action | [422,423] | |
Akt Thr308 and Ser473 and GSK-3β Ser9 phosphorylation | D2R-signaling | Akt-GSK-3β cascade | Neuroprotective action | [273,390] | |
Clozapine, olanzapine, quetiapine | ErbB kinases, PIK3CD | D2R-signaling | ErbB4-PI3K-Akt pathway | Antiproliferative, neuroprotective action | [424] [425] |
Haloperidol | Akt Thr308 and Ser473 and GSK-3β Ser9 phosphorylation. | D2R-signaling | Akt-GSK-3β cascade | Neuroprotective action | [273,390] |
ERK1/2 | D2R-signaling | Akt/mTOR pathway | Neuroprotective action | [426] | |
Lumateperone | NMDA and AMPA receptors | D1R-signaling | mTOR pathway | Neuroprotective role | [426] |
3.5.2. Neuroinflammation Mechanisms in Schizophrenia
3.5.3. Antipsychotics and Their Potential Anti-Inflammatory Effects
3.6. Intracellular Signaling in Schizophrenia: Implication for Dopamine Transmission
Antipsychotic Modulation of Dopamine Intracellular Signaling
3.7. An Emerging Field: The Repositioning of Antipsychotics in Medicine Implication for Non-Canonical Mechanisms
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
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de Bartolomeis, A.; Ciccarelli, M.; De Simone, G.; Mazza, B.; Barone, A.; Vellucci, L. Canonical and Non-Canonical Antipsychotics’ Dopamine-Related Mechanisms of Present and Next Generation Molecules: A Systematic Review on Translational Highlights for Treatment Response and Treatment-Resistant Schizophrenia. Int. J. Mol. Sci. 2023, 24, 5945. https://doi.org/10.3390/ijms24065945
de Bartolomeis A, Ciccarelli M, De Simone G, Mazza B, Barone A, Vellucci L. Canonical and Non-Canonical Antipsychotics’ Dopamine-Related Mechanisms of Present and Next Generation Molecules: A Systematic Review on Translational Highlights for Treatment Response and Treatment-Resistant Schizophrenia. International Journal of Molecular Sciences. 2023; 24(6):5945. https://doi.org/10.3390/ijms24065945
Chicago/Turabian Stylede Bartolomeis, Andrea, Mariateresa Ciccarelli, Giuseppe De Simone, Benedetta Mazza, Annarita Barone, and Licia Vellucci. 2023. "Canonical and Non-Canonical Antipsychotics’ Dopamine-Related Mechanisms of Present and Next Generation Molecules: A Systematic Review on Translational Highlights for Treatment Response and Treatment-Resistant Schizophrenia" International Journal of Molecular Sciences 24, no. 6: 5945. https://doi.org/10.3390/ijms24065945