Table 3.
Summary table of the main characteristics of neurotransmitter systems involved in LIDs.
| Neurotransmitter | Receptor | Therapeutic Target | Effect on LIDs | |
|---|---|---|---|---|
| Serotonergic system | Serotonin | 5-HT1A 5-HT1B |
5-HT1A and 5-HT1B Receptor Agonists | - Density of serotonergic terminals in the striatum directly correlates with the severity of LIDs - Serotonergic neurons convert exogenous levodopa into dopamine and release it without autoregulatory feedback |
| 5-HT2A 5-HT2C |
5-HT2A Receptors Antagonists | |||
| 5-HT3 |
|
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| Glutamatergic system | Glutamate | mGluR | MGluR antagonist | - Altered trafficking - Hyperactive |
| NMDA | NMDA receptor antagonist (GluN2A/B subunit) | - Altered trafficking - Alteration of subunit composition - Supersensitivity in the putamen following long-term levodopa |
||
| AMPA | AMPA receptor antagonist | - Altered trafficking - Increased index of rectification (IR) of AMPA current in striatal medium spiny neurons - Increased activity of Ca2+ -permeable AMPAR due to hyperphosphorylation of GluR1 subunit |
||
| Noradrenergic system | Noradrenaline | α-1/2 | α receptor antagonist | - NA loss causes parkinsonism and spontaneous dyskinesias in DBH knock-out mice - NA infusion in the striatum promotes LID in hemiparkinsonian rats - NAT activity should re-uptake DA and reduce LIDs - Controversial evidence |
| β-1/2 | β receptor antagonist | |||
| Cholinergic system | Acetylcholine | nAChR (α4β2* and α6β2* subtypes) | β2* nAChR agonist | β2 subtype reduces LIDs, but nAChR vary over the course of PD |
| mAChR (m1 to m5) | Variable results with muscarinic antagonists | Not established | ||
| Opioid system | Enkephalin | δ | δ—receptor selective antagonist | - Elevated levels of dynorphin B, α-neoendorphin and Dynorphin A in the dorsolateral striatum and SN - μ and δ receptors promote LIDs - κ receptor reduces LIDs |
| β-endorphin Endomorphin |
μ | μ—receptor selective antagonist | ||
| Dynorphin A Dynorphin B α-neoendorphin β-neoendorphin |
κ | κ—receptor selective agonist | ||
| Endocannabinoid system | Anandamide 2-AG |
CB1/2 | CB-receptor agonist | - The stimulation of the CB1 receptors reduces LIDs by: ● Desensitization of DA receptors ● Normalizing aberrant glutamate release - Net anti-dyskinetic effect - CB1 receptors can also promote LIDs by dopamine synthesis in serotonergic raphe-striatal fibers |
| TRP | Not established | Not established | ||
| PPAR | Not established | Not established | ||
| Adenosinergic system | Adenosine | A2A | - A2A receptor antagonist | - Not clearly established, but the activation of this receptor in the striatum regulates amplification of dopamine and glutamate release - A direct anti-dyskinetic effect seems unlikely |
| A2B | Not established | Not established (poorly expressed in CNS) | ||
| A3 | Not established | Not established (poorly expressed in CNS) |