Article ; Online: The selective 5-HT 1A receptor agonist, NLX-112, overcomes tetrabenazine-induced catalepsy and depression-like behavior in the rat.
2022 Volume 33, Issue 5, Page(s) 333–341
Abstract: Tetrabenazine, a preferential inhibitor of the vesicular monoamine transporter type 2, depletes the brain monoamines dopamine, serotonin and norepinephrine. Tetrabenazine and deutetrabenazine (Austedo ®) are used to treat chorea associated with ... ...
| Abstract | Tetrabenazine, a preferential inhibitor of the vesicular monoamine transporter type 2, depletes the brain monoamines dopamine, serotonin and norepinephrine. Tetrabenazine and deutetrabenazine (Austedo ®) are used to treat chorea associated with Huntington's disease. However, both compounds are known to aggravate Parkinsonism and depression observed in Huntington's disease patients. NLX-112 (a.k.a. befiradol/F13640) is a highly selective, potent and efficacious serotonin 5-HT 1A agonist. In animal models, it has robust efficacy in combating other iatrogenic motor disorders such as L-DOPA-induced dyskinesia and has marked antidepressant-like activity in rodent tests. In the present study, we investigated, in rats, the efficacy of NLX-112 to counteract tetrabenazine-induced catalepsy (a model of Parkinsonism) and tetrabenazine-induced potentiation of immobility in the forced swim test (FST, a model to detect antidepressant-like activity). The prototypical 5-HT 1A agonist, (±)8-OH-DPAT, and the 5-HT 1A partial agonist/dopamine D2 receptor blocker, buspirone, were used as comparators. Both NLX-112 and (±)8-OH-DPAT (0.16-2.5 mg/kg p.o. or s.c., respectively) abolished catalepsy induced by tetrabenazine (2 mg/kg i.p.). In comparison, buspirone (0.63-5.0 mg/kg p.o.) was ineffective and even tended to potentiate tetrabenazine-induced catalepsy at 0.63 mg/kg. In the FST, NLX-112 and (±)8-OH-DPAT (0.63 mg/kg) strongly reduced immobility when administered alone but also significantly opposed potentiation of immobility induced by tetrabenazine (1.5 mg/kg i.p.). Buspirone (0.63 and 2.5 mg/kg p.o.) had no effect by itself or against tetrabenazine. These results strongly suggest that selective and highly efficacious 5-HT 1A agonists, such as NLX-112, may be useful in combating tetrabenazine-induced Parkinsonism and/or depression in Huntington's disease patients. |
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| MeSH term(s) | 8-Hydroxy-2-(di-n-propylamino)tetralin/pharmacology ; Animals ; Antidepressive Agents/pharmacology ; Buspirone/pharmacology ; Catalepsy/chemically induced ; Catalepsy/drug therapy ; Depression/chemically induced ; Depression/drug therapy ; Huntington Disease/chemically induced ; Huntington Disease/drug therapy ; Parkinsonian Disorders ; Piperidines ; Pyridines ; Rats ; Receptor, Serotonin, 5-HT1A ; Serotonin ; Serotonin 5-HT1 Receptor Agonists/pharmacology ; Serotonin Receptor Agonists/pharmacology ; Tetrabenazine |
| Chemical Substances | Antidepressive Agents ; Piperidines ; Pyridines ; Serotonin 5-HT1 Receptor Agonists ; Serotonin Receptor Agonists ; Receptor, Serotonin, 5-HT1A (112692-38-3) ; Serotonin (333DO1RDJY) ; 8-Hydroxy-2-(di-n-propylamino)tetralin (78950-78-4) ; befiradol (RAT9OHA1YH) ; Buspirone (TK65WKS8HL) ; Tetrabenazine (Z9O08YRN8O) |
| Language | English |
| Publishing date | 2022-06-09 |
| Publishing country | England |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 1027374-8 |
| ISSN | 1473-5849 ; 0955-8810 |
| ISSN (online) | 1473-5849 |
| ISSN | 0955-8810 |
| DOI | 10.1097/FBP.0000000000000681 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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