Negative allosteric modulation of metabotropic glutamate receptor 5 attenuates alcohol self-administration in baboons.
Pharmacol Biochem Behav
; 208: 173227, 2021 09.
Article
em En
| MEDLINE
| ID: mdl-34224733
ABSTRACT
Many of the behavioral symptoms that define alcohol use disorder (AUD) are thought to be mediated by amplified glutamatergic activity. As a result, previous preclinical studies have investigated glutamate receptor inhibition as a potential pharmacotherapy for AUD, particularly the metabotropic glutamate receptor 5 (mGlu5). In rodents, mGlu5 negative allosteric modulators (NAMs) have been shown to decrease alcohol self-administration. However, their effect on non-human primates has not previously been explored. To bridge this gap, the effects of mGlu5 NAM pretreatment on sweetened alcohol (8% w/v in diluted KoolAid) self-administration in female baboons were evaluated. Two different mGlu5 NAMs were tested 1) 3-2((-Methyl-4-thiazolyl) ethynyl) pyridine (MTEP) which was administered at a dose of 2 mg/kg IM; and 2) auglurant (N-(5-fluoropyridin-2-yl)-6-methyl-4-(pyrimidin-5-yloxy)picolinamide), a newly developed NAM, which was tested under two different routes (0.001, 0.01, 0.03, 0.1 mg/kg IM and 0.1, 0.3, 1.0 mg/kg PO). MTEP decreased both fixed ratio and progressive ratio responding for sweetened alcohol. Auglurant, administered IM, decreased alcohol self-administration at doses that did not affect self-administration of an alcohol-free sweet liquid reward (0.01 to 0.1 mg/kg). Oral administration of auglurant was not effective in decreasing alcohol self-administration. Our results extend positive findings from rodent studies on mGlu5 regulation of alcohol drinking to female baboons and further strengthen the rationale for targeting mGlu5 in clinical trials for AUD.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Ácidos Picolínicos
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Piridinas
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Tiazóis
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Alcoolismo
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Receptor de Glutamato Metabotrópico 5
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Aminopiridinas
Limite:
Animals
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Female
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Humans
Idioma:
En
Revista:
Pharmacol Biochem Behav
Ano de publicação:
2021
Tipo de documento:
Article