Ibudilast attenuates cocaine self-administration and prime- and cue-induced reinstatement of cocaine seeking in rats.
Neuropharmacology
; 201: 108830, 2021 12 15.
Article
em En
| MEDLINE
| ID: mdl-34626665
ABSTRACT
Ibudilast is a non-selective phosphodiesterase (PDE) inhibitor and glial cell modulator which has shown great promise for the treatment of drug and alcohol use disorders in recent clinical studies. However, it is unknown whether and how ibudilast affects cocaine seeking behavior. Here we show that systemic administration of ibudilast dose-dependently reduced cocaine self-administration under fixed- and progressive-ratio reinforcement schedules in rats and shifted cocaine dose-response curves downward. In addition, ibudilast decreased cocaine prime- and cue-induced reinstatement of cocaine seeking. These results indicate that ibudilast was effective in reducing the reinforcing effects of cocaine and relapse to cocaine seeking. Chronic cocaine exposure induces cAMP-related neuroadaptations in the reward circuitry of the brain. To investigate potential mechanisms for ibudilast-induced attenuation of cocaine self-administration, we recorded from ventral tegmental area (VTA) dopamine neurons in ex vivo midbrain slices prepared from rats that had undergone saline and cocaine self-administration. We found cocaine self-administration led to a decrease in inhibitory postsynaptic currents (IPSCs), an increase in the AMPAR/NMDAR ratio, and an increase in the excitation to inhibition (E/I) ratio. Ibudilast pretreatments enhanced GABAergic inhibition and did not further change cocaine-induced potentiation of excitation, leading to normalization of the E/I ratio. Restoration of the balance between excitation and inhibition in VTA dopamine neurons may contribute to the attenuation of cocaine self-administration by ibudilast.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Inibidores de Fosfodiesterase
/
Piridinas
/
Esquema de Reforço
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Comportamento Animal
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Cocaína
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Transtornos Relacionados ao Uso de Cocaína
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Sinais (Psicologia)
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Comportamento de Procura de Droga
Tipo de estudo:
Etiology_studies
Limite:
Animals
Idioma:
En
Revista:
Neuropharmacology
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Estados Unidos