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1.
Biol Psychiatry ; 79(6): 430-42, 2016 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-25579851

RESUMEN

BACKGROUND: Despite worldwide consumption of moderate amounts of alcohol, the neural mechanisms that mediate the transition from use to abuse are not fully understood. METHODS: Here, we conducted a high-throughput screen of the amygdala proteome in mice after moderate alcohol drinking (n = 12/group) followed by behavioral studies (n = 6-8/group) to uncover novel molecular mechanisms of the positive reinforcing properties of alcohol that strongly influence the development of addiction. RESULTS: Two-dimensional difference in-gel electrophoresis with matrix assisted laser desorption ionization tandem time-of-flight identified 29 differentially expressed proteins in the amygdala of nondependent C57BL/6J mice following 24 days of alcohol drinking. Alcohol-sensitive proteins included calcium/calmodulin-dependent protein kinase II alpha (CaMKIIα) and a network of functionally linked proteins that regulate neural plasticity and glutamate-mediated synaptic activity. Accordingly, alcohol drinking increased α-amino-3-hydroxy-5-methyl-4-isooxazole receptor (AMPAR) in central amygdala (CeA) and phosphorylation of AMPAR GluA1 subunit at a CaMKII locus (GluA1-Ser831) in CeA and lateral amygdala. Further, CaMKIIα-Thr286 and GluA1-Ser831 phosphorylation was increased in CeA and lateral amygdala of mice that lever-pressed for alcohol versus the nondrug reinforcer sucrose. Mechanistic studies showed that targeted pharmacologic inhibition of amygdala CaMKII or AMPAR activity specifically inhibited the positive reinforcing properties of alcohol but not sucrose. CONCLUSIONS: Moderate alcohol drinking increases the activity and function of plasticity-linked protein networks in the amygdala that regulate the positive reinforcing effects of the drug. Given the prominence of positive reinforcement in the etiology of addiction, we propose that alcohol-induced adaptations in CaMKIIα and AMPAR signaling in the amygdala may serve as a molecular gateway from use to abuse.


Asunto(s)
Consumo de Bebidas Alcohólicas/efectos adversos , Amígdala del Cerebelo/metabolismo , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Etanol/farmacología , Receptores AMPA/metabolismo , Animales , Ácido Glutámico/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Plasticidad Neuronal/efectos de los fármacos , Fosforilación/efectos de los fármacos , Proteoma/metabolismo , Transducción de Señal/efectos de los fármacos
2.
Psychopharmacology (Berl) ; 232(18): 3417-30, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-26123321

RESUMEN

RATIONALE: Extracellular-signal regulated protein kinase (ERK1/2) is activated by ethanol in reward-related brain regions. Accordingly, systemic inhibition of ERK1/2 potentiates ethanol reinforcement. However, the brain region(s) that mediate this effect are unknown. OBJECTIVE: This study aims to pharmacologically inhibit ERK1/2 in the medial prefrontal cortex (PFC), nucleus accumbens (NAC), and amygdala (AMY) prior to ethanol or sucrose self-administration, and evaluate effects of operant ethanol self-administration on ERK1/2 phosphorylation (pERK1/2). METHODS: Male C57BL/6J mice were trained to lever press on a fixed-ratio-4 schedule of 9% ethanol + 2% sucrose (ethanol) or 2% sucrose (sucrose) reinforcement. Mice were sacrificed immediately after the 30th self-administration session and pERK1/2 immunoreactivity was quantified in targeted brain regions. Additional groups of mice were injected with SL 327 (0-1.7 µg/side) in PFC, NAC, or AMY prior to self-administration. RESULTS: pERK1/2 immunoreactivity was significantly increased by operant ethanol (g/kg = 1.21 g/kg; BAC = 54.9 mg/dl) in the PFC, NAC (core and shell), and AMY (central nucleus) as compared to sucrose. Microinjection of SL 327 (1.7 µg) into the PFC selectively increased ethanol self-administration. Intra-NAC injection of SL 327 had no effect on ethanol- but suppressed sucrose-reinforced responding. Intra-AMY microinjection of SL 327 had no effect on either ethanol- or sucrose-reinforced responding. Locomotor activity was unaffected under all conditions. CONCLUSIONS: Operant ethanol self-administration increases pERK1/2 activation in the PFC, NAC, and AMY. However, ERK1/2 activity only in the PFC mechanistically regulates ethanol self-administration. These data suggest that ethanol-induced activation of ERK1/2 in the PFC is a critical pharmacological effect that mediates the reinforcing properties of the drug.


Asunto(s)
Amígdala del Cerebelo/efectos de los fármacos , Depresores del Sistema Nervioso Central/administración & dosificación , Etanol/administración & dosificación , Quinasas MAP Reguladas por Señal Extracelular/antagonistas & inhibidores , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Núcleo Accumbens/efectos de los fármacos , Corteza Prefrontal/efectos de los fármacos , Aminoacetonitrilo/análogos & derivados , Aminoacetonitrilo/farmacología , Amígdala del Cerebelo/metabolismo , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Depresores del Sistema Nervioso Central/farmacología , Condicionamiento Operante , Etanol/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Actividad Motora/efectos de los fármacos , Núcleo Accumbens/metabolismo , Fosforilación/efectos de los fármacos , Corteza Prefrontal/metabolismo , Inhibidores de Proteasas/farmacología , Refuerzo en Psicología , Recompensa , Autoadministración
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