Influence of noradrenergic and orexinergic systems on the reinforcement effects of ethanol

A dependência de drogas, dentre as quais ao álcool, envolve complexos processos fisiológicos e pode ser caracterizada não somente por suas propriedades comportamentais e fenotípicas, mas também pelas várias adaptações celulares e moleculares associadas ao seu uso repetido. Neste estudo avaliamos a manipulação farmacológica de dois sistemas de neurotransmissão utilizando dois modelos animais para avaliação dos efeitos reforçadores do etanol. Na primeira etapa deste estudo, avaliamos os efeitos da administração de drogas que atuam nos sistemas noradrenérgico ou orexinérgico sobre o desenvolvimento e expressão da sensibilização comportamental. A prazosina (um antagonista alfa1-adrenérgico) e a ioimbina (um antagonista alfa2-adrenérgico) reduziram os níveis de atividade dos animais durante o desenvolvimento e também na expressão da sensibilização ao etanol. A fenilefrina (um agonista alfa1-adrenérgico) reduziu os níveis de atividade somente na expressão. O SB334867-A (um antagonista de receptor de orexina tipo 1) não modificou a atividade locomotora dos animais. Na segunda etapa deste estudo, avaliamos o papel do receptor de orexina tipo 1 do córtex pré-límbico e da área tegmental ventral, em um modelo de restabelecimento da busca pelo etanol. A administração de SB334867-A intra córtex pré-límbico ou intra-área tegmental ventral reduziu o restabelecimento da busca dos animais pelo álcool, mas não pela sacarose. Os resultados do presente estudo sugerem que estes dois sistemas participam modulando a principal via de recompensa cerebral e que manipulações farmacológicas podem interferir na busca pelo álcool e nos comportamentos relacionados aos seus efeitos reforçadores, que poderão servir de base para futuras ações terapêuticas.BV UNIFESP: Teses e dissertaçõe

Influence of disulfiram co-administration on the stimulant and reinforcing effects of ethanol

O dissulfiram, um inibidor das enzimas aldeído desidrogenase e dopamina beta-hidroxilase, tem sido utilizado no tratamento de dependentes de álcool. Caso um paciente sob tratamento com dissulfiram consuma bebidas alcoólicas, devido ao acúmulo de acetaldeído, ele sentirá uma série de sintomas desagradáveis tais como náusea, taquicardia, rubor facial, dores de cabeça, que dependendo da dose podem levar a parada cardíaca e respiratória. Conhecendo a possibilidade de sofrer estes efeitos, o paciente evitaria o consumo de álcool. Entretanto, há relatos de aumento do efeito estimulante do etanol após a ingestão concomitante de bebidas alcoólicas e dissulfiram. No Estudo I, verificamos que a administração aguda de diferentes doses de dissulfiram (combinada ou não com etanol) não modifica a atividade locomotora de camundongos. Além disso, a administração combinada de 2,0 g/kg de etanol e 15 mg/kg de dissulfiram impediu o desenvolvimento de sensibilização ao efeito estimulante do etanol, em animais testados imediatamente após a administração de etanol (teste imediato). No Estudo II, animais tratados com as mesmas doses de dissulfiram e etanol acima mencionadas, não desenvolveram preferência condicionada ao lugar induzida pelo etanol. Camundongos que receberam administrações repetidas de etanol e foram testados imediatamente após a administração da droga, apresentaram resposta locomotora estimulada quando desafiados imediatamente com veículo e 15 mg/kg de dissulfiram, indicando existir interação (ou "sensibilização cruzada") entre etanol e dissulfiram. Em resumo, a administração simultânea de dissulfiram não aumenta o efeito estimulante do etanol, mas bloqueia o desenvolvimento da sensibilização e da preferência condicionada ao lugar induzido por 2,0 g/kg de etanol..BV UNIFESP: Teses e dissertaçõe

The role of orexins/hypocretins in alcohol use and abuse: an appetitive-reward relationship

Orexins (hypocretins) are neuropeptides synthesized in neurons located in the lateral (LH), perifornical, and dorsomedial (DMH) hypothalamus. These neurons innervate many regions in the brain and modulate multiple other neurotransmitter systems. As a result of these extensive projections and interactions orexins are involved in numerous functions, such as feeding behavior, neuroendocrine regulation, the sleep-wake cycle, and reward-seeking. This review will summarize the literature to date which has evaluated a role of orexins in the behavioral effects of alcohol, with a focus on understanding the importance of this peptide and its potential as a clinical therapeutic target for alcohol use disorders.NHMRC (Australia)Pratt FoundationVictorian Government's Operational Infrastructure Support ProgramConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Besen FoundationUniv Melbourne, Florey Neurosci Inst, Behav Neurosci Div, Addict Neurosci Lab, Parkville, Vic 3010, AustraliaUniversidade Federal de São Paulo, Escola Paulista Med, Dept Psicobiol, São Paulo, BrazilUniv Melbourne, Ctr Neurosci, Parkville, Vic 3010, AustraliaUniversidade Federal de São Paulo, Escola Paulista Med, Dept Psicobiol, São Paulo, BrazilWeb of Scienc

Alpha1-adrenergic drugs affect the development and expression of ethanol-induced behavioral sensitization

Background: According to the incentive sensitization theory, addiction is caused primarily by drug-induced sensitization in the brain mesocorticolimbic systems. After repeated ethanol administration, some animals develop psychomotor sensitization, a phenomenon which occurs simultaneously with the incentive sensitization. Recent evidence suggests the involvement of norepinephrine (NE) in drug addiction, with a critical role in the ethanol reinforcing properties. in this study we evaluated the influence of an agonist (phenylephrine) and an antagonist (prazosin) of alpha1-adrenergic receptors on the development and expression of behavioral sensitization to ethanol. Male Swiss mice, previously treated with ethanol or saline, were challenged with the combined administration of ethanol (or saline) with alpha1-adrenergic drugs. Prazosin (0.1; 0.5 and 1.0 mg/kg) and phenylephrine (1.0 and 2.0 mg/kg) administration blocked the expression of behavioral sensitization to ethanol. in another set of experiments, mice treated with 0.5 mg/kg of prazosin + ethanol did not present the development of behavioral sensitization. However, when challenged with ethanol alone, they showed the same sensitized levels of locomotor activity of those presented by mice previously treated with ethanol and saline. Phenylephrine (1.0 mg/kg) treatment did not affect the development of behavioral sensitization. Based on this data, we concluded that the alteration of alphal-adrenergic receptors functioning, by the administration agonists or antagonists, affected the locomotor sensitization to the stimulant effect of ethanol, suggesting that the normal functioning of the noradrenergic system is essential to its development and expression. (C) 2013 Elsevier B.V. All rights reserved.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Associacao Fundo de Incentivo a Pesquisa(AFIP)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Universidade Federal de São Paulo UNIFESP, Escola Paulista Med, Dept Psicobiol, BR-04024002 São Paulo, BrazilUniversidade Federal de São Paulo UNIFESP, Escola Paulista Med, Dept Psicobiol, BR-04024002 São Paulo, BrazilCNPq: 143273/2008-6CNPq: 474601/2007-2Web of Scienc

Orexin-1 receptor signalling in the prelimbic cortex and ventral tegmental area regulates cue-induced reinstatement of ethanol-seeking in iP rats

Orexins (hypocretins) are hypothalamic neuropeptides that innervate the entire neuraxis, including the prelimbic cortex and ventral tegmental area and have been implicated in ethanol-seeking behaviour. The present study aimed to use the orexin-1 (OX1) receptor antagonist SB-334867 to examine the role of prelimbic cortex and ventral tegmental area OX1 receptors in cue-induced reinstatement of ethanol-seeking. Ethanol-preferring rats (iP) rats were trained to self-administer ethanol (10percent v/v, FR3) or sucrose (0.2-1percent w/v, FR3) in the presence of reward-associated cues before being implanted with indwelling guide cannulae. Rats then underwent extinction training for 11 days. On test days, rats were given a microinjection of vehicle or SB-334867 (3g/side) and presented with reward-associated cues to precipitate reinstatement. Results show SB-334867 infused into the prelimbic cortex attenuated cue-induced reinstatement of ethanol-seeking, but not sucrose-seeking. OX1 antagonism in the ventral tegmental area also attenuated cue-induced reinstatement of ethanol-seeking. These findings suggest that OX1 receptors located in the prelimbic cortex and ventral tegmental area are part of a circuit driving cue-mediated ethanol-seeking behaviour.National Health and Medical Research Council of AustraliaAustralian Research CouncilAustralian Postgraduate AwardBesen Family FoundationVictorian GovernmentUniv Melbourne, Florey Inst Neurosci & Mental Hlth, 30 Royal Parade, Parkville, Vic 3052, AustraliaUniv Fed Sao Paulo, Dept Psicobiol, Sao Paulo, BrazilUniv New S Wales, Sch Psychol, Sydney, NSW 2052, AustraliaUniv Cambridge, Expt Psychol, Cambridge CB2 1TN, EnglandUniv Fed Sao Paulo, Dept Psicobiol, Sao Paulo, BrazilNHMRCA: 1021227Web of Scienc

Biomedical research in the Asia Pacific region can inform the prevention and treatment of alcohol-related disorders

Since the cloning of the many subunits of the GABAA receptor a plethora of studies were undertaken in order to understand how chronic ethanol exposure as well as ethanol withdrawal could interfere with their gene expression. Ticku’s laboratory was one of the first to study this effect of ethanol and for many years until his last publications a great effort was made to elucidate the cellular location, subunit composition and functional role of native GABAA receptors important in order to develop better drugs. More work needs to be done to understand how ethanol can interfere with the molecular mechanisms underlying the expression of the various GABAA receptor subunits and the assembly of subunit combinations to form functional receptors. In this presentation we will discuss some effects of chronic ethanol exposure and ethanol withdrawal on GABAA receptor subunit expression and related receptor function obtained by our research group using neuronal cell cultures. We will show that some changes in gene expression and function evident during ethanol withdrawal can be selectively blocked by drugs such as diazepam, flumazenil or c-hydroxybutyrate, whereas neither gaboxadol nor neuroactive steroids are effective. Moreover, some ethanol withdrawal-induced changes in gene expression seem to be steroids mediated since they can be blocked by the 5a-reductase inhibitor finasteride