RESUMO
Alcohol dependence remains among the most common substance abuse problems worldwide, and compulsive alcohol consumption is a significant public health concern. Alcohol is an addictive drug that alters brain function through interactions with multiple neurotransmitter systems. These neurotransmitter systems mediate the reinforcing effects of alcohol. Specifically, the serotonergic system is important in mediating alcohol reward, preference, dependence, and craving. In this review chapter, we first discuss the serotonin system as it relates to alcoholism, and then outline interactions between this system and other neurotransmitter systems. We emphasize the serotonin transporter and its possible role in alcoholism, then present several serotonergic receptors and discuss their contribution to alcoholism, and finally assess the serotonin system as a target for pharmacotherapy, with an emphasis on current and potential treatments.
Assuntos
Alcoolismo/metabolismo , Modelos Animais de Doenças , Serotonina/metabolismo , Pesquisa Translacional Biomédica , Alcoolismo/terapia , Animais , Humanos , Neurotransmissores/metabolismo , Receptores de Serotonina/metabolismoRESUMO
G-protein-coupled receptors (GPCRs) represent diverse, multifamily groups of cell signaling receptors involved in many cellular processes. We identified Xenopus laevis GPR84 as a member of the A18 subfamily of GPCRs. During development, GPR84 is detected in the embryonic lens placode, differentiating lens fiber cells, retina, and cornea. Anti-sense morpholino oligonucleotide-mediated knockdown and RNA rescue experiments demonstrate GPR84's importance in lens, cornea, and retinal development. Examination of cell proliferation using an antibody against histone H3 S10P reveals significant increases in the lens and retina following GPR84 knockdown. Additionally, there was also an increase in apoptosis in the retina and lens, as revealed by TUNEL assay. Reciprocal transplantation of the presumptive lens ectoderm between uninjected controls and morpholino-injected embryos demonstrates that GPR84 is necessary in the retina for proper development of the retina, as well as other eye tissues including the lens and cornea.
Assuntos
Olho/embriologia , Olho/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Proteínas de Xenopus/metabolismo , Animais , Embrião não Mamífero/metabolismo , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Cristalino/embriologia , Cristalino/metabolismo , Filogenia , Receptores Acoplados a Proteínas G/classificação , Receptores Acoplados a Proteínas G/genética , Retina/embriologia , Retina/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteínas de Xenopus/classificação , Proteínas de Xenopus/genética , Xenopus laevisRESUMO
Seven hundred and thirty-four unique genes were recovered from a cDNA library enriched for genes up-regulated during the process of lens regeneration in the frog Xenopus laevis. The sequences represent transcription factors, proteins involved in RNA synthesis/processing, components of prominent cell signaling pathways, genes involved in protein processing, transport, and degradation (e.g., the ubiquitin/proteasome pathway), matrix metalloproteases (MMPs), as well as many other proteins. The findings implicate specific signal transduction pathways in the process of lens regeneration, including the FGF, TGF-beta, MAPK, Retinoic acid, Wnt, and hedgehog signaling pathways, which are known to play important roles in eye/lens development and regeneration in various systems. In situ hybridization revealed that the majority of genes recovered are expressed during embryogenesis, including in eye tissues. Several novel genes specifically expressed in lenses were identified. The suite of genes was compared to those up-regulated in other regenerating tissues/organisms, and a small degree of overlap was detected.
