RESUMO
Given that the κ opioid receptor (KOR) system has been implicated in psychostimulant abuse, we evaluated whether the selective KOR antagonist norbinaltorphimine dihydrochloride (nor-BNI) would attenuate the escalation of methamphetamine (METH) intake in an extended-access self-administration model. Systemic nor-BNI decreased the escalation of intake of long-access (LgA) but not short-access (ShA) self-administration. nor-BNI also decreased elevated progressive-ratio (PR) breakpoints in rats in the LgA condition and continued to decrease intake after 17 d of abstinence, demonstrating that the effects of a nor-BNI injection are long lasting. Rats with an ShA history showed an increase in prodynorphin immunoreactivity in both the nucleus accumbens (NAc) core and shell, but LgA animals showed a selective increase in the NAc shell. Other cohorts of rats received nor-BNI directly into the NAc shell or core and entered into ShA or LgA. nor-BNI infusion in the NAc shell, but not NAc core, attenuated escalation of intake and PR responding for METH in LgA rats. These data indicate that the development and/or expression of compulsive-like responding for METH under LgA conditions depends on activation of the KOR system in the NAc shell and suggest that the dynorphin-KOR system is a central component of the neuroplasticity associated with negative reinforcement systems that drive the dark side of addiction.
Assuntos
Estimulantes do Sistema Nervoso Central/administração & dosagem , Metanfetamina/administração & dosagem , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Receptores Opioides kappa/metabolismo , Análise de Variância , Animais , Condicionamento Operante/efeitos dos fármacos , Encefalinas/metabolismo , Masculino , Naltrexona/análogos & derivados , Naltrexona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Precursores de Proteínas/metabolismo , Ratos , Ratos Wistar , Reforço Psicológico , AutoadministraçãoRESUMO
Effects of withdrawal from ethanol drinking in chronic intermittent ethanol vapor (CIE)-exposed dependent rats and air-exposed nondependent rats on proliferation and survival of progenitor cells in the hippocampus and the medial prefrontal cortex (mPFC) were investigated. Rats were injected with 5'-Bromo 2-deoxyuridine 72 h post-CIE to measure proliferation (2 h-old cells) and survival (29-day-old cells) of progenitors born during a time-point previously reported to elicit a proliferative burst in the hippocampus. Hippocampal and mPFC brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase B receptor (TrkB) expression were measured 3 h or 21d post-CIE to evaluate neurotrophic signaling during a time point preceding the proliferative burst and survival of newly born progenitors. CIE rats demonstrated elevated drinking compared to nondependent rats and CIE rats maintained elevated drinking following protracted abstinence. Withdrawal from CIE increased BDNF levels in the hippocampus and mPFC, and subsequently increased proliferation in the hippocampus and mPFC compared to nondependent rats and controls. Protracted abstinence from CIE reduced BDNF expression to control levels, and subsequently reduced neurogenesis compared to controls and nondependent rats in the hippocampus. In the mPFC, protracted abstinence reduced BDNF expression to control levels, whereas increased oligodendrogenesis in dependent rats compared to nondependent rats and controls. These results suggest a novel relationship between BDNF and progenitors in the hippocampus and mPFC, in which increased ethanol drinking may alter hippocampal and cortical function in alcohol dependent subjects by altering the cellular composition of newly born progenitors in the hippocampus and mPFC.
Assuntos
Células-Tronco Adultas/fisiologia , Alcoolismo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Etanol/administração & dosagem , Hipocampo/fisiologia , Córtex Pré-Frontal/fisiologia , Receptor trkB/metabolismo , Células-Tronco Adultas/efeitos dos fármacos , Células-Tronco Adultas/metabolismo , Animais , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Neuroglia/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/fisiologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Ratos , Ratos Wistar , Autoadministração , Transdução de Sinais/efeitos dos fármacos , Síndrome de Abstinência a SubstânciasRESUMO
In rodents, chronic intermittent ethanol vapor exposure (CIE) produces alcohol dependence, alters the activity of pyramidal neurons and decreases the number of glial progenitors in the medial prefrontal cortex (mPFC). Adult male Wistar rats were exposed to CIE and were injected with mitotic markers to label and phenotype proliferating cells to test the hypothesis that CIE produces concurrent alterations in the structure of pyramidal neurons and the cell cycle kinetics and developmental stages of glial progenitors in the mPFC. Medial prefrontal cortical tissue was processed for Golgi-Cox staining, immunohistochemistry and Western blotting analysis. CIE increased dendritic arborization and spine densities within basal and apical dendrites of pyramidal neurons via aberrant reorganization of actin cytoskeleton-associated molecules. CIE concomitantly increased the expression of total NR2B subunits without affecting phosphorylation of NR2B at Tyr-1472 or levels of PSD-95. CIE reduced the length of S-phase of the cell cycle of glial progenitors and reduced proliferation and differentiation of progenitors into bHLH transcription factor Olig2-expressing premyelinating oligodendrocyte progenitor cells (OPCs). CIE also produced a corresponding hyperphosphorylation of Olig2, and reduced expression of myelin basic protein. Our findings demonstrate that CIE-induced alterations in OPCs and myelin-related proteins are associated with profound alterations in the structure of pyramidal neurons. In sum, our results not only provide evidence that alcohol dependence leads to pathological changes in the mPFC, which may in part define a cellular basis for cognitive impairments associated with alcoholism, but also show dependence-associated morphological changes in the PFC at the single neuron level.
Assuntos
Alcoolismo/patologia , Etanol/farmacologia , Neuroglia/metabolismo , Neuroglia/patologia , Córtex Pré-Frontal/citologia , Células Piramidais/patologia , Administração por Inalação , Alcoolismo/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Western Blotting , Proliferação de Células/efeitos dos fármacos , Espinhas Dendríticas/patologia , Modelos Animais de Doenças , Proteína 4 Homóloga a Disks-Large , Etanol/administração & dosagem , Imuno-Histoquímica , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Proteínas da Mielina/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neuroglia/efeitos dos fármacos , Fator de Transcrição 2 de Oligodendrócitos , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Córtex Pré-Frontal/efeitos dos fármacos , Células Piramidais/efeitos dos fármacos , Células Piramidais/metabolismo , Ratos , Receptores de N-Metil-D-Aspartato/metabolismo , Fatores de TempoRESUMO
Alcoholism, or alcohol use disorder, is a major public health concern that is a considerable risk factor for morbidity and disability; therefore, effective treatments are urgently needed. Here, we demonstrated that the glucocorticoid receptor (GR) antagonist mifepristone reduces alcohol intake in alcohol-dependent rats but not in nondependent animals. Both systemic delivery and direct administration into the central nucleus of the amygdala, a critical stress-related brain region, were sufficient to reduce alcohol consumption in dependent animals. We also tested the use of mifepristone in 56 alcohol-dependent human subjects as part of a double-blind clinical and laboratory-based study. Relative to placebo, individuals who received mifepristone (600 mg daily taken orally for 1 week) exhibited a substantial reduction in alcohol-cued craving in the laboratory, and naturalistic measures revealed reduced alcohol consumption during the 1-week treatment phase and 1-week post-treatment phase in mifepristone-treated individuals. Mifepristone was well tolerated and improved liver-function markers. Together, these results support further exploration of GR antagonism via mifepristone as a therapeutic strategy for alcoholism.
Assuntos
Consumo de Bebidas Alcoólicas/tratamento farmacológico , Alcoolismo/tratamento farmacológico , Antagonistas de Hormônios/administração & dosagem , Mifepristona/administração & dosagem , Receptores de Glucocorticoides/antagonistas & inibidores , Administração Oral , Adulto , Consumo de Bebidas Alcoólicas/fisiopatologia , Alcoolismo/fisiopatologia , Animais , Feminino , Antagonistas de Hormônios/efeitos adversos , Humanos , Masculino , Mifepristona/efeitos adversos , RatosRESUMO
Early pioneering work in the field of biochemistry identified phosphorylation as a crucial post-translational modification of proteins with the ability to both indicate and arbitrate complex physiological processes. More recent investigations have functionally linked phosphorylation of extracellular signal-regulated kinase (ERK) to a variety of neurophysiological mechanisms ranging from acute neurotransmitter action to long-term gene expression. ERK phosphorylation serves as an intracellular bridging mechanism that facilitates neuronal communication and plasticity. Drugs of abuse, including alcohol and opioids, act as artificial yet powerful rewards that impinge upon natural reinforcement processes critical for survival. The graded progression from initial exposure to addiction (or substance dependence) is believed to result from drug- and drug context-induced adaptations in neuronal signaling processes across brain reward and stress circuits following excessive drug use. In this regard, commonly abused drugs as well as drug-associated experiences are capable of modifying the phosphorylation of ERK within central reinforcement systems. In addition, chronic drug and alcohol exposure may drive ERK-regulated epigenetic and structural alterations that underlie a long-term propensity for escalating drug use. Under the influence of such a neurobiological vulnerability, encountering drug-associated cues and contexts can produce subsequent alterations in ERK signaling that drive relapse to drug and alcohol seeking. Current studies are determining precisely which molecular and regional ERK phosphorylation-associated events contribute to the addiction process, as well as which neuroadaptations need to be targeted in order to return dependent individuals to a healthy state.
RESUMO
A major challenge for the successful treatment of drug addiction is the long-lasting susceptibility to relapse and multiple processes that have been implicated in the compulsion to resume drug intake during abstinence. Recently, the orexin/hypocretin (Orx/Hcrt) system has been shown to play a role in drug-seeking behavior. The Orx/Hcrt system regulates a wide range of physiological processes, including feeding, energy metabolism, and arousal. It has also been shown to be recruited by drugs of abuse. Orx/Hcrt neurons are predominantly located in the lateral hypothalamus that projects to the paraventricular nucleus of the thalamus (PVT), a region that has been identified as a "way-station" that processes information and then modulates the mesolimbic reward and extrahypothalamic stress systems. Although not thought to be part of the "drug addiction circuitry", recent evidence indicates that the PVT is involved in the modulation of reward function in general and drug-directed behavior in particular. Evidence indicates a role for Orx/Hcrt transmission in the PVT in the modulation of reward function in general and drug-directed behavior in particular. One hypothesis is that following repeated drug exposure, the Orx/Hcrt system acquires a preferential role in mediating the effects of drugs vs. natural rewards. The present review discusses recent findings that suggest maladaptive recruitment of the PVT by drugs of abuse, specifically Orx/Hcrt-PVT neurotransmission.