RESUMEN
Percutaneous delivery is explored as alternative pathway for addressing the drawbacks associated with the oral administration of otherwise efficacious drugs. Short of breaching the skin by physical means, the preference goes to formulation strategies that augment passive diffusion across the skin. One such strategy lies in the use of skin penetration and permeation enhancers notably of hydroxylated solvents like propylene glycol (PG), ethanol (EtOH), and diethylene glycol monoethyl ether (Transcutol®, TRC). In a previous publication, we focused on the role of Transcutol® as enhancer in neat or diluted systems. Herein, we explore its' role in complex formulation systems, including patches, emulsions, vesicles, solid lipid nanoparticles, and micro or nanoemulsions. This review discusses enhancement mechanisms associated with hydroalcoholic solvents in general and TRC in particular, as manifested in multi-component formulation settings alongside other solvents and enhancers. The principles that govern skin penetration and permeation, notably the importance of drug diffusion due to solubilization and thermodynamic activity in the vehicle (formulation), drug solubilization and partitioning in the stratum corneum (SC), and/or solvent drag across the skin into deeper tissue for systemic absorption are discussed. Emphasized also are the interplay between the drug properties, the skin barrier function and the formulation parameters that are key to successful (trans)dermal delivery.
Asunto(s)
Administración Cutánea , Glicoles de Etileno , Permeabilidad , Absorción Cutánea , Piel , Solventes , Absorción Cutánea/fisiología , Absorción Cutánea/efectos de los fármacos , Glicoles de Etileno/química , Humanos , Piel/metabolismo , Animales , Solventes/química , Química Farmacéutica/métodos , Solubilidad , Sistemas de Liberación de Medicamentos/métodos , Emulsiones/química , Nanopartículas/química , Etanol/química , Etanol/administración & dosificaciónRESUMEN
The neurohormone oxytocin (OT) has been proposed as a treatment for alcohol and nicotine use disorders. The aim of the present study was to examine whether intravenous (IV) OT decreases alcohol oral self-administration and consumption in nonhuman primates under a 6-h alcohol access procedure as well as alcohol and nicotine (IV) self-administration under 6-h concurrent access conditions. The subjects were five male baboons (Papio anubis) that self-administered oral alcohol (4% w/v) during 6-h sessions under a fixed ratio 3 (FR3) schedule per drink. Baseline levels of alcohol self-administration were established and then OT treatment was initiated. A single dose of OT (20, 40, 80, 120 IU, IV) or its vehicle (saline) was administered before and again in the middle of the 6-h drinking session for 5 consecutive days (total oxytocin dose of 40, 80, 160, 240 IU/day). After each 5-day treatment, baseline levels of alcohol self-administration were reestablished before the next 5-day OT treatment. In addition, the effect of OT on concurrent alcohol and IV nicotine self-administration was explored in 3 of the baboons where alcohol and nicotine were concurrently available during the 6-hr session each under an FR3 schedule for each drug. Establishment of baseline self-administration and 5-day OT treatments were completed as in the alcohol only study. There was a significant overall reduction in alcohol consumption with OT compared to placebo. On post-hoc analysis, after correcting for multiple comparisons, the 40 and 80 IU doses of OT significantly reduced alcohol consumption compared with vehicle, and consumption did not vary significantly within each 5-day treatment period. OT, qualitatively, also reduced the coadministration of both alcohol and nicotine in each baboon for at least one of the OT doses administered. These results underscore the therapeutic potential of oxytocin as a treatment of alcohol use disorder and possibly, co-use of nicotine.
Asunto(s)
Consumo de Bebidas Alcohólicas , Etanol , Nicotina , Oxitocina , Autoadministración , Animales , Oxitocina/administración & dosificación , Oxitocina/farmacología , Masculino , Etanol/administración & dosificación , Nicotina/administración & dosificación , Papio , Relación Dosis-Respuesta a Droga , Papio anubisRESUMEN
Endodontic irrigation protocols are not only used to clean and disinfect the root canal system, but also to condition the canal wall dentine for subsequent root filling. In this study we tested whether a final irrigation step with saline solution or 80% ethanol improved root canal sealabilty by two popular sealers, an epoxy resin (AH Plus) and a hydraulic calcium silicate cement-based product (BioRoot RCS). Root canals in extracted single-rooted human teeth were instrumented and filled with a matched gutta-percha cone and sealer. During instrumentation and prior to root filling, sealer-specific irrigation protocols were applied. These involved a combined sodium hypochlorite/1-hydroxyethylidene-1,1-diphosphonic acid application, which was followed by irrigation with ethylenediaminetetraacetic acid (EDTA) for AH Plus. Protocols were followed by a 5-ml ultimate rinse with saline solution or 80% ethanol. No such final rinse was the control (N = 9). Canals were then dried with matched paper points. One week after root filling and storage of the teeth at 37°C in a humid environment, Rhodamine B was used to trace leakage. Two-way ANOVA revealed that the type of sealer had a significant (P < 0.05) impact on apical dye penetration while the final rinse did not (P > 0.05). AH Plus provided the slightly better seal (P < 0.05). Leakage occurred between the sealer and the dentin with AH Plus, and between the sealer-to-dentin as well as the sealer-to-gutta-percha interface with BioRoot RCS. In summary and under current conditions, there was no benefit from applying saline or ethanol as an ultimate rinsing solution prior to drying the canal with matched paper points.
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Etanol , Materiales de Obturación del Conducto Radicular , Solución Salina , Humanos , Etanol/administración & dosificación , Solución Salina/administración & dosificación , Irrigantes del Conducto Radicular/administración & dosificación , Resinas Epoxi , Preparación del Conducto Radicular/métodos , Preparación del Conducto Radicular/instrumentación , Obturación del Conducto Radicular/métodos , Filtración Dental/prevención & control , Hipoclorito de Sodio/administración & dosificación , Compuestos de CalcioRESUMEN
BACKGROUND: Chronic alcohol users often exhibit an increased minimum alveolar concentration (MAC) of sevoflurane, yet the specific mechanism remains unclear. It has been reported that ethanol exposure can upregulate the protein expression and enzyme activity of cytochrome P450 2E1 (CYP2E1). CYP2E1 is a key enzyme that converts 2-5% of sevoflurane into equimolar amounts of hexafluoroisopropanol (HFIP) and F-. This study aims to explore whether ethanol exposure could alter sevoflurane metabolism through CYP2E1 modulation, potentially explaining the increased MAC observed in alcohol users. METHODS: Eighty adult male Sprague-Dawley (SD) rats were randomly divided into two groups and received either 50% ethanol (dose: 3 g/kg) or 0.9% saline twice daily by gavage. After 1, 2, 3, and 4 weeks of gavage, ten rats were randomly selected from each group to undergo 1-hour anesthesia with 2.3% sevoflurane. Blood samples were collected after anesthesia to measure the concentration of free HFIP using gas chromatography. Additionally, the left lobe tissue of the liver was collected for the analysis of CYP2E1 protein expression by Western blot and CYP2E1 enzyme activity by colorimetric assay. Correlations between these parameters were analyzed using Pearson's correlation. RESULTS: In the ethanol group, CYP2E1 expression, activity, and the concentration of free HFIP were significantly higher at all time points compared to the control group (P < 0.05), except for protein expression in the first week (P > 0.05). Within-group comparisons indicated no significant changes in any of the parameters for the control group (P > 0.05). In the ethanol group, there was no difference in free HFIP concentration between the first and second weeks (P > 0.05), but a significant increase was observed in the third and fourth weeks (P < 0.01); protein expression and enzyme activity significantly varied over time, especially showing a notable increase from the first to the third and fourth weeks (P < 0.05). Correlation analysis revealed strong positive correlations between free HFIP concentration and CYP2E1 activity (r = 0.7898), free HFIP concentration and CYP2E1 expression (r = 0.8418), and CYP2E1 activity and expression (r = 0.8740), all with P < 0.001. CONCLUSIONS: Ethanol exposure increased both the expression and enzymatic activity of CYP2E1, consequently enhancing the metabolism of sevoflurane.
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Anestésicos por Inhalación , Citocromo P-450 CYP2E1 , Etanol , Hígado , Éteres Metílicos , Ratas Sprague-Dawley , Sevoflurano , Animales , Citocromo P-450 CYP2E1/metabolismo , Masculino , Etanol/administración & dosificación , Etanol/farmacología , Hígado/metabolismo , Hígado/efectos de los fármacos , Ratas , Factores de TiempoRESUMEN
Cognitive flexibility enables individuals to alter their behavior in response to changing environmental demands, facilitating optimal behavior in a dynamic world. The inability to do this, called behavioral inflexibility, is a pervasive behavioral phenotype in alcohol use disorder (AUD), driven by disruptions in cognitive flexibility. Research has repeatedly shown that behavioral inflexibility not only results from alcohol exposure across species but can itself be predictive of future drinking. Like many high-level executive functions, flexible behavior requires healthy functioning of the prefrontal cortex (PFC). The scope of this review addresses two primary themes: first, we outline tasks that have been used to investigate flexibility in the context of AUD or AUD models. We characterize these based on the task features and underlying cognitive processes that differentiate them from one another. We highlight the neural basis of flexibility measures, focusing on the PFC, and how acute or chronic alcohol in humans and non-human animal models impacts flexibility. Second, we consolidate findings on the molecular, physiological and functional changes in the PFC elicited by alcohol, that may contribute to cognitive flexibility deficits seen in AUD. Collectively, this approach identifies several key avenues for future research that will facilitate effective treatments to promote flexible behavior in the context of AUD, to reduce the risk of alcohol related harm, and to improve outcomes following AUD. This article is part of the Special Issue on "PFC circuit function in psychiatric disease and relevant models".
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Alcoholismo , Corteza Prefrontal , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/fisiología , Corteza Prefrontal/fisiopatología , Humanos , Animales , Alcoholismo/fisiopatología , Alcoholismo/psicología , Etanol/farmacología , Etanol/administración & dosificación , Cognición/fisiología , Cognición/efectos de los fármacos , Función Ejecutiva/fisiología , Función Ejecutiva/efectos de los fármacosRESUMEN
Early life sleep is important for neuronal development. Using the highly social prairie vole rodent model, we have previously reported that early life sleep disruption (ELSD) during the preweaning period results in interference with social bonding and increases ethanol consumption following a stressor in adulthood. Furthermore, ELSD increases parvalbumin expression and reduces glutamatergic neurotransmission in cortical regions in adult prairie voles. To understand the impact of ELSD on the lifespan, an examination of an earlier time in life is necessary. The aim of the present study was to examine behavioral outcomes of ELSD on adolescent prairie voles. Given the known effects of ELSD on development of neuronal systems involved in mood and social motivation, we hypothesized that anxiety, risk, and reward-related behaviors would be impacted by ELSD in adolescent prairie voles. We report that both male and female adolescent prairie voles that experienced ELSD showed heightened anxiety-like behavior compared to age-matched controls (CONs) as measured by a light-dark box. Additionally, both male and female ELSD voles showed reductions in both ethanol preference and consumption, and affiliative behavior compared to CONs. These results suggest that adolescent prairie voles of both sexes experience heightened anxiety-like behavior and reduced reward-seeking behaviors after ELSD. These results further suggest that early life sleep is critically important for neurotypical behaviors in adolescence.
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Ansiedad , Arvicolinae , Conducta Animal , Animales , Arvicolinae/fisiología , Masculino , Femenino , Ansiedad/fisiopatología , Conducta Animal/fisiología , Interacción Social , Consumo de Bebidas Alcohólicas , Factores Sexuales , Privación de Sueño/fisiopatología , Etanol/administración & dosificación , Etanol/farmacología , Comportamiento de Búsqueda de Drogas/fisiologíaRESUMEN
BACKGROUND: Ethanol elicits a rapid stimulatory effect and a subsequent, prolonged sedative response, which are potential predictors of EtOH consumption by decreasing adenosine signaling; this phenomenon also reflects the obvious sex difference. cAMP (cyclic Adenosine Monophosphate)-PKA (Protein Kinase A) signaling pathway modulation can influence the stimulatory and sedative effects induced by EtOH in mice. This study's objective is to clarify the role of phosphodiesterase (PDE) in mediating the observed sex differences in EtOH responsiveness between male and female animals. METHODS: EtOH was administered i.p. for 7 days to identify the changes in PDE isoforms in response to EtOH treatment. Additionally, EtOH consumption and preference of male and female C57BL/6J mice were assessed using the drinking-in-the-dark and 2-bottle choice tests. Further, pharmacological inhibition of PDE7A heterozygote knockout mice was performed to investigate its effects on EtOH-induced stimulation and sedation in both male and female mice. Finally, Western blotting analysis was performed to evaluate the alterations in cAMP-PKA/Epac2 pathways. RESULTS: EtOH administration resulted in an immediate upregulation in PDE7A expression in female mice, indicating a strong association between PDE7A and EtOH stimulation. Through the pharmacological inhibition of PDE7A KD mice, we have demonstrated for the first time, to our knowledge, that PDE7A selectively attenuates EtOH responsiveness and consumption exclusively in female mice, whichmay be associated with the cAMP-PKA/Epac2 pathway and downstream phosphorylation of CREB and ERK1/2. CONCLUSIONS: Inhibition or knockdown of PDE7A attenuates EtOH responsivenessand consumption exclusively in female mice, which is associated with alterations in the cAMP-PKA/Epac2 signaling pathways, thereby highlighting its potential as a novel therapeutic target for alcohol use disorder.
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Consumo de Bebidas Alcohólicas , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 7 , Etanol , Ratones Endogámicos C57BL , Ratones Noqueados , Animales , Masculino , Femenino , Etanol/farmacología , Etanol/administración & dosificación , Consumo de Bebidas Alcohólicas/metabolismo , Ratones , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 7/metabolismo , Caracteres Sexuales , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , AMP Cíclico/metabolismo , Depresores del Sistema Nervioso Central/farmacología , Depresores del Sistema Nervioso Central/administración & dosificación , Transducción de Señal/efectos de los fármacos , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismoRESUMEN
Alcohol use disorder (AUD) is a highly prevalent public health problem. The ghrelin system has been identified as a potential target for therapeutic intervention for AUD. Previous work showed that systemic administration of the growth hormone secretagogue receptor (GHSR) antagonist DLys reduced alcohol intake and preference in male mice. Yet, it is unclear whether central or peripheral GHSRs mediated these effects. We hypothesized that alcohol consumption is driven by central GHSRs and addressed this hypothesis by testing the effects of central administration of DLys. Male C57BL/6J mice consumed alcohol in a two-bottle choice procedure (10% ethanol versus water). DLys (2â nmol) was administered intracerebroventricularly for 7â days to examine alcohol intake and preference. DLys decreased alcohol intake and preference but had no effect on food intake. The effects on alcohol intake and preference persisted after several administrations, indicating lack of tolerance to DLys' effects. These results suggest that central administration of DLys is sufficient to reduce alcohol drinking and that DLys remains effective after several administrations when given intracerebroventricularly. Moreover, this work suggests that the effects of intracerebroventricularly administered DLys are specific to alcohol and do not generalize to other calorie-driven behaviors.
Asunto(s)
Consumo de Bebidas Alcohólicas , Ratones Endogámicos C57BL , Receptores de Ghrelina , Animales , Masculino , Receptores de Ghrelina/antagonistas & inhibidores , Ratones , Etanol/administración & dosificación , Etanol/farmacología , Inyecciones Intraventriculares , Conducta de Elección/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Preferencias Alimentarias/efectos de los fármacos , Glicina/análogos & derivados , TriazolesRESUMEN
BACKGROUND: Chronic alcohol drinking increases the risk of alcohol use disorders, causing various neurological disorders. However, the impact of different ethanol levels on a spectrum of behaviors during chronic drinking remains unclear. In this study, we established an intermittent access to ethanol in a two-bottle choice (IA2BC) procedure to explore the dose-dependent effects of ethanol on the behavioral performance of C57BL/6â¯J mice. METHODS: Adult male C57BL/6â¯J mice were provided voluntary access to different ethanol concentrations (0â¯%, 5â¯%, 10â¯%, and 20â¯% ethanol) under a 12-week IA2BC paradigm. A battery of behavioral tests was administered to assess alterations in pain threshold, anxiety-like behaviors, locomotor activity, motor coordination, and cognition. Ethanol consumption and preference were monitored during each session. Moreover, the liver, heart, and lung tissues were examined using pathological microscopy. RESULTS: The average (standard deviation) ethanol consumption of mice under the IA2BC paradigm increased dose-dependently to 5.1 (0.2), 8.7 (0.7), and 15.9 (0.8) g/kg/24â¯h with 5â¯%, 10â¯%, and 20â¯% ethanol, respectively. However, there is no significant difference in ethanol preference among all the ethanol groups. Chronic ethanol drinking caused hyperalgesia, cognitive impairment, and motor incoordination, but caused no changes in body temperature, locomotor activity, or anxiety-like behaviors. Minor histopathological alterations in the liver were detected; however, no major abnormal pathology was observed in the heart or lungs. CONCLUSION: These findings clarify the link between ethanol dosage and behavioral changes in mice over a 12-week IA2BC paradigm, thereby bridging the knowledge gap regarding the effects of chronic ethanol drinking on neurological disorders.
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Consumo de Bebidas Alcohólicas , Ansiedad , Conducta Animal , Etanol , Ratones Endogámicos C57BL , Animales , Masculino , Etanol/farmacología , Etanol/administración & dosificación , Ratones , Ansiedad/inducido químicamente , Conducta Animal/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Umbral del Dolor/efectos de los fármacos , Conducta de Elección/efectos de los fármacos , Conducta de Elección/fisiología , Depresores del Sistema Nervioso Central/farmacología , Depresores del Sistema Nervioso Central/administración & dosificación , Locomoción/efectos de los fármacosRESUMEN
Existing maze apparatuses used in rodents often exclusively assess spatial discriminability as a means to evaluate learning impairments. Spatial learning in such paradigms is reportedly spared by moderate prenatal alcohol exposure in rats, suggesting that spatial reinforcement alone is insufficient to delineate executive dysfunction, which consistently manifests in humans prenatally-exposed to alcohol. To address this, we designed a single-session continuous performance task in the T-maze apparatus that requires rats to discriminate within and between simultaneously-presented spatial (left or right) and tactile (sandpaper or smooth) stimuli for food reinforcement across four sequential discrimination stages: simple discrimination, intradimensional reversal 1, extradimensional shift, and intradimensional reversal 2. This design incorporates elements of working memory, attention, and goal-seeking behavior which collectively contribute to the executive function construct. Here, we found that rats prenatally-exposed to alcohol performed worse in both the tactile intradimensional reversal and extradimensional shift; alternatively, rats prenatally-exposed to alcohol acquired the extradimensional shift faster when shifting from the tactile to spatial dimension. In line with previous work, moderate prenatal alcohol exposure spared specifically spatial discrimination in this paradigm. However, when tactile stimuli were mapped into the spatial dimension, rats prenatally-exposed to alcohol required more trials to discriminate between the dimensions. We demonstrate that tactile stimuli can be operantly employed in a continuous performance T-maze task to detect discriminatory learning impairments in rats exposed to moderate prenatal alcohol. The current paradigm may be useful for assessing features of executive dysfunction in rodent models of fetal alcohol spectrum disorders.
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Etanol , Aprendizaje por Laberinto , Efectos Tardíos de la Exposición Prenatal , Animales , Embarazo , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Femenino , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Etanol/farmacología , Etanol/administración & dosificación , Etanol/efectos adversos , Masculino , Ratas , Ratas Long-Evans , Percepción Espacial/efectos de los fármacos , Percepción Espacial/fisiología , Discriminación en Psicología/efectos de los fármacos , Discriminación en Psicología/fisiología , Percepción del Tacto/fisiología , Percepción del Tacto/efectos de los fármacos , Memoria a Corto Plazo/efectos de los fármacos , Memoria a Corto Plazo/fisiología , Trastornos del Espectro Alcohólico Fetal/fisiopatología , Tacto/fisiología , Tacto/efectos de los fármacosRESUMEN
Alcohol use disorder (AUD) is a chronic relapsing disease that is deleterious at individual, familial, and societal levels. Although AUD is one of the highest preventable causes of death in the USA, therapies for the treatment of AUD are not sufficient given the heterogeneity of the disorder and the limited number of approved medications. To provide better pharmacological strategies, it is important to understand the neurological underpinnings of AUD. Evidence implicates the endogenous dynorphin (DYN)/κ-opioid receptor (KOR) system recruitment in dysphoric and negative emotional states in AUD to promote maladaptive behavioral regulation. The nucleus accumbens shell (AcbSh), mediating motivational and emotional processes that is a component of the mesolimbic dopamine system and the extended amygdala, is an important site related to alcohol's reinforcing actions (both positive and negative) and neuroadaptations in the AcbSh DYN/KOR system have been documented to induce maladaptive symptoms in AUD. We have previously shown that in other nodes of the extended amygdala, site-specific KOR antagonism can distinguish different symptoms of alcohol dependence and withdrawal. In the current study, we examined the role of the KOR signaling in the AcbSh of male Wistar rats in operant alcohol self-administration, measures of negative affective-like behavior, and physiological symptoms during acute alcohol withdrawal in alcohol-dependence. To induce alcohol dependence, rats were exposed to chronic intermittent ethanol vapor for 14 h/day for three months, during which stable escalation of alcohol self-administration was achieved and pharmacological AcbSh KOR antagonism ensued. The results showed that AcbSh KOR antagonism significantly reduced escalated alcohol intake and negative affective-like states but did not alter somatic symptoms of withdrawal. Understanding the relative contribution of these different drivers is important to understand and inform therapeutic efficacy approaches in alcohol dependence and further emphasis the importance of the KOR/DYN system as a target for AUD therapeutics.
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Consumo de Bebidas Alcohólicas , Alcoholismo , Núcleo Accumbens , Receptores Opioides kappa , Síndrome de Abstinencia a Sustancias , Animales , Núcleo Accumbens/metabolismo , Núcleo Accumbens/efectos de los fármacos , Receptores Opioides kappa/antagonistas & inhibidores , Receptores Opioides kappa/metabolismo , Masculino , Alcoholismo/tratamiento farmacológico , Alcoholismo/psicología , Alcoholismo/metabolismo , Ratas , Síndrome de Abstinencia a Sustancias/metabolismo , Síndrome de Abstinencia a Sustancias/psicología , Síndrome de Abstinencia a Sustancias/tratamiento farmacológico , Consumo de Bebidas Alcohólicas/psicología , Etanol/administración & dosificación , Etanol/farmacología , Autoadministración , Antagonistas de Narcóticos/farmacología , Pirrolidinas/farmacología , Pirrolidinas/administración & dosificación , Conducta Animal/efectos de los fármacosRESUMEN
Chronic ethanol exposure produces neuroadaptations in the medial prefrontal cortex (mPFC) that are thought to facilitate maladaptive behaviors that interfere with recovery from alcohol use disorder. Despite evidence that different cortico-subcortical projections play distinct roles in behavior, few studies have examined the physiological effects of chronic ethanol at the circuit level. The rostromedial tegmental nucleus (RMTg) is functionally altered by chronic ethanol exposure. Our recent work identified dense input from the mPFC to the RMTg, yet the effects of chronic ethanol exposure on this circuitry is unknown. In the current study, we examined physiological changes after chronic ethanol exposure in prelimbic (PL) and infralimbic (IL) mPFC neurons projecting to the RMTg. Adult male Long-Evans rats were injected with fluorescent retrobeads into the RMTg and rendered dependent using a 14-day chronic intermittent ethanol (CIE) vapor exposure paradigm. Whole-cell patch-clamp electrophysiological recordings were performed in fluorescently-labeled (RMTg-projecting) and -unlabeled (projection-undefined) layer 5 pyramidal neurons 7-10 days following ethanol exposure. CIE exposure significantly increased intrinsic excitability as well as spontaneous excitatory and inhibitory postsynaptic currents (sE/IPSCs) in RMTg-projecting IL neurons. In contrast, no lasting changes in excitability were observed in RMTg-projecting PL neurons, although a CIE-induced reduction in excitability was observed in projection-undefined PL neurons. CIE exposure also increased the frequency of sEPSCs in RMTg-projecting PL neurons. These data uncover novel subregion- and circuit-specific neuroadaptations in the mPFC following chronic ethanol exposure and reveal that the IL mPFC-RMTg projection is uniquely vulnerable to long-lasting effects of chronic ethanol exposure. This article is part of the Special Issue on "PFC circuit function in psychiatric disease and relevant models".
Asunto(s)
Etanol , Corteza Prefrontal , Ratas Long-Evans , Animales , Etanol/farmacología , Etanol/administración & dosificación , Masculino , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/fisiología , Ratas , Neuronas/efectos de los fármacos , Neuronas/fisiología , Depresores del Sistema Nervioso Central/farmacología , Adaptación Fisiológica/efectos de los fármacos , Adaptación Fisiológica/fisiología , Vías Nerviosas/efectos de los fármacos , Técnicas de Placa-Clamp , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/fisiología , Células Piramidales/efectos de los fármacos , Células Piramidales/fisiologíaRESUMEN
Alcohol use disorder (AUD) is a common psychiatric condition with substantial global mortality. Despite extensive research into its pathophysiology, the cognitive predispositions driving alcohol dependence are less understood. This study explores whether biased cognition, specifically traits of optimism and pessimism, predicts susceptibility to alcohol-seeking behaviors using an animal model. Rats were initially tested for judgement bias through Ambiguous Cue Interpretation tests. Those identified as 'optimistic' or 'pessimistic' were further examined for their tendency to escalate alcohol intake using the intermittent access 2-bottle choice (2BC) paradigm. Additionally, we assessed how judgement bias influenced the development of compulsive alcohol-seeking behavior in a Seeking-Taking (ST) and Seeking-Taking Punishment tasks, alcohol-seeking motivation in the Progressive Ratio Schedule of Reinforcement paradigm, the speed of extinction, and reinstatement after abstinence. Neurochemical analyses were conducted to investigate trait-specific differences in neurotransmitter-related gene expression and receptor densities in the brain. We used TaqMan Gene Expression Array Cards to analyze expression levels of genes linked to serotonergic, dopaminergic, glutamatergic, and GABAergic pathways, and alcohol metabolism in various brain regions. Receptor densities for 5-HT1A, 5-HT2A, and D2 were measured using autoradiography analysis. Behaviorally, 'optimistic' rats showed significantly lower alcohol consumption in the 2BC paradigm compared to 'pessimistic' rats. This lowered intake correlated with decreased monoamine oxidase-A (Maoa) expression in the medial prefrontal cortex (mPFC) and increased metabotropic glutamate receptor 2 (Grm2) expression in the amygdala (Amy). Additionally, we observed significant interactions between judgement bias and alcohol intake in the expression of several genes in the mPFC, nucleus accumbens (Nacc), orbitofrontal cortex (OFC), and Amy, as well as in 5-HT2A receptor binding in the Nacc. Overall, these results suggest that optimism is linked to lower alcohol consumption and related neurochemical changes, indicating a potential cognitive mechanism in AUD risk.
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Consumo de Bebidas Alcohólicas , Juicio , Optimismo , Animales , Masculino , Ratas , Consumo de Bebidas Alcohólicas/psicología , Consumo de Bebidas Alcohólicas/metabolismo , Optimismo/psicología , Juicio/fisiología , Comportamiento de Búsqueda de Drogas/fisiología , Motivación/fisiología , Alcoholismo/psicología , Alcoholismo/metabolismo , Etanol/administración & dosificación , Pesimismo/psicología , Encéfalo/metabolismo , Extinción Psicológica/fisiologíaRESUMEN
Terpene-based eutectic mixtures (EMs) are attractive platforms for transdermal delivery due to their solubilizing potential and ability to alter the barrier function of the stratum corneum (SC). Despite this, little is known about the effect of diluting EMs with co-solvents (CSs) on their solubility- and permeation-enhancing properties. Furthermore, insufficient attention has been paid to comparing these platforms with traditional solvents, such as propylene glycol (PG) or ethanol (EtOH). To address this gap, the present study investigates the impact of the CS content in EM:CS blends on the transdermal delivery of clotrimazole (CLOT). Two CSs, PG and EtOH, and two terpene-based EMs, menthol:thymol and thymol:ß-citronellol, were used. Each of the EMs was investigated at two different molar ratios between the terpenes, with one being their eutectic point, to explore its potential benefit for skin permeation. At each step, properties of the blends were compared with those of pure CSs. The EM:CS blends showed a better solubilizing potential for CLOT than EMs or CSs on their own. A higher content of CSs in the blends resulted in a higher skin permeation and retention of CLOT, and a lower degree of disarrangement of the SC structure. Furthermore, the blends of EMs at their EPs led to overall poorer permeation profiles, implying that the permeation rate is more affected by the properties of the individual terpenes than by the specific ratio at the eutectic point between them. In conclusion, addition of CSs to the EMs promotes permeation and retention of CLOT, while reducing the skin impairment caused by the terpenes.
Asunto(s)
Administración Cutánea , Etanol , Mentol , Propilenglicol , Absorción Cutánea , Piel , Solubilidad , Solventes , Terpenos , Absorción Cutánea/efectos de los fármacos , Animales , Solventes/química , Terpenos/química , Terpenos/administración & dosificación , Piel/metabolismo , Etanol/química , Etanol/administración & dosificación , Mentol/química , Mentol/administración & dosificación , Propilenglicol/química , Clotrimazol/administración & dosificación , Clotrimazol/química , Clotrimazol/farmacocinética , Permeabilidad , Timol/química , Timol/administración & dosificación , Porcinos , Sistemas de Liberación de MedicamentosRESUMEN
Alcohol consumption leads to significant neurochemical and neurobiological changes, contributing to the development of alcohol use disorders (AUDs), which exhibit sex- and age-dependent variations according to clinical data. However, preclinical studies often neglect these factors when investigating alcohol consumption patterns. In this study, we present data on male and female rats continuously exposed to a 20 % ethanol solution for one month. The animals were divided into two groups based on their age at the onset of drinking (8 and 12 weeks old). Interestingly, 12-week-old males consumed significantly less alcohol than both 12-week-old females and 8-week-old animals, indicating that alcohol consumption patterns vary with sex and age in our model. Additionally, to advance in the study of the neurobiological alterations induced by ethanol intake in the mesocorticolimbic system (MCLS) that may participate in its reinforcing properties and the maintenance of alcohol drinking behavior, we measured catalase activity-an enzyme involved in alcohol metabolism and related to ethanol reinforcement-in the nucleus accumbens (NAc) of these animals. Furthermore, we measured the levels of mu (MOR), kappa (KOR), delta (DOR), and nociceptin (NOP) opioid receptors in the NAc, as the endogenous opioidergic system plays a pivotal role in regulating the MCLS and alcohol reinforcement. MOR levels were lower in high alcohol-consuming groups (8-week-old males and all females). Both DOR and NOP levels decreased with age, whereas KOR levels remained unchanged. Our findings suggest that the age at onset of alcohol consumption critically influences alcohol intake, particularly in males. Additionally, females consistently showed higher alcohol intake regardless of age, highlighting inherent sex-specific differences. The dynamic changes in catalase activity and opioid receptor expression suggest the involvement of these factors in modulating alcohol consumption.
Asunto(s)
Consumo de Bebidas Alcohólicas , Etanol , Núcleo Accumbens , Animales , Masculino , Núcleo Accumbens/metabolismo , Femenino , Ratas , Consumo de Bebidas Alcohólicas/metabolismo , Etanol/administración & dosificación , Etanol/metabolismo , Caracteres Sexuales , Ratas Wistar , Catalasa/metabolismo , Factores de Edad , Péptidos Opioides/metabolismo , Encéfalo/metabolismo , Factores SexualesRESUMEN
RATIONALE: Although the mesocorticolimbic dopamine (DA) system is the main neurochemical substrate that regulates the addictive and reinforcing effects of ethanol (EtOH), other neurotransmitter systems, such as the acetylcholine (Ach) system, modulate DAergic function in the nucleus accumbens (nAcc). Previously, we reported that intra-nAcc administration of the nicotinic Ach receptor agonist cytisine increased oral EtOH self-administration. GABAB receptors in the nAcc are expressed in DAergic terminals, inhibit the regulation of DA release into the nAcc, and could modulate the effects of cytisine on oral EtOH self-administration. The present study assessed the effects of intra-nAcc administration of the GABAB receptor agonist baclofen (BCF) on the impacts of cytisine on oral EtOH self-administration. METHODS: Male Wistar rats were deprived of water for 23.30 h and then trained to press a lever to receive EtOH on an FR3 schedule until a stable response rate of 80 % was achieved. After this training, the rats received an intra-nAcc injection of the nAch receptor agonist cytisine, BCF, and cytisine or 2-hydroxysaclofen, BCF, and cytisine before they were given access to EtOH on an FR3 schedule. RESULTS: Intra-nAcc injections of cytisine increased oral EtOH self-administration; this effect was reduced by BCF, and 2-hydroxysaclofen blocked the effects of BCF. CONCLUSIONS: These findings suggest that the reinforcing effects of EtOH are modulated not only by the DA system but also by other neurotransmitter systems involved in regulating DA release from DAergic terminals.
Asunto(s)
Alcaloides , Azocinas , Baclofeno , Condicionamiento Operante , Etanol , Agonistas de Receptores GABA-B , Agonistas Nicotínicos , Núcleo Accumbens , Quinolizinas , Ratas Wistar , Autoadministración , Animales , Masculino , Baclofeno/farmacología , Baclofeno/administración & dosificación , Ratas , Alcaloides/farmacología , Alcaloides/administración & dosificación , Azocinas/farmacología , Azocinas/administración & dosificación , Quinolizinas/farmacología , Quinolizinas/administración & dosificación , Agonistas de Receptores GABA-B/farmacología , Agonistas de Receptores GABA-B/administración & dosificación , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Etanol/administración & dosificación , Etanol/farmacología , Condicionamiento Operante/efectos de los fármacos , Agonistas Nicotínicos/farmacología , Agonistas Nicotínicos/administración & dosificación , Administración Oral , Consumo de Bebidas Alcohólicas/tratamiento farmacológico , Consumo de Bebidas Alcohólicas/psicología , Alcaloides de QuinolizidinaRESUMEN
Alcohol exposure in adolescence is considered a major cause of cognitive impairments later in life including spatial learning and memory. Integrated stress response (ISR), a program of conservative translation and transcription, is crucial in synaptic plasticity and memory. Although previous studies have elucidated ISR in different brain areas involved in learning and memory disorders, the impact of ISR on learning and memory following adolescent alcohol exposure remains unclear. Here, we demonstrated that adolescent intermittent ethanol (AIE) exposure caused spatial learning and memory impairment, combined with neuronal damage in the medial prefrontal cortex (mPFC), nucleus accumbens (NAc) and hippocampus (HIP) in adult rats. Moreover, integrated stress response inhibitor (ISRIB) administration not only improved spatial learning and memory impairment and neuronal damage but also inhibited the endoplasmic reticulum stress (ER) and reversed changes in synaptic proteins. These findings suggested that ISRIB ameliorates AIE exposure-induced spatial learning and memory deficits by improving neural morphology and synaptic function through inhibiting ER stress signaling pathway in the mPFC, NAc and HIP in adulthood. Our findings may enhance comprehension of cognitive function and neuronal effects of adolescent ethanol exposure and ISRIB treatment may be an underlying potential option for addressing alcohol-induced learning and memory deficits.
Asunto(s)
Etanol , Trastornos de la Memoria , Ratas Sprague-Dawley , Aprendizaje Espacial , Animales , Masculino , Etanol/toxicidad , Etanol/administración & dosificación , Ratas , Trastornos de la Memoria/inducido químicamente , Trastornos de la Memoria/tratamiento farmacológico , Trastornos de la Memoria/metabolismo , Aprendizaje Espacial/efectos de los fármacos , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Estrés del Retículo Endoplásmico/efectos de los fármacos , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiologíaRESUMEN
Ablation cancer therapy using percutaneous intra-tumoral injection of ethanol is a promising method for targeted and effective locoregional cancer therapy. Magnetic gelatin microsphere (MGM) colloidal ethanol solution is developed as a potential injectable tumor ablation agent. The MGM was fabricated by electrostatic interactions among gelatin, acrylic acid, and acrylic acid-coated iron oxide nanoparticles. The fabricated MGM was dispersed in ethanol solution to form injectable MGM colloidal ethanol solution. The MGM colloidal ethanol solution can be easily infused and undergo in situ gelation via solvent exchange from ethanol to water in an artificial tissue. Furthermore, the MGM colloidal ethanol solution allowed doxorubicin (Dox) chemo-agent loading and its sustained release upon the formation of a drug depot by in situ gelation in artificial tissues. Our in vitro study demonstrated that locally delivered ethanol and Dox with MGM colloidal ethanol solution promoted the anti-cancer therapeutic efficacy with a significantly suppressed cancer cell recovery rate. Overall, our developed injectable MGM colloidal ethanol solution that can be transformed to a hydrogel drug depot at the injection site holds clinical potential for a new class of chemo-ablation agents.
Asunto(s)
Coloides , Doxorrubicina , Etanol , Gelatina , Hidrogeles , Doxorrubicina/farmacología , Doxorrubicina/administración & dosificación , Doxorrubicina/química , Coloides/química , Gelatina/química , Etanol/química , Etanol/farmacología , Etanol/administración & dosificación , Humanos , Hidrogeles/química , Hidrogeles/administración & dosificación , Hidrogeles/farmacología , Microesferas , Neoplasias/tratamiento farmacológico , Animales , Línea Celular Tumoral , AcrilatosRESUMEN
Alcohol-related cognitive impairment (ARCI) is highly prevalent among patients with alcohol abuse and dependence. The pathophysiology of ARCI, pivotal for refined therapeutic approaches, is not fully elucidated, posing a risk of progression to severe neurological sequelae such as Korsakoff's syndrome (KS) and Alcohol-Related Dementia (ARD). This study ventures into the underlying mechanisms of chronic alcohol-induced neurotoxicity, notably glutamate excitotoxicity and cytoskeletal disruption, and explores the therapeutic potential of Memantine, a non-competitive antagonist of the N-methyl-d-aspartate (NMDA) receptor known for its neuroprotective effect against excitotoxicity. Our investigation centers on the efficacy of Memantine in mitigating chronic alcohol-induced cognitive and hippocampal damages in vivo. Male C57BL/6J mice were subjected to 30 % (v/v, 6.0 g/kg) ethanol via intragastric administration alongside Memantine co-treatment (10 mg/kg/day, intraperitoneally) for six weeks. The assessment involved Y maze, Morris water maze, and novel object recognition tests to evaluate spatial and recognition memory deficits. Histopathological evaluations of the hippocampus were conducted to examine the extent of alcohol-induced morphological changes and the potential protective effect of Memantine. The findings reveal that Memantine significantly improves chronic alcohol-compromised cognitive functions and mitigates hippocampal pathological changes, implicating a moderating effect on the disassembly of actin cytoskeleton and microtubules in the hippocampus, induced by chronic alcohol exposure. Our results underscore Memantine's capability to attenuate chronic alcohol-induced cognitive and hippocampal morphological harm may partly through regulating cytoskeleton dynamics, offering valuable insights into innovative therapeutic strategies for ARCI.
Asunto(s)
Disfunción Cognitiva , Modelos Animales de Enfermedad , Hipocampo , Memantina , Ratones Endogámicos C57BL , Animales , Memantina/farmacología , Masculino , Ratones , Hipocampo/efectos de los fármacos , Hipocampo/patología , Hipocampo/metabolismo , Disfunción Cognitiva/tratamiento farmacológico , Etanol/toxicidad , Etanol/administración & dosificación , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/administración & dosificación , Alcoholismo/tratamiento farmacológico , Alcoholismo/patología , Alcoholismo/complicaciones , Aprendizaje por Laberinto/efectos de los fármacos , Antagonistas de Aminoácidos Excitadores/farmacología , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/metabolismoRESUMEN
The white-tufted marmoset is a small, nonhuman primate that is rapidly gaining popularity as a model organism, especially for neuroscience research. To date, little work in the alcohol research field has utilized the marmoset. As a step toward establishing the marmoset as a research model for alcohol experimentation, a series of exploratory studies were undertaken to characterize ethanol drinking behavior. A voluntary drinking paradigm was established whereby the common marmoset would consume pharmacologically relevant amounts of ethanol. To facilitate ethanol consumption, ethanol was mixed with a marshmallow flavored solution (hereafter called marshmallow juice) to mask the presumed adverse taste of ethanol. Using marshmallow juice flavored solutions, marmosets readily consumed ethanol up to 1 g/kg during 10 min binge-like drinking sessions or up to 5 g/kg during â¼4 h drinking sessions. Consumption of 1.0-1.5 g/kg during a 30 min session resulted in blood ethanol concentrations of 49-73 mg/dl, which are predicted to be pharmacologically relevant. In animals that were stably consuming ethanol in marshmallow juice, gradually reducing the concentration of the marshmallow juice flavoring resulted in markedly reduced ethanol consumption. Lastly, when offered a choice between ethanol in marshmallow juice and marshmallow juice alone, marmosets displayed a very strong preference for the marshmallow juice solution without ethanol. From these studies, it is concluded that marmosets will voluntarily consume ethanol if the taste is masked with a sweet solution such as marshmallow juice. These studies represent the first report of alcohol consumption and preference in the white-tufted marmoset.