RESUMEN
We evaluated the contribution of brown adipose tissue (BAT) sympathetic innervation on central leptin-mediated weight loss. In a short- and long-term study, F344BN rats were submitted to either a denervation of interscapular BAT (Denervated) or a sham operation (Sham). Animals from each group received the Ob (Leptin) or green fluorescent protein (GFP; Control) gene through a single injection of recombinant adeno-associated virus delivered centrally. Changes in body weight were recorded for 14 or 35 days, after which adipose tissues and skeletal muscles were weighed. In both studies, hypothalamic phosphorylated STAT3 (P-STAT3) was significantly higher in Sham-Leptin and Denervated-Leptin groups compared with their respective Control groups ( P < 0.01), indicating that leptin signaling was enhanced at the end point. We measured uncoupling protein 1 (UCP1), a marker of BAT thermogenic activity, and found a significant induction in Leptin in Sham animals ( P < 0.001) but not in Denervated animals, demonstrating that BAT UCP1 protein was only induced in Sham rats. Both Sham-Leptin and Denervated-Leptin rats lost ~15% of their initial body weight ( P < 0.001) by day 14 and reached a maximum of 18% body weight loss that stabilized over week 3 of treatment, indicating that sympathetic outflow to BAT is not required for leptin-mediated weight loss. In summary, interscapular BAT (iBAT) denervation did not prevent body weight loss following central leptin gene delivery. The present data show that sympathetic innervation of iBAT is not essential for leptin-induced body weight loss.
Asunto(s)
Tejido Adiposo Pardo/inervación , Técnicas de Transferencia de Gen , Leptina/administración & dosificación , Leptina/genética , Sistema Nervioso Simpático/fisiología , Pérdida de Peso/genética , Tejido Adiposo Pardo/metabolismo , Animales , Peso Corporal/genética , Desnervación , Dependovirus/genética , Regulación de la Expresión Génica , Infusiones Intraventriculares , Masculino , Ratas , Ratas Endogámicas F344 , Ratas Transgénicas , Termogénesis/efectos de los fármacos , Termogénesis/genética , Proteína Desacopladora 1/metabolismo , Pérdida de Peso/fisiologíaRESUMEN
Reducing body weight has been shown to lower blood pressure in obesity-related hypertension. However, success of those lifestyle interventions is limited due to poor long-term compliance. Emerging evidence indicates that feeding schedule plays a role on the regulation of blood pressure. With two studies, we examined the role of feeding schedule on energy homeostasis and blood pressure. In study 1, rats were fed a high-fat diet (HFD) ad libitum for 24 h (Control) or for 12 h during the dark phase (time-restricted feeding, TRF). In study 2, rats fed a HFD were administered a long-acting α-MSH analog at either light onset [melanotan II (MTII) light] or dark onset (MTII dark) or saline (Control). MTII light animals ate most of their calories during the active phase, similar to the TRF group. In study 1, Control and TRF rats consumed the same amount of food and gained the same amount of weight and fat mass. Interestingly, systolic and mean arterial pressure (MAP) was lower in the TRF group. In study 2, food intake was significantly lower in both MTII groups relative to Control. Although timing of injection affected light versus dark phase food consumption, neither body weight nor fat mass differed between MTII groups. Consistent with study 1, rats consuming their calories during the active phase displayed lower MAP. These data indicate that limiting feeding to the active phase reduces blood pressure without the necessity of reducing calories or fat mass, which could be relevant to obesity-related hypertension.
Asunto(s)
Ciclos de Actividad , Presión Arterial/efectos de los fármacos , Metabolismo Energético/efectos de los fármacos , Ayuno , Hipertensión/dietoterapia , Obesidad/dietoterapia , Péptidos Cíclicos/administración & dosificación , alfa-MSH/análogos & derivados , Adiposidad/efectos de los fármacos , Animales , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Ingestión de Energía , Conducta Alimentaria/efectos de los fármacos , Hipertensión/metabolismo , Hipertensión/fisiopatología , Masculino , Obesidad/metabolismo , Obesidad/fisiopatología , Fotoperiodo , Ratas Endogámicas BN , Ratas Endogámicas F344 , Factores de Tiempo , alfa-MSH/administración & dosificaciónRESUMEN
Recent evidence indicate that melanotan II (MTII) reduces body mass independently of caloric reduction. Because MTII induces a transient hypophagia, caloric reduction is still considered a primary mechanism for MTII-mediated body mass loss. To examine the contribution of caloric reduction to long-term body mass loss in response to MTII, we centrally infused MTII or vehicle in ad libitum fed (MTII and Control) animals in comparison with a group of animals that were pair-fed (PF) to the MTII group. Food intake and body mass were recorded daily, and body composition was assessed biweekly. The present study demonstrates that central MTII-mediated body mass loss is only partially mediated by caloric restriction, and the long-term body mass loss is independent of the initial hypophagia. More importantly, central MTII administration induced a rapid but sustained fat mass loss, independently of caloric reduction. MTII-treated animals preserved their lean/fat mass ratio throughout the study, whereas PF animals underwent a transient reduction of lean/fat mass ratio that was only normalized when food intake returned to Control level. In summary, it can be concluded that activation of the central melanocortin system in rats persistently reduces body and fat mass independently of caloric reduction.
Asunto(s)
Tejido Adiposo/citología , Peso Corporal , Restricción Calórica , Melanocortinas/metabolismo , Tejido Adiposo/efectos de los fármacos , Animales , Peso Corporal/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Masculino , Péptidos Cíclicos/farmacología , Ratas , alfa-MSH/análogos & derivados , alfa-MSH/farmacologíaRESUMEN
The authors have previously demonstrated that a low and intermittent peripheral dose of rapamycin (1 mg/kg three times/week) to rats inhibited mTORC1 signalling, but avoided the hyperlipidemia and diabetes-like syndrome associated with higher doses of rapamycin. The dosing regimen reduced food intake, body weight, adiposity, serum leptin and triglycerides. mTORC1 signalling was inhibited in both liver and hypothalamus, suggesting some of the actions, in particular the decrease in food intake, may be the results of a central mechanism. To test this hypothesis, rapamycin (30 µg/day for 4 weeks) was infused into 23-25-month-old F344xBN rats by intracerebroventricular (icv) mini pumps. Our results demonstrated that central infusion did not alter food intake or body weight, although there was a tendency for a decrease in body weight towards the end of the study. mTORC1 signalling, evidenced by decreased phosphorylation of S6 protein at end of 4 weeks, was not activated in liver, hypothalamus or hindbrain. Fat and lean mass, sum of white adipose tissues, brown adipose tissue, serum glucose, insulin and leptin levels remained unchanged. Thus, these data suggest that the anorexic and body weight responses evident with peripheral rapamycin are not the result of direct central action. The tendency for decreased body weight towards the end of study, suggests that there is either a slow transport of centrally administered rapamycin into the periphery, or that there is delayed action of rapamycin at sites in the brain.
Asunto(s)
Anorexia/tratamiento farmacológico , Anorexia/fisiopatología , Sirolimus/farmacología , Animales , Anorexia/metabolismo , Peso Corporal/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Ingestión de Energía/efectos de los fármacos , Ratas , Sirolimus/uso terapéutico , Resultado del TratamientoRESUMEN
Development of 5-HT2C agonists for treatment of neuropsychiatric disorders, including psychoses, substance abuse, and obesity, has been fraught with difficulties, because the vast majority of reported 5-HT2C selective agonists also activate 5-HT2A and/or 5-HT2B receptors, potentially causing hallucinations and/or cardiac valvulopathy. Herein is described a novel, potent, and efficacious human 5-HT2C receptor agonist, (-)-trans-(2S,4R)-4-(3'[meta]-bromophenyl)-N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine (-)-MBP), that is a competitive antagonist and inverse agonist at human 5-HT2A and 5-HT2B receptors, respectively. (-)-MBP has efficacy comparable to the prototypical second-generation antipsychotic drug clozapine in three C57Bl/6 mouse models of drug-induced psychoses: the head-twitch response elicited by [2,5]-dimethoxy-4-iodoamphetamine; hyperlocomotion induced by MK-801 [(5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (dizocilpine maleate)]; and hyperlocomotion induced by amphetamine. (-)-MBP, however, does not alter locomotion when administered alone, distinguishing it from clozapine, which suppresses locomotion. Finally, consumption of highly palatable food by mice was not increased by (-)-MBP at a dose that produced at least 50% maximal efficacy in the psychoses models. Compared with (-)-MBP, the enantiomer (+)-MBP was much less active across in vitro affinity and functional assays using mouse and human receptors and also translated in vivo with comparably lower potency and efficacy. Results indicate a 5-HT2C receptor-specific agonist, such as (-)-MBP, may be pharmacotherapeutic for psychoses, without liability for obesity, hallucinations, heart disease, sedation, or motoric disorders.
Asunto(s)
2-Naftilamina/análogos & derivados , Antipsicóticos/farmacología , Receptor de Serotonina 5-HT2A/metabolismo , Receptor de Serotonina 5-HT2B/metabolismo , Receptor de Serotonina 5-HT2C/metabolismo , Agonistas del Receptor de Serotonina 5-HT2/farmacología , Antagonistas del Receptor de Serotonina 5-HT2/farmacología , 2-Naftilamina/química , 2-Naftilamina/farmacología , Anfetamina/farmacología , Animales , Antipsicóticos/química , Estimulantes del Sistema Nervioso Central/farmacología , Conducta Alimentaria/efectos de los fármacos , Células HEK293 , Humanos , Hipercinesia/tratamiento farmacológico , Hipercinesia/etiología , Masculino , Ratones Endogámicos C57BL , Actividad Motora/efectos de los fármacos , Trastornos Psicóticos/tratamiento farmacológico , Trastornos Psicóticos/etiología , Trastornos Psicóticos/fisiopatología , Ensayo de Unión Radioligante , Agonistas del Receptor de Serotonina 5-HT2/química , Antagonistas del Receptor de Serotonina 5-HT2/química , Estereoisomerismo , Factores de TiempoRESUMEN
During translational studies to develop 4-phenyl-2-dimethylaminotetralin (PAT) compounds for neuropsychiatric disorders, the (2R,4S)-trans-(+)- and (2S,4R)-trans-(-)-enantiomers of the analog 6-hydroxy-7-chloro-PAT (6-OH-7-Cl-PAT) demonstrated unusual pharmacology at serotonin (5-HT) 5-HT2 G protein-coupled receptors (GPCRs). The enantiomers had similar affinities (Ki) at human (h) 5-HT2A receptors (≈ 70 nM). In an in vivo mouse model of 5-HT2A receptor activation [(±)-(2,5)-dimethoxy-4-iodoamphetamine (DOI)-elicited head twitch], however, (-)-6-OH-7-Cl-PAT was about 5-fold more potent than the (+)-enantiomer at attenuating the DOI-elicited response. It was discovered that (+)-6-OH-7-Cl-PAT (only) had ≈ 40-fold-lower affinity at mouse (m) compared with h5-HT2A receptors. Molecular modeling and computational ligand docking studies indicated that the 6-OH moiety of (+)- but not (-)-6-OH-7-Cl-PAT could form a hydrogen bond with serine residue 5.46 of the h5-HT2A receptor. The m5-HT2A as well as m5-HT2B, h5-HT2B, m5-HT2C, and h5-HT2C receptors have alanine at position 5.46, obviating this interaction; (+)-6-OH-7-Cl-PAT also showed ≈ 50-fold lower affinity than (-)-6-OH-7-Cl-PAT at m5-HT2C and h5-HT2C receptors. Mutagenesis studies confirmed that 5-HT2A S5.46 is critical for (+)- but not (-)-6-OH-7-Cl-PAT binding, as well as function. The (+)-6-OH-7-Cl-PAT enantiomer showed partial agonist effects at h5-HT2A wild-type (WT) and m5-HT2A A5.46S point-mutated receptors but did not activate m5-HT2A WT and h5-HT2A S5.46A point-mutated receptors, or h5-HT2B, h5-HT2C, and m5-HT2C receptors; (-)-6-OH-7-Cl-PAT did not activate any of the 5-HT2 receptors. Experiments also included the (2R,4S)-trans-(+)- and (2S,4R)-trans-(-)-enantiomers of 6-methoxy-7-chloro-PAT to validate hydrogen bonding interactions proposed for the corresponding 6-OH analogs. Results indicate that PAT ligand three-dimensional structure impacts target receptor binding and translational outcomes, supporting the hypothesis that GPCR ligand structure governs orthosteric binding pocket molecular determinants and resulting pharmacology.
Asunto(s)
Conducta Animal/efectos de los fármacos , Conducta/efectos de los fármacos , Receptor de Serotonina 5-HT2A/efectos de los fármacos , Receptor de Serotonina 5-HT2A/metabolismo , Tetrahidronaftalenos/farmacología , Sustitución de Aminoácidos , Anfetaminas/farmacología , Animales , Relación Dosis-Respuesta a Droga , Humanos , Hidrólisis , Ligandos , Masculino , Ratones , Ratones Endogámicos C57BL , Modelos Moleculares , Fosfatidilinositoles/metabolismo , Mutación Puntual/genética , Ensayo de Unión Radioligante , Receptor de Serotonina 5-HT2A/genética , Agonistas del Receptor de Serotonina 5-HT2/farmacología , Agonistas de Receptores de Serotonina/farmacología , Especificidad de la Especie , Estereoisomerismo , Relación Estructura-Actividad , Tetrahidronaftalenos/químicaRESUMEN
BACKGROUND: Many studies of cocaine-responsive gene expression have focused on changes occurring during cocaine exposure, but few studies have examined the persistence of these changes with cocaine abstinence. Persistent changes in gene expression, as well as alterations induced during abstinence may underlie long-lasting drug craving and relapse liability. RESULTS: Whole-genome expression analysis was conducted on a rat cocaine binge-abstinence model that has previously been demonstrated to engender increased drug seeking and taking with abstinence. Gene expression changes in two mesolimbic terminal fields (mPFC and NAc) were identified in a comparison of cocaine-naïve rats with rats after 10 days of cocaine self-administration followed by 1, 10, or 100 days of enforced abstinence (n = 6-11 per group). A total of 1,461 genes in the mPFC and 414 genes in the NAc were altered between at least two time points (ANOVA, p < 0.05; +/- 1.4 fold-change). These genes can be subdivided into: 1) changes with cocaine self-administration that do not persist into periods of abstinence, 2) changes with cocaine self-administration that persist with abstinence, 3) and those not changed with cocaine self-administration, but changed during enforced abstinence. qPCR analysis was conducted to confirm gene expression changes observed in the microarray analysis. CONCLUSIONS: Together, these changes help to illuminate processes and networks involved in abstinence-induced behaviors, including synaptic plasticity, MAPK signaling, and TNF signaling.
Asunto(s)
Trastornos Relacionados con Cocaína/genética , Cocaína/administración & dosificación , Inhibidores de Captación de Dopamina/administración & dosificación , Expresión Génica , Núcleo Accumbens/metabolismo , Corteza Prefrontal/metabolismo , Síndrome de Abstinencia a Sustancias/genética , Análisis de Varianza , Animales , Cocaína/farmacología , Trastornos Relacionados con Cocaína/metabolismo , Modelos Animales de Enfermedad , Inhibidores de Captación de Dopamina/farmacología , Masculino , Núcleo Accumbens/efectos de los fármacos , Análisis de Secuencia por Matrices de Oligonucleótidos , Reacción en Cadena de la Polimerasa , Corteza Prefrontal/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Autoadministración , Síndrome de Abstinencia a Sustancias/metabolismo , Factores de TiempoRESUMEN
Dopamine neurotransmission is associated with high susceptibility to cocaine abuse. Positron emission tomography was used in 12 rhesus macaques to determine if dopamine D2 receptor availability was associated with the rate of cocaine reinforcement, and to study changes in brain dopaminergic function during maintenance of and abstinence from cocaine. Baseline D2 receptor availability was negatively correlated with rates of cocaine self-administration. D2 receptor availability decreased by 15-20% within 1 week of initiating self-administration and remained reduced by approximately 20% during 1 year of exposure. Long-term reductions in D2 receptor availability were observed, with decreases persisting for up to 1 year of abstinence in some monkeys. These data provide evidence for a predisposition to self-administer cocaine based on D2 receptor availability, and demonstrate that the brain dopamine system responds rapidly following cocaine exposure. Individual differences in the rate of recovery of D2 receptor function during abstinence were noted.
Asunto(s)
Conducta Adictiva , Encéfalo/fisiología , Cocaína/administración & dosificación , Receptores de Dopamina D2/metabolismo , Refuerzo en Psicología , Animales , Conducta Animal/fisiología , Encéfalo/anatomía & histología , Alimentos , Moduladores del GABA/metabolismo , Humanos , Lorazepam/metabolismo , Macaca mulatta , Masculino , Tomografía de Emisión de Positrones , Autoadministración , Factores de TiempoRESUMEN
In recent years a number of beneficial health effects have been ascribed to the renin-angiotensin system (RAS) that extend beyond lowering blood pressure, primarily mediated via the angiotensin-converting enzyme-2 (ACE2)/angiotensin (1-7) or Ang(1-7)/MAS receptor axis. Moreover, once thought as merely a systemic effector, RAS components exist within tissues. The highest tissue concentrations of ACE2 mRNA are located in the gut making it an important target for altering RAS function. Indeed, genetically engineered recombinant probiotics are promising treatment strategies offering delivery of therapeutic proteins with precision. An Ang(1-7) secreting Lactobacillus paracasei (LP) or LP-A has been described for regulation of diabetes and hypertension; however, we are the first to the best of our knowledge to propose this paradigm as it relates to aging. In this Research Practice manuscript, we provide proof of concept for using this technology in a well-characterized rodent model of aging: the Fisher344 x Brown Norway Rat (F344BN). Our primary findings suggest that LP-A increases circulating levels of Ang(1-7) both acutely and chronically (after 8 or 28 treatment days) when administered 3× or 7×/week over 4 weeks. Our future preclinical studies will explore the impact of this treatment on gut and other age-sensitive distal tissues such as brain and muscle.
Asunto(s)
Envejecimiento/sangre , Angiotensina I/sangre , Angiotensina I/efectos de los fármacos , Lacticaseibacillus paracasei , Fragmentos de Péptidos/sangre , Fragmentos de Péptidos/efectos de los fármacos , Probióticos/administración & dosificación , Angiotensina II/sangre , Enzima Convertidora de Angiotensina 2/sangre , Animales , Esquema de Medicación , Masculino , Modelos Animales , Vehículos Farmacéuticos , Prueba de Estudio Conceptual , Ratas , Ratas Endogámicas BN , Ratas Endogámicas F344 , Proteínas RecombinantesRESUMEN
To (1) investigate the efficacy of multiple doses of an orally delivered probiotic bacteria Lactobacillus paracasei (LP) modified to express angiotensin (1-7) (LP-A) in altering physiologic parameters relevant to the gut-brain axis in older rats and to (2) compare this strategy with subcutaneous delivery of synthetic Ang(1-7) peptide on circulating Ang(1-7) concentrations and these gut-brain axis parameters. Male 24-month-old F344BN rats received oral gavage of LP-A, or subcutaneous injection of Ang(1-7) for 0×, 1×, 3×, or 7×/week over 4 weeks. Circulating RAS analytes, inflammatory cytokines, and tryptophan and its downstream metabolites were measured by ELISA, electrochemiluminescence, and LC-MS respectively. Microbiome taxonomic analysis of fecal samples was performed via 16S-based PCR. Inflammatory and tryptophan-related mRNA expression was measured in colon and pre-frontal cortex. All dosing regimens of LP-A induced beneficial changes in fecal microbiome including overall microbiota community structure and α-diversity, while the 3×/week also significantly increased expression of the anti-inflammatory species Akkermansia muciniphila. The 3×/week also increased serum serotonin and the neuroprotective analyte 2-picolinic acid. In the colon, LP-A increased quinolinate phosphoribosyltransferase expression (1×/week) and increased kynurenine aminotransferase II (1× and 3×/week) mRNA expression. LP-A also significantly reduced neuro-inflammatory gene expression in the pre-frontal cortex (3×/week: COX2, IL-1ß, and TNFα; 7×/week: COX2 and IL-1ß). Subcutaneous delivery of Ang(1-7) increased circulating Ang(1-7) and reduced angiotensin II, but most gut-brain parameters were unchanged in response. Oral-but not subcutaneous-Ang(1-7) altered physiologic parameters related to gut-brain axis, with the most effects observed in 3×/week oral dosing regimen in older rats.
Asunto(s)
Probióticos , Angiotensina I , Animales , Encéfalo , Masculino , Fragmentos de Péptidos , RatasRESUMEN
RATIONALE AND OBJECTIVE: Although many contingencies operating in the natural environment include continuous dimensions of responses and reinforcers, previous studies of drug self-administration have almost exclusively used discrete dimensions of responses (e.g., a lever press) and reinforcers (e.g., 1.0 mg/kg/injection cocaine). Therefore, the present study provides an initial examination under experimental conditions with both responses and reinforcers measured along continuous dimensions. MATERIALS AND METHODS: Cocaine-maintained responding was studied in rats under a novel, hold-down schedule of reinforcement wherein the duration of the response was directly related to the magnitude of the reinforcer. These conditions were established by activating the syringe pump when the lever was pressed down and turning the pump off when the lever was released. The concentration of cocaine available in the syringe was varied across sessions. RESULTS: Cocaine self-administration was readily maintained under these conditions and remained stable across sessions. Responding was concentration dependent, with the number of responses and total duration of the response inversely related to concentration, and overall session intake of cocaine was stable across concentrations. In general, the duration of the responses were less than 0.5 s and did not vary as a function of concentration. CONCLUSIONS: Stability of responding under these schedule conditions was acquired quickly. This schedule of reinforcement may be useful for comparing across drug classes, can be extended for use with other types of responses and reinforcers, and may be more representative of the natural world where response-reinforcer contingencies are more likely to be experienced along continuous, rather than discrete, dimensions.
Asunto(s)
Conducta Animal/efectos de los fármacos , Cocaína/administración & dosificación , Esquema de Refuerzo , Animales , Relación Dosis-Respuesta a Droga , Masculino , Ratas , Ratas Sprague-Dawley , AutoadministraciónRESUMEN
Cocaine-responsive gene expression changes have been described after either no drug abstinence or short periods of abstinence. Little data exist on the persistence of these changes after long-term abstinence. Previously, we reported that after discrete-trial cocaine self-administration and 10 days of forced abstinence, incubation of cocaine reinforcement was observable by a progressive ratio schedule. The present study used rat discrete-trial cocaine self-administration and long-term forced abstinence to examine extinction responding, mRNA abundance of known cocaine-responsive genes, and chromatin remodeling. At 30 and 100 days of abstinence, extinction responding increased compared to 3-day abstinent rats. Decreases in both medial prefrontal cortex (mPFC) and nucleus accumbens c-fos, Nr4a1, Arc, and EGR1 mRNA were observed, and in most cases persisted, for 100 days of abstinence. The signaling peptides CART and neuropeptide Y (NPY) transiently increased in the mPFC, but returned to baseline levels following 10 days of abstinence. To investigate a potential regulatory mechanism for these persistent mRNA changes, levels of histone H3 acetylation at promoters for genes with altered mRNA expression were examined. In the mPFC, histone H3 acetylation decreased after 1 and 10 days of abstinence at the promoter for EGR1. H3 acetylation increased for NPY after 1 day of abstinence and returned to control levels by 10 days of abstinence. Behaviorally, these results demonstrate incubation after discrete-trial cocaine self-administration and prolonged forced abstinence. This incubation is accompanied by changes in gene expression that persist long after cessation of drug administration and may be regulated by chromatin remodeling.
Asunto(s)
Trastornos Relacionados con Cocaína/genética , Trastornos Relacionados con Cocaína/fisiopatología , Expresión Génica/fisiología , Sistema Límbico/metabolismo , Sistema Límbico/fisiopatología , Animales , Conducta Animal/efectos de los fármacos , Cromatina/genética , Cromatina/metabolismo , Extinción Psicológica , Proteínas Inmediatas-Precoces/biosíntesis , Proteínas Inmediatas-Precoces/genética , Inmunoprecipitación , Masculino , Neuropéptidos/biosíntesis , Neuropéptidos/genética , Ratas , Ratas Sprague-Dawley , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Autoadministración , Síndrome de Abstinencia a Sustancias/genética , Síndrome de Abstinencia a Sustancias/fisiopatología , Transcripción GenéticaRESUMEN
Opioids are the most effective compounds available for the relief of pain, yet there are a number of side effects that are of great concern to clinicians. For example, opioids are powerful reinforcers, and the treatment of pain using opioids could lead to the development of addiction. In addition, there is an increasing body of literature demonstrating that the repeated administration of opioids could lead to a phenomenon called opioid-induced hyperalgesia (i.e., increased sensitivity to painful stimulation). Studies examining these potential adverse effects are necessary in the development of novel analgesics. Furthermore, most studies of pain sensitivity and pain relief use reflex-based procedures to identify analgesics; however, it is argued here that operant-based procedures provide measures that are more analogous to the human condition (i.e., the mechanisms of pain are similar to those in humans) and should be useful in the assessment of novel analgesics. A series of studies examining the effects of opioids and the influence of variables such as age are discussed to demonstrate the utility of this approach.
Asunto(s)
Analgésicos Opioides/farmacología , Condicionamiento Operante/efectos de los fármacos , Dimensión del Dolor/efectos de los fármacos , Animales , Conducta Animal/efectos de los fármacos , Calor , Naloxona/farmacología , Antagonistas de Narcóticos/farmacología , Dolor/tratamiento farmacológico , Ratas , Refuerzo en PsicologíaRESUMEN
Disruption of the dopaminergic system has been implicated in the etiology of many pathological conditions, including drug addiction. Here we used positron emission tomography (PET) imaging to study brain dopaminergic function in individually housed and in socially housed cynomolgus macaques (n = 20). Whereas the monkeys did not differ during individual housing, social housing increased the amount or availability of dopamine D2 receptors in dominant monkeys and produced no change in subordinate monkeys. These neurobiological changes had an important behavioral influence as demonstrated by the finding that cocaine functioned as a reinforcer in subordinate but not dominant monkeys. These data demonstrate that alterations in an organism's environment can produce profound biological changes that have important behavioral associations, including vulnerability to cocaine addiction.
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Encéfalo/metabolismo , Cocaína/administración & dosificación , Receptores de Dopamina D2/metabolismo , Predominio Social , Animales , Conducta Animal , Encéfalo/diagnóstico por imagen , Vivienda para Animales , Macaca fascicularis , Masculino , Autoadministración , Medio Social , Aislamiento Social , Tomografía Computarizada de EmisiónRESUMEN
The obesity epidemic is multi-generational and is particularly debilitating in the aging population, necessitating the use of pharmaceutical interventions. Recent evidence suggests that increasing the activity of the angiotensin converting enzyme-2 [ACE2]/angiotensin-(1-7)[Ang-(1-7)]/Mas receptor (MasR) axis in obese animal models leads to significant reductions in body weight. It was hypothesized that activation of ACE2 via diminazene aceturate (DIZE) will significantly reduce body weight of rats fed a high fat diet. Young and old (4 and 23â¯months, respectively) male Fisher 344â¯×â¯Brown Norway rats were fed 60% high fat diet for one week, and subsequently given either 15â¯mg/kg/day DIZE s.c. or vehicle for three weeks. DIZE treatment resulted in a significant reduction of food intake and body weight in both young and old animals. However, that decrease was so dramatic in the older animals that they all nearly stopped eating. Interestingly, the TD-NMR assessments revealed that the weight-loss was primarily a result of decreased body fat percentage, with a relative preservation of lean mass. Tissue weights confirm the significant loss of white adipose tissue (WAT), with no change in muscle weights. Gene expression and serum ACE2 activity analyses implied that increased activation of the ACE2/Ang-(1-7)/MasR axis plays a role in reducing fat mass. Collectively, our results suggest that DIZE may be a useful tool in the study of obesity; however, caution is recommended when using this compound in older animals due to severe anorectic effects, although there is a mechanism by which muscle is preserved.
Asunto(s)
Adiposidad/efectos de los fármacos , Angiotensina I/metabolismo , Diminazeno/análogos & derivados , Obesidad/metabolismo , Fragmentos de Péptidos/metabolismo , Peptidil-Dipeptidasa A/metabolismo , Factores de Edad , Angiotensina I/genética , Enzima Convertidora de Angiotensina 2 , Animales , Diminazeno/farmacología , Modelos Animales de Enfermedad , Expresión Génica , Masculino , Fragmentos de Péptidos/genética , Peptidil-Dipeptidasa A/sangre , Peptidil-Dipeptidasa A/genética , Ratas , Ratas Endogámicas F344 , Sistema Renina-Angiotensina/efectos de los fármacosRESUMEN
We recently showed that male rats exhibit lower hypophagia and body weight loss compared to female rats following central leptin delivery, suggesting a role for oestradiol in leptin responsiveness. Accordingly, we delivered Ob (leptin) or GFP (control) gene into the brain of male rats that were simultaneously treated with oestradiol or vehicle. In a reciprocal approach, we compared oestradiol-deficient (OVX) with intact females (sham) that received leptin or control vector. Changes in food intake), body weight and body composition were examined. In males, oestradiol and leptin resulted in lower cumulative food intake (15%) and endpoint body weight (5%), although rats receiving dual treatment (oestradiol-leptin) ate 28% less and weighed 22% less than vehicle-control. Changes in food intake were unique to each treatment, with a rapid decrease in vehicle-leptin followed by gradual renormalisation. By contrast, hypophagia in oestradiol-control was of lower amplitude and sporadic. Leptin selectively targeted fat mass and endpoint abdominal fat mass was 65%-80% lower compared to their respective control groups. In females, both leptin groups had lower body weight (endpoint values 20% lower than control groups) with the highest extent in sham animals (endpoint value was 28% less in sham-leptin than in sham-control). OVX rats rapidly started regaining their lost body weight reminiscent of the pattern in males. Leptin rapidly and robustly reduced fat mass with endpoint values 30%-35% less than control treated animals. It appears that leptin and oestradiol decreased food intake and body weight via different mechanisms, with the pattern of oestradiol-leptin being reminiscent of that observed in females and the pattern of OVX-leptin reminiscent of that observed in males. Oestrogen status did not influence initial fat mass loss by leptin. It can be concluded that oestradiol modulates the long-term response to central leptin overexpression, although its actions on energy homeostasis are additive and independent of those of leptin.
Asunto(s)
Tejido Adiposo/fisiología , Ingestión de Alimentos/fisiología , Estradiol/fisiología , Hipotálamo/fisiología , Leptina/fisiología , Tejido Adiposo/efectos de los fármacos , Animales , Depresores del Apetito/administración & dosificación , Ingestión de Alimentos/efectos de los fármacos , Estradiol/administración & dosificación , Estrógenos/administración & dosificación , Estrógenos/fisiología , Femenino , Leptina/administración & dosificación , Leptina/genética , Masculino , Ovariectomía , Ratas Sprague-Dawley , Ratas Transgénicas , Caracteres SexualesRESUMEN
RATIONALE: Cross-sensitization between cocaine and amphetamine has been demonstrated in different behavioral paradigms. There is a relative paucity of studies examining whether cross-sensitization occurs between amphetamine and cocaine when both are self-administered. OBJECTIVE: The current study was designed to test whether animals sensitized to the reinforcing effects of cocaine would show cross-sensitization of the reinforcing effects of amphetamine, using a self-administration paradigm. MATERIALS AND METHODS: Male, Sprague-Dawley rats were trained to self-administer cocaine and given limited or high exposure to cocaine under a fixed ratio (FR) 1 procedure. After the initial exposure to cocaine, animals self-administered cocaine (1.5 mg/kg per injection) under a progressive ratio (PR) procedure. Subsequently, breakpoints on a PR schedule and rates of intake on an FR schedule maintained by different doses of amphetamine were assessed. RESULTS: Animals with high initial exposure to cocaine (40 injections of 1.5 mg/kg per injection per day for 5 days) showed stable breakpoints throughout testing. Animals given limited initial cocaine exposure (20 injections of 0.75 mg/kg per injection for 1 day) produced a gradual increase in breakpoints maintained by cocaine over time (i.e., sensitization of the reinforcing effects of cocaine). When subsequently tested with amphetamine, the dose-effect curve was shifted upward in the limited-exposure group relative to the high-exposure group, suggesting cross-sensitization of the reinforcing effects of amphetamine. CONCLUSIONS: Sensitization of the reinforcing effects of cocaine resulted in cross-sensitization of the reinforcing effects of amphetamine. This phenomenon occurs even when both drugs are self-administered.
Asunto(s)
Anfetamina/farmacología , Estimulantes del Sistema Nervioso Central/farmacología , Cocaína/farmacología , Inhibidores de Captación de Dopamina/farmacología , Refuerzo en Psicología , Anfetamina/administración & dosificación , Animales , Conducta Animal/efectos de los fármacos , Estimulantes del Sistema Nervioso Central/administración & dosificación , Cocaína/administración & dosificación , Condicionamiento Operante/efectos de los fármacos , Inhibidores de Captación de Dopamina/administración & dosificación , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Masculino , Ratas , Ratas Sprague-Dawley , Esquema de Refuerzo , AutoadministraciónRESUMEN
Procedures have been developed which provide extremely stable patterns of cocaine self-administration in rats and these have been useful in lesion and drug pretreatment studies aimed at understanding the neurobiology of cocaine reinforcement. The issue now is whether studying the neurobiology of reinforcement is the same as studying the neurobiology of addiction. If the goal is to understand a progressive and deteriorating disorder, then the self-administration procedures should model specific aspects of the progressive stages of the addiction process. Here we review theoretical strategies for modeling the addiction process and present data from a series of experiments from our laboratory showing conditions which produce a progressive change in the motivation to self-administer cocaine in rats. This phenomenon is revealed by an escalation in breakpoints on a progressive ratio schedule. The effect, which is robust and persistent, depends on dose and speed of injection. Interestingly, high drug intake can retard the development of this effect, which we argue indicates that the addiction process has a developmental sequence. Finally, we suggest that specific parameters (dose, price and availability) can be used to examine the transition from recreational use to binge-like intake.
Asunto(s)
Trastornos Relacionados con Cocaína/psicología , Animales , Condicionamiento Operante/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Motivación , Ratas , Refuerzo en Psicología , AutoadministraciónRESUMEN
Hypothalamic inflammation and increased oxidative stress are believed to be mechanisms that contribute to obesity. 4-Hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (tempol), a free radical scavenger, has been shown to reduce inflammation and oxidative stress. We hypothesized that brain infusion of tempol would reduce oxidative stress, and thus would reduce food intake and body weight and improve body composition in rats with age-related obesity and known elevated oxidative stress. Furthermore, we predicted an associated increase in markers of leptin signalling, including the silent mating type information regulator 2 homolog 1 (SIRT1)/5'AMP-activated protein kinase (AMPK) pathway and the signal transducer and activator of transcription 3 (STAT3) pathway. For this purpose, osmotic minipumps were placed in the intracerebroventricular region of young (3 months) and aged (23 months) male Fischer 344 x Brown Norway rats for the continuous infusion of tempol or vehicle for 2 weeks. Tempol significantly decreased (p < 0.01) nicotinamide adenine dinucleotide phosphate oxidase activity in the hypothalamus but failed to reduce food intake or weight gain and did not alter body composition. SIRT1 activity and Acetyl p53 were decreased and phosphorylation of AMPK was increased with age, but they were unchanged with tempol. Basal phosphorylation of STAT3 was unchanged with age or tempol. These results indicate that tempol decreases oxidative stress but fails to alter feeding behaviour, body weight, or body composition. Moreover, tempol does not modulate the SIRT1/AMPK/p53 pathway and does not change leptin signalling. Thus, a reduction in hypothalamic oxidative stress is not sufficient to reverse age-related obesity.
Asunto(s)
Envejecimiento , Disfunción Cognitiva/prevención & control , Óxidos N-Cíclicos/administración & dosificación , Depuradores de Radicales Libres/administración & dosificación , Hipotálamo/efectos de los fármacos , Nootrópicos/administración & dosificación , Estrés Oxidativo/efectos de los fármacos , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Disfunción Cognitiva/etiología , Cruzamientos Genéticos , Óxidos N-Cíclicos/efectos adversos , Óxidos N-Cíclicos/uso terapéutico , Ingestión de Energía/efectos de los fármacos , Depuradores de Radicales Libres/efectos adversos , Depuradores de Radicales Libres/uso terapéutico , Hipotálamo/metabolismo , Bombas de Infusión Implantables , Infusiones Intraventriculares , Masculino , Proteínas del Tejido Nervioso/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Nootrópicos/efectos adversos , Nootrópicos/uso terapéutico , Obesidad/tratamiento farmacológico , Obesidad/fisiopatología , Ratas Endogámicas BN , Ratas Endogámicas F344 , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/efectos de los fármacos , Sirtuina 1/metabolismo , Marcadores de SpinRESUMEN
[This corrects the article DOI: 10.1038/ncomms14477.].