RESUMEN
Ceftriaxone (CTX) decreases locomotor activation produced by initial cocaine exposure and attenuates development of behavioral sensitization produced by repeated cocaine exposure. An important question that has not yet been answered is whether or not CTX reduces behavioral sensitization to cocaine in cases in which the antibiotic is administered only during the period of cocaine absence that follows repeated cocaine exposure and precedes reintroduction to cocaine. We investigated this question using C57BL/6 mice. Mice pretreated with cocaine (15mg/kg×14 days) and then challenged with cocaine (15mg/kg) after 30 days of cocaine absence displayed sensitization of locomotor activity. For combination experiments, CTX injected during the 30 days of cocaine absence attenuated behavioral sensitization produced by cocaine challenge. In the case in which CTX was injected together with cocaine for 14 days, development of behavioral sensitization to cocaine challenge was also reduced. CTX attenuated the increase in locomotor activity produced by acute cocaine exposure; however, its efficacy was dependent on the dose of cocaine as inhibition was detected against 30mg/kg, but not 15mg/kg, of cocaine. These results from mice indicate that CTX attenuates locomotor activity produced by acute and repeated cocaine exposure and counters cocaine's locomotor activating properties in a paradigm in which the antibiotic is injected during the period of forced cocaine absence that follows repeated cocaine exposure.
Asunto(s)
Antibacterianos/farmacología , Ceftriaxona/farmacología , Estimulantes del Sistema Nervioso Central/farmacología , Cocaína/farmacología , Actividad Motora/efectos de los fármacos , Animales , Estimulantes del Sistema Nervioso Central/administración & dosificación , Cocaína/administración & dosificación , Relación Dosis-Respuesta a Droga , Antagonismo de Drogas , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
We report significantly decreased white matter protein levels in the nucleus accumbens in an adult mouse model of chronic cocaine abuse. Previous studies from human cocaine abuse patients show disruption of white matter and myelin loss, thus supporting our observations. Understanding the neuropathological mechanisms for white matter disruption in cocaine abuse patients is complicated by polydrug use and other comorbid factors, hindering the development of effective therapeutic strategies to ameliorate damage or compliment rehabilitation programs. In this context, our data further demonstrate that cocaine-induced loss of white matter proteins is absent in mice treated with the ß-lactam antibiotic, ceftriaxone, during cocaine withdrawal. Other studies report that ceftriaxone, a glutamate transporter subtype-1 activator, is neuroprotective in murine models of multiple sclerosis, thereby demonstrating potential therapeutic properties for diseases with white matter loss. Cocaine-induced white matter abnormalities likely contribute to the cognitive, motor, and psychological deficits commonly afflicting cocaine abusers, yet the underlying mechanisms responsible for these changes remain unknown. Our observations describe an adult animal model for the study of cocaine-induced myelin loss for the first time, and highlight a potential pharmacological intervention to ameliorate cocaine-induced white matter loss.
Asunto(s)
Ceftriaxona/administración & dosificación , Cocaína/efectos adversos , Proteínas del Tejido Nervioso/metabolismo , Núcleo Accumbens/metabolismo , Núcleo Accumbens/patología , Síndrome de Abstinencia a Sustancias/metabolismo , beta-Lactamas/administración & dosificación , Envejecimiento/metabolismo , Animales , Caspasa 3/metabolismo , Ceftriaxona/farmacología , Ceftriaxona/uso terapéutico , Transportador 2 de Aminoácidos Excitadores/metabolismo , Ratones , Ratones Endogámicos C57BL , Núcleo Accumbens/efectos de los fármacos , Oligodendroglía/efectos de los fármacos , Oligodendroglía/enzimología , Oligodendroglía/patología , Síndrome de Abstinencia a Sustancias/tratamiento farmacológico , beta-Lactamas/farmacología , beta-Lactamas/uso terapéuticoRESUMEN
Mounting evidence suggests a potential link between cocaine abuse, disruptions in hypothalamic-pituitary-thyroid axis signaling, and neuroplasticity, but molecular mechanisms remain unknown. Neurogranin (Ng) is a gene containing a thyroid hormone-responsive element within its first intron that is involved in synaptic plasticity. Transcriptional activation requires heterodimerization of thyroid hormone receptor (TR) and retinoid X receptor (RXR) bound by their respective ligands, tri-iodothryonine and 9-cis-retinoic acid (9-cis-RA), and subsequent binding of this complex to the thyroid hormone-responsive element of the Ng gene. In this study, the effects of chronic cocaine abuse on Ng expression in euthyroid and hypothyroid mice were assessed. In cocaine-treated mice, decreased Ng expression was observed in the absence of changes in levels of thyroid hormones or other hypothalamic-pituitary-thyroid signaling factors. Therefore, we hypothesized that cocaine decreases Ng expression via alterations in 9-cis-RA availability and TR/RXR signaling. In support of this hypothesis, RXR-γ was significantly decreased in brains of cocaine-treated mice while CYP26A1, the main enzyme responsible for neuronal RA degradation, was significantly increased. Results from this study provide the first evidence for a direct effect of cocaine abuse on TR/RXR signaling, RA metabolism, and transcriptional regulation of Ng, a gene essential for adult neuroplasticity.
Asunto(s)
Cocaína/farmacología , Neurogranina/biosíntesis , Receptores de Hormona Tiroidea/efectos de los fármacos , Receptores X Retinoide/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Animales , Antitiroideos , Western Blotting , Sistema Enzimático del Citocromo P-450/biosíntesis , Sistema Enzimático del Citocromo P-450/genética , Depresión Química , Ensayo de Inmunoadsorción Enzimática , Técnica del Anticuerpo Fluorescente , Hipotiroidismo/inducido químicamente , Hipotiroidismo/fisiopatología , Hipotiroidismo/psicología , Yoduro Peroxidasa/biosíntesis , Masculino , Ratones , Ratones Endogámicos C57BL , Propiltiouracilo , ARN/biosíntesis , ARN/aislamiento & purificación , Reacción en Cadena en Tiempo Real de la Polimerasa , Ácido Retinoico 4-Hidroxilasa , Conducta Estereotipada/efectos de los fármacos , Hormonas Tiroideas/sangre , Tretinoina/metabolismoRESUMEN
No medication is approved to treat cocaine addiction, but mounting evidence suggests that glutamate-directed approaches may reduce cocaine dependence and relapse. We tested the hypotheses that the glutamate transporter subtype 1 activator, ceftriaxone, disrupts acquisition of cocaine self-administration, motivation to self-administer cocaine, and conditioned place preference in mice. Repeated ceftriaxone (200 mg/kg) reduced the ability of mice to acquire cocaine and the motivation to self-administer cocaine after successful acquisition without affecting acquisition of or motivation for sweet food. Repeated ceftriaxone had no effect on cocaine-conditioned place preference. These results suggest that a ß-lactam antibiotic reduces the direct reinforcing strength of cocaine without producing nonspecific deficits in conditioned learning processes.
Asunto(s)
Antibacterianos/farmacología , Trastornos Relacionados con Cocaína/psicología , Cocaína/farmacología , Condicionamiento Operante/efectos de los fármacos , Alimentos , Motivación/efectos de los fármacos , beta-Lactamas/farmacología , Animales , Ceftriaxona/farmacología , Relación Dosis-Respuesta a Droga , Transportador 2 de Aminoácidos Excitadores/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Esquema de Refuerzo , Refuerzo en Psicología , Recompensa , AutoadministraciónRESUMEN
Acetaminophen (APAP) produces antinociception and hypothermia. Because the antinociceptive effect in rats is partially dependent on opioid and cannabinoid CB1 receptor activation, we determined if activation of these receptors also contributes to the hypothermic effect of APAP. Rats injected with APAP (100, 250, 375 or 500 mg/kg, i.p.) displayed dose-related hypothermia. For combined administration, the hypothermic effect of APAP (400 mg/kg, i.p.) was not altered by pretreatment with: naltrexone (10 mg/kg, s.c.), a non-selective opioid antagonist; naltrindole (1 mg/kg, s.c.), a delta opioid antagonist; nor-binaltorphimine (10 mg/kg, i.p.), a kappa opioid antagonist; SR 141716A (3 mg/kg, i.m.), a cannabinoid CB1 receptor antagonist; or JTC-801(1 mg/kg, i.p.), a nociceptin/orphanin FQ peptide (NOP) receptor antagonist. The demonstration that APAP produces hypothermia independent of opioid, cannabinoid CB1 or NOP receptor activation is contrary to its antinociceptive effect, which requires opioid and cannabinoid CB1 receptor activation.