RESUMEN
PURPOSE: Nonadherence to antipsychotic medications is a major obstacle preventing optimal outcomes for patients with schizophrenia. Extended release systems exist in the form of depot injections, but these formulations exhibit several disadvantages. To address these concerns, we previously demonstrated proof of concept for an antipsychotic implant containing risperidone and the biodegradable polymer poly(lactic-co-glycolic) acid (PLGA). METHODS: We build upon recently published data by utilizing a scalable single-screw extrusion system for the production of PLGA-risperidone implants. Implants were composed of 40% risperidone and 60% PLGA, with varying ratios of lactide to glycolide (50:50, 65:35, 75:25 or 85:15). Risperidone release was assessed in vitro and in vivo in rats, and Level A, B and C correlations (IVIVCs) attempted for all. Bioavailability was verified with locomotor testing RESULTS: Level B analysis yielded the greatest correlation between in vitro and in vivo data (R (2) = 0.9425), while Level C yielded the lowest (R (2) = 0.8336). Although, based on qualitative results, a Level A correlation was not achieved, it did produce an R (2) of 0.9261. Locomotor testing demonstrated that peak serum concentrations coincide with significant reductions in activity. CONCLUSION: Data demonstrate the applicability of our modeling system and advance long-term, implantable antipsychotics toward clinical application.
Asunto(s)
Implantes Absorbibles , Sistemas de Liberación de Medicamentos , Ácido Láctico/administración & dosificación , Ácido Poliglicólico/administración & dosificación , Risperidona/administración & dosificación , Esquizofrenia/tratamiento farmacológico , Animales , Antipsicóticos/administración & dosificación , Humanos , Masculino , Modelos Animales , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Ratas , Ratas Sprague-DawleyRESUMEN
Ketamine is an NMDA receptor antagonist with a variety of uses, ranging from recreational drug to pediatric anesthetic and chronic pain reliever. Despite its value in the clinical setting, little is known about the immediate and long-lasting effects of repeated ketamine treatment. We assessed the effects of chronic administration of a subanesthetic dose of ketamine on contextual fear conditioning, detection of pitch deviants and auditory gating. After four, but not two, weeks of daily ketamine injections, mice exhibited decreased freezing in the fear conditioning paradigm. Gating of the P80 component of auditory evoked potentials was also significantly altered by treatment condition, as ketamine caused a significant decrease in S1 amplitude. Additionally, P20 latency was significantly increased as a result of ketamine treatment. Though no interactions were found involving test week, stimulus and treatment condition, these results suggest that repeated ketamine administration impairs fear memory and has lasting effects on encoding of sensory stimuli.
Asunto(s)
Percepción Auditiva/efectos de los fármacos , Condicionamiento Clásico/efectos de los fármacos , Potenciales Evocados Auditivos/efectos de los fármacos , Antagonistas de Aminoácidos Excitadores/farmacología , Hipocampo/efectos de los fármacos , Ketamina/farmacología , Estimulación Acústica , Análisis de Varianza , Animales , Percepción Auditiva/fisiología , Electrodos Implantados , Electrochoque , Antagonistas de Aminoácidos Excitadores/administración & dosificación , Miedo , Reacción Cataléptica de Congelación/efectos de los fármacos , Hipocampo/fisiología , Ketamina/administración & dosificación , Masculino , Ratones , Ratones Endogámicos C57BL , Discriminación de la Altura Tonal/efectos de los fármacos , Discriminación de la Altura Tonal/fisiologíaRESUMEN
The usage patterns and biological effects of cigarette smoking differ significantly among men and women. This study seeks to clarify the interaction that exists between nicotine and biological gender by investigating changes in brain electrical activity after acute nicotine treatment. The P20, N40, and P80 components of the auditory evoked potential were examined in male and female C57BL/6J mice using a paired-stimulus gating paradigm. Consistent with previously published data, acute nicotine resulted in increased gating of the P20 but a decrease in that of N40. Nicotine also resulted in a lengthening of P20 latency but a decrease in that of N40 and P80. The P80 latencies of male and female subjects were differentially affected by nicotine, as males appeared to be more sensitive to its shortening effect. Males and females also exhibited differences in N40 and P80 amplitudes, both of which were smaller in males. The effects of gender on auditory evoked potential amplitude suggest dimorphic signaling in the N40 and P80 generators. Whether this electrophysiological sexual dimorphism has functional consequences for sensory or cognitive abilities requires additional research. (PsycINFO Database Record (c) 2008 APA, all rights reserved).
Asunto(s)
Potenciales Evocados Auditivos/efectos de los fármacos , Nicotina/farmacología , Agonistas Nicotínicos/farmacología , Caracteres Sexuales , Estimulación Acústica/métodos , Análisis de Varianza , Animales , Electroencefalografía/métodos , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Tiempo de Reacción/efectos de los fármacosRESUMEN
An endophenotype is a heritable trait that is generally considered to be more highly, associated with a gene-based neurological deficit than a disease phenotype itself. Such, endophenotypic deficits may therefore be observed in the non-affected relatives of disease patients. Once endophenotypes have been established for a given illness, such as schizophrenia, mechanisms of, action may then be established and treatment options developed in order to target such measures. The, current paper describes and assesses the merits and limitations of utilizing behavioral and, electrophysiological endophenotypes of schizophrenia in mice. Such endophenotypic deficits include: decreased auditory event related potential (ERP) amplitude and gating (specifically, that of the P20, N40, P80 and P120); impaired mismatch negativity (MMN); changes in theta and gamma frequency, analyses; decreased pre-pulse inhibition (PPI); impaired working and episodic memories (for instance, novel object recognition [NOR], contextual and cued fear conditioning, latent inhibition, Morris and, radial arm maze identification and nose poke); sociability; and locomotor activity. A variety of, pharmacological treatments, including ketamine, MK-801 and phencyclidine (PCP) can be used to, induce some of the deficits described above, and numerous transgenic mouse strains have been, developed to address the mechanisms responsible for such endophenotypic differences. We also, address the viability and validity of using such measures regarding their potential clinical implications, and suggest several practices that could increase the translatability of preclinical data.