RESUMEN
Pomaglumetad methionil (POM), a group 2 metabotropic glutamate receptor (mGluR2/3) agonist, showed promise as a novel antipsychotic in preclinical research but failed to show efficacy in clinical trials, though it has been suggested that it may be effective in certain patient populations, including early in disease patients. We used the methyazoxymethanol acetate (MAM) rat model of schizophrenia to determine whether POM may prevent the development of dopamine (DA) system dysfunction in a model representative of the hyperdopaminergic state thought to underlie psychosis, compared to control (SAL) rats. MAM and SAL rats were administered either POM (3 mg/kg, i.p.), vehicle (1 ml/kg), or no injection during postnatal day (PD) 31-40. In either late adolescence (PD 47-56) or adulthood (PD 83-96), novel object recognition (NOR) was tested, followed by anesthetized in vivo electrophysiological recordings of VTA DA neuron activity or ventral hippocampal (vHPC) pyramidal neuron activity. MAM rats treated with POM demonstrated increased NOR in adulthood compared to no injection MAM rats, but not compared to vehicle-treated MAM rats. POM-treated MAM rats demonstrated normalized DA neuron population activity and vHPC pyramidal neuron activity compared to vehicle and no injection MAM rats in both late adolescence and adulthood. No significant differences were observed across treatment groups in SAL rats. These results suggest that peripubertal mGluR2/3 agonist administration can prevent the emergence of vHPC pyramidal neuron hyperactivity and increased DA neuron population activity in adult MAM rats.
Asunto(s)
Aminoácidos/farmacología , Antipsicóticos/farmacología , Conducta Animal/efectos de los fármacos , Agonistas de Aminoácidos Excitadores/farmacología , Hipocampo/efectos de los fármacos , Receptores de Glutamato Metabotrópico/agonistas , Esquizofrenia/tratamiento farmacológico , Área Tegmental Ventral/efectos de los fármacos , Factores de Edad , Aminoácidos/administración & dosificación , Animales , Modelos Animales de Enfermedad , Agonistas de Aminoácidos Excitadores/administración & dosificación , Masculino , Acetato de Metilazoximetanol/farmacología , Neurotoxinas/farmacología , RatasRESUMEN
INTRODUCTION: Patients with schizophrenia (SCZ) smoke at a rate of 4-5 times higher than the general population, contributing to negative health consequences in this group. One possible explanation for this increased smoking is that individuals with SCZ find nicotine (NIC) more reinforcing. However, data supporting this possibility are limited. METHODS: The present experiments examined self-administration of NIC, alone or in combination with other reinforcers, across a range of doses in the methylazoxymethanol acetate (MAM) rodent model of SCZ. RESULTS: MAM and control animals did not differ in NIC self-administration across a range of doses and schedules of reinforcement, in both standard 1-hour self-administration sessions and 23-hour extended access sessions. However, MAM animals responded less for sucrose or reinforcing visual stimuli alone or when paired with NIC. CONCLUSIONS: To the extent that MAM-treated rats are a valid model of SCZ, these results suggest that increased NIC reinforcement does not account for increased smoking in SCZ patients. IMPLICATIONS: This study is the first to utilize nicotine self-administration, the gold standard for studying nicotine reinforcement, in the methylazoxymethanol acetate model of schizophrenia, which is arguably the most comprehensive animal model of the disease currently available. Our assessment found no evidence of increased nicotine reinforcement in methylazoxymethanol acetate animals, suggesting that increased reinforcement may not perpetuate increased smoking in schizophrenia patients.
Asunto(s)
Modelos Animales de Enfermedad , Acetato de Metilazoximetanol/toxicidad , Nicotina/administración & dosificación , Refuerzo en Psicología , Esquizofrenia/inducido químicamente , Animales , Animales Recién Nacidos , Relación Dosis-Respuesta a Droga , Femenino , Masculino , Inhibidores de la Síntesis de la Proteína/toxicidad , Ratas , Ratas Sprague-Dawley , Autoadministración , Sacarosa/administración & dosificaciónRESUMEN
BACKGROUND: Loss of parvalbumin interneurons in the hippocampus is a robust finding in schizophrenia brains. Rats exposed during embryonic day 17 to methylazoxymethanol acetate exhibit characteristics consistent with an animal model of schizophrenia, including decreased parvalbumin interneurons in the ventral hippocampus. We reported previously that peripubertal administration of diazepam prevented the emergence of pathophysiology in adult methylazoxymethanol acetate rats. METHODS: We used an unbiased stereological method to examine the impact of peripubertal diazepam treatment on parvalbumin interneuron number in the ventral subiculum, dentate gyrus of the hippocampus and the basolateral amygdala. RESULTS: Methylazoxymethanol acetate rats with peripubertal diazepam showed significantly more parvalbumin interneurons (3355±173 in the ventral subiculum, 1211±76 in the dentate gyrus) than methylazoxymethanol acetate without diazepam (2375±109 and 824±54, respectively). No change was found in the basolateral amygdala. CONCLUSIONS: Peripubertal diazepam attenuated the decrease of parvalbumin in the ventral hippocampus of methylazoxymethanol acetate rats.
Asunto(s)
Antipsicóticos/administración & dosificación , Conducta Animal/efectos de los fármacos , Diazepam/administración & dosificación , Hipocampo/efectos de los fármacos , Interneuronas/efectos de los fármacos , Acetato de Metilazoximetanol , Parvalbúminas/metabolismo , Esquizofrenia/prevención & control , Psicología del Esquizofrénico , Animales , Modelos Animales de Enfermedad , Regulación hacia Abajo , Esquema de Medicación , Femenino , Edad Gestacional , Hipocampo/metabolismo , Hipocampo/fisiopatología , Interneuronas/metabolismo , Embarazo , Efectos Tardíos de la Exposición Prenatal , Ratas Sprague-Dawley , Esquizofrenia/inducido químicamente , Esquizofrenia/metabolismo , Esquizofrenia/fisiopatología , Maduración SexualRESUMEN
Aulacoscelinae beetles have an ancient relationship with cycads (Cycadophyta: Zamiaceae), which contain highly toxic azoxyglycoside (AZG) compounds. How these "primitive" leaf beetles deal with such host-derived compounds remains largely unknown. Collections were made of adult Aulacoscelis appendiculata from Zamia cf. elegantissima in Panama, A. vogti from Dioon edule in Mexico, and Janbechynea paradoxa from Zamia boliviana in Bolivia. Total AZG levels were quantified in both cycad leaves and adult beetles by high performance liquid chromatography (HPLC). On average, cycad leaves contained between 0.5-0.8% AZG (frozen weight, FW), while adult beetles feeding on the same leaves contained even higher levels of the compounds (average 0.9-1.5% FW). High AZG levels were isolated from reflex bleeding secreted at the leg joints when beetles were disturbed. Nuclear magnetic resonance and mass spectroscopy identified two AZGs, cycasin and macrozamin, in the reflex bleeding; this is the first account of potentially plant-derived compounds in secretions of the Aulacoscelinae. These data as well as the basal phylogenetic position of the Aulacoscelinae suggest that sequestration of plant secondary metabolites appeared early in leaf beetle evolution.