RESUMEN
Previous work has indicated an association between seizures early in life and increased risk of psychiatric disorders, including schizophrenia. However, because early-life seizures are commonly treated with antiepileptic drugs (AEDs) such as phenobarbital, the possibility that drug treatment may affect later-life psychiatric outcomes needs to be evaluated. We therefore tested the hypothesis that phenobarbital exposure in the neonatal rat increases the risk of schizophrenia-like behavioral abnormalities in adulthood. Thus, in this study, we examined the effects of a single acute neonatal exposure to phenobarbital on adult behavioral outcomes in the rat neonatal ventral hippocampal (nVH) lesion model of schizophrenia. We compared these outcomes to those in rats a) without nVH lesions and b) with nVH lesions, without phenobarbital. The tasks used for behavioral evaluation were: amphetamine-induced locomotion, prepulse inhibition, elevated plus-maze, and novel object recognition task. We found that neonatal phenobarbital treatment (in the absence of nVH lesions) was sufficient to disrupt sensorimotor gating (as tested by prepulse inhibition) in adulthood to an extent equivalent to nVH lesions. Additionally, neonatal phenobarbital exposure enhanced the locomotor response to amphetamine in adult animals with and without nVH lesions. Our findings suggest that neonatal exposure to phenobarbital can predispose to schizophrenia-like behavioral abnormalities. Our findings underscore the importance of examining AED exposure early in life as a potential risk factor for later-life neuropsychiatric abnormalities in clinical populations.
Asunto(s)
Fenobarbital/toxicidad , Esquizofrenia/inducido químicamente , Factores de Edad , Animales , Animales Recién Nacidos , Femenino , Embarazo , Ratas , Ratas Sprague-Dawley , Esquizofrenia/patologíaRESUMEN
We investigated the cellular and subcellular distributions of neuregulin tyrosine kinase receptor ErbB4 in the postnatal rat frontal cortex and hippocampus by light-, confocal- and electron-microscopic immunocytochemistry. At birth, ErbB4-immunoreactivity (ErbB4-IR) was prominent in the apical cytoplasm and dendrites of cortical plate neurons and hippocampal pyramidal cells. Throughout postnatal development and in adulthood, ErbB4-IR in both regions remained confined to the somatodendritic compartment of neurons, which increased in number to reach the adult pattern by the end of the first postnatal month (P30). At all ages examined, double-labeling experiments revealed that ErbB4-IR always co-localized with the neuronal marker neuronal nuclei (NeuN) and never with glial markers Nestin or glial fibrillary acidic protein (GFAP). Immunoperoxidase labeling at the ultrastructural level confirmed the exclusive localization of ErbB4-IR in somatodendrites, and notably in dendritic spines. Immunogold labeling showed preponderant ErbB4-IR in the cytoplasm, where it was associated with microtubules. Furthermore, ErbB4-IR was abundant in the nucleus of adult cortical and hippocampal neurons, suggesting a role for ErbB4 nuclear signaling in the brain beyond embryonic development. Taken together, these results show that ErbB4 is expressed by neuronal somatodendrites in cerebral cortex and hippocampus from birth to adulthood, and support a role for neuregulins in dendritic growth and plasticity.
Asunto(s)
Corteza Cerebral/crecimiento & desarrollo , Corteza Cerebral/metabolismo , Receptores ErbB/metabolismo , Hipocampo/crecimiento & desarrollo , Hipocampo/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Envejecimiento/fisiología , Animales , Animales Recién Nacidos , Compartimento Celular/fisiología , Diferenciación Celular/fisiología , Núcleo Celular/metabolismo , Núcleo Celular/ultraestructura , Corteza Cerebral/ultraestructura , Proteínas de Unión al ADN , Espinas Dendríticas/metabolismo , Espinas Dendríticas/ultraestructura , Hipocampo/ultraestructura , Inmunohistoquímica , Masculino , Microscopía Confocal , Microscopía Inmunoelectrónica , Microtúbulos/metabolismo , Microtúbulos/ultraestructura , Neurregulina-1 , Plasticidad Neuronal/fisiología , Neuronas/metabolismo , Neuronas/ultraestructura , Proteínas Nucleares/metabolismo , Células Piramidales/metabolismo , Células Piramidales/ultraestructura , Ratas , Ratas Sprague-Dawley , Receptor ErbB-4RESUMEN
Neonatal ventral hippocampal (nVH) lesions in rats result in adult onset of a number of behavioral and cognitive abnormalities analogous to those seen in schizophrenia, including hyperresponsiveness to stress and psychostimulants and deficits in working memory, sensorimotor gating and social interaction. Molecular and neurochemical alterations in the prefrontal cortex (PFC) and nucleus accumbens (NAcc) of nVH-lesioned animals suggest developmental reorganization of these structures following neonatal lesions. To determine whether nVH lesions lead to neuronal morphological changes, we investigated the effect of nVH lesion on dendritic structure and spine density of pyramidal neurons of the PFC and medium spiny neurons of the NAcc. Bilateral ibotenic acid-induced lesion of the VH was made in Sprague-Dawley pups at postnatal day 7 (P7); and at P70, neuronal morphology was quantified by modified Golgi-Cox staining. The results show that length of basilar dendrites and branching and the density of dendritic spines on layer 3 pyramidal neurons were significantly decreased in rats with nVH lesions. Medium spiny neurons from the NAcc showed a decrease in the density of dendritic spines without significant changes in dendritic length or arborization. The data, comparable to those observed in the PFC of schizophrenic patients, suggest that developmental loss of excitatory projections from the VH may lead to altered neuronal plasticity in the PFC and the NAcc that may contribute to the behavioral changes in these animals.
Asunto(s)
Dendritas/efectos de los fármacos , Agonistas de Aminoácidos Excitadores/toxicidad , Hipocampo/efectos de los fármacos , Ácido Iboténico/toxicidad , Núcleo Accumbens/efectos de los fármacos , Corteza Prefrontal/efectos de los fármacos , Factores de Edad , Animales , Animales Recién Nacidos , Conducta Animal , Femenino , Hipocampo/fisiología , Masculino , Actividad Motora/efectos de los fármacos , Neuronas/citología , Neuronas/efectos de los fármacos , Núcleo Accumbens/patología , Núcleo Accumbens/fisiología , Corteza Prefrontal/patología , Corteza Prefrontal/fisiología , Embarazo , Ratas , Ratas Sprague-Dawley , Tinción con Nitrato de Plata/métodos , Factores de TiempoRESUMEN
Converging evidence in schizophrenia suggests prefrontal cortical neuronal deficits that correlate with exaggerated subcortical dopamine (DA) functions: Excitotoxic lesion of the ventral hippocampus (VH) in neonatal rats is widely considered a putative animal model of schizophrenia as they lead to characteristic post-pubertal emergence of behavioral and cognitive abnormalities suggesting a developmental change in the neural circuits comprising the prefrontal cortex (PFC) and subcortical DA. Nerve growth factor inducible-B (NGFI-B, also known as Nur77), an orphan nuclear receptor and transcriptional regulator, is constitutively expressed in the target structures of DA pathways. It acts as an immediate early gene with rapid modulation of its mRNA expression by stress, DA and antipsychotic drugs. The present study assessed the effects of neonatal VH (nVH) lesion and amphetamine treatment on the expression of NGFI-B mRNA in pre- and post-pubertal rats. Sprague-Dawley rat pups received bilateral injection of ibotenic acid or phosphate buffered saline in VH at postnatal (PD) 7. At PD35 and PD56, groups of sham and lesioned animals were administered with D-amphetamine (1.5 mg/kg) or saline and killed 20 min later. In situ hybridization analyses showed that the basal level of NGFI-B mRNA in saline-treated lesioned rats was significantly reduced in the medial PFC (mPFC) and cingulate cortex (CC) only at post-pubertal (PD56) age. No significant difference in NGFI-B mRNA levels was seen in the dorsal striatum or nucleus accumbens (NAcc). Amphetamine treatment increased the expression of NGFI-B mRNA in the mPFC, CC, striatum and NAcc in both control and lesioned animals of both ages. Interestingly, however, striatal and NAcc regions of lesioned rats showed a significantly greater effect of amphetamine at PD56. The data suggest that nVH lesions lead to delayed changes in PFC gene expression along with functional DAergic hyperactivity in subcortical regions.
Asunto(s)
Anfetamina/farmacología , Estimulantes del Sistema Nervioso Central/farmacología , Cuerpo Estriado/efectos de los fármacos , Proteínas de Unión al ADN/metabolismo , Hipocampo/patología , Núcleo Accumbens/efectos de los fármacos , Corteza Prefrontal/metabolismo , Factores de Transcripción/metabolismo , Animales , Animales Recién Nacidos , Cuerpo Estriado/anatomía & histología , Cuerpo Estriado/metabolismo , Proteínas de Unión al ADN/genética , Femenino , Ácido Iboténico/toxicidad , Hibridación in Situ , Masculino , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares , Núcleo Accumbens/metabolismo , Corteza Prefrontal/efectos de los fármacos , Embarazo , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores Citoplasmáticos y Nucleares , Receptores de Esteroides , Factores de Transcripción/genéticaRESUMEN
It has been demonstrated that not only do rats neonatally lesioned in the ventral hippocampus (VH) develop behavioural hypersensitivity to amphetamine postpubertally, but also that the expression of the sensitivity is strain specific. For example, excitotoxic VH lesions at postnatal day (PD) 7 lead to significant increases in amphetamine-induced locomotion in postpubertal Fischer rats, but not in Lewis rats. However, as it is likely that the effect of strain differences are due to a combination of genetics and environment, we examined the contributions of the environment of the pups in determining the behavioural outcome following neonatal VH lesions. Fisher and Lewis rat pups were cross-fostered at birth, and then at PD7 lesioned bilaterally in the VH with ibotenic acid. ANOVA analysis of postpubertal amphetamine-induced locomotor data revealed a significant effect of the strain of the dams raising the pups but no effect of the strain of the pup. In addition, a post hoc analysis revealed that lesioned Fisher or Lewis rats raised by Fisher, but not those raised by Lewis, dams demonstrated amphetamine-induced hyperlocomotion relative to nonlesioned controls. Observations of the maternal behaviour of Fischer and Lewis dams revealed significant differences in the frequency of arched-back nursing between the two strains. Interestingly, a correlation of the frequency of arched back nursing vs novelty- or amphetamine-induced locomotion revealed that the lesioned rats were significantly more affected by increases in arched-back nursing compared to the controls. The results suggest that the genetic background of the pups does not significantly affect the behavioural outcome following neonatal VH lesions; however, the results do suggest an important role of early environmental variables on the behavioural outcome of neonatal VH lesions.
Asunto(s)
Animales Recién Nacidos/fisiología , Conducta Animal/fisiología , Ambiente , Hipocampo/fisiología , Anfetamina/farmacología , Animales , Conducta Animal/efectos de los fármacos , Estimulantes del Sistema Nervioso Central/farmacología , Femenino , Hipocampo/efectos de los fármacos , Conducta Materna/efectos de los fármacos , Conducta Materna/fisiología , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Embarazo , Ratas , Ratas Endogámicas F344 , Ratas Endogámicas Lew , Especificidad de la EspecieRESUMEN
Recent advances in experimental genomics, coupled with the wealth of sequence information available for a variety of organisms, have the potential to transform the way pharmacological research is performed. At present, high-density DNA microarrays allow researchers to quickly and accurately quantify gene-expression changes in a massively parallel manner. Although now well established in other biomedical fields, such as cancer and genetics research, DNA microarrays have only recently begun to make significant inroads into pharmacology. To date, the major focus in this field has been on the general application of DNA microarrays to toxicology and drug discovery and design. This review summarizes the major microarray findings of relevance to neuropsychopharmacology, as a prelude to the design and analysis of future basic and clinical microarray experiments. The ability of DNA microarrays to monitor gene expression simultaneously in a large-scale format is helping to usher in a post-genomic age, where simple constructs about the role of nature versus nurture are being replaced by a functional understanding of gene expression in living organisms.
Asunto(s)
Envejecimiento/genética , Regulación de la Expresión Génica , Genoma Humano , Enfermedades Neurodegenerativas/genética , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Animales , Humanos , Neurofarmacología , RatasRESUMEN
Repeated, intermittent administration of psychostimulant drugs such as D-amphetamine (AMPH) produces a state of behavioral sensitization to the drug that can last up to weeks to months. The molecular basis of this enhanced sensitivity to AMPH is poorly understood; however, adaptive changes in the mesocorticolimbic dopamine system has been postulated to be of primary importance. In the present investigation we used Western blotting to examine the expression of candidate presynaptic proteins involved in regulating neurotransmitter release and synaptic plasticity. Specifically, syntaxin 1, synaptophysin and synapsin I protein levels were examined in the nucleus accumbens (Nacc) and ventral tegmental area (VTA) of Sprague-Dawley rats following AMPH-sensitization. Animals received five repeated administrations of AMPH (1.5 mg/kg, i.p. on alternate days) followed by 14 days of withdrawal. Levels of syntaxin 1 and synaptophysin were found to be significantly reduced in the Nacc core of sensitized animals compared to saline-treated and untreated controls. However, syntaxin 1 expression was significantly increased in the Nacc shell subregion of sensitized animals. No significant difference in the level of synapsin I was noted in any of the brain regions. Further, expression of none of the synaptic proteins was significantly altered in the VTA of sensitized animals. Given the importance of syntaxin and synaptophysin in learning and memory processes and in the regulation of neurotransmitter release, changes in these proteins suggest their involvement in the associative learning aspects of sensitization and differential neurotransmitter release in the Nacc subregions.
Asunto(s)
Trastornos Relacionados con Anfetaminas/metabolismo , Dextroanfetamina/farmacología , Dopaminérgicos/farmacología , Proteínas del Tejido Nervioso/metabolismo , Núcleo Accumbens/metabolismo , Terminales Presinápticos/metabolismo , Membranas Sinápticas/metabolismo , Trastornos Relacionados con Anfetaminas/fisiopatología , Animales , Antígenos de Superficie/efectos de los fármacos , Antígenos de Superficie/metabolismo , Western Blotting , Dopamina/metabolismo , Masculino , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Proteínas del Tejido Nervioso/efectos de los fármacos , Vías Nerviosas/citología , Vías Nerviosas/efectos de los fármacos , Vías Nerviosas/metabolismo , Plasticidad Neuronal/efectos de los fármacos , Plasticidad Neuronal/fisiología , Núcleo Accumbens/citología , Núcleo Accumbens/efectos de los fármacos , Terminales Presinápticos/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Sinapsinas/efectos de los fármacos , Sinapsinas/metabolismo , Membranas Sinápticas/efectos de los fármacos , Sinaptofisina/efectos de los fármacos , Sinaptofisina/metabolismo , Sintaxina 1 , Área Tegmental Ventral/citología , Área Tegmental Ventral/efectos de los fármacos , Área Tegmental Ventral/metabolismoAsunto(s)
Neurofarmacología , Neuropsicología , Psicofarmacología , Sociedades Médicas , Alberta , Animales , HumanosRESUMEN
Current research into schizophrenia has remained highly fragmented, much like the clinical presentation of the disease itself. Differing theories as to the cause and progression of schizophrenia, as well as the heterogeneity of clinical symptoms, have made it difficult to develop a coherent framework suitable for animal modelling. However, a number of limited animal models have been developed to explore various causative theories and to test specific mechanistic hypotheses. Historically, these models have been based on the manipulation of neurotransmitter systems believed to be involved in schizophrenia. In recent years, the emphasis has shifted to targeting relevant brain regions in an attempt to explore potential etiologic hypotheses. The specific animal models developed within these frameworks are described in this review. Emphasis is placed on the critical evaluation of currently available models because these models help to shape the direction of future research.
Asunto(s)
Encéfalo/fisiopatología , Modelos Animales de Enfermedad , Neurotransmisores/fisiología , Esquizofrenia/fisiopatología , Animales , Mapeo Encefálico , Predicción , Humanos , Investigación , Esquizofrenia/etiologíaRESUMEN
Exposure to chronic phencyclidine (PCP) has been reported to mimic certain aspects of schizophrenia in normal subjects as well as to exacerbate symptoms in schizophrenic patients. Analogous to schizophrenics, adult rats with neonatal ventral hippocampal (VH) lesions have been shown to display enhanced sensitivity to both stress and psychostimulants. In order to examine whether repeated PCP treatment can modulate behavior when administered to neonatal VH-lesioned animals, we examined locomotor activity and immobility time in the forced swimming test (FST) in neonatal VH-lesioned rats following repeated PCP treatment. Receptor autoradiography studies were also performed for dopamine (DA) and N-methyl-D-aspartate (NMDA) receptors to identify neurochemical correlates of the altered behavior in these animals. Though repeated PCP administration resulted in increased levels of locomotor activity and rearing in both VH-lesioned as well as sham rats, the effects were much more enhanced in the lesioned rats compared to sham. However, repeated PCP treatment induced hypolocomotion during the habituation period in both sham and lesioned rats. In the FST paradigm, lesioned rats displayed an altered retention of acquired immobility. Repeated PCP administration increased DA D1-like receptors in the caudate-putamen in lesioned rats and decreased striatal D2-like receptors in both sham and lesioned rats. Moreover, repeated PCP administration in lesioned rats decreased NMDA binding sites in the prefrontal cortex while increasing labelling in the subcortical regions. These results suggest that repeated administration of PCP can qualitatively and quantitatively affect behaviors in neonatal VH-lesioned rats related to abnormal neurodevelopmental processes presumably via prefrontal glutamatergic and subcortical dopaminergic dysfunctions.
Asunto(s)
Animales Recién Nacidos/fisiología , Conducta Animal/efectos de los fármacos , Química Encefálica/efectos de los fármacos , Antagonistas de Aminoácidos Excitadores/farmacología , Hipocampo/fisiología , Fenciclidina/farmacología , Animales , Autorradiografía , Depresión/psicología , Antagonistas de Aminoácidos Excitadores/metabolismo , Femenino , Hipocampo/anatomía & histología , Hipocampo/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Ratas , Ratas Endogámicas F344 , Receptores de Dopamina D1/efectos de los fármacos , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/efectos de los fármacos , Receptores de Dopamina D2/metabolismo , Receptores de N-Metil-D-Aspartato/efectos de los fármacos , Conducta Estereotipada/efectos de los fármacos , Natación/psicologíaRESUMEN
Olfactory bulbectomized (OBX) rats show a variety of behavioral and biochemical deficits that parallel human depression. We investigated the expression of glutamate receptor subtypes in cortical and subcortical brain regions following bilateral olfactory bulbectomy in adult rats. Quantitative receptor autoradiography using [(125)I]MK-801 (NMDA receptor), [(3)H]AMPA (AMPA receptor), and [(3)H]kainate (kainate receptor) was performed on brain sections at 1-5 weeks following olfactory bulbectomy. Our results show an elevation of NMDA receptors in the medial prefrontal cortex within 1 week following bulbectomy, which persisted up to at least 5 weeks post-bulbectomy. Neither kainate nor AMPA receptors were altered in any brain region examined. The potential significance of these results is discussed in light of experimental findings supporting a role for NMDA receptors in the mechanism of action of antidepressant drugs and the pathophysiology of major depression.
Asunto(s)
Bulbo Olfatorio/fisiología , Corteza Prefrontal/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Animales , Autorradiografía , Masculino , Ratas , Ratas Sprague-Dawley , Receptores AMPA/metabolismo , Receptores de Ácido Kaínico/metabolismo , Factores de TiempoRESUMEN
Dopamine is intimately involved in cognitive processes in the brain. Of the several subtypes of dopamine receptors, the possible role of dopamine D1-like receptors in brain functions, especially in learning and memory, has recently generated much interest. However, molecularly the D1-like receptors are comprised of at least two subtypes, namely D-1 and D-5, and it has not been possible to ascertain which of these two receptor classes is responsible for these functions due to the lack of selective ligands. In the present study, utilizing a combined antisense-in vivo dialysis approach, we show that the D-5 subtype is the dopamine D1-like receptor involved in modulating hippocampal acetylcholine (ACh) release, a transmitter implicated in a variety of cognitive processes. This is one of the first evidence for a functional role for the D-5 receptor.
Asunto(s)
Acetilcolina/metabolismo , Hipocampo/fisiología , Oligodesoxirribonucleótidos Antisentido/farmacología , Receptores de Dopamina D1/fisiología , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/farmacología , Animales , Autorradiografía , Benzazepinas/farmacocinética , Ventrículos Cerebrales/efectos de los fármacos , Ventrículos Cerebrales/fisiología , Colina O-Acetiltransferasa/metabolismo , Cuerpo Estriado/fisiología , Giro Dentado/fisiología , Hipocampo/efectos de los fármacos , Infusiones Parenterales , Masculino , Oligodesoxirribonucleótidos Antisentido/administración & dosificación , Racloprida/farmacocinética , Ratas , Ratas Sprague-Dawley , Receptores de Dopamina D1/análisis , Receptores de Dopamina D1/genética , Receptores de Dopamina D2/análisis , Receptores de Dopamina D3 , Receptores de Dopamina D5 , Tionucleótidos , TritioRESUMEN
The medial prefrontal cortex modulates the nucleus accumbens dopamine response to stress and has been implicated in feedback regulation of hypothalamic-pituitary-adrenal axis activation by stress. Here we report on the effects of bilateral neonatal (postnatal day 7) ibotenate-induced lesions to the medial prefrontal cortex on nucleus accumbens dopamine and neuroendocrine function in adult rats. Voltammetry was used to monitor the dopamine response to each of five, once-daily exposures to tail-pinch stress whereas alterations in neuroendocrine function were determined from the plasma corticosterone response to a single 20-min episode of restraint stress. Potential lesion-induced deficits in sensory-motor gating were assessed by measuring prepulse inhibition of the acoustic startle response before and after repeated stress. Our data show that each daily stress episode elicited larger and longer-lasting dopamine increases in prefrontal cortex-lesioned animals than in sham-lesioned controls. Furthermore, greater stress-induced elevations in plasma corticosterone were seen in lesioned animals than in their sham-lesioned counterparts. However, while repeated stress potentiated startle responses in animals of both groups, there was no effect of lesion on the amplitude or on prepulse inhibition of the startle response.Together, these findings indicate that neonatal prefrontal cortex damage can lead to changes in mesolimbic dopamine and neuroendocrine function during adulthood. They also add to a growing body of experimental and clinical evidence implicating abnormal prefrontal cortex neuronal development in the pathophysiology of schizophrenia and other disorders linked to central dopamine dysfunction.
Asunto(s)
Degeneración Nerviosa/inducido químicamente , Degeneración Nerviosa/fisiopatología , Neurotoxinas/farmacología , Núcleo Accumbens/metabolismo , Núcleo Accumbens/fisiopatología , Corteza Prefrontal/fisiopatología , Estrés Fisiológico/fisiopatología , Animales , Animales Recién Nacidos , Corticosterona/sangre , Desnervación , Dopamina/metabolismo , Masculino , Neuronas/patología , Neuronas/fisiología , Núcleo Accumbens/patología , Corteza Prefrontal/patología , Ratas , Ratas Sprague-Dawley , Reflejo de Sobresalto/fisiologíaRESUMEN
Neonatal damage to the ventral hippocampus (VH) can lead, during adulthood, to behaviours that are believed to reflect enhanced mesocorticolimbic dopamine (DA) transmission. In the present study, the effects of neonatal excitotoxic lesions to the VH on spontaneous locomotor activity and stress-elicited increases in extracellular nucleus accumbens (NAcc) DA levels were examined in adult rats. Male pups received, on postnatal day 7, bilateral injections of either an ibotenic acid solution (lesioned) or vehicle (sham-lesioned) into the VH. At 3-4 months of age, animals were assessed during five daily sessions for changes in spontaneous locomotor activity associated with habituation to a novel environment. Voltammetry was used in separate groups of sham- and VH-lesioned animals to monitor the NAcc DA response to each of five once-daily exposures to tail-pinch stress. The results indicate that while VH-lesioned animals seem to habituate to novelty, they remain hyperactive relative to sham-lesioned controls. In contrast, however, stress consistently elicited in VH-lesioned animals smaller and shorter-lasting increases in NAcc DA than in sham-lesioned controls. These data suggest that neonatal excitotoxic damage to VH leads to changes in DA function that persist into adulthood. The blunted response to stress seen in VH-lesioned animals indicates that one consequence of such damage is a functional hyporeactivity in meso-NAcc DA neurons. The fact that these animals are spontaneously more active suggests compensatory changes in DA function that are efferent to DA terminals in NAcc.
Asunto(s)
Dopamina/fisiología , Hipocampo/fisiología , Núcleo Accumbens/fisiología , Estrés Fisiológico/fisiopatología , Transmisión Sináptica/fisiología , Animales , Animales Recién Nacidos , Electroquímica , Masculino , Actividad Motora/fisiología , Ratas , Ratas Sprague-DawleyRESUMEN
We analysed the expression of dopamine receptor subtypes in the subthalamic nucleus by means of reverse transcriptase-polymerase chain reaction. We also studied, using autoradiography, all pharmacologically characterized dopamine receptors in four subregions of the subthalamic nucleus. For comparison, dopamine receptor subtypes were also evaluated in brain regions where they are more abundant and well characterized. The radioligands used were: [3H]SCH-23390, [3H]emonapride and [3H]2-dipropylamino-7-hydroxy-1,2,3,4-tetrahydronaphthalene for dopamine D1, D2 and D3 receptors, respectively; and [3H]YM-09151-2 in the presence of raclopride for dopamine D4 receptors. Finally, we also evaluated the effect of unilateral 6-hydroxydopamine injection into the medial forebrain bundle on dopamine receptor levels expressed in the ipsilateral subthalamic nucleus. The lesion was estimated by decrease in the binding of [3H]WIN-35428, a specific dopamine transporter label. D1, D2 and D3 receptor messenger RNAs and binding sites were present in the subthalamic nucleus, but no messenger RNA for D4 receptors was found, although specific binding sites for these receptors were observed. As compared to the intact side, the 6-hydroxydopamine lesion did not change D1 receptors, increased D2 receptors, and decreased D3 receptors and the dopamine transporter. The results suggest that postsynaptic D1, D2 or D3 receptors can mediate the effect of dopamine on subthalamic nucleus neuronal activity. D4 receptors would mediate exclusively presynaptic effects. These results reinforce the idea that dopamine receptors in the subthalamic nucleus may play an important role in the physiology of the basal ganglia and in the pathophysiology of Parkinson's disease.
Asunto(s)
Antagonistas de Dopamina/farmacocinética , Receptores Dopaminérgicos/genética , Receptores Dopaminérgicos/metabolismo , Núcleos Talámicos/metabolismo , Animales , Autorradiografía/métodos , Benzamidas/farmacocinética , Benzazepinas/farmacocinética , Masculino , Ensayo de Unión Radioligante , Ratas , Ratas Wistar , Receptores de Dopamina D1/genética , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/genética , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3 , Receptores de Dopamina D4 , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Tetrahidronaftalenos/farmacocinética , TritioRESUMEN
Antisense oligodeoxynucleotides against muscarinic m2 and m4 receptors were used to investigate the role of these receptor subtypes as negative autoreceptors in the regulation of acetylcholine (ACh) release in the rat hippocampus. Following the continuous infusion of antisenses into the third ventricle (1 microgram microliter-1 h-1, 3 days), 3H-AF-DX 384/muscarinic M2-like binding was significantly decreased in the medial septum by the antisense against the m2 receptor whereas M2-like binding in the dorsal striatum was decreased by the antisense against the m4 receptor. In contrast, 3H-pirenzepine/muscarinic M1-like binding was unaffected by either antisense treatment in any of the brain areas investigated. When perfused into the hippocampus via a dialysis probe, the purported muscarinic M2 receptor antagonist AF-DX 384 (100 nM) increased hippocampal ACh release in freely moving rats. This effect of AF-DX 384 was significantly attenuated by the m2, but not the m4, receptor antisense treatment. Hippocampal choline acetyltransferase activity was not affected by either antisense treatments. Taken together, these results suggest that the molecularly defined muscarinic m2 receptor regulates hippocampal ACh release by acting as a negative autoreceptor. In contrast, the molecularly defined m4 receptor is unlikely to be directly involved in the negative regulation of ACh release in the rat hippocampus. Therefore, inhibiting muscarinic m2 receptor function may be an alternative approach to regulate the release of ACh in neurodegenerative diseases associated with impaired cholinergic functions.
Asunto(s)
Autorreceptores/genética , Hipocampo/química , Receptores Muscarínicos/genética , Acetilcolina/análisis , Acetilcolina/metabolismo , Animales , Elementos sin Sentido (Genética) , Autorreceptores/metabolismo , Química Encefálica/efectos de los fármacos , Química Encefálica/fisiología , Colina O-Acetiltransferasa/análisis , Colina O-Acetiltransferasa/metabolismo , Cromatografía de Gases y Espectrometría de Masas , Hipocampo/enzimología , Masculino , Microdiálisis , Antagonistas Muscarínicos/farmacología , Parasimpatolíticos/farmacología , Pirenzepina/análogos & derivados , Pirenzepina/farmacología , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Receptor Muscarínico M2 , Receptor Muscarínico M4 , Receptores Muscarínicos/metabolismo , TritioRESUMEN
Previous reports have shown that the inbred strains of rat, Lewis (LEW) and Fischer 344 (F344), differ in several behavioural and biochemical indices of mesolimbic dopamine (DA) function. Specifically, these two strains differ in their behavioural and neurochemical response to novel environments, and acute amphetamine or cocaine challenge as well as in their susceptibility to addiction. To investigate if differences in DA D1-like, D2-like, D3 receptors and DA transporter could be correlated with these behavioural differences between strains, a comparative autoradiographic study of DA receptors and transporter within the striatal and accumbal regions was undertaken. We observed strain and region specific differences in binding levels for DA D2-like and D3 receptors and for the DA transporter. Namely, DA transporter levels in the striatum, nucleus accumbens and olfactory tubercle of LEW rats were significantly lower than in F344 rats. DA D3 densities in the shell of the nucleus accumbens and olfactory tubercle of LEW rats were lower than the levels found in the F344 rats. Finally, LEW rats have a lower levels of D2-like receptors in the striatum and the core of the nucleus accumbens compared to F344 rats. These data suggest that differences in DA transporter and DA receptors may in part contribute to differences in DA related behaviour seen between these two strains.
Asunto(s)
Proteínas Portadoras/metabolismo , Glicoproteínas de Membrana/metabolismo , Proteínas de Transporte de Membrana , Proteínas del Tejido Nervioso/metabolismo , Receptores Dopaminérgicos/metabolismo , Análisis de Varianza , Animales , Autorradiografía , Ganglios Basales/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Masculino , Ratas , Ratas Endogámicas F344 , Ratas Endogámicas LewRESUMEN
NCAM-180 knockout mice, which have documented deficits in neural migration, were used to determine whether developmental abnormalities could lead to morphological changes and alterations in sensory motor gating mechanisms. Measurement of the lateral ventricle showed that NCAM-180-/- mice had marked increases in both the left and right anterior horns of the lateral ventricle. Furthermore, these mice also displayed a reduction of prepulse inhibition that was differentially affected by the dopamine agonist apomorphine. These results are discussed in light of the known increase in lateral ventricle size and reduction in prepulse inhibition that are seen in schizophrenia.
Asunto(s)
Ventrículos Cerebrales/patología , Moléculas de Adhesión de Célula Nerviosa/genética , Inhibición Neural/fisiología , Reflejo de Sobresalto/fisiología , Estimulación Acústica , Análisis de Varianza , Animales , Movimiento Celular/fisiología , Femenino , Lateralidad Funcional/fisiología , Masculino , Ratones , Ratones NoqueadosRESUMEN
Olfactory bulb (OB) of mammals contains a large population of dopaminergic interneurons within the glomerular layer. Dopamine has been shown in vivo to modulate several aspects of olfactory information processing. The dopamine receptors of olfactory bulb and mucosa are assessed here at the levels of mRNAs and radioligand binding sites with presently available tools. D1A mRNA was found in OB glomerular-, plexiform-, mitral-cell and granular layers, but not in olfactory mucosa. D1B mRNA was absent in olfactory bulb and mucosa. D1-like binding sites were detected with two distinct radioligands, in glomerular-, plexiform-, mitral cell- and granular layers of OB but not in olfactory mucosa. We thus demonstrate the previously doubtful presence of D1-like receptors in OB. D2 mRNAs were localized in the glomerular and granular layers of OB and in olfactory mucosa; lesser amounts of D3 mRNAs were found in OB glomerular and granular layer, but not in olfactory mucosa. No D4 mRNA was detected in either structure. High densities of D2-like, [125I]Iodosulpride-labelled binding sites, were revealed within lamina propria of olfactory mucosa, and confirmed in the olfactory nerve- and glomerular layers of OB. A faint but significant density of [3H]7-hydroxy-dipropyl-aminotetralin (OH-DPAT) labelled, D3 binding sites was detected in olfactory nerve- and glomerular layers of OB, but not in olfactory mucosa. Competition of [125I]Iodosulpride specific binding by three D2/D3 selective drugs yielded kinetics typical of the D2 receptor subtype in olfactory bulb and mucosa. Olfactory nerve- and glomerular layers of OB are proved thus to contain a predominant contingent of D2 receptors and a minor population of D3 receptors, while olfactory mucosa expresses only D2 receptors.