Search

Abstract: High caloric intake during early postnatal development can have long term consequences for the offspring. We previously reported that the adult offspring of dams fed a high-fat diet during the last week of gestation and throughout lactation display blunted locomotor response to amphetamine (AMP) and reduced sensitization to the drug compared to offspring of control diet dams. Here, we report that the subsensitivity of high-fat offspring to AMP''s locomotor stimulant action reflects, at least in part, altered regulation of nucleus accumbens (NAc) dopamine (DA) transmission. When compared to controls, the DA response of high-fat animals to AMP, as measured with microdialysis, was attenuated in the NAc, but unaffected in the prefrontal cortex (PFC). A relatively higher activity of NAc synaptosomal DA transporter sites without changes in vesicular monoamine transporter (VMAT) uptake capacity was also observed in high-fat offspring. Moreover, ventral tegmental area (VTA) D2 receptor mRNA levels were decreased in high-fat offspring, suggesting a reduction in DA release-regulating D2 autoreceptors in terminal regions such as the NAc. The magnitude of locomotor response to D2/3 receptor activation (with quinpirole) was greater in high-fat than in control animals despite having comparable postsynaptic D2 mRNA levels in the NAc. Finally, while operant responding for a sugar-enriched food reward did not differ between diet groups, high-fat offspring displayed increased operant responding for a fat-enriched reward compared to controls. These findings add to mounting evidence that early life exposure to elevated dietary maternal fat can lead to long lasting changes in DA-mediated behavioral responses to stimulant drugs and fat-enriched foods. [Copyright &y& Elsevier]

Abstract: Calcineurin (PP2B) is a Ca2+-dependent protein phosphatase enriched in the brain that takes part in intracellular signaling pathways regulating synaptic plasticity and neuronal functions. Calcineurin-dependent pathways are important for complex brain functions such as learning and memory. More recently, they have been suggested to play a role in the processing of emotional information. The aim of this study was to investigate whether calcineurin may be involved in the effect of antidepressants. We first found that chronic antidepressant treatment in mice leads to an increase of calcineurin levels in the hippocampus. We then studied the behavioral and molecular responses to fluoxetine of mice with a genetic overactivation of calcineurin in the hippocampus (constitutively-activated calcineurin transgenic mouse line #98, CN98 mice). We observed that CN98 mice are more sensitive to the behavioral effect of fluoxetine and desipramine tested in the tail suspension test. Moreover, the basal expression of growth factor brain-derived neurotrophic factor and subunit 1 of AMPA glutamate receptor, GluR1, both of which are modified after chronic antidepressant administration, are altered in the hippocampus of CN98 mice. These results suggest that calcineurin-dependent dephosphorylation plays an important role in the mechanisms of action of antidepressants, providing a new starting point for developing improved therapeutic treatments for depression. [Copyright &y& Elsevier]

Abstract: Neurotransmitter transporters play an important role in the control of synaptic transmission by ensuring the clearance of transmitters liberated in the synaptic cleft. In the case of monoaminergic neurotransmitters, this clearance is carried out by high-affinity reuptake transporters located in the plasma membrane of the presynaptic terminals. Recently plasma membrane monoamine transporter (PMAT), a transporter from the SLC29 (equilibrative nucleoside transporter) family, was shown to transport in vitro monoaminergic neurotransmitters, in particular dopamine and serotonin, nearly as efficiently as the high-affinity transporters. This transporter, well expressed in CNS, represents an interesting candidate for the control and modulation of aminergic pathways. We performed an extensive study of the distribution of PMAT in the rat brain. Our results highlight PMAT expression in brain regions which play a pivotal role in significant CNS functions and human neuropathologies. Using in situ hybridization immunohistochemistry co-labeling, PMAT mRNA was found in various neuron subtypes, including glutamatergic neurons of the hippocampus, mitral cells of the olfactory bulbs and GABAergic neurons in the substantia nigra pars reticulata and hypothalamus. Paradoxically, rat PMAT mRNA was found in some but not all monoaminergic nuclei. It was on the contrary predominantly expressed in major cholinergic groups throughout the brain, including brainstem motor nuclei, components of the basal forebrain cholinergic system and cholinergic interneurons of the striatum. These systems, implicated in locomotion, associative and spatial memory and reward-related learning, are disrupted at early stages of Parkinson’s and Alzheimer’s disease. Taken together, our observations support a role for PMAT in monoamine uptake in cholinergic neurons. [Copyright &y& Elsevier]

We have recently identified a third subtype of glutamate vesicular transporter (VGLUT) named VGLUT3. In the present study, we provide a detailed account of the regional and cellular distributions of VGLUT3 in the rat brain, using specific nucleotide probes and antisera. The distribution of VGLUT3 protein was compared with that of the other vesicular transporters (VGLUT1 and VGLUT2). All the areas expressing VGLUT3 also contain high levels of VGLUT1 and -2 proteins, but, at a finer level of analysis, the distribution of the three subtypes differs. Unlike VGLUT1 and -2, VGLUT3 expression is limited to discrete cell populations. Neurons containing VGLUT3 transcript are essentially observed in the caudate-putamen, the olfactory tubercle, the nucleus accumbens, the hippocampus, the interpeduncular nucleus and the dorsal and medial raphe nuclei. More scattered populations of VGLUT3 expressing neurons are found in the cerebral cortex. The distribution of the VGLUT3 protein, as determined with specific antisera, overlaps with that of the transcript in the caudate-putamen, olfactory tubercles, hippocampus, cortex, interpeduncular nucleus, and raphe nuclei, suggesting that VGLUT3 is essentially present in local projection neurons in these regions. Microscopic examination reveals staining of terminals and perikarya. Furthermore, co-localization studies indicate that VGLUT3 is present in GABAergic interneurons in the hippocampus, as well as in the interpeduncular nucleus. However, other regions, such as the substantia nigra (pars compacta), the ventral tegmental area, and the parabigeminal nucleus, receive a dense VGLUT3 terminal labeling although they do not contain VGLUT3 expressing neurons. In these regions, VGLUT3 immunoreactivity may be present in terminals of long projecting neurons. This subclass of glutamatergic afferents differs from other “classical” excitatory terminals that express VGLUT1 or VGLUT2.The distribution of VGLUT3 in the rat brain suggests an unsuspected function of vesicular glutamate transport in subsets of interneurons and in neuromodulatory neurons. [Copyright &y& Elsevier]

Psychostimulants and antipsychotic drugs increase mRNA expression of the neuropeptide neurotensin (NT) in the striatum and nucleus accumbens. In the present study, we used mice lacking the dopamine transporter (DAT) to investigate the consequences of a chronic hyperdopaminergic state on NT gene expression. NT mRNA expression was examined under basal conditions and after administration of haloperidol or amphetamine using in situ hybridization with a digoxigenin-labeled NT cRNA probe. DAT−/− mice exhibited a striking increase in the number of NT mRNA-expressing perikarya in the substantia nigra and ventral tegmental area, as well as a less pronounced increase in the lateral septum compared with wild-type littermates. No changes were detected in other regions expressing NT mRNA. Acute administration of haloperidol (1 mg/kg) induced a significant increase in the number of NT mRNA-expressing neurons in the dorsomedial and dorsolateral striatum of wild-type mice but failed to stimulate NT gene expression in DAT mutants. In contrast, a higher dose of haloperidol (5 mg/kg) stimulated striatal NT mRNA expression both in DAT+/+ and DAT−/− mice. Amphetamine (10 mg/kg) increased the number of hybridized neurons in the nucleus accumbens shell and fundus striati of wild-type and DAT−/− mice, indicating that the drug acted through a target other than DAT, such as the serotonin or the norepinephrine transporters. The up-regulation of NT mRNA observed in DAT−/− mice may represent an adaptive mechanism in response to constitutive hyperdopaminergia. These results illustrate the profound alterations in the NT system induced by chronic stimulation of DA receptors and underscore the potential clinical relevance of NT/DA interactions in schizophrenia and drug abuse. [Copyright &y& Elsevier]