The dopamine D1 receptor agonist SKF 38393 improves temporal order memory performance in maternally deprived rats.

Previously, we showed that maternal deprivation (MD) (3h/day, postnatal-day 1-14) impaired the performance at adulthood in the object temporal order memory task (TMT) that principally implicates the medial prefrontal cortex (mPFC). Dopamine (DA) transmission in the PFC may play a critical role in the achievement of the TMT. Here, to investigate whether MD could results in dysfunction of the DA system in the mPFC, we assessed in this region the tissue contents and extracellular levels of DA and its metabolites, as the density of D1 receptor.

Both chronic treatments by epothilone D and fluoxetine increase the short-term memory and differentially alter the mood status of STOP/MAP6 KO mice.

Recent evidence underlines the crucial role of neuronal cytoskeleton in the pathophysiology of psychiatric diseases. In this line, the deletion of STOP/MAP6 (Stable Tubule Only Polypeptide), a microtubule-stabilizing protein, triggers various neurotransmission and behavioral defects, suggesting that STOP knockout (KO) mice could be a relevant experimental model for schizoaffective symptoms. To establish the predictive validity of such a mouse line, in which the brain serotonergic tone is dramatically imbalanced, the effects of a chronic fluoxetine treatment on the mood status of STOP KO mice were characterized.

The deletion of STOP/MAP6 protein in mice triggers highly altered mood and impaired cognitive performances.

The microtubule-associated Stable Tubulie Only Polypeptide (STOP; also known as MAP6) protein plays a key role in neuron architecture and synaptic plasticity, the dysfunctions of which are thought to be implicated in the pathophysiology of psychiatric diseases. The deletion of STOP in mice leads to severe disorders reminiscent of several schizophrenia-like symptoms, which are also associated with differential alterations of the serotonergic tone in somas versus terminals. In STOP knockout (KO) compared with wild-type mice, serotonin (5-HT) markers are found to be markedly accumulated in the raphe nuclei and, in contrast, deeply depleted in all serotonergic projection areas.

Severe serotonin depletion after conditional deletion of the vesicular monoamine transporter 2 gene in serotonin neurons: neural and behavioral consequences.

The vesicular monoamine transporter type 2 gene (VMAT2) has a crucial role in the storage and synaptic release of all monoamines, including serotonin (5-HT). To evaluate the specific role of VMAT2 in 5-HT neurons, we produced a conditional ablation of VMAT2 under control of the serotonin transporter (slc6a4) promoter. VMAT2(sert-cre) mice showed a major (-95%) depletion of 5-HT levels in the brain with no major alterations in other monoamines.

Organic cation transporter 2 controls brain norepinephrine and serotonin clearance and antidepressant response.

High-affinity transporters for norepinephrine (NE) and serotonin (5-HT), which ensure neurotransmitter clearance at the synapse, are the principal targets of widely used antidepressant drugs. Antidepressants targeting these high-affinity transporters, however, do not provide positive treatment outcomes for all patients. Other monoamine transport systems, with lower affinity, have been detected in the brain, but their role is largely unknown.

The deletion of the microtubule-associated STOP protein affects the serotonergic mouse brain network.

The deletion of microtubule-associated protein stable tubule only polypeptide (STOP) leads to neuroanatomical, biochemical and severe behavioral alterations in mice, partly alleviated by antipsychotics. Therefore, STOP knockout (KO) mice have been proposed as a model of some schizophrenia-like symptoms. Preliminary data showed decreased brain serotonin (5-HT) tissue levels in STOP KO mice.

[Involvement of central neurotransmission systems in schizophrenia].

Psychiatric disorders have a high prevalence in all countries and cultures and have a high cost in socio-economic terms. The participation of dopaminergic neurotransmission in the pathophysiology of schizophrenia is well known. However, until recently, the nature of dopaminergic dysfunctions had not been elucidated.

Microtubule-associated STOP protein deletion triggers restricted changes in dopaminergic neurotransmission.

The microtubule-associated stable tubule only polypeptide (STOP) protein plays a key-role in neuron architecture and synaptic plasticity. Recent studies suggest that schizophrenia is associated with alterations in the synaptic connectivity. Mice invalidated for the STOP gene display phenotype reminiscent of some schizophrenic-like symptoms, such as behavioral disturbances, dopamine (DA) hyper-reactivity, and possible hypoglutamatergia, partly improved by antipsychotic treatment.

Sustained increase of alpha7 nicotinic receptors and choline-induced improvement of learning deficit in STOP knock-out mice.

Mice deficient in the microtubule stabilizing protein STOP (stable tubule only polypeptide) show synaptic plasticity anomalies in hippocampus, dopamine hyper-reactivity in the limbic system and severe behavioral deficits. Some of these disturbances are alleviated by long-term antipsychotic treatment. Therefore, this mouse line represents a pertinent model for some aspects of schizophrenia symptomatology.

Maternal deprivation and handling modify the effect of the dopamine D3 receptor agonist, BP 897 on morphine-conditioned place preference in rats.

Rationale: Maternal deprivation and handling can lead to a vulnerability to opiate dependence. However, the involvement of the dopamine D3 receptors has not been investigated.

Objectives: This study analysed the effects of a selective partial D3 receptor agonist, BP 897, on morphine-conditioned place preference (CPP) in deprived and handled rats.

Functional alterations of nicotinic neurotransmission in dopamine transporter knock-out mice.

Mice lacking the dopamine (DA) transporter (DAT) gene exhibit a phenotype reminiscent of schizophrenia and attention deficit hyperactivity disorder (ADHD), including hyperDAergia, hyperactivity and deficits in cognitive performance, which are alleviated by antipsychotic agents. Numerous studies suggest a dysfunction of nicotinic neurotransmission in schizophrenia and show increased tobacco intake in schizophrenic and ADHD patients, possibly as a self-medication. Thus, we examined the potential alteration of nicotinic neurotransmission in DAT knock-out (KO) mice.

Nicotine improves cognitive deficits of dopamine transporter knockout mice without long-term tolerance.

Various studies suggest a dysfunction of nicotinic neurotransmission in schizophrenia and establish that patients suffering from schizophrenia and attention deficit hyperactivity disorder (ADHD) have a high tobacco consumption, potentially for the purpose of self-medication. Owing to its neuroprotective and procognitive effects, transdermal nicotine was proposed to be an effective treatment of some neurodegenerative and psychiatric diseases. Mice deficient in the dopamine transporter (DAT KO) exhibit a phenotype reminiscent of schizophrenia and ADHD, including hyperdopaminergia, hyperactivity, paradoxical calming by methylphenidate and cognitive deficits, some of which being improved by antipsychotic agents.

Altered expression and functions of serotonin 5-HT1A and 5-HT1B receptors in knock-out mice lacking the 5-HT transporter.

By taking up serotonin (5-hydroxytryptamine, 5-HT) released in the extracellular space, the 5-HT transporter (5-HTT) regulates central 5-HT neurotransmission. Possible adaptive changes in 5-HT neurotransmission in knock-out mice that do not express the 5-HT transporter were investigated with special focus on 5-HT1A and 5-HT1B receptors. Specific labelling with radioligands and antibodies, and competitive RT-PCR, showed that 5-HT1A receptor protein and mRNA levels were significantly decreased in the dorsal raphe nucleus (DRN), increased in the hippocampus and unchanged in other forebrain areas of 5-HTT-/- vs.

Homeostatic regulation of serotonergic function by the serotonin transporter as revealed by nonviral gene transfer.

With the aim of exploring the relationship between the serotonin transporter (5-HTT or SERT) and the activity level of serotonin (5-HT) neurotransmission, in vivo expression of this protein was specifically altered using a nonviral DNA transfer method. Plasmids containing the entire coding sequence or a partial antisense sequence of the 5-HTT gene were complexed with the cationic polymer polyethylenimine and injected into the dorsal raphe nucleus of adult male rats. Significant increase or decrease in both [(3)H]citalopram binding and [(3)H]5-HT synaptosomal uptake were observed in various brain areas up to 2 weeks after a single administration of the sense plasmid or 7 d after injection of the short antisense plasmid, respectively.

Adaptive changes of serotonin 5-HT2A receptors in mice lacking the serotonin transporter.

The serotonin transporter (5-HTT) plays a key-role in the control of serotoninergic neurotransmission and is the target of some antidepressants. Possible adaptive changes in brain 5-HT2A receptors were investigated in knock-out mice that do not express the 5-HTT. Autoradiographic labeling of these receptors by the selective antagonist [3H]MDL 100,907 and saturation experiments with cortical membranes revealed: (1) a new localization of these receptors in the external field of striatum (possibly in striosomes); (2) regional variations in adaptive changes in the density of 5-HT2A receptors in 5-HT(-/-) mutants (-30-40% in the claustrum, cerebral cortex and lateral striatum; no significant change in the striatum core) as compared to wild-type mice.

Induction of serotonin transporter by hypoxia in pulmonary vascular smooth muscle cells. Relationship with the mitogenic action of serotonin.

-The increased delivery of serotonin (5-hydroxytryptamine, 5-HT) to the lung aggravates the development of hypoxia-induced pulmonary hypertension in rats, possibly through stimulation of the proliferation of pulmonary artery smooth muscle cells (PA-SMCs). In cultured rat PA-SMCs, 5-HT (10(-8) to 10(-6) mol/L) induced DNA synthesis and potentiated the mitogenic effect of platelet-derived growth factor-BB (10 ng/mL). This effect was dependent on the 5-HT transporter (5-HTT), since it was prevented by the 5-HTT inhibitors fluoxetine (10(-6) mol/L) and paroxetine (10(-7) mol/L), but it was unaltered by ketanserin (10(-6) mol/L), a 5-HT2A receptor antagonist.

Up- and down-expression of the dopamine transporter by plasmid DNA transfer in the rat brain.

The functional role of the dopamine transporter (DAT) in central dopaminergic neurotransmission was assessed further by investigating the consequences on dopamine (DA) turn-over of up- and down-regulation of this protein induced by a non-viral gene transfer approach. For this purpose, expression plasmids containing the sense or antisense coding sequence of DAT complexed with the cationic polymer, polyethylenimine (PEI), were injected into the rat substantia nigra, the brain region containing the majority of DA cell bodies. Before in vivo injection, the efficacies of the different DNA constructs were assessed by transfection studies into LLC-PK1 cells.

Immuno-localization of serotonin 5-HT6 receptor-like material in the rat central nervous system.

In order to map the recently cloned serotonin 5-HT6 receptor in the rat brain and spinal cord, polyclonal antibodies were raised against a synthetic octadecapeptide corresponding to a specific portion (Leu398-Val415) of the C-terminal domain of this receptor. Antibodies were detected by enzyme-linked immunosorbent assay as soon as one month after the first injection to rabbits of the peptide coupled to keyhole limpet hemocyanin. Immunoautoradiographic experiments with antibodies affinity-purified on Affi-Gel coupled to the peptide antigen showed that 5-HT6-like immunoreactive material was abundant in the olfactory tubercle (plexiform layer), cerebral cortex (frontal and entorhinal areas), nucleus accumbens, striatum, hippocampus (strata oriens and radiatum of the CA1 area, molecular layer of the dentate gyrus) and the molecular layer of the cerebellum.

Quantitative RT-PCR distribution of serotonin 5-HT6 receptor mRNA in the central nervous system of control or 5,7-dihydroxytryptamine-treated rats.

Possible adaptive changes of the recently cloned serotonin 5-HT6 receptor after the selective lesion of serotoninergic neurons by an intracerebral administration of 5,7-dihydroxytryptamine were investigated using competitive RT-PCR (reverse transcription followed by polymerase chain reaction) for the measurement of 5-HT6-mRNA in various areas of the rat central nervous system. In control rats, 5-HT6-mRNA was the most abundant in the nucleus accumbens, followed by the olfactory tubercle and the striatum. High levels of 5-HT6-mRNA were also found in the hypothalamus and the hippocampus, whereas the cerebral cortex, the substantia nigra, and the spinal cord contained moderate levels of the transcript.

Dopamine D3 receptor gene: organization, transcript variants, and polymorphism associated with schizophrenia.

DNA fragments from a genomic library were used to establish the partial structure of the human dopamine D3 receptor gene (DRD3). Its coding sequence contains 6 exons and stretches over 40,000 base pairs. The complete DRD3 transcript and three shorter variants, in which the second and/or third exon are deleted, were detected in similar proportions in brains from four controls and three psychiatric patients.

Purification, cDNA cloning, functional expression, and characterization of a 26-kDa endogenous mammalian carboxypeptidase inhibitor.

The recent demonstration of the occurrence in rat brain and other nonpancreatic tissues of carboxypeptidase A (CPA) gene transcripts without associated catalytic activity could be ascribed to the presence of a soluble endogenous protein inhibitor. This tissue carboxypeptidase inhibitor (TCI), detected by the inhibition of added bovine pancreatic CPA, was purified from rat brain. Peptides were obtained by partial proteolysis of purified TCI, a protein of approximately 30 kDa, and starting from their sequences, a full-length cDNA encoding a 223-amino acid protein containing three potential phosphorylation sites was cloned from a cDNA library.

Lack of association between alcohol-dependence and D3 dopamine receptor gene in three independent samples.

Numerous studies on the involvement of dopamine receptors in the genetics of alcoholism focused on associations between a polymorphism of the D2 dopamine receptor (DRD2) gene and alcohol dependence. However, the results of these studies are conflicting. Another receptor, the D3 dopamine receptor (DRD3), may be of additional interest since it is specifically located in the limbic area, and in particular in the nucleus accumbens which plays a significant role in the reward process of addiction behavior.

Differentiation alters the expression of the two splice variants of the serotonin 5-HT3 receptor-A mRNA in NG108-15 cells.

The serotonin 5-HT3-A receptor (5-HT3R-A) mRNA has been shown recently to be expressed as two forms (5-HT3R-AL and 5-HT3R-AS) varying by the presence or the absence of a sequence of 18 bases in the region corresponding to the second cytoplasmic domain of the receptor, and generated by alternative splicing at the level of the 3' acceptor site of exon 9. As the long form of the receptor exhibits a potential phosphorylation site that is disrupted by the alternative splicing, the hypothesis of functional identity and stochastic expression of these two variants was questioned. In the present study, we used quantitative reverse transcriptase-polymerase chain reaction to examine the possible influence of culture conditions on the expression and the alternative splicing of 5-HT3R-A mRNA in NG108-15 clonal cells.

Activation of dopamine D4 receptor inhibits an L-type calcium current in cerebellar granule cells.

The functions of the D4 receptor, a newly cloned D2-like receptor, as well as the identity of cells expressing it, are still poorly defined. Using quantitative polymerase chain reaction we detected the messenger RNA of the D4, but not other D2-like receptor, in cultured granule cells from neonatal rat cerebellum. In these neurons, dopamine reduced high-voltage-activated calcium current, with a pharmacology corresponding to that of the D4 receptor.

Chronic alcoholization alters the expression of 5-HT1A and 5-HT1B receptor subtypes in rat brain.

The expression of central 5-HT1A and 5-HT1B receptors was studied in several brain areas of rats subjected to a 2-week period of chronic alcoholization, followed by 18 h withdrawal. Quantitative autoradiography indicated that the ethanol treatment provoked an increase (approximately +30%) in the labeling by [3H]8-hydroxy-2-(di-n-propylamino)tetralin ([3H]8-OH-DPAT) and [3H]N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexane carboxamide ([3H]WAY-100635) of 5-HT1A autoreceptors in the dorsal raphe nucleus, accompanied by a concomitant decrease in the labeling of postsynaptic 5-HT1A receptors in the hippocampus (approximately -20%), anterior (approximately -30%) and posterior (approximately -32%) cortices. These changes were associated with a tendency toward an increase and decrease in 5-HT1A mRNA levels in the anterior raphe area and hippocampus, respectively, suggesting that the changes observed are due to modifications in 5-HT1A receptor protein synthesis.