[Pleasure: Neurobiological conception and Freudian conception]. / Le plaisir : conception neurobiologique et conception freudienne.

Despite many controversies the debate between psychoanalysis and neuroscience remains intense, all the more since the Freudian theory stands as a reference for a number of medical practitioners and faculty psychiatrists, at least in France. Instead of going on arguing we think that it may be more constructive to favour dialogue through the analysis of a precise concept developed in each discipline. The Freudian theory of pleasure, because it is based on biological principles, appears an appropriate topic to perform this task. In this paper, we aim at comparing Freud's propositions to those issued from recent findings in Neuroscience. Like all emotions, pleasure is acknowledged as a motivating factor in contemporary models. Pleasure can indeed be either rewarding when it follows satisfaction, or incentive when it reinforces behaviours. The Freudian concept of pleasure is more univocal. In Freud's theory, pleasure is assumed to be the result of the discharge of the accumulated excitation which will thus reduce the tension. This quantitative approach corresponds to the classical scheme that associates satisfaction and pleasure. Satisfaction of a need would induce both a decrease in tension and the development of pleasure. However, clinical contradictions to this model, such as the occasional co-existence between pleasure and excitation, drove Freud to suggest different theoretical reversals. Freud's 1905 publication, which describes how preliminary sexual pleasures contribute to an increased excitation and a sexual satisfaction, is the only analysis which provides an adapted answer to the apparent paradox of pleasure and excitation co-existence. Studies on the neurobiological mechanisms responsible for the development of pleasure may help to fill this gap in the Freudian theory. Activity of the mesolimbic dopaminergic pathway is strongly associated with the reward system. Experimental studies performed in animals have shown that increased dopaminergic activity in the ventral tegmental area (VTA, where dopaminergic cell bodies lie) results either from an unexpected reward or, after recognition of the reward characteristics, from the anticipation of the reward. Therefore, anticipation of a satisfaction activates neurochemical pleasure mechanisms and reinforces behaviour which facilitates its obtention. In this way, pleasure contributes to an increased level of organism excitation. In addition to these data, neuroscience studies have confirmed, as proposed by Freud, the homeostatic role of pleasure when the latter is triggered by an internal need. However, these studies have also indicated that, unlike proposed by Freud, pleasure is not only the result of obtaining a satisfaction but has also a role in the promotion of action. In sum, neuroscience suggest that the Freudian model favours the hedonic modality of reward circuit to the detriment of its motivational modality.

Repeated exposure to MDMA triggers long-term plasticity of noradrenergic and serotonergic neurons.

3,4-Methylenedioxymethamphetamine (MDMA or 'ecstasy') is a psychostimulant drug, widely used recreationally among young people in Europe and North America. Although its neurotoxicity has been extensively described, little is known about its ability to strengthen neural circuits when administered in a manner that reproduces human abuse (i.e. repeated exposure to a low dose). C57BL/6J mice were repeatedly injected with MDMA (10 mg kg(-1), intraperitoneally) and studied after a 4-day or a 1-month withdrawal. We show, using in vivo microdialysis and locomotor activity monitoring, that repeated injections of MDMA induce a long-term sensitization of noradrenergic and serotonergic neurons, which correlates with behavioral sensitization. The development of this phenomenon, which lasts for at least 1 month after withdrawal, requires repeated stimulation of α(1B)-adrenergic and 5-hydroxytryptamine (5-HT)(2A) receptors. Moreover, behavioral and neuroendocrine assays indicate that hyper-reactivity of noradrenergic and serotonergic networks is associated with a persistent desensitization of somatodendritic α(2A)-adrenergic and 5-HT1A autoreceptor function. Finally, molecular analysis including radiolabeling, western blot and quantitative reverse transcription-polymerase chain reaction reveals that mice repeatedly treated with MDMA exhibit normal α(2A)-adrenergic and 5-HT(1A) receptor binding, but a long-lasting downregulation of Gαi proteins expression in both locus coeruleus and dorsal raphe nucleus. Altogether, our results show that repeated MDMA exposure causes strong neural and behavioral adaptations and that inhibitory feedback mediated by α(2A)-adrenergic and 5-HT(1A) autoreceptors has an important role in the physiopathology of addictive behaviors.

Genetic diversity and population structure of an insular tree, Santalum austrocaledonicum in New Caledonian archipelago.

We present a study of the genetic diversity and structure of a tropical tree in an insular system. Santalum austrocaledonicum is endemic to the archipelago of New Caledonia and is exploited for oil extraction from heartwood. A total of 431 individuals over 17 populations were analysed for eight polymorphic microsatellite loci. The number of alleles per locus ranged from 3 to 33 and the observed heterozygosity per population ranged from 0.01 in Mare to 0.74 in Ile des Pins. The genetic diversity was lowest in the most recent islands, the Loyautes, and highest in the oldest island, Grande Terre, as well as the nearby small Ile des Pins. Significant departures from panmixia were observed for some loci-population combinations (per population FIS = 0-0.03 on Grande-Terre and Ile des Pins, and 0-0.67 on Loyautes). A strong genetic differentiation among all islands was observed (FST = 0.22), and the amount of differentiation increased with geographic distance in Iles Loyaute and in Grande Terre. At both population and island levels, island age and isolation seem to be the main factors influencing the amount of genetic diversity. In particular, populations from recent islands had large average FIS that could not be entirely explained by null alleles or a Wahlund effect. This result suggests that, at least in some populations, selfing occurred extensively. Conclusively, our results indicate a strong influence of insularity on the genetic diversity and structure of Santalum austrocaledonicum.

Anatomical study of the paraspinal approach to the lumbar spine.

The original description of the paraspinal posterior approach to the lumbar spine was for spinal fusion, especially regarding lumbosacral spondylolisthesis treatment. In spite of the technical details described by Wiltse, exact location of the area where the sacrospinalis muscle has to be split remains somewhat unclear. The goal of this study was to provide topographic landmarks to facilitate this surgical approach. Thirty cadavers were dissected in order to precisely describe the anatomy of the trans-muscular paraspinal approach. The level of the natural cleavage plane between the multifidus and the longissimus part of the sacrospinalis muscle was noted and measurements were done between this level and the midline at the level of the spinous process of L4. A natural cleavage plane between the multifidus and the longissimus part of the sacrospinalis muscle was present in all cases. There was a fibrous separation between the two muscular parts in 55 out of 60 cases. The mean distance between the level of the cleavage plane and the midline was 4 cm (2.4-5.5 cm). In all cases, small arteries and veins were present, precisely at the level of the cleavage plane. We found it possible to easily localize the anatomical cleavage plane between the multifidus part and the longissimus part of the sacrospinalis muscle. First the superficial muscular fascia is opened near the midline, exposing the posterior aspect of the sacrospinalis muscle. Then, the location of the muscular cleft can be found by identifying the perforating vessels leaving the anatomical inter-muscular space.

Late spinal dislocation after treatment of spinal arteriovenous malformation. A case of Charcot spinal arthropathy.

Neuropathic arthropathy of the spine is a destructive condition of the spine which is secondary to a loss of the protective proprioceptive reflexes. In the majority of cases, it occurs in patients who have suffered from traumatic medullary lesions and is responsible for destruction of the vertebral bodies and considerable spinal deformity. We report a case of neurogenic lumbar arthropathy in a patient with a spinal arteriovenous malformation. This vascular lesion caused considerable disturbances of proprioception. The course was favorable with regard to the deformity after correction and fusion by posterior approach.

Cortical alpha 1-adrenergic regulation of acute and sensitized morphine locomotor effects.

The role of alpha1-adrenergic transmission was tested on locomotor effects of acute or repeated morphine (5 mg/kg, i.p.) administration. Prazosin, an alpha1-adrenergic antagonist, administered 30 min before morphine, either systemically (0.5 mg/kg, i.p.) or locally and bilaterally into the prefrontal cortex (200 pmol/side) reduced the stimulatory influence of morphine on locomotion. The progressive increase of the locomotor response induced by repeated morphine injections was blocked by a prazosin pretreatment but not the behavioral sensitization on the test day. These data suggest that blockade of cortical alpha1-adrenergic receptors reduces the expression of acute and sensitized locomotor responses to morphine, but does not prevent the induction of behavioral sensitization.

A major locus for several phenotypes of myoclonus--dystonia on chromosome 7q.

Myoclonus--dystonia is a genetically heterogeneous autosomal dominant disorder caused by a mutation in the D2 dopamine receptor on chromosome 11 and a locus on chromosome 7q21-q31. The authors tested linkage to the chromosome 7q candidate region in four families with either myoclonic dystonia (n = 3) or essential myoclonus (n = 1). Age at onset ranged from 0.5 to 38 years. Only four patients from two families had a positive response to alcohol. Lod scores were positive in all four families, suggesting that chromosome 7q21-q31 is a major locus for myoclonus-dystonia with several phenotypes.

Stimulation of metabotropic but not ionotropic glutamatergic receptors in the nucleus accumbens is required for the D-amphetamine-induced release of functional dopamine.

We have previously shown that a large part of the D-amphetamine-induced release of dopamine in the nucleus accumbens is not associated with an increase in locomotor activity, and that "functional" dopamine release (i.e. release of dopamine associated with locomotor activity) requires the distal facilitation of noradrenergic transmission through alpha1-adrenergic receptors in the prefrontal cortex. To determine the role of monosynaptic or polysynaptic projections from the prefrontal cortex to the nucleus accumbens in these amphetamine responses, either AMPA/kainate (6-cyano-7-nitroquinoxaline-2,3-dione, CNQX, 300microM), N-methyl-D-aspartate (D(-)-2-amino-5-phosphono-pentanoic acid, APV, 500microM) or metabotropic [(+)-alpha-methyl-4-carboxy-phenylglycine, MCPG, 10mM] glutamate receptor antagonists were infused through a dialysis probe in the rat nucleus accumbens. CNQX and MCPG but not APV reduced the "non-functional" release of dopamine evoked by local (3microM) and systemic D-amphetamine (2mg/kg i.p.) treatments. However, the locomotor hyperactivity and functional dopamine release induced by systemic D-amphetamine were abolished by MCPG, but neither by CNQX nor by APV. MCPG treatment also abolished the hyperlocomotor activity and functional dopamine release evoked by bilateral morphine injection into the ventral tegmental area. The dopamine release evoked by this morphine treatment was 16-fold lower than that induced by the systemic D-amphetamine injection, although similar behavioral activations were observed. Altogether, our results further aid the discrimination of functional and non-functional release of dopamine. We suggest that the activation of metabotropic glutamate receptors in the nucleus accumbens is required for functional dopamine release following systemic D-amphetamine injection.

Sequential improvement of anxiety, depression and anhedonia with sertraline treatment in patients with major depression.

OBJECTIVE: To establish the therapeutic effect profile of sertraline in major depression. It was hypothesized that the antidepressant effect of sertraline showed three phases: Phase 1 where improvements in anxiety are most pronounced; Phase 2 where the greatest improvements are in depressive symptoms; and Phase 3 where the symptoms of anhedonia show the most improvement. To test this hypothesis, an 8-week, open-label study was conducted. METHODS: Patients with a major depressive episode (DSM-IV) and a score > or = 24 on the 17-item HAM-D were enrolled and treated with sertraline 50-150 mg/day. The three symptomatic clusters, anxiety, depression and hedonia, were defined a priori using the Inventory of Depressive Symptomatology-Clinician rated (IDS-C). Periods of interest were: Days 0-7 for anxiety, Days 7-21 for depression and Days 21-56 for anhedonia. Raters were blinded as to the constitution of the clusters and periods. RESULTS: 140 patients were recruited. Improvement in the anxiety cluster of the IDS-C was greatest during Days 0-7, whereas over Days 7-21 most improvement was observed in the depression cluster and the greatest improvement in the hedonic cluster occurred during Days 21-56. CONCLUSION: These preliminary results are consistent with the hypothesis that the therapeutic effects of sertraline occur in a sequential manner. The symptoms of anxiety improved first, followed by depression and then anhedonia.

Levodopa-responsive dystonia. GTP cyclohydrolase I or parkin mutations?

Autosomal dominant DOPA-responsive dystonia (DRD) is usually caused by mutation in the gene encoding guanosine triphosphate-cyclohydrolase I (GTPCH I). We studied 22 families with a phenotype of levodopa-responsive dystonia by sequencing the six coding exons, the 5'-untranslated region and the exon-intron boundaries of the GTPCH I gene. Eleven heterozygous mutations were identified, including five missense mutations, one splice site mutation, two small deletions and two nonsense mutations, in 12 families that included 27 patients and 13 asymptomatic carriers. Six mutations were new and five had already been reported. Four of the mutations caused truncation of the GTPCH I protein. One family carried a base-pair change in the 5'-untranslated region, not detected in controls, that could be responsible for the phenotype. Three of the remaining 10 families had deletions in the parkin gene on chromosome 6, underlining how difficult it is to distinguish, in some cases, between DRD and parkin mutations. No mutations were identified in seven families. The clinical spectrum extended from the classical DRD phenotype to parkinsonism with levodopa-induced dyskinesias, and included spastic paraplegia as well as the absence of dystonia.

A locus for an axonal form of autosomal recessive Charcot-Marie-Tooth disease maps to chromosome 1q21.2-q21.3.

Charcot-Marie-Tooth disease (CMT) is a heterogeneous group of disorders that affect the peripheral nervous system. Three loci are known for the autosomal dominant forms of axonal CMT (CMT2), but none have yet been identified for autosomal recessive axonal CMT (ARCMT2). We have studied a large consanguineous Moroccan ARCMT2 family with nine affected sibs. The onset of CMT was in the 2d decade in all affected individuals who presented with a severe motor and sensory neuropathy, with proximal muscle involvement occurring in some patients. After exclusion of known loci for CMT2 and for demyelinating ARCMT2, a genomewide search was performed. Evidence for linkage was found with markers on chromosome 1q. The maximum pairwise LOD score was above the threshold value of 3.00, for markers D1S514, D1S2715, D1S2777, and D1S2721, and it reached 6.10 at the loci D1S2777, D1S2721, and D1S2624, according to multipoint LOD-score analysis. These markers defined a region of homozygosity that placed the gene in a 4.4-cM interval. Moreover, a recombination event detected in an unaffected 48-year-old individual excludes the D1S506 marker, thereby reducing the interval to 1.7 cM. In addition, the P0 gene, an attractive candidate because of both its location on chromosome 1q and its role in myelin structure, was excluded by physical mapping and direct sequencing.

Ginkgo biloba extract EGb761 reduces the development of amphetamine-induced behavioral sensitization: effects on hippocampal type II corticosteroid receptors.

Pretreatment of rats with the extract of Ginkgo biloba termed EGb761 reduced the behavioral sensitization induced by successive D-amphetamine administrations (0.5 mg/kg) as estimated by increasing values of locomotor activity. EGb761 pretreatment also prevented the reduced density of [3H]dexamethasone binding sites in the dentate gyrus and the CA1 hippocampal regions of D-amphetamine treated animals. These observations suggest that EGb761, by reducing glucocorticoid levels, could modulate the activity of the neuronal systems involved in the expression of the behavioral sensitization.

Integrity of the mesocortical dopaminergic system is necessary for complete expression of in vivo hippocampal-prefrontal cortex long-term potentiation.

The prefrontal cortex receives dopaminergic inputs from the ventral tegmental area and excitatory inputs from the hippocampus. Both afferent pathways target in close proximity dendritic spines of pyramidal cells in layer V-VI of the prefrontal cortex. In view of the prominent role of dopamine in cognitive functions we examined the effects of ventral tegmental area stimulation on the induction of long-term potentiation in the hippocampal-prefrontal cortex pathway of anesthetized rats. Stimulation of the ventral tegmental area at a frequency known to evoke dopamine overflow in the prefrontal cortex produces a long-lasting enhancement of the magnitude of the hippocampal-prefrontal cortex long-term potentiation. The role of dopamine was further examined by investigating the effects of prefrontocortical dopamine depletion induced by an electrolytic ventral tegmental area lesion. A significant correlation (r = 0.8; P < 0.001; n = 14) was obtained between cortical dopamine levels and cortical long-term potentiation amplitude, a depletion of more than 50% of cortical levels corresponding to a dramatic decrease in hippocampal-prefrontal cortex long-term potentiation. However, a recovery to normal long-term potentiation was observed 1 h after tetanic stimulation. In contrast to the effects on long-term potentiation, ventral tegmental area stimulation, when applied at low or high frequency, decreases the amplitude of the hippocampal-prefrontal cortex postsynaptic synaptic response. The present study demonstrates the importance of the integrity of the mesocortical dopaminergic system for long-term potentiation to occur in the hippocampal-prefrontal cortex pathway and suggests a frequency-dependent effect of dopamine on hippocampal-prefrontal cortex transmission.

A functional model of some Parkinson's disease symptoms using a Guided Propagation Network.

This paper presents a computational model of Parkinson's Disease (PD) symptoms. Based on psychophysiological data, the underlying system (Guided Propagation Network) implements coincidence detection between internal flows and stimuli, and can be dynamically controlled for representing the action of neuromodulators such as dopamine (DA). By modelling the DA deficit involved in PD through a decrease of response thresholds in the production modules of a GPN, four symptoms are observed in experiments carried out on a computer simulation, and then attributed to a lack of synchrony between 'proprioceptive stimuli' and internal flows: reduced intensity, increased rate, saccades and spontaneous repetitions.

Alpha1-adrenergic, D1, and D2 receptors interactions in the prefrontal cortex: implications for the modality of action of different types of neuroleptics.

The activation of rat mesocortical dopaminergic (DA) neurons evoked by the electrical stimulation of the ventral tegmental area (VTA) induces a marked inhibition of the spontaneous activity of prefrontocortical cells. In the present study, it was first shown that systemic administration of either clozapine (a mixed antagonist of D1, D2, and alpha1-adrenergic receptors) (3-5 mg/kg, i.v.), prazosin (an alpha1-adrenergic antagonist) (0.2 mg/kg, i.v.), or sulpiride (a D2 antagonist) (30 mg/kg, i.v.), but not SCH 23390 (a D1 antagonist) (0.2 mg/kg, i.v.), reversed this cortical inhibition. Second, it was found that following the systemic administration of prazosin, the VTA-induced cortical inhibition reappeared when either SCH 23390 or sulpiride was applied by iontophoresis into the prefrontal cortex. Third, it was seen that, whereas haloperidol (0.2 mg/kg, i.v.), a D2 antagonist which also blocks alpha1-adrenergic receptors, failed to reverse the VTA-induced inhibition, the systemic administration of haloperidol plus SCH 23390 (0.2 mg/kg, i.v.) blocked this inhibition. Finally, it was verified that the cortical inhibitions obtained following treatments with either "prazosin plus sulpiride" or "prazosin plus SCH 23390" were blocked by a superimposed administration of either SCH 23390 or sulpiride, respectively. These data indicate that complex interactions between cortical D2, D1, and alpha1-adrenergic receptors are involved in the regulation of the activity of prefrontocortical cells innervated by the VTA neurons. They confirm that the physiological stimulation of cortical alpha1-adrenergic receptors hampers the functional activity of cortical D1 receptors and suggest that the stimulations of cortical D1 and D2 receptors exert mutual inhibition on each other's transmission.

The alpha-synuclein Ala53Thr mutation is not a common cause of familial Parkinson's disease: a study of 230 European cases. European Consortium on Genetic Susceptibility in Parkinson's Disease.

We report the results of a screen of 230 European familial index cases of Parkinson's disease for the recently described Ala53Thr mutation in the alpha-synuclein gene in an autosomal dominant Parkinson's disease kindred. No mutations were found from this broad white population, and we therefore conclude that although of great interest, this mutation is a very rare cause of familial Parkinson's disease.