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.

[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.

Opposed Behavioural Outputs of Increased Dopamine Transmission in Prefrontocortical and Subcortical Areas: A Role for the Cortical D-1 Dopamine Receptor.

The possibility that the dopaminergic neurons innervating the medial prefrontal cortex (mPFC) can inhibit locomotor behaviour has been suggested in several studies. The evidence remains indirect, however, because the manipulations tested aimed exclusively at permanently depleting mPFC dopamine. Here we demonstrate in rats that acute increases in dopamine transmission in this site by local injections of amphetamine inhibit the known locomotor-activating effects of amphetamine in the nucleus accumbens (N.Acc.). Further, intra-mPFC injections of the D-1 dopamine receptor antagonist SCH-23390, but not other dopamine antagonists with greater affinities for noradrenergic, serotonergic and D-2 dopamine receptors, enhanced the locomotion induced by intra-N.Acc. amphetamine. These findings provide direct evidence for the inhibition of locomotor activity by mPFC dopamine and suggest that it is acting at D-1 dopamine receptors in this site.

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.

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.

Striatal opiate mu-receptors are not located on dopamine nerve endings in the rat.

In rat striatal slices, the autoradiographic analysis of [3H]naloxone binding allows one to define highly labelled patches corresponding to the striosomes and representing about 17% of the total striatal volume, surrounded by a poorly labelled zone, the matrix. Previous studies have shown that the density of these mu-opiate receptor binding sites is decreased by about 28% following destruction of the striatal dopamine innervation suggesting a partial localization of these receptors on dopamine presynaptic nerve endings. These results were confirmed but, in addition, we have shown that a chronic (30 days) blockade of dopamine transmission obtained by treatment of the animals with a long acting neuroleptic induces a similar decrease of mu binding sites. Further experiments made with D-Pen2,D-Pen5-[tyrosyl-3-5(n)-3H] enkephalin, a selective delta opiate receptor agonist, have revealed that the density of delta opiate binding sites is decreased (30%) in rats with striatal dopamine denervation but not in those treated with the long acting neuroleptic. These data indicate that part of these delta receptors is located on dopamine nerve terminals but are not in favour of the presence of mu receptors on these nerve terminals. The decrease in [3H]naloxone binding sites induced by prolonged interruption of dopamine transmission can be attributed to postsynaptic events.

Autoradiographic identification of D1 dopamine receptors labelled with [3H]dopamine: distribution, regulation and relationship to coupling.

On the basis of experiments made on striatal membranes, Leff and Creese [Molec. Pharmac. (1985) 27, 184-192] have proposed that tritiated dopamine binds to a high-affinity agonist state of D1 dopamine receptors (D1h) which adopt this conformation when they are associated with the GTP-binding protein involved in the transduction process. Quantitative autoradiography was thus used to look for the distribution of these D1h sites in the rat brain and to compare it with that of D1 receptors labelled with [3H]7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benz aze pine [( 3H]SCH23390), a D1 antagonist. The effects of unilateral 6-hydroxydopamine lesion of the ascending dopamine pathways on the density of [3H]dopamine D1h and [3H]SCH23390 binding sites in the striatum and the nucleus accumbens were also analysed. In the striatum, when D2 receptors were blocked by spiroperidol (20 nM), [3H]dopamine was found to bind specifically to dopamine receptors of the D1 type. Complementary experiments made with dopamine uptake blockers indicated that high-affinity dopamine uptake sites were not labelled by [3H]dopamine under our experimental conditions. The anatomical distribution of [3H]dopamine D1h binding sites was found to be markedly different from that of [3H]SCH23390 binding sites. This was particularly the case in the substantia nigra, some amygdaloid nuclei and the prefrontal cortex--structures in which the ratios between [3H]SCH23390 and [3H]dopamine binding sites were more than seven-fold higher than that observed in the striatum. [3H]SCH23390 binding was not significantly affected in either the striatum or the nucleus accumbens six weeks after a complete unilateral destruction of ascending dopamine pathways. In contrast, a marked decrease in [3H]dopamine D1h binding sites was found in both structures, but this effect was lower in the medioventral (-60%) than in the laterodorsal (-81%) part of the striatum, even though dopamine denervation was uniform throughout the structure. Preincubation of the sections with dopamine (0.5 microM) led to a partial recovery (+126%) in the lesioned striatum and an increase of [3H]dopamine labelling in the control striatum (+68%). This suggest that the presence of dopamine stabilizes the D1h state of D1 receptors. The absence or low amount of dopamine, either due to dopamine denervation or naturally occurring (prefrontal cortex), would then impair the [3H]dopamine D1h binding. In addition, a lower coupling of D1 receptors with adenylate cyclase was observed in the substantia nigra when compared to that in the striatum: this may explain the relatively weak [3H]dopamine binding in the substantia nigra.(ABSTRACT TRUNCATED AT 400 WORDS)

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.

Inhibitory effects of ventral tegmental area stimulation on the activity of prefrontal cortical neurons: evidence for the involvement of both dopaminergic and GABAergic components.

The medial prefrontal cortex of the rat receives dopamine and non-dopaminergic projections from the ventral tegmental area. Both electrical stimulation of the ventral tegmental area and local application of dopamine induce an inhibition of the spontaneous activity of most prefrontal cortical neurons, including efferent neurons. In the present study, the techniques of extracellular recording and microiontophoresis were used in anesthetized rats in order to determine whether these dopamine- and ventral tegmental area-induced inhibitory responses involve GABAergic components. Prefrontal cortex output neurons were identified by antidromic activation from subcortical structures. The inhibitory responses evoked by the local application of dopamine were blocked by the iontophoretic application of the D2 antagonist sulpiride, and the GABAA antagonist bicuculline in 89 and 57% of the cases, respectively. In addition, sulpiride and bicuculline abolished the inhibition induced by ventral tegmental area stimulation in 54 and 51% of the prefrontal cortical cells tested, respectively. The implication of a non-dopaminergic mesocortical system in the ventral tegmental area-induced inhibition was further analysed using rats pre-treated with alpha-methylparatyrosine to deplete dopamine stores. The proportion of prefrontal cortical cells inhibited by ventral tegmental area stimulation was markedly reduced (39%) in alpha-methylparatyrosine-treated rats, when compared to controls (86%). Remaining ventral tegmental area-induced inhibition was no longer affected by sulpiride, but in all cases blocked by the local microiontophoretic application of bicuculline. The present results suggest that: (1) the dopamine-induced inhibition of prefrontal cortex neurons could involve cortical GABAergic interneurones; (2) the non-dopaminergic mesocortical system exerts also an inhibitory influence on prefrontal cortical cells and appears to be GABAergic.

Contribution of an alpha 1-adrenergic receptor subtype to the expression of the "ventral tegmental area syndrome".

Bilateral electrolytic lesions of the rat ventral tegmental area, a mesencephalic structure containing the cell bodies of ascending dopaminergic neurons, induce a behavioural syndrome characterized by a permanent locomotor hyperactivity. Acute intraperitoneal injections of prazosin, an alpha 1-adrenergic receptor antagonist, at a dose (0.5 mg/kg) which does not affect locomotor activities of control animals, abolished locomotor hyperactivities of lesioned rats. Antagonists of other monoaminergic receptors (propranolol, ritanserin, yohimbine), and also another antagonist of alpha 1-adrenergic receptors, 2-(2',6'-dimenthoxyphenoxyethyl)-aminomethyl-1,4-benzodioxan (WB4101) were ineffective. Comparisons of autoradiograms of brain slices incubated in the presence of 1 nM [3H]prazosin or 10 nM [3H]WB4101 indicated clear topographical differences. [3H]Prazosin labelling is present in the septum and in layer III of the cerebral cortex but absent in the striatum. [3H]WB 4101 labelling is diffuse in the superficial layers of the cerebral cortex and present in the striatum. In addition, intraperitoneal injection of WB4101 displaces, only weakly, [3H]prazosin binding in layer III of the cerebral cortex (-18%) while it decreases by 50% [3H]prazosin binding in the more superficial cortical layers. These observations strongly suggest that the binding site labelled by [3H]prazosin is different from alpha 1A- and alpha 1B-adrenergic receptor subtypes labelled by [3H]WB4101. Finally, it is proposed that the prazosin-induced blockade of the locomotor hyperactivity exhibited by ventral tegmental area lesioned animals is linked to the previously demonstrated regulatory role of noradrenergic neurons on cortical dopamine transmission.

Antimalarial and cytotoxic potential of four quassinoids from Hannoa chlorantha and Hannoa klaineana, and their structure-activity relationships.

Hannoa chlorantha and Hannoa klaineana (Simaroubaceae) are used in traditional medicine of Central African countries against fevers and malaria. Four stem bark extracts from H. klaineana and four quassinoids from H. chlorantha were examined in vitro against Plasmodium falciparum NF 54. The extracts displayed good activities, while the quassinoids were highly active, with IC50 values well below 1 microgram ml-1, those of chaparrinone and 15-desacetylundulatone being much lower than 0.1 microgram ml-1 (0.037 and 0.047 microgram ml-1, respectively). Chaparrinone is five times more active than 14-hydroxychaparrinone against P. falciparum, indicating that the hydroxyl function at C-14 is unfavourable for antiplasmodial activity. As 14-hydroxychaparrinone has a seven-times higher cytotoxic activity against P-388 cells than chaparrinone, the latter compound has the better antiplasmodial therapeutic index. All four quassinoids were evaluated in vivo in a standard 4-day test as well. 15-Desacetylundulatone was proven to be the most active compound, almost totally suppressing the parasitaemias of OF1 mice for at least 7 days, while both chaparrinone and 14-hydroxychaparrinone were active for at least 4 days. Quassinoids have ED50 values much lower than 50 mg kg-1 body weight day-1 and none of them caused obvious side effects. The keto function at C-2 in 15-desacetylundulatone is apparently of crucial importance for its high activity. 6-alpha-Tigloyloxyglaucarubol was not active at all. Chaparrinone is considered the most interesting of the investigated quassinoids and its in-vivo antimalarial potential will be examined further.

Increased sensitivity to amphetamine and facilitation of amphetamine self-administration after 6-hydroxydopamine lesions of the amygdala.

The effects of 6-OHDA lesions of dopamine terminals within the amygdala were investigated on i) (+) amphetamine-induced locomotor hyperactivity and ii) the acquisition of intravenous self-administration of (+) amphetamine. The lesioned rats exhibited increased locomotor activity in response to (+) amphetamine (0.75 and 1.5 mg/kg), but not at the higher dose (3 mg/kg). Self-administration of (+) amphetamine was also significantly greater than in controls. Biochemical analysis of the 6-OHDA-induced lesions of the amygdala indicated increased turnover of dopamine (DOPAC/DA) in the nucleus accumbens. We hypothesize that the behavioural effects were mediated by amygdala-accumbens interactions.

Autoradiography of CCK receptors in the rat brain using [(3)H]Boc[Nle(28)(31)]CCK(27)-(33) and [(125)I]bolton-hunter CCK(8). Functional significance of subregional distributions.

[(3)H]Boc[Nle(28,31)]CCK(27)-(33) ([(3)H]BDNL-CCK(7)) is a new ligand for cholecystokinin (CCK) receptors, endowed with a high specific activity (100 Ci/mmol). Binding sites for this ligand were visualized in the rat brain by autoradiography [(3)H]BDNL-CCK(7) binds specifically to an apparent single class of CCK receptors on rat striatum sections with a K(d) of 1.76 nM and a B(max) of 57 fmol/mg protein. Unsulfated CCK(8) was two times less potent than sulfated CCK(8) to displace binding of [(3)H]BDNL-CCK(7). Binding sites for [(3)H]BDNL-CCK(7) were present in many brain regions, the highest concentrations occurring in cortex, olfactory bulbs, nucleus accumbens, and medium to high concentrations in striatum, hippocampus, and several nuclei of thalamus, hypothalamus and amygdala. In the same experimental conditions, the binding sites for [(125)I]BH-CCK(8) showed similar specificity and localization. We thus used both ligands to investigate the subregional distributions of CCK receptors in nucleus accumbens and hippocampus, where a highly organized topography of action of CCK has been reported. In nucleus accumbens, the CCK binding sites were concentrated in the anterior portion of the nucleus, whereas very low densities were observed within medial posterior nucleus accumbens, where injection of CCK has been shown to potentiate dopamine-induced hyperlocomotion. p]In hippocampus, CCK receptors were concentrated in the polymorphic zone of the hilus of the dentate gyrus and in stratum lacunosum moleculare of Ammon's horn. Very few receptors were observed in other regions of hippocampus, including stratum pyramidale and stratum moleculare. This is in contrast with the presence of numerous CCK terminals and the potent effect of CCK in these areas. The distributions of CCK receptors reported here in both nucleus accumbens and hippocampus were discussed in correlation with the distribution of CCK neurons and terminals, the related anatomical pathways, and the pharmacological profiles of the effects of CCK in these regions.

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.

Extensive co-localization of neurotensin with dopamine in rat meso-cortico-frontal dopaminergic neurons.

In mammalian brain, dopaminergic (DA) cell bodies located in the ventral mesencephalon give rise to meso-cortical, meso-limbic and meso-striatal systems. Among these, the meso-cortical DA pathway is particularly involved in the processing of emotional and cognitive responses. We demonstrate that the rat meso-cortical neurons specifically contain, in addition to DA, another transmitter, Neurotensin. If this co-localization exists in man, it may provide an anatomical substratum for the biological theory of schizophrenia as well as an indication that potential anti-psychotic drugs which act differentially on the DA ascending transmissions can be developed.

Involvement of prefrontal dopamine neurones in behavioural blockade induced by controllable vs uncontrollable negative events in rats.

The present study was undertaken to investigate the involvement of dopaminergic (DA) neurones afferent to the prefrontal cortex in stress-related behaviours induced by controllable vs uncontrollable negative events. Rats were either sham-operated or given a bilateral infusion of 6-hydroxydopamine (4 micrograms in 0.4 microliter) into the prefrontal cortex which resulted in a specific and almost complete (80%) reduction of local DA. Three weeks after surgery, sham and lesioned rats were subjected to one of the following experimental procedures involving (1) controllable or (2) uncontrollable events: (1) the punished drinking test and a FR1/FR7 schedule of food/shock presentation; (2) the forced swimming test and the learned helplessness paradigm. DA depletion in the prefrontal cortex resulted in an increase in punished responding in the drinking test and under the FR schedule; the anti-punishment effects of diazepam (2 mg/kg) were not modified. Lesions also induced a reduction in immobility duration in the forced swimming test but failed to affect the induction of escape deficits in rats trained for learned helplessness. In the latter two models, DA depletion in the prefrontal cortex did not modify the antidepressant effects of desipramine (32 mg/kg and 24 mg/kg/day, respectively). These results suggest that controllable and acute aversive situations may be modulated by DA neurones in the prefrontal cortex. DA neurones, however, may not be crucial in the modulation of delayed and uncontrollable stress-related behaviours. Taken together, the present findings suggest that an increased tendency to perseverate could be the main behavioural feature associated with DA lesion in the prefrontal cortex. Acute vs delayed consequences of negative events could be an additional relevant factor for the involvement of DA neurons in stress-related behaviours.

Topographical distributions of 32K and 48K cAMP-regulated phosphoproteins: relationships to dopamine and serotonin innervations in striatum, substantia nigra and cerebral cortex.

The topographical distribution of a cAMP-regulated phosphoprotein of an apparent molecular weight (Mr) of 32,000 (32K) was examined in homogenates prepared from microdiscs punched out from serial frozen slices of the striatum. The amount of this phosphoprotein progressively diminished from the rostral to the caudal part of the striatum as did both the dopamine-innervation and the dopamine (D1)-sensitive adenylate cyclase. After kainic acid lesion of the rostral part of the striatum, the 32K phosphoprotein disappeared in this area and we observed a 48% decrease in the amount of 32K phosphoprotein found in the substantia nigra. 6-Hydroxydopamine lesions of the nigro-striatal dopaminergic pathway did not affect the 32K phosphoprotein either in striatum or substantia nigra. These results suggest that in the nigro-striatal pathway, the 32K phosphoprotein is closely associated with dopaminoceptive neurons containing D1 receptors. In the cerebral cortex the association of 32K phosphoprotein with dopaminoceptive neurons is more questionable since we did not find a higher density of this phosphoprotein in areas containing a high amount of D1 receptor (frontal cerebral cortex) than in areas containing a low amount of D1 receptor (parietal cerebral cortex). In the course of this study we found another cAMP-regulated phosphoprotein of an Mr of 48,000 (48K). The amount of this phosphoprotein increased progressively from the rostral to the caudal part of the striatum, a pattern of distribution close to that of serotonin terminals. This protein was also present in the substantia nigra. Kainic acid lesioning of the rostral part of the striatum did not affect the amount of the 48K phosphoprotein within the substantia nigra.(ABSTRACT TRUNCATED AT 250 WORDS)

Dopaminergic innervation of the rat prefrontal cortex: a fluorescence histochemical study.

After the destruction of the noradrenergic ascending pathways, the localization of frontal cortical fields receiving fibers from the dopaminergic mesocortical system has been studied in rats, using a glyoxylic-paraformaldehyde method. The dopaminergic innervation was distributed in two main areas. The area of highest density was a medial field which spread in the medial cortex anterior and dorsal to the genu of the corpus callosum. It did not reach the shoulder region except in the foremost part of the frontal lobe where dopaminergic fibers were scattered in the whole cortex, including the molecular layer. A deep sulcal field was situated between the dorsal bank of the rhinal sulcus and the lateral cortex above it. In addition, a moderately dense band of dopaminergic fibers was observed between the corpus callosum and the anterior commissura, beside the accumbens nucleus. Similar data were obtained with dopamine uptake experiments on reserpine-treated but otherwise normal animals. The frontal areas receiving dopaminergic innervation coincide strikingly with the 'prefrontal cortex' as defined by neuroanatomical studies, which is assumed to be more or less equivalent to the prefrontal cortex of primates and derives direct projections from the amygdala. The functional implications of these findings are discussed.

Reduction of dopamine utilization in the prefrontal cortex but not in the nucleus accumbens after selective destruction of noradrenergic fibers innervating the ventral tegmental area in the rat.

The present study was made to determine the role of the noradrenergic (NA) neurons which innervate the ventral tegmental area (VTA) in the regulation of VTA dopaminergic (DA) neurons projecting to the prefrontal cortex and the nucleus accumbens. For this purpose, a 6-hydroxydopamine lesion was made in benztropine pretreated rats medially just above the decussatio of the pedunculus cerebellaris superior in order to specifically destroy the NA fibers innervating the VTA without affecting those projecting to the prefrontal cortex. Seven days later the ratio of DOPAC and DA levels was estimated in the prefrontal cortex and the nucleus accumbens and used as an index of DA utilization. In the lesioned rats the DOPAC/DA ratio was significantly decreased in the prefrontal cortex but not in the nucleus accumbens. These results suggest that the NA neurons which innervate the VTA exert a specific tonic excitatory influence on the mesocortico-prefrontal DA neurons.

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.