[Neurobiology in the neuropharmacology of antipsychotic drugs].
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Adrenergic beta-1 Receptor Antagonists↗
Biomedical subjects
J P Tassin
Publications and source records attributed to J P Tassin.
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.
Adrenergic alpha-1 Receptor Antagonists↗
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.
2-Amino-5-phosphonovalerate↗
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.
Adolescent↗
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.
Amphetamine↗
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.
Animals↗
Importance of the noradrenaline-dopamine coupling in the locomotor activating effects of D-amphetamine.
The locomotor hyperactivity induced by systemic or local (nucleus accumbens) D-amphetamine injections can be blocked by systemic or local (prefrontal cortex) injections of prazosin, an alpha1-adrenergic antagonist (Blance et al., 1994). Microdialysis studies performed on freely moving animals indicated that prazosin (0.5 mg/kg, i.p.) does not modify the increase in the extracellular dopamine (DA) levels in the nucleus accumbens that are induced by D-amphetamine (2.0 mg/kg, i.p.), but it inhibits the D-amphetamine-induced locomotor hyperactivity (-63%, p < 0.0001). No behavioral activation occurred after the bilateral local perfusion of 3 microM D-amphetamine in the nucleus accumbens, although it led to a fivefold increase in extracellular DA levels. This increase in extracellular DA levels was not affected by prazosin (0.5 mg/kg, i.p.). When an intraperitoneal injection of D-amphetamine (0.5 mg/kg) was superimposed to the continuous local perfusion of 3 microM D-amphetamine, it induced a 64% increase in the extracellular DA levels in the nucleus accumbens, and this response was associated with simultaneous behavioral activation. Both the increases in extracellular DA levels and in locomotor activity were completely blocked by a pretreatment with prazosin, injected either systemically (0.5 mg/kg, i.p.) or locally and bilaterally into the prefrontal cortex (500 pmol/side). Complementary experiments indicated that the focal application of D-amphetamine requires at least a 4.8-fold higher increase in DA output compared with systemic D-amphetamine for the behavioral effects to be elicited. Altogether, these results suggest that locomotor activating effects of D-amphetamine are caused by the stimulation of cortical alpha1-adrenergic receptors by noradrenaline, which increases the release of a functional part of subcortical DA.
Adrenergic Agents↗
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.
Animals↗
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.
Animals↗
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.
Computer Simulation↗
Norepinephrine-dopamine interactions in the prefrontal cortex and the ventral tegmental area: relevance to mental diseases.
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Adrenergic Fibers↗
Simultaneous determination of cytotoxic (adriamycin, vincristine) and modulator of resistance (verapamil, S 9788) drugs in human cells by high-performance liquid chromatography and ultraviolet detection.
Multidrug resistance (MDR), which was described for structurally and mechanistically unrelated anticancer agents, was modulated in vitro by a series of compounds which were of different chemical origin. In this situation, the selection of a correct assay dosage to study the MDR modulation mechanism was a problem. We developed a high-performance liquid chomatography (HPLC) method which enabled the simultaneous determination of three major cytotoxins (adriamycin, daunorubicin, vincristine) and two well-known modulators (S 9788, verapamil). This assay was fully validated and was used to follow, for the first time, the uptake and accumulation behaviour of adriamycin and S 9788 co-incubated with resistant and sensitive cell lines (KB-3-1; KB-A1).
Antibiotics, Antineoplastic↗
[Deficit schizophrenia: from pharmacology to clinical practice].
After having rapidly recapitulated the various arguments which suggest that meso-subcortical dopaminergic neurons are hyperreactive in the productive form of schizophrenia, we suggest in this article that dysfunction of noradrenergic neurons gives rise to this disorder whether of the productive or deficitary variety. In the specific case of deficitary schizophrenia, noradrenergic transmission appears to be desensitized, most likely following intense and repeated activation. Our results in fact show that activation of noradrenergic neurons inhibits cortical dopaminergic transmission mediated by D1 receptors and enhances the functional role of subcortical dopaminergic neurons. On the basis of these data, the lack of noradrenergic transmission would lead to a cortico/subcortical imbalance in favour of cortical areas. Deficitary schizophrenics would then find themselves stalled in a short-term memory situation without external data they could process. The therapeutic effect of substituted benzamides on negative schizophrenic patients may be explained by the observation that these products increase the release of noradrenaline in the frontal cortex and reactive subcortical dopaminergic neurons by blocking D2-type autoreceptors.
Antipsychotic Agents↗
[Schizophrenia and neural transmission: an excess of analogical treatment?].
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Antipsychotic Agents↗
Blockade of prefronto-cortical alpha 1-adrenergic receptors prevents locomotor hyperactivity induced by subcortical D-amphetamine injection.
The stimulation of cortical dopaminergic D1 receptors can counteract the increased locomotor activity evoked by D-amphetamine application in the nucleus accumbens (Vezina et al., Eur. J. Neurosci., 3, 1001-1007, 1991). Moreover, an alpha 1 antagonist, prazosin, prevents the locomotor hyperactivity induced by electrolytic lesions of the ventral tegmental area (Trovero et al., Neuroscience, 47, 69-76, 1992). Attempts were thus made to see whether blockade of alpha 1-adrenergic receptors in the rat prefrontal cortex could reduce nucleus accumbens D-amphetamine-evoked locomotor activity. Rats implanted chronically and bilaterally with cannulae into the medial prefrontal cortex and the nucleus accumbens were used for this purpose and locomotor activity was monitored in circular corridors. Preliminary experiments indicated that intraperitoneal injection of prazosin (0.06 mg/kg) reduces the locomotor hyperactivity induced by the peripheral administration of D-amphetamine (0.75 mg/kg). This effect of prazosin was not observed when locomotor hyperactivity was obtained by an intraperitoneal injection of scopolamine (0.8 mg/kg). Bilateral nucleus accumbens injections of D-amphetamine (4.0 nmol/side) markedly increased locomotor activity, as estimated in a 30 min period. Prior (20 min) bilateral injections of either prazosin or WB-4101 (0.16 pmol) into the medial prefrontal cortex abolished the nucleus accumbens D-amphetamine-evoked response. The recovery of the nucleus accumbens D-amphetamine-evoked response was closely dependent on the amount of prazosin used, very prolonged inhibitory effects of the drug being seen with a high amount (> 4 days with 160 pmol). In contrast, whatever the amount of WB-4101 used (0.16-160 pmol), recovery occurred within 3 days.(ABSTRACT TRUNCATED AT 250 WORDS)
Adrenergic alpha-1 Receptor Antagonists↗
Injections of 6-hydroxydopamine into the ventral tegmental area destroy mesolimbic dopamine neurons but spare the locomotor activating effects of nicotine in the rat.
The locomotor response to nicotine was assessed four weeks following destruction of mesolimbic dopamine (DA) neurons in rats by infusion of 6-hydroxydopamine into the ventral tegmental area. Resulting depletions of nucleus accumbens (N.Acc.) DA of up to 100% of control concentrations did not block the acute locomotor response to nicotine (0.4 mg/kg, base, s.c.). Such depletions also did not prevent the progressive enhancement of nicotine's locomotor effects when injections were repeated daily for nine days. These results suggest that mesolimbic DA is not necessary for the elicitation of locomotor activation by nicotine.
Animals↗
Blockade of D-1 dopamine receptors in the medial prefrontal cortex produces delayed effects on pre- and postsynaptic indices of dopamine function in the nucleus accumbens.
The present experiments assessed the acute and delayed effects of D-1 dopamine (DA) receptor blockade in the medial prefrontal cortex (mPFC) on pre- and postsynaptic indices of DA neurotransmission in the nucleus accumbens (N.Acc). Different groups of rats received intra-mPFC injections of saline (control animals) or the D-1 DA receptor antagonist SCH-23390 (0.25 microgram/side). Acutely, intra-mPFC injections of this antagonist did not affect spontaneous locomotion but significantly increased the locomotion induced by intra-N.Acc. amphetamine (1.5 micrograms/side), in agreement with our earlier findings [Vezina et al. (1991) Eur. J. Neurosci., 3:1001-1007]. When tested two days post-injection, however, mPFC-SCH-23390 preexposed animals showed lower levels of locomotor activity than Control animals in response to intra-N.Acc. injections of amphetamine. This effect was not observed in other animals preexposed two days earlier to mPFC injections of amphetamine (2.5 micrograms/side) or the D-2 DA receptor antagonist sulpiride (1.0 microgram/side). Animals preexposed two days earlier to mPFC SCH-23390 also showed higher levels of locomotor activity (+98%) when tested with intra-N.Acc. injections of the D-1 DA receptor agonist SKF-38393 (1.0 microgram/side) and a 36% increase in maximal DA-sensitive adenylate cyclase activity in comparison to Control animals. These effects were no longer observed in animals tested seven days following the mPFC SCH-23390 injections. These results demonstrate delayed actions resulting from cortical D-1 DA receptor blockade.(ABSTRACT TRUNCATED AT 250 WORDS)
Adenylyl Cyclases↗
[Interrelations between neuromediators implicated in depression and antidepressive drugs].
The concept that specific neurons modulate information processing rather than they convey sensory or motor signals seems to be well established. In any representation of the primary pathways responsible for the processing of sensory stimuli or motor outputs, it is notable that noradrenergic, serotonergic or dopaminergic neurons do not appear to be involved. Noradrenergic and serotonergic cells are activated by non specific stimuli coming from all sensory modalities, whereas dopaminergic neurons are activated by stimuli related to motivation, and which have previously taken a significance over the animal's history. Dopaminergic neurons activation therefore depends upon cortical processings which necessitate the participation of noradrenergic and serotonergic neurons. Up to now the clinical efficacy of antidepressants has been correlated with their biochemical property to desensitize cortical beta 1-adrenergic receptors. This does not necessarily mean that this desensitization is essential, but rather that these receptors are extremely sensitive to modifications of noradrenergic transmission and that a reactivation of noradrenergic transmission is central for depression relief. Taking into account data from the literature and results obtained in our laboratory, we propose: 1) that the reactivation of serotonergic neurons is essential to reactivate noradrenergic cells; 2) that the presence of a normal noradrenergic transmission is necessary to obtain a functional subcortical dopaminergic transmission.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗