RESUMO
AIM: A French governmental institute published, in February 2004, a report assessing the efficacy of psychotherapies in the light of the biomedical literature. It concluded that cognitive psychotherapies effectively cure common mental disorders, while the efficacy of psychodynamic therapies is not proven by scientific studies. Because many French mental health professionals are practicing with reference to psychoanalysis, this conclusion stirred up heated controversy. Since February 2004, numerous studies assessing psychodynamic therapies have been published in peer-reviewed biomedical journals. Moreover, these primary studies have been meta-analyzed in dozens of review articles. Here, we systematically review these meta-analysis articles. METHODS: A systematic search for meta-analyses assessing psychodynamic therapies was performed using PubMed and identified 71 articles published from January 2004 to December 2019. Among them, 25 articles were judged to be relevant because they reported meta-analyses assessing the symptoms of common mental disorders in at least three distinct cohorts of adult patients. Although the primary studies included in these 25 meta-analysis articles often overlap, the selection criteria, calculation methods and results always differ between them. Therefore, we reviewed all of them without further selection. From all the meta-analyses reported in these 25 articles, we systematically present here the most compelling ones, i.e. those calculated from the largest number of primary studies. Results were quantified in terms of effect size (i.e. standardized mean difference). Effect sizes below 0.25 were considered as without clinical significance, whereas those superior to 0.8 were regarded as robust. Because short-term psychodynamic therapies had been assessed in 20 meta-analysis articles published until 2017, we did not search for more recent primary studies. However, because the most recent meta-analysis article about long-term psychodynamic therapies was published in 2013, we also searched, using PubMed, for primary studies assessing psychodynamic therapies lasting for at least one year and published from January 2013 to December 2019. Among the 57 publications retrieved by PubMed, three were identified as randomized controlled trials not included in meta-analyses and were extensively described here. RESULTS: Eight meta-analysis articles have assessed symptom improvement at treatment termination by comparing with baseline symptoms. According to all of them, psychodynamic therapies alleviate symptoms and their effect sizes are always robust. Three meta-analysis articles compared psychodynamic therapies with inactive treatments (e.g. placebo medication, waiting list) and reported clinically significant differences in favor of psychodynamic therapies. Ten meta-analysis articles compared, at treatment termination, psychodynamic therapies to active treatments, including medication and cognitive psychotherapies. Nine of them reported no difference. Only one article concluded that psychodynamic therapies are clinically inferior to cognitive psychotherapies (d=-0.28). Seven meta-analysis articles compared psychodynamic therapies to active treatment at follow-up (i.e. months or years after treatment termination). Five of them reported no significant difference, one reported a medium effect size in favor of psychodynamic therapies over various active treatments (d=0.38), while the other reported a clinically significant difference in favor of cognitive psychotherapies (d=-0.55). Because short-term treatments are often insufficient to prevent relapse, investigations about long-term treatments (i.e. more than one year) are needed, but such published studies are still scarce. Five meta-analysis articles and three primary studies published since 2013 compared long-term psychodynamic therapies to various active treatments of similar duration. According to them, psychodynamic therapies were at least as effective as other active treatments. CONCLUSION: A systematic review about psychodynamic therapies, published in 2015 in Lancet Psychiatry, included 64 randomized controlled trials of which 37 were published after 2003. Therefore, most quality studies assessing psychodynamic therapies have been published since 2003 and have been reviewed in recent meta-analysis articles. All together, this recent literature leads to the conclusion that psychodynamic therapies are as effective as active treatments, including cognitive psychotherapies, to help patients suffering from common mental disorders (unipolar depression, anxiety disorders, eating disorders and personality disorders). Beside this overall conclusion, it appears that randomized controlled trials are not well suited for answering why psychotherapies work in some patients but not in others, and how they work in general. Other approaches are needed, including case studies.
Assuntos
Terapia Cognitivo-Comportamental , Transtorno Depressivo , Adulto , Doença Crônica , Humanos , PsicoterapiaRESUMO
The effect of endogenous dopamine on the activity of target neurons recorded with patch clamp or Ca2+ imaging techniques in slices has been studied to date with intra-striatal stimuli. Yet, this approach is severely handicapped by the nonphysiological and nonspecific stimulation of local neurons and fibers within the striatum. We now report a new juvenile and adult mouse slice preparation in which a component of the nigro-striatal dopaminergic pathway is preserved in its entirety, from cell bodies to axon terminals. This tilted parasagittal slice (380-400 microm) just medial to the subthalamic nucleus contains functional nigro-striatal neurons as assessed by morphological examination of tyrosine hydroxylase positive cell bodies and axons, combined with electrochemical assays of dopamine release in the striatum in response to stimulation of the substantia nigra pars compacta. The nigro-striatal slice constitutes a suitable in vitro preparation to determine the impact of endogenously released dopamine on target neurons of the striatum.
Assuntos
Corpo Estriado/citologia , Dopamina/metabolismo , Neurônios/fisiologia , Substância Negra/citologia , Fatores Etários , Animais , Animais Recém-Nascidos , Axônios/metabolismo , Biofísica , Dendritos/metabolismo , Inibidores da Captação de Dopamina/farmacologia , Estimulação Elétrica/métodos , Eletroquímica , Técnicas In Vitro , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Vias Neurais/fisiologia , Neurônios/citologia , Neurônios/efeitos dos fármacos , Nomifensina/farmacologia , Técnicas de Patch-Clamp , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
Most neurotransmitters inhibit their own release through autoreceptors. However, the physiological functions of these presynaptic inhibitions are still poorly understood, in part because their time course and functional characteristics have not been described in vivo. Dopamine inhibits its own release through D2 autoreceptors. Here, the part played by autoinhibition in the relationship between impulse flow and dopamine release was studied in vivo in real time. Dopamine release was evoked in the striatum of anesthetized mice by electrical stimulation of the medial forebrain bundle and was continuously monitored by amperometry using carbon fiber electrodes. Control experiments performed in mice lacking D2 receptors showed no autoinhibition of dopamine release. In wild-type mice, stimulation at 100 Hz with two to six pulses linearly inhibited further release, whereas single pulses were inefficient. Dopaminergic neurons exhibit two discharge patterns: single spikes forming a tonic activity below 4 Hz and bursts of two to six action potentials at 15 Hz. Stimulation mimicking one burst (four pulses at 15 Hz) promoted extracellular dopamine accumulation and thus inhibited further dopamine release. This autoinhibition was maximal between 150 and 300 msec after stimulation and disappeared within 600 msec. This delayed and prolonged time course is not reflected in extracellular DA availability and thus probably attributable to mechanisms downstream from autoreceptor stimulation. Thus, in physiological conditions, autoinhibition has two important roles. First, it contributes to the attenuation of extracellular dopamine during bursts. Second, autoinhibition elicited by one burst transiently attenuates further dopamine release elicited by tonic activity.
Assuntos
Dopamina/metabolismo , Homeostase/fisiologia , Inibição Neural/fisiologia , Terminações Pré-Sinápticas/metabolismo , Receptores de Dopamina D2/metabolismo , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Análise de Variância , Animais , Autorreceptores/antagonistas & inibidores , Autorreceptores/metabolismo , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Antagonistas de Dopamina/farmacologia , Antagonistas dos Receptores de Dopamina D2 , Estimulação Elétrica , Eletrodos Implantados , Haloperidol/farmacologia , Feixe Prosencefálico Mediano/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Inibição Neural/efeitos dos fármacos , Terminações Pré-Sinápticas/efeitos dos fármacos , Tempo de Reação/fisiologia , Receptores de Dopamina D2/deficiência , Receptores Pré-Sinápticos/metabolismo , Reprodutibilidade dos TestesRESUMO
Amphetamine (AMPH) is known to raise extracellular dopamine (DA) levels by inducing stimulation-independent DA efflux via reverse transport through the DA transporter and by inhibiting DA re-uptake. In contrast, recent studies indicate that AMPH decreases stimulation-dependent vesicular DA release. One candidate mechanism for this effect is the AMPH-mediated redistribution of DA from vesicles to the cytosol. In addition, the inhibition of stimulation-dependent release may occur because of D2 autoreceptor activation by DA that is released via reverse transport. We used the D2 receptor antagonist sulpiride and mice lacking the D2 receptor to address this issue. To evaluate carefully AMPH effects on release and uptake, we recorded stimulated DA overflow in striatal slices by using continuous amperometry and cyclic voltammetry. Recordings were fit by a random walk simulation of DA diffusion, including uptake with Michaelis-Menten kinetics, that provided estimates of DA concentration and uptake parameters. AMPH (10 microm) promoted the overflow of synaptically released DA by decreasing the apparent affinity for DA uptake (K(m) increase from 0.8 to 32 microm). The amount of DA released per pulse, however, was decreased by 82%. This release inhibition was prevented partly by superfusion with sulpiride (47% inhibition) and was reduced in D2 mutant mice (23% inhibition). When D2 autoreceptor activation was minimal, the combined effects of AMPH on DA release and uptake resulted in an enhanced overflow of exocytically released DA. Such enhancement of stimulation-dependent DA overflow may occur under conditions of low D2 receptor activity or expression, for example as a result of AMPH sensitization.
Assuntos
Anfetamina/farmacologia , Proteínas de Transporte/metabolismo , Dopamina/metabolismo , Glicoproteínas de Membrana , Proteínas de Membrana Transportadoras , Proteínas do Tecido Nervoso , Receptores de Dopamina D2/metabolismo , Vesículas Sinápticas/metabolismo , Animais , Transporte Biológico/efeitos dos fármacos , Simulação por Computador , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Antagonistas dos Receptores de Dopamina D2 , Proteínas da Membrana Plasmática de Transporte de Dopamina , Inibidores da Captação de Dopamina/farmacologia , Estimulação Elétrica , Eletroquímica , Exocitose/efeitos dos fármacos , Técnicas In Vitro , Camundongos , Camundongos Endogâmicos , Camundongos Knockout , Modelos Neurológicos , Inibição Neural/efeitos dos fármacos , Receptores de Dopamina D2/deficiência , Sulpirida/farmacologiaRESUMO
Sciatic nerve stimulation, which strongly activates noradrenergic locus coeruleus (NA-LC) neurons, was used in anaesthetized rats as a model to study the transneuronal control of catechol metabolism in this nucleus. We show, using in vivo electrochemistry and biochemical post-mortem assays, that a prolonged (20 min) unilateral sciatic nerve electrical stimulation led to a reversible enhancement (80 - 130%) of both endogenous and in vivo extracellular levels of 3,4-dihydroxyphenylacetic acid (DOPAC) within the contralateral LC region. An elevation in DOPAC levels was also observed in the ipsilateral nucleus but was always significantly lower. The response was abolished by a pretreatment with kynurenic acid, a non-selective excitatory amino acid (EAA) antagonist known to block footshock-induced excitations of NA-LC neurons: in antagonist-treated rats, the stimulation induced a non-significant effect (+ 30%) on endogenous DOPAC levels, which contrasted with the highly significant effect (+ 113%) observed in vehicle-treated animals. As the major source of EAA afferents to the LC originates in the nucleus paragigantocellularis, we made an attempt to suppress activation by a section of these fibres. An incision performed obliquely (45 degrees ) between LC and PGi greatly and significantly attenuated, but did not totally suppress, the increase in DOPAC endogenous content due to the stimulation. These experiments indicate that a peripheral stimulus provokes an activation of catecholamine metabolism within the soma - dendritic region of the NA-LC cells. They suggest that this effect may be mediated, at least in part, by afferent pathways originating from the medulla which utilize an EAA as transmitter.
RESUMO
Mesolimbic dopaminergic neurons discharge either in a single spike mode or in a bursting pattern. In order to investigate the influence of these patterns on dopamine release, extracellular dopamine was electrochemically monitored in vivo in the olfactory tuberculum of anaesthetized rats by means of two approaches. In the first, a pure signal, unequivocally corresponding to extracellular dopamine, was recorded every minute from pargyline treated rats by differential normal pulse voltammetry combined with electrochemically treated carbon fibre electrodes. In the second, the differential current solely due to oxidation of all the catechols was monitored every 1 s in drug-free rats by differential pulse amperometry. In basal conditions this current was mainly due to extracellular DOPAC. However, electrical stimulation of the dopaminergic pathway for 20 s elicited an immediate increase in this signal. This effect was due to evoked dopamine release since it was strongly enhanced by amphetamine (2 mg/kg) or pargyline (75 mg/kg) injections. As studied with both approaches, the evoked increase in extracellular dopamine concentration was immediate and lasted as long as the stimulation. The amplitude of the effect depended on the frequency of the stimulation (from 3 to 14 Hz) in an exponential manner but never exceeded 1 microM dopamine. Bursting stimulations (frequency within the trains: 14 Hz) were twice as potent as regularly spaced ones, having the same average frequency (5 Hz). In conditions which mimicked the spontaneous activity of dopaminergic neurons when they switch from one pattern to the other (4 Hz regularly spaced stimulation versus trains at a mean frequency of 6 Hz), the bursting stimulations were found to be up to 6 times more potent. Therefore, as regards the functional efficacy of DA neurons, bursting might be much more important than mean firing frequency.
Assuntos
Dopamina/fisiologia , Mesencéfalo/fisiologia , Neurônios/fisiologia , Animais , Estimulação Elétrica , Eletrofisiologia , Masculino , Mesencéfalo/metabolismo , Bulbo Olfatório/fisiologia , Ratos , Ratos EndogâmicosRESUMO
The paraventricular hypothalamic nucleus receives a dense noradrenergic innervation. Electrochemically treated carbon fibre electrodes were implanted in the paraventricular nucleus of anaesthetized rats and their locations were histologically controlled after each experiment. Differential normal pulse voltammograms showed an oxidation peak at +50 mV. This peak was mainly due to 3,4-dihydroxyphenylacetic acid synthesized by noradrenergic terminals since: it appeared at the same oxidation potential as 3,4-dihydroxyphenylacetic acid in vitro; it was rapidly suppressed after inhibition of tyrosine hydroxylase by alpha-methyl-p-tyrosine or monoamine oxidase by pargyline; blockade of dopamine-beta-hydroxylase by FLA 63 induced a marked increase in this signal, whereas this drug was without effect in dopaminergic terminals fields (striatum, zona incerta); stimulation of alpha 2 noradrenergic receptors by clonidine (50 micrograms/kg) decreased the peak height and this effect was reversed by piperoxane (30 mg/kg). This oxidation peak corresponded to a 3,4-dihydroxyphenylacetic acid concentration of 2 microM. On the other hand, when recorded from rats which were treated with pargyline 3 h before recording, a small peak appeared at +100 mV. This signal was attributed to the oxidation of extracellular noradrenaline on the basis of the following arguments: it appeared at the same potential as noradrenaline in vitro; desipramine (25 mg/kg) induced a 4-fold increase in this peak height; piperoxan (2 mg/kg) enhanced this signal and reversed the decrease induced by clonidine (50 micrograms/kg); electrical stimulations (bipolar electrode, square pulses, 0.3 ms, 200 microA, 15 Hz for 40 s) in the rostral part of the A1 group were followed by an immediate, short-lasting 4-fold increase in the signal.
Assuntos
Catecolaminas/metabolismo , Norepinefrina/metabolismo , Núcleo Hipotalâmico Paraventricular/metabolismo , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Animais , Desipramina/farmacologia , Dopamina/metabolismo , Estimulação Elétrica , Eletroquímica , Eletrodos Implantados , Masculino , Metiltirosinas/farmacologia , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Pargilina/farmacologia , Piperoxano/farmacologia , Ratos , Ratos Endogâmicos , Fatores de Tempo , alfa-MetiltirosinaRESUMO
Dopamine is generally considered to be an inhibitory neurotransmitter in the central nervous system. Dopamine release in the nucleus accumbens can be evoked by chemical stimulation of the afferent cell bodies using N-methyl-D-aspartate microinjection in the ventral tegmental area. We report here that following such injections most neurons of the nucleus accumbens were excited. This excitation was abolished if dopaminergic neurons were lesioned and was blocked by antagonists of the D1 dopamine receptors. Finally, excitatory responses to electrical stimulation of the hippocampus were strongly facilitated by endogenously released dopamine. We suggest, therefore, that under physiological conditions, dopamine acting on D1 receptors is actually an excitatory neurotransmitter.
Assuntos
Dopamina/fisiologia , Núcleo Accumbens/metabolismo , Receptores de Dopamina D1/fisiologia , Tegmento Mesencefálico/metabolismo , Potenciais de Ação/efeitos dos fármacos , Animais , Benzazepinas/farmacologia , Antagonistas de Dopamina/farmacologia , Estimulação Elétrica , Haloperidol/farmacologia , Masculino , Microinjeções , N-Metilaspartato/administração & dosagem , N-Metilaspartato/farmacologia , Neurônios/metabolismo , Ratos , Ratos Wistar , Receptores de Dopamina D1/efeitos dos fármacos , Tegmento Mesencefálico/efeitos dos fármacosRESUMO
As shown by electrophysiological analysis, the release of the sympathetic co-transmitter adenosine 5'-triphosphate (ATP) from individual release sites is monoquantal and intermittent; the average release probability may be as low as 0.01. Indirect evidence from biochemical studies of noradrenaline overflow is compatible with a similar monoquantal, low probability release of noradrenaline as well. In the present study our first aim was to address this issue more directly in rat tail artery, using continuous amperometry to monitor in real time the release of noradrenaline from a relatively small number of sympathetic nerve varicosities. The results seem to provide the first direct evidence that noradrenaline, similarly to ATP, may be released intermittently during nerve stimulation at low frequency. Our second aim was to use the same technique to study the release of noradrenaline caused by nerve stimulation with single pulses or short trains (two to eight pulses) at high frequencies. The results show that during stimulation at 20 Hz the peak amplitude of the noradrenaline oxidation current response grew linearly with the train length, but at 50 Hz the curve describing this growth was sigmoid in shape.
Assuntos
Norepinefrina/metabolismo , Sistema Nervoso Simpático/metabolismo , Animais , Artérias/inervação , Estimulação Elétrica/métodos , Masculino , Ratos , Ratos Sprague-Dawley , Cauda/irrigação sanguíneaRESUMO
At the skeletal neuromuscular junction the released neurotransmitter, acetylcholine, is eliminated within some milliseconds. This time course is known with great precision through the electrical response of target cells. At the sympathetic neuroeffector junction the fast electrical response is not mediated by noradrenaline but by a cotransmitter: ATP. The slow electrical response and the slow component of smooth muscle contraction are principally mediated by noradrenaline. These responses are two orders of magnitude slower than the electrical response to ATP. Therefore, great uncertainty remains regarding the kinetics of noradrenaline appearance and elimination. Here, the local noradrenaline concentration at the surface of the isolated rat tail artery was electrochemically monitored in real time using a carbon fibre electrode. We have shown that the time course of the neurogenically released noradrenaline is at least one order of magnitude faster than the resulting contraction. The kinetics of noradrenaline inactivation by neuronal reuptake were also precisely measured.
Assuntos
Músculo Liso Vascular/metabolismo , Neurônios/metabolismo , Norepinefrina/metabolismo , Sistema Nervoso Simpático/metabolismo , Animais , Cádmio/farmacologia , Cálcio/fisiologia , Estimulação Elétrica , Eletroquímica , Eletrodos , Meia-Vida , Técnicas In Vitro , Cinética , Músculo Liso Vascular/inervação , Músculo Liso Vascular/fisiologia , Neurônios/fisiologia , Ratos , Sistema Nervoso Simpático/fisiologia , Tetrodotoxina/farmacologiaRESUMO
Extracellular dopamine concentration has been monitored in the striatum of pargyline treated, anaesthetized rats using differential normal pulse voltammetry. The catechol oxidation current recorded with electrochemically treated carbon fiber electrodes disappeared when the dopaminergic terminals were selectively destroyed by 6-hydroxydopamine. Calibration of the basal oxidation current revealed that the extracellular dopamine concentration was 26 nM. Brief and moderate electrical stimulation of the nigrostriatal pathway at the level of the medial forebrain bundle induced a large increase in the dopamine current. The observed elevation in the dopamine signal lasted as long as the stimulation. It varied with the frequency (0-25 Hz) of the pulses in an exponential manner. Stimulation pulses distributed in a bursted pattern were twice as potent as an equivalent number of pulses regularly spaced. High frequency stimulations (50 Hz) were also investigated in anaesthetized rats (without pargyline) with untreated carbon fiber electrodes; they induced a very large increase in the dopamine extracellular concentration (up to 8-15 microM). Interruption of the dopaminergic impulse flow either by an electrolytic lesion or by a low dose of apomorphine (0.05 mg/kg) caused an immediate decrease of the dopamine current. The time courses and amplitudes (-70%) of these effects were identical. Subsequent injection of haloperidol (0.5 mg/kg) reversed the apomorphine effect up to +360% of the control basal value. Administration of dopaminergic antagonists such as haloperidol (0.05 and 0.5 mg/kg) or metoclopramide (2 mg/kg) significantly increased the dopamine current up to 317, 340 and 215% of the respective control values. Nomifensine (4 mg/kg) produced a big increase (+417%) of the extracellular dopamine levels. The effect of electrical stimulation of the dopaminergic pathway was potentiated by drugs such as amphetamine (2 mg/kg), nomifensine (4 mg/kg) or haloperidol (0.05 and 0.5 mg/kg) but was not altered by apomorphine (0.05 mg/kg). The study by in vivo voltammetry of the variations in the striatal extracellular dopamine concentrations shows that the release of dopamine is under the influence of both the frequency of impulse flow and of dopaminergic striatal autoreceptors.
Assuntos
Corpo Estriado/fisiologia , Dopamina/metabolismo , Receptores Dopaminérgicos/fisiologia , Animais , Dopamina/análise , Dopamina/fisiologia , Estimulação Elétrica , Eletroquímica , Masculino , Feixe Prosencefálico Mediano/fisiologia , Modelos Neurológicos , Ratos , Transmissão SinápticaRESUMO
Evoked dopamine release was monitored in vivo from the olfactory tubercle of anaesthetized rats by differential pulse amperometry combined with carbon fibre electrodes which, in most cases, were electrochemically treated. Dopamine release was evoked by electrical stimulation of the ascending dopaminergic pathway. The dopamine release evoked by burst stimulation (20 s with a mean frequency of 6 Hz) was dose-dependently decreased by D,L-apomorphine (25-800 micrograms/kg, s.c.) or by quinpirole (50 micrograms/kg, s.c.) while the opposite effect was observed with haloperidol (12.5 micrograms/kg-0.5 mg/kg, s.c.) or with D,L-sulpiride (2-200 mg/kg, s.c.). Neither the D1 agonist SKF 38393 (10 mg/kg, s.c.) nor the D1 antagonist SCH 23390 (0.5 mg/kg, s.c.) affected the evoked dopamine release. Moreover, sulpiride competitively antagonized the effects of apomorphine. The relative amplitude of the apomorphine inhibition was inversely correlated with the stimulation frequency (6 or 9 Hz). The increase induced either by haloperidol or by sulpiride was positively related to the stimulation frequency (from 3 to 9 Hz) and reached a stable value (+700% of the pre-drug-evoked dopamine release) with higher frequencies (from 9 to 20 Hz). This increase also depended on the duration of the stimulation: both single-train (10 pulses) or burst stimulations for 20 s, whose frequency inside the trains was in both cases 14 Hz, evoked a dopamine release which was minimally affected by sulpiride or haloperidol. In conclusion, in physiological conditions the amplitude of the impulse flow-dependent dopamine release is regulated by the extrasynaptic extracellular dopamine concentration which varies from 10 to 100 nM. This presynaptic autoinhibition is mediated by autoreceptors of the D2 type and is involved in the nonlinear relationship between impulse flow and dopamine release.
Assuntos
Dopamina/metabolismo , Bulbo Olfatório/metabolismo , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/farmacologia , Animais , Apomorfina/farmacologia , Benzazepinas/farmacologia , Estimulação Elétrica , Ergolinas/farmacologia , Potenciais Evocados/efeitos dos fármacos , Haloperidol/farmacologia , Masculino , Microeletrodos , Bulbo Olfatório/efeitos dos fármacos , Quimpirol , Ratos , Ratos Endogâmicos , Receptores Dopaminérgicos/efeitos dos fármacos , Receptores Dopaminérgicos/fisiologia , Taxa Secretória/efeitos dos fármacos , Sulpirida/farmacologiaRESUMO
Evoked noradrenaline release was monitored every 1 s in vivo from the hypothalamic paraventricular nucleus by differential pulse amperometry at +105 mV combined with carbon fiber electrodes. Noradrenaline release was evoked by electrical stimulations of the ventrolateral medulla for 20s every 10 min at a physiological frequency (3-20 Hz) (see accompanying paper). The evoked noradrenaline release was dose-dependently attenuated by clonidine (10-100 micrograms/kg, i.v.) and strongly enhanced by alpha-2 antagonists: yohimbine (2 mg/kg), piperoxane (2 mg/kg) and idazoxan (0.05-1 mg/kg). Moreover, the effect of clonidine (50 micrograms/kg) was prevented by yohimbine (5 mg/kg) or idazoxan (1 mg/kg). Haloperidol (50 micrograms/kg) or propranolol (10 mg/kg) did not affect evoked noradrenaline release while prazosin (0.05-1 mg/kg) induced a moderate increase. However, prazosin did not prevent the effect of clonidine (50 micrograms/kg). Reserpine (5 mg/kg) pretreatment for 1 h induced a pronounced decrease in the evoked noradrenaline release and abolished the effect of yohimbine (2 mg/kg). Pretreatment by desipramine 30 min before injection abolished the effect of clonidine (50 micrograms/kg) but not of yohimbine (2 mg/kg). The amplitude of the yohimbine (2 mg/kg) effect depended on the frequency of the stimulation: it was maximal between 3 and 7 Hz and gradually declined from 10 to 20 Hz. These results show that noradrenaline release is presynaptically controlled by an alpha-2 adrenoreceptor and suggest that, in physiological conditions, endogenous extracellular noradrenaline inhibits its own phasic release. In conclusion, noradrenergic terminals act as a high pass filter which converts impulse flow into noradrenaline release and the features of this filter are modulated by extracellular noradrenaline via an alpha-2 adrenoreceptor.
Assuntos
Clonidina/farmacologia , Norepinefrina/metabolismo , Núcleo Hipotalâmico Paraventricular/metabolismo , Receptores Adrenérgicos alfa/fisiologia , Ioimbina/farmacologia , Animais , Relação Dose-Resposta a Droga , Estimulação Elétrica , Masculino , Núcleo Hipotalâmico Paraventricular/fisiologia , Ratos , Ratos Endogâmicos , Receptores Adrenérgicos alfa/efeitos dos fármacosRESUMO
The hypothalamic paraventricular nucleus is densely innervated by noradrenergic terminals mainly originating in the A1 group within the ventrolateral medulla. An oxidation signal corresponding to extracellular catechols was recorded from the paraventricular nucleus of urethane anaesthetized rats every 1 s by differential pulse amperometry at + 105 mV combined with carbon fiber electrodes. In basal conditions, both extracellular noradrenaline and DOPAC, which are synthesized by noradrenergic terminals, contributed to this oxidation signal. Electrical stimulations of the rostral part of the A1 group were applied for 10 or 20 s every 10 min at physiological frequency (3-20 Hz). They induced an immediate increase in the oxidation signal which lasted as long as the stimulation. This increase was due to the evoked noradrenaline release since it was enhanced by pargyline, desipramine and amphetamine and it was attenuated by alpha-methyl-p-tyrosine and reserpine. The amplitude of the evoked noradrenaline release depended non-linearly on the frequency of the stimulation (from 3 to 20 Hz). When expressed per pulse, noradrenaline release was facilitated four-fold as the frequency increased from 3 to 20 Hz. Central noradrenergic neurons exhibit a tonic activity in a single spike discharge pattern with a mean frequency below 5 Hz but they respond to physiological stimuli by short bursts of action potentials at 20 Hz. Therefore, the present data show that noradrenergic terminals convert physiological impulse flow into noradrenaline release as a high pass filter which enhances the signal-to-noise ratio in response to phasic stimuli.
Assuntos
Norepinefrina/metabolismo , Núcleo Hipotalâmico Paraventricular/metabolismo , Animais , Desipramina/farmacologia , Estimulação Elétrica , Eletroquímica , Masculino , Metiltirosinas/farmacologia , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Núcleo Hipotalâmico Paraventricular/fisiologia , Ratos , Ratos Endogâmicos , alfa-MetiltirosinaRESUMO
Central dopaminergic neurons exhibit two kinds of discharge activity: single spikes and bursts of two to six action potentials. Since these neurons can switch from one discharge pattern to the other whereas the mean discharge rate remains little affected, bursts may be more potent in triggering the release of their neurotransmitter, dopamine. Electrical stimulations mimicking the bursting pattern were actually twice as potent as regularly spaced stimulations to enhance the dopamine extracellular concentration. This suggested that dopamine release might be facilitated by increasing the impulse flow frequency. The high extracellular overflow evoked by a burst might also be due to accumulation of the released dopamine whereas, at lower frequencies, dopamine might be readily eliminated between every action potential. In the present study the dopamine overflow evoked by electrical stimulation of the dopaminergic pathway was measured in vivo by carbon fibre electrodes combined with continuous amperometry. We observed a small facilitation of the release per pulse during stimulations mimicking a burst but only in mesolimbic areas. The high extra-cellular dopamine level evoked by a burst was mainly due to accumulation of the released dopamine.
Assuntos
Potenciais de Ação , Corpo Estriado/fisiologia , Dopamina/fisiologia , Neurônios/fisiologia , Núcleo Accumbens/fisiologia , Condutos Olfatórios/fisiologia , Animais , Estimulação Elétrica , Masculino , Nomifensina/farmacologia , Ratos , Ratos Sprague-Dawley , Taxa Secretória/efeitos dos fármacosRESUMO
The release of dopamine in the nucleus accumbens of anaesthetized rats was evoked either by electrical stimulation of the mesolimbic dopaminergic pathway or by local ejection of N-methyl-D-aspartate in the ventral tegmental area. Untreated carbon-fibre electrodes implanted in the nucleus accumbens were held at +400 mV versus a reference electrode, and the oxidation current was continuously monitored. Despite a poor selectivity to dopamine versus other oxidizable compounds such as ascorbic acid, the evoked responses were solely due to dopamine overflow in the extracellular fluid since they were closely correlated with the stimulations and exhibited all the expected characteristics related to a dopamine release. First, these effects were closely consistent with the anatomy of the mesolimbic dopaminergic system. Second, the responses to electrical stimulations were abolished by a tetrodotoxin ejection in the vicinity of the carbon-fibre electrode and they were strongly, but reversibly, diminished (60% decrease) when cadmium was substituted for calcium in an artificial cerebrospinal fluid ejected close to the electrode. Third, their maximal amplitudes were enhanced by amphetamine, pargyline, nomifensine and haloperidol. Fourth, inhibition of dopamine reuptake by nomifensine induced a five-fold decrease in the rate of decline of the evoked oxidation current. Fifth, contribution of noradrenaline and serotonin to the observed effects seems unlikely since specific reuptake blockers (desipramine and sertraline, respectively) did not alter them. Dopaminergic neurons discharge either in a single spike mode with a mean firing rate below 5 Hz or in a bursting pattern (intraburst frequency: 10 to 20 Hz).(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Dopamina/metabolismo , Eletroquímica , Núcleo Accumbens/metabolismo , Fibras Simpáticas Pós-Ganglionares/metabolismo , Potenciais de Ação/efeitos dos fármacos , Anfetamina/farmacologia , Animais , Estimulação Elétrica , Masculino , Compostos Nitrosos/farmacologia , Nomifensina/farmacologia , Ratos , Ratos Sprague-DawleyRESUMO
The anteroventral thalamic nucleus is innervated by noradrenergic terminals exclusively originating in the locus coeruleus, a densely packed cell group located in the dorsotegmental part of the pons. In urethane-anaesthetized rats, electrical stimulations of locus coeruleus axons (dorsal noradrenergic bundle; 14 Hz, 20 s) evoked a rapid increase in the signal (catechol oxidation current) measured within the anteroventral thalamic nucleus by the use of carbon fibre electrodes combined with electrochemistry. This effect was reproducible and immediately reversible. Evoked changes in this current were found to be due to oxidation of noradrenaline released from terminals. The amplitude of the evoked noradrenaline release varied non-linearly with the frequency of stimulation. We investigated the influence of locus coeruleus activation on noradrenaline release measured in the anteroventral thalamic nucleus every second by means of differential pulse amperometry: (i) chemical activation of locus coeruleus by local injection of glutamate (0.2-0.8 nmol) immediately and consistently evoked noradrenaline release in a dose-dependent manner; and (ii) peripheral stimulation of the sciatic nerve (20 s)--known to enhance the firing rate of locus coeruleus neurons-evoked a noradrenaline release similar to that produced by a stimulation of the dorsal noradrenergic bundle at 8-10 Hz. Pharmacological and kinetic characteristics of the noradrenaline release were the same for central or peripheral stimulation of locus coeruleus neurons. Our results indicate that in vivo electrochemistry, because of its sensitivity and its high space and time resolution, is well suited for studies of evoked noradrenaline release from locus coeruleus terminals. This approach allowed us to describe the characteristics of central noradrenaline release evoked by central and peripheral stimulations of short duration. In particular, we observed a very close relationship between impulse flow and evoked noradrenaline release.
Assuntos
Locus Cerúleo/fisiologia , Norepinefrina/metabolismo , Núcleos Talâmicos/fisiologia , Animais , Axônios/fisiologia , Clonidina/farmacologia , Desipramina/farmacologia , Estimulação Elétrica , Eletroquímica/métodos , Potenciais Evocados , Glutamatos/metabolismo , Ácido Glutâmico , Masculino , Oxirredução , Pargilina/farmacologia , Ratos , Ratos Sprague-Dawley , Nervo Isquiático/fisiologia , Núcleos Talâmicos/efeitos dos fármacos , Ioimbina/farmacologiaRESUMO
The aim of this study was to find out if clearance of noradrenaline released from sympathetic nerve terminals in rat isolated tail artery is a physiological variable and if so, to determine its role for the noradrenaline-mediated neurogenic contraction. The per pulse release of noradrenaline induced by electrical nerve stimulation and the fluctuations of the level of noradrenaline at the receptors driving the contractions were assessed from the electrochemically determined noradrenaline oxidation current at a carbon fibre electrode at the surface of the artery. Both were compared with the noradrenaline-mediated neurogenic contraction. The effects on these parameters of cocaine or desipramine, or of corticosterone, were used to assess the relative roles of neuronal and extraneuronal uptake, respectively. The effects of cocaine or desipramine, which enhance the noradrenaline level at the receptors by blocking neuronal reuptake, were compared with those of yohimbine, presumed to act exclusively by enhancing the per pulse release of noradrenaline. The results seem to support the following tentative conclusions. Clearance of released noradrenaline occurs by neuronal uptake and diffusion, while extraneuronal uptake is negligible. The noradrenaline-induced neurogenic contraction is mediated via adrenoceptors on cells near the plane of the nerve plexus; the excitation spreads from these cells throughout the syncytium. The contractile response to exogenous noradrenaline may also be mediated via receptors on the innervated key cells. Reuptake of noradrenaline into the releasing varicosities, i.e. in "active junctions", is highly efficient for single quanta but rapidly saturated by repeated release, while reuptake of noradrenaline in the "surround" of active junctions is probably rarely saturated and more independent of nerve activity. Saturation of the transporter by repeated release of quanta from the same varicosity and the consequent accumulation of "residual" noradrenaline and increased diffusion out of the junction and recruitment of noradrenaline receptors in the surround may be the cause of the rapid growth of the contraction during a high frequency train. Diffusion of released noradrenaline away from the postjunctional receptors is restricted by a local nerve activity-dependent buffering mechanism which, in spite of fading of the per pulse release, helps maintain the noradrenaline concentration at the receptors and the contraction during long high-frequency trains. Reactivation of the clearance mechanisms upon cessation of nerve activity accelerates the relaxation.(ABSTRACT TRUNCATED AT 400 WORDS)
Assuntos
Junção Neuromuscular/fisiologia , Norepinefrina/metabolismo , Sistema Nervoso Simpático/fisiologia , Transmissão Sináptica/fisiologia , Cauda/irrigação sanguínea , Antagonistas Adrenérgicos alfa/farmacologia , Animais , Artérias/inervação , Estimulação Elétrica , Técnicas In Vitro , Masculino , Neurônios/metabolismo , Norepinefrina/antagonistas & inibidores , Norepinefrina/farmacocinética , Ratos , Ratos Endogâmicos , Vasoconstrição/fisiologiaRESUMO
Amino acids were pressure-ejected in the ventral tegmental area of rats which were anesthetized with chloral hydrate and treated with pargyline. The extracellular dopamine concentration was recorded from the nucleus accumbens with an electrochemically treated carbon fiber electrode combined either with differential normal pulse voltammetry or with differential pulse amperometry. In distinct rats the discharge activity of single dopaminergic neurons was monitored in the ventral tegmental area while amino acids were pressure-injected at a distance of 200-300 microns from the recorded cell. GABA (24 and 50 nl, 1 M) induced a complete and reversible inhibition of the firing rate lasting for 3-6 min and a decrease in the basal extracellular dopamine level (-54% and -66%, respectively). Glutamate (32 nl, 10 mM), N-methyl-D-aspartate and quisqualate (100 microM) stimulated the firing rate and enhanced the dopamine extracellular concentration up to 10-times the basal one (18 nM). These increases subsided within 1-5 min. Their amplitude depended on the ejected volume (from 16 to 65 nl). At the time-resolution of the method (some seconds) all these variations in the dopamine release appeared closely time-correlated with those of the firing rate. When the mean discharge rate is considered, N-methyl-D-aspartate was as potent as quisqualate but the former promoted burst firing while the latter induced a sustained activity. As regards dopamine release, N-methyl-D-aspartate was twice as potent as quisqualate. This further shows that dopaminergic terminals convert physiological impulse flow into dopamine release as a high pass filter which favors bursts of action potentials.
Assuntos
Encéfalo/fisiologia , Dopamina/metabolismo , Glutamatos/farmacologia , N-Metilaspartato/farmacologia , Neurônios/fisiologia , Núcleo Accumbens/fisiologia , Ácido Quisquálico/farmacologia , Ácido gama-Aminobutírico/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Eletrofisiologia , Potenciais Evocados/efeitos dos fármacos , Glutamatos/administração & dosagem , Ácido Glutâmico , Masculino , N-Metilaspartato/administração & dosagem , Neurônios/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacos , Pargilina/administração & dosagem , Pargilina/farmacologia , Ácido Quisquálico/administração & dosagem , Ratos , Ratos Wistar , Técnicas Estereotáxicas , Ácido gama-Aminobutírico/administração & dosagemRESUMO
Differential pulse voltammetry used with electrochemically pretreated carbon fibre microelectrodes enables separation between the two peaks corresponding to the ascorbic acid and catechol oxidation currents. The effects of haloperidol and sulpiride on the 3,4-dihydroxyphenylacetic acid peak recorded in the nucleus accumbens and olfactory tubercle of rats were studied. Chloral hydrate anaesthetized preparations and chronic preparations were used. A microdevice was designed to implant electrodes in freely moving rats. Voltammograms were recorded every minute in each structure in acute preparations and every 2 min in chronic preparations. In acute preparations haloperidol induced a similar dose-dependent increase in the catechol oxidation peak in both structures. Sulpiride at all doses only induced an increase in the olfactory tubercle. In chronic preparations haloperidol and sulpiride had even larger effects on the 3,4-dihydroxyphenylacetic acid peak in both regions. In these preparations sulpiride induced a significant increase in nucleus accumbens. The effects induced by haloperidol in the two regions were greater than those induced by sulpiride. The main conclusions of this study are that the results of voltammetry agree with biochemical results on the effects of haloperidol and sulpiride on dopamine metabolism. An interaction of chloral hydrate with the effects of the two neuroleptics was also observed.