RESUMEN
Whereas a cardinal role for beta-amyloid protein (Abeta) has been postulated as a major trigger of neuronal injury in Alzheimer's disease, the pathogenic mechanism by which Abeta deranges nerve cells remains largely elusive. Here we report correlative in vitro and in vivo evidence that an excitotoxic cascade mediates Abeta neurotoxicity in the rat magnocellular nucleus basalis (MBN). In vitro application of Abeta to astrocytes elicits rapid depolarization of astroglial membranes with a concomitant inhibition of glutamate uptake. In vivo Abeta infusion by way of microdialysis in the MBN revealed peak extracellular concentrations of excitatory amino acid neurotransmitters within 20-30 min. Abeta-triggered extracellular elevation of excitatory amino acids coincided with a significantly enhanced intracellular accumulation of Ca2+ in the Abeta injection area, as was demonstrated by 45Ca2+ autoradiography. In consequence of these acute processes delayed cell death in the MBN and persistent loss of cholinergic fibre projections to the neocortex appear as early as 3 days following the Abeta-induced toxic insult. Such a sequence of Abeta toxicity was effectively antagonized by the N-methyl-D-aspartate (NMDA) receptor ligand dizocilpine maleate (MK-801). Moreover, Abeta toxicity in the MBN decreases with advancing age that may be associated with the age-related loss of NMDA receptor expression in rats. In summary, the present results indicate that Abeta compromises neurons of the rat MBN via an excitotoxic pathway including astroglial depolarization, extracellular glutamate accumulation, NMDA receptor activation and an intracellular Ca2+ overload leading to cell death.
Asunto(s)
Péptidos beta-Amiloides/toxicidad , Astrocitos/metabolismo , Núcleo Basal de Meynert/metabolismo , Ácido Glutámico/metabolismo , Enfermedad de Alzheimer/inducido químicamente , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Animales , Ácido Aspártico/metabolismo , Astrocitos/citología , Núcleo Basal de Meynert/patología , Calcio/metabolismo , Radioisótopos de Calcio , Células Cultivadas , Modelos Animales de Enfermedad , Maleato de Dizocilpina/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Microdiálisis , Degeneración Nerviosa/metabolismo , Degeneración Nerviosa/patología , Fármacos Neuroprotectores/farmacología , Neurotoxinas/toxicidad , Ratas , Receptores de N-Metil-D-Aspartato/metabolismo , Taurina/metabolismoRESUMEN
1. The aim of the present study was to evaluate the contribution of serotonin (5-HT) and dopamine (DA) receptor antagonism to the distinct inhibitory effects of the atypical antipsychotics clozapine and risperidone on SNR neurons, we have shown previously. 2. Utilizing extracellular recordings in the SNR in chloral hydrate anaesthetized rats, raclopride, a selective DA D2/D3 receptor antagonist and LY 53857, a 5-HT2A:2c receptor antagonist were studied separately and in combination for their effects on the firing rate of the SNR neurons. 3. Both raclopride and LY 53857 induced a slight but significant increase in the firing rate of the SNR neurons in a limited dose range. 4. Upon pretreatment with a single dose of raclopride, LY 53857 induced a dose-dependent inhibitory effect on the firing rate of the SNR neurons. 5. Concurrent 5-HT2 and moderate DA D2 receptor antagonism can mimic the in vivo effects of the atypical antipsychotics clozapine and risperidone on the firing rate of SNR neurons.
Asunto(s)
Antipsicóticos/farmacología , Clozapina/farmacología , Receptores Dopaminérgicos/fisiología , Receptores de Serotonina/fisiología , Risperidona/farmacología , Sustancia Negra/fisiología , Animales , Enfermedades de los Ganglios Basales/inducido químicamente , Electrofisiología , Masculino , Neuronas/efectos de los fármacos , Neuronas/fisiología , Ratas , Ratas Wistar , Receptores Dopaminérgicos/efectos de los fármacos , Receptores de Serotonina/efectos de los fármacos , Sustancia Negra/efectos de los fármacosRESUMEN
To gain insight into the mechanism of action of the anti-epileptic, gabapentin, the effects of gabapentin on the in vivo extracellular gamma-aminobutyric acid (GABA) levels in the rat substantia nigra reticulata were studied using microdialysis. In order to investigate possible interference with different GABA-ergic compartments in the substantia nigra reticulata, we studied the effects of gabapentin under basal, K(+)-, nipecotic acid- and glutamate-stimulated conditions. Intraperitoneally (i.p.) administered gabapentin, at a dose of 100 mg/kg, did not significantly affect extracellular GABA levels under any condition. Thus, our data do not support the involvement of nigral GABA release in the mechanism of action of the anti-epileptic gabapentin.
Asunto(s)
Acetatos/farmacología , Aminas , Anticonvulsivantes/farmacología , Ácidos Ciclohexanocarboxílicos , Microdiálisis , Prolina/análogos & derivados , Animales , Gabapentina , Ácido Glutámico/farmacología , Masculino , Ácidos Nipecóticos/farmacología , Potasio/farmacología , Ratas , Ratas Wistar , Sustancia Negra/efectos de los fármacos , Sustancia Negra/metabolismo , Ácido gamma-Aminobutírico/efectos de los fármacos , Ácido gamma-Aminobutírico/metabolismoRESUMEN
In the present study, a series of thiophene analogs of 2-aminotetralins and hexahydronaphthoxazines were studied in vivo for their ability to decrease striatal dopamine release, their effects on locomotor activity, and their behavioral characteristics in reserpinized rats, in order to investigate whether a thiophene moiety can act as a bioisostere for the phenol moiety. In general, the new compounds showed lower in vivo activities than 5-hydroxy-2-(N,N,-di-n-propylamino)tetralin (5-OH-DPAT). However, the introduction of the thiophene moiety gave a significant improvement of the relative oral bioavailability, compared to 5-OH-DPAT. Our results suggest that the thiophene moiety can act as a bioisostere for a phenol group in hydroxylated 2-aminotetralins. For the thianaphthoxazines it was not possible to discriminate between bioisosterism for a phenyl or a phenol moiety. The tetrahydrobenzo[b]thiophenes could be used as lead compounds for the development of novel dopamine receptor ligands with improved relative oral bioavailability.
Asunto(s)
8-Hidroxi-2-(di-n-propilamino)tetralin/análogos & derivados , Naftalenos/farmacología , Tetrahidronaftalenos/farmacología , Tiofenos/farmacocinética , 8-Hidroxi-2-(di-n-propilamino)tetralin/farmacocinética , Administración Oral , Animales , Unión Competitiva/efectos de los fármacos , Disponibilidad Biológica , Inyecciones Subcutáneas , Masculino , Microdiálisis , Actividad Motora/efectos de los fármacos , Naftalenos/administración & dosificación , Neostriado/efectos de los fármacos , Neostriado/metabolismo , Ratas , Ratas Wistar , Receptores de Dopamina D1/efectos de los fármacos , Receptores de Dopamina D2/efectos de los fármacos , Receptores de Dopamina D3 , Receptores de Serotonina/efectos de los fármacos , Receptores de Serotonina/metabolismo , Reserpina/farmacología , Simpaticolíticos/farmacología , Tetrahidronaftalenos/administración & dosificación , Tiofenos/administración & dosificación , Tiofenos/farmacologíaRESUMEN
In the present study, R-(-)-apomorphine and three of its analogs were studied for their potency in decreasing the release of dopamine in the striatum after subcutaneous administration and for their oral bioavailability using the microdialysis technique in freely moving rats. The analogs R-(-)-N-n-propylnorapomorphine and R-(-)-11-hydroxy-N-n-propylnoraporphine displayed a higher potency than R-(-)-apomorphine in decreasing the release of dopamine in the striatum. A high dose of R-(-)-11-hydroxyaporphine, a dopamine D(2) receptor partial agonist, had a small effect on the release of dopamine in the striatum. The catechols R-(-)-N-n-propylnorapomorphine and R-(-)-apomorphine displayed a comparable oral bioavailability (1%), while the mono-hydroxy analog R-(-)-11-hydroxy-N-n-propylnoraporphine displayed a slightly higher oral bioavailability (3%). In conclusion, R-(-)-N-n-propylnorapomorphine and R-(-)-11-hydroxy-N-n-propylnoraporphine did not show a substantial improvement in bioavailability. However, due to the clear difference in their efficacy in decreasing dopamine release, in spite of the similar agonist binding affinities to the dopamine D(2) receptor of the two analogs compared to R-(-)-apomorphine, they could be useful alternatives for apomorphine in the treatment of Parkinson's disease.
Asunto(s)
Apomorfina/farmacología , Agonistas de Dopamina/farmacología , Receptores de Dopamina D2/agonistas , Administración Oral , Animales , Apomorfina/análogos & derivados , Apomorfina/farmacocinética , Área Bajo la Curva , Disponibilidad Biológica , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Dopamina/metabolismo , Agonistas de Dopamina/farmacocinética , Relación Dosis-Respuesta a Droga , Inyecciones Subcutáneas , Masculino , Microdiálisis , Ratas , Ratas Wistar , Receptores de Dopamina D2/metabolismoRESUMEN
A putative tetrapeptide beta-amyloid (Abeta) antagonist (propionyl-Ile-Ile-Gly-Leu [Pr-IIGL]) based on the [31-34] sequence of Abeta was previously shown to rescue astrocytes from Abeta-induced membrane depolarization and subsequent long-term elevations of the intracellular Ca2+ concentration in vitro. Here we provide in vivo evidence that the Pr-IIGL tetrapeptide effectively attenuates the excitotoxic action of Abeta(1-42) on cholinergic neurons of the rat magnocellular nucleus basalis (MBN). We also demonstrate by means of microdialysis that administration of Pr-IIGL abolished Abeta(1-42)-induced increases in extracellular aspartate and glutamate concentrations in the MBN, which coincide with a significant preservation of cholinergic MBN neurons and their cortical projections. This neuroprotective effect was associated with preserved exploratory behavior in an open-field paradigm, and improved memory retention in a step-through passive avoidance task. Our data presented here indicate for the first time the efficacy of short, modified functional Abeta antagonists in ameliorating Abeta excitotoxicity in vivo.
Asunto(s)
Péptidos beta-Amiloides/toxicidad , Núcleo Basal de Meynert/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Oligopéptidos/farmacología , Fragmentos de Péptidos/toxicidad , Acetilcolinesterasa/metabolismo , Péptidos beta-Amiloides/antagonistas & inhibidores , Animales , Ácido Aspártico/metabolismo , Reacción de Prevención/efectos de los fármacos , Núcleo Basal de Meynert/anatomía & histología , Núcleo Basal de Meynert/metabolismo , Conducta Animal/efectos de los fármacos , Espacio Extracelular/efectos de los fármacos , Espacio Extracelular/metabolismo , Ácido Glutámico/metabolismo , Histocitoquímica , Masculino , Microdiálisis , Actividad Motora/efectos de los fármacos , Fragmentos de Péptidos/antagonistas & inhibidores , Ratas , Ratas Wistar , Taurina/metabolismoRESUMEN
RATIONALE: Previously, we have shown that the atypical antipsychotics clozapine and risperidone, unlike haloperidol, decreased the firing rate of substantia nigra reticulata (SNR) neurons. As the SNR receives substantial input from the striatum, an area where motoric side-effects of antipsychotics are thought to be mediated, the SNR might be an interesting brain structure with regard to motor side-effects. OBJECTIVE: The newly developed atypical antipsychotic olanzapine was studied for its effects on the firing rate of SNR cells. In addition, to gain insight in the implications of our experimental setup for clinical use, responses upon clozapine, olanzapine and haloperidol were studied after chronic treatment. METHODS: In chloralhydrate-anaesthetized male Wistar rats, extracellular recordings were made from SNR neurons upon intravenously (i.v.) administered cumulative doses of the antipsychotics. Naive rats and rats that were subcutaneously (SC) injected for 21 days with an antipsychotic were used. RESULTS: Olanzapine (50-1600 mg/kg; i.v.), significantly inhibited the firing rate of the SNR neurons. Upon 21 days of treatment with a daily SC injection of 20 mg/kg clozapine, the challenge on day 22 with cumulative injections of clozapine (200 6400 mg/kg; i.v.) significantly inhibited the firing rate of the SNR neurons. Olanzapine (50-1600 mg/kg; i.v.) also significantly inhibited the SNR activity when pretreated with olanzapine in an SC administered dose of 1 mg/kg, but not 5 mg/kg. Haloperidol (12.5-800 microg/kg; i.v.) did not significantly affect the SNR activity in rats pretreated with SC administered 0.5 mg/kg haloperidol. CONCLUSIONS: Upon acute and chronic administration of clozapine and olanzapine versus haloperidol, differential effects on SNR neuronal firing could be obtained. The experimental setup seem to be valid for further studies into the mechanism of action of typical versus (relatively low doses of) atypical antipsychotics. The implications of the inhibitory effect of atypical antipsychotics on the SNR firing rate are presently unknown, but could be associated with the lower propensity to induced motoric side-effects. On the other hand, the SNR activity might also reflect non-motoric activity possibly related to negative symptoms.
Asunto(s)
Antipsicóticos/farmacología , Neuronas/efectos de los fármacos , Pirenzepina/análogos & derivados , Sustancia Negra/efectos de los fármacos , Animales , Antipsicóticos/administración & dosificación , Antipsicóticos/efectos adversos , Enfermedades de los Ganglios Basales/inducido químicamente , Benzodiazepinas , Clozapina/administración & dosificación , Clozapina/efectos adversos , Clozapina/farmacología , Haloperidol/administración & dosificación , Haloperidol/efectos adversos , Haloperidol/farmacología , Masculino , Neuronas/fisiología , Olanzapina , Pirenzepina/administración & dosificación , Pirenzepina/efectos adversos , Pirenzepina/farmacología , Ratas , Ratas Wistar , Sustancia Negra/fisiologíaRESUMEN
Upon a physiological and pharmacological challenge, the responsiveness of extracellular glutamate levels in the prefrontal cortex, ventral tegmental area and locus coeruleus were studied using microdialysis. A 10-min handling period was used as a mild stressful stimulus. In all three brain areas, handling induced an immediate and short-lasting increase in glutamate levels, but the responses were highly variable. Only in the ventral tegmental area and the locus coeruleus, but not in the prefrontal cortex, the increases were significantly different from basal values. In rats with relatively low basal glutamate levels, both in the ventral tegmental area and locus coeruleus, handling had a more pronounced effect on glutamate levels than in rats with high basal levels, although in some rats with relatively low basal levels of glutamate, handling had hardly any effect. Potassium stimulation also induced variable responses in all three brain areas. Again, relatively low basal glutamate levels were more responsive to the stimulation than higher basal values, although there appeared to be a lower limit. These data suggest that relatively high basal levels contain sources of glutamate that mask the neuronal pool of glutamate and are therefore less responsive to physiological or pharmacological stimulation. However, this interpretation was questioned by the findings that basal levels and handling-induced increases in glutamate levels were found to be (partly) TTX-independent. As carrier-mediated release as a possible non-exocytotic release mechanism has only been described in vivo under pathological conditions, it seems plausible to ascribe TTX-independent glutamate increases to aspecific, non-neuronal processes. This interpretation was further supported by the observation that in all three brain areas, other amino acids, i.e., aspartate, taurine, glutamine, serine, alanine and glycine also increased upon handling in a very similar way as glutamate did. Thus, these results question a direct correlation between stimulated extracellular glutamate levels induced by handling and measured by microdialysis and glutamatergic neurotransmission.
Asunto(s)
Química Encefálica/fisiología , Ácido Glutámico/metabolismo , Manejo Psicológico , Estrés Fisiológico/metabolismo , Aminoácidos/análisis , Aminoácidos/metabolismo , Animales , Química Encefálica/efectos de los fármacos , Espacio Extracelular/metabolismo , Ácido Glutámico/análisis , Locus Coeruleus/metabolismo , Masculino , Microdiálisis , Potasio/farmacología , Corteza Prefrontal/metabolismo , Ratas , Ratas Wistar , Estimulación Química , Tetrodotoxina/farmacología , Área Tegmental Ventral/metabolismoRESUMEN
A series of 2- or 8-trifluoromethylsulfonyloxy (TfO) and 2- or 8-methylsulfonyloxy (MsO) 11-piperazinyldibenzodiazepines, -oxazepines, and -thiazepines were synthesized and evaluated in pharmacological models for their potential clozapine-like properties. In receptor binding assays, the 2-TfO analogues (18a, GMC2-83; 24, GMC3-06; and previously reported GMC1-169, 9a) of the dibenzazepines have profiles comparable to that of clozapine, acting on a variety of CNS receptors except they lack M1 receptor affinity. Introduction of 2-TfO to clozapine leads to compound 9e (GMC61-39) which has a similar binding profile as that of clozapine including having M1 receptor affinity. Interestingly, the MsO analogues, as well as the 8-TfO analogues, have no or weak dopaminergic and serotonergic affinities, but all 8-sulfonyloxy analogues do have M1 affinities. In behavioral studies performed to indicate the potential antipsychotic efficacy and the propensity to induce EPS, 2-TfO analogues blocked effectively the apomorphine-induced climbing in mice in a dose-dependent manner with ED50 values (mg/kg) of 2.1 sc for 9a, 1.3 po for 18a, 2.6 sc for 24, and 8.2 sc for 9e. On the other hand, they showed a clear dose separation with regard to their ED50 values (mg/kg) for indicating catalepsy in rats (>44 sc for 9a, 28 po for 18a, 30 sc for 24, and >50 sc for 9e, respectively), thus implicating a more favorable therapeutic ratio (K/A, ED50 climbing/ED50 catalepsy) in comparison with typical neuroleptics such as haloperidol and isoclozapine. Furthermore, compound 18a was also demonstrated to be an orally potent DA antagonist with an ED50 value of 0.7 mg/kg po in the ex vivo L-DOPA accumulation model. The present study contributes to the SAR of 11-piperazinyldibenzazepines, and the 2-TfO analogues of 11-piperazinyldibenzazepines are promising candidates as clozapine-like atypical antipsychotics with low propensity to induce EPS.
Asunto(s)
Antipsicóticos/síntesis química , Benzazepinas/síntesis química , Piperazinas/síntesis química , Animales , Antipsicóticos/química , Antipsicóticos/metabolismo , Antipsicóticos/farmacología , Benzazepinas/química , Benzazepinas/metabolismo , Benzazepinas/farmacología , Encéfalo/metabolismo , Células CHO , Catalepsia/inducido químicamente , Cricetinae , Antagonistas de Dopamina/síntesis química , Antagonistas de Dopamina/química , Antagonistas de Dopamina/metabolismo , Antagonistas de Dopamina/farmacología , Humanos , Técnicas In Vitro , Masculino , Ratones , Estructura Molecular , Piperazinas/química , Piperazinas/metabolismo , Piperazinas/farmacología , Ratas , Ratas Wistar , Receptor Muscarínico M1 , Receptores Adrenérgicos alfa/metabolismo , Receptores Dopaminérgicos/efectos de los fármacos , Receptores Dopaminérgicos/metabolismo , Receptores Histamínicos H1/metabolismo , Receptores Muscarínicos/metabolismo , Receptores de Serotonina/metabolismo , Relación Estructura-ActividadRESUMEN
Stimulation of the mediodorsal and midline thalamic nuclei excites cortical neurons and induces c-fos expression in the prefrontal cortex. Data in the literature data suggest that pyramidal neurons are the most likely cellular targets. In order to determine whether cortical interneurons are also impacted by activation of mediodorsal/midline thalamic nuclei, we studied the effects of thalamic stimulation on (1) Fos protein expression in gamma-aminobutyric acid (GABA)-immunoreactive neurons and on (2) extracellular GABA levels in the prefrontal cortex of rats. Perfusion of the GABA-A receptor antagonist bicuculline for 20 minutes through a dialysis probe implanted into the mediodorsal thalamus induced Fos-like immunoreactivity (IR) approximately 1 hour later in the thalamus and in the medial prefrontal cortex of freely moving rats. Immunohistochemical double-labeling for Fos-like IR and GABA-like IR showed that about 8% of Fos-like IR nuclei in the prelimbic and infralimbic areas were located in GABA-like IR neurons. Fos-like IR was detected in three major subsets of GABAergic neurons defined by calbindin, parvalbumin, or vasoactive intestinal peptide (VIP)-like IR. Dual probe dialysis showed that the extracellular levels of GABA in the prefrontal cortex did not change in response to thalamic stimulation. These data indicate that activation of thalamocortical neurons indeed affects the activity of GABAergic neurons as shown by the induction of Fos-like IR but that these metabolic changes are not reflected in changes of extracellular GABA levels that are sampled by microdialysis.
Asunto(s)
Neuronas/metabolismo , Proteínas Oncogénicas v-fos/metabolismo , Corteza Prefrontal/metabolismo , Células Piramidales/metabolismo , Tálamo/fisiología , Ácido gamma-Aminobutírico/metabolismo , Animales , Recuento de Células , Espacio Extracelular/metabolismo , Inmunohistoquímica , Masculino , Microdiálisis , Perfusión , Corteza Prefrontal/citología , Ratas , Ratas WistarRESUMEN
To gain insight into the role of striatal dopamine in basal ganglia functioning, dopaminergic drugs alone and in combination with the glutamate receptor agonist kainic acid were infused in the lateral striatum via a microdialysis probe, while single-unit recordings of substantia nigra reticulata neurons were made in chloral hydrate-anaesthetized rats. Striatal infusion of dopaminergic drugs did not significantly affect the firing rate of substantia nigra reticulata neurons, which was related to the low activity of striatal cells under basal conditions, illustrated by the lack of effect of striatal infusion of TTX on substantia nigra reticulata activity. Under glutamate-stimulated conditions, striatal infusion of d-amphetamine potentiated the inhibition of substantia nigra reticulata neurons induced by striatal kainic acid. Thus, under stimulated but not basal conditions, the modulatory role of dopamine in the striatum could be demonstrated. Dopamine potentiated the inhibitory effect of striatal kainic acid on the firing rate of the basal ganglia output neurons.
Asunto(s)
Cuerpo Estriado/metabolismo , Dopamina/metabolismo , Ácido Glutámico/metabolismo , Sustancia Negra/fisiología , Potenciales de Acción/efectos de los fármacos , Análisis de Varianza , Animales , Dextroanfetamina/farmacología , Ácido Kaínico/farmacología , Masculino , Ratas , Ratas WistarRESUMEN
Microdialysis has become a frequently used method to study extracellular levels of GABA and glutamate in the central nervous system. However, the fact that the major part of GABA and glutamate as measured by microdialysis does not fulfill the classical criteria for exocytotic release questions the vesicular origin of the amino acids in dialysates. Glial metabolism or reversal of the (re)uptake sites has been suggested to be responsible for the pool of nonexocytotically released amino-acid transmitters that seem to predominate over the neuronal exocytotic pool. The origin of extracellular GABA and glutamate levels and, as a consequence, the implications of changes in these levels upon manipulations are therefore obscure. This review critically analyzes what microdialysis data signify, i.e., whether amino-acid neurotransmitters sampled by microdialysis represent synaptic release, carrier-mediated release, or glial metabolism. The basal levels of GABA and glutamate are virtually tetrodotoxin- and calcium-independent. Given the fact that evidence for nonexocytotic release mediated by reversal of the uptake sites as a release mechanism relevant for normal neurotransmission is so far limited to conditions of "excessive stimulation," basal levels most likely reflect a nonneuronal pool of amino acids. Extracellular GABA and glutamate concentrations can be enhanced by a wide variety of pharmacological and physiological manipulations. However, it is presently impossible to ascertain that the stimulated GABA and glutamate in dialysates are of neuronal origin. On the other hand, under certain stimulatory conditions, increases in amino-acid transmitters can be obtained in the presence of tetrodotoxin, again suggesting that aspecific factors not directly related to neurotransmission underlie these changes in extracellular levels. It is concluded that synaptic transmission of GABA and glutamate is strictly compartmentalized and as a result, these amino acids can hardly leak out of the synaptic cleft and reach the extracellular space where the dialysis probe samples.
Asunto(s)
Química Encefálica/fisiología , Ácido Glutámico/metabolismo , Microdiálisis , Ácido gamma-Aminobutírico/metabolismo , Animales , Humanos , Enfermedades del Sistema Nervioso/metabolismoRESUMEN
By examining the effect of dopamine (DA) D3 receptor stimulation on locomotor activity and extracellular levels of DA in striatum we show that inhibition of locomotor activity induced by DA D3 receptor-selective agonists is mediated by two interacting mechanisms: (1) directly via the stimulation of DA D3 receptors that inhibit locomotor activity, and (2) indirectly via a decrease in extracellular levels of DA. Thus, the moderately DA D3 receptor-selective agonist R-(+)-7-OH- DPAT (R-(+)-7-hydroxy-2-(N,N-di-n-propylamino)tetralin) decreased locomotor activity after administration of 10 nmol/kg and extracellular DA levels in accumbens and striatum after administration of 30 nmol/kg. A decrease in locomotor activity that coincided with a decrease in extracellular DA levels in striatum was observed after administration of 100 nmol/kg of the DA D3 receptor-selective agonist PD128907 ((+)-trans-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano[4,3 b]-1,4-oxasin-9-ol. In combination with the partial, DA D3 receptor-selective agonist PD151328 (2-[4[3-(4-phenyl)-1- piperazinyl)propoxy]phenyl]-benzamidazole), a reversal of the attenuating effect of PD128907 on locomotor activity was observed, without an effect on extracellular levels of DA. In combination with a low--10 nmol/kg--dose of haloperidol, a reversal of the inhibitory effect of PD128907 on locomotor activity was observed that coincided with an increase in extracellular levels of DA. In the presence of 0.5 mg/kg amphetamine, PD128907 decreased amphetamine-induced locomotor activity. This effect could be reversed by PD151328.
Asunto(s)
Cuerpo Estriado/efectos de los fármacos , Agonistas de Dopamina/farmacología , Dopamina/metabolismo , Locomoción/efectos de los fármacos , Receptores de Dopamina D2/efectos de los fármacos , Tetrahidronaftalenos/farmacología , Animales , Benzopiranos/farmacología , Relación Dosis-Respuesta a Droga , Masculino , Oxazinas/farmacología , Ratas , Ratas Wistar , Receptores de Dopamina D3RESUMEN
A combination of electrical stimulation and microdialysis was used to study the nigrothalamic gamma aminobutyric acid (GABA)ergic system and its regulatory mechanisms in awake rats. Extracellular GABA levels in the ventromedial nucleus of the thalamus were detected in 3-min fractions collected before, during and after a 10-min stimulation period of the substantia nigra reticulata. Electrical stimulation of the substantia nigra reticulata increased the GABA levels to 155% of basal values in the ventromedial thalamus only during the first 3-min interval upon stimulation. The increase in GABA levels was tetrodotoxin-dependent, implicating an exocytotic origin. The basal levels of extracellular GABA in the ventromedial thalamus were of nonexocytotic origin. To study the mechanism underlying the fast compensatory response in neuronal GABA release after nigral stimulation, local infusions into the ventromedial thalamus of reuptake inhibitors and GABA antagonists were performed and the effect of nigral stimulation was examined under the various applications. Local infusion of the reuptake inhibitors nipecotic acid (500 microM) and SKF 89976-A (20 and 50 microM) increased extracellular GABA levels to 350%, 180% and 600%, respectively, of basal values in the ventromedial thalamus tetrodotoxin-independently. Under these conditions, the increase in extracellular GABA was absent (nipecotic acid) or suppressed (20% of basal values; SKF 89976-A for both doses), leaving it unsolved whether or not the uptake system was responsible for the fast compensation in neuronal GABA after stimulation. The GABA-A antagonist bicucilline (50 microM) was ineffective when infused locally in the ventromedial thalamus, but prolonged the increase in neuronal GABA release after nigral stimulation; the GABA levels were increased during two 3-min samples to approximately 165%, indicating a functional role for GABA-A receptors in regulating the release of GABA from nigrothalamic GABAergic neurons. The GABA-B receptor antagonist CGP 35348 (50 microM) did not affect GABA levels when infused locally in the ventromedial thalamus and neither affected the response in neuronal GABA after stimulation. This finding does not support a role for GABA-B receptors in controlling the release from the nigrothalamic neurons.
Asunto(s)
Sustancia Negra/metabolismo , Tálamo/metabolismo , Ácido gamma-Aminobutírico/metabolismo , Animales , Estimulación Eléctrica , Masculino , Microdiálisis , Ratas , Ratas Wistar , Sustancia Negra/fisiología , Vigilia/fisiologíaRESUMEN
Risperidone has proven to be effective as an antipsychotic drug and has fewer extrapyramidal side-effects than classic neuroleptics. In addition to its dopamine D2 receptor antagonistic properties, this antipsychotic agent is a potent 5-HT2 receptor antagonist. The atypical antipsychotic, clozapine, also possesses both dopamine D2 and 5-HT2 receptor affinity next to affinities for other receptors. To gain an insight in the consequences for basal ganglia activity of treatment with these atypical neuroleptics vs. typical neuroleptics, the effects of cumulative doses of risperidone, clozapine and haloperidol on the firing rate of substantia nigra reticulata neurons were studied. Extracellular recordings were performed in chloralhydrate-anaesthetized male Wistar rats. Both risperidone (50-3200 micrograms/kg i.v.) and clozapine (100-6400 micrograms/kg i.v.) dose dependently decreased substantia nigra reticulata activity maximally to 70% of the basal activity. With both treatments, a dose of 800 micrograms/kg was significantly effective. In contrast, haloperidol (12.5-800 micrograms/kg i.v.) gradually induced a slight increase in substantia nigra reticulata activity, which was identical to the substantia nigra reticulata activity after saline treatment. Therefore, these results indicate that typical and atypical neuroleptics affect differentially the output of the basal ganglia in the substantia nigra reticulata. To evaluate the involvement of 5-HT2 receptors in the effect of risperidone, the 5-HT2 receptor agonist, quipazine (0.5 mg/kg i.p.), was administered 15 min preceding risperidone treatment. A 4-fold higher dose of risperidone was needed to significantly affect the substantia nigra reticulata firing rate. Thus, the 5-HT2 component of the effect of risperidone is, at least partly, responsible for the difference in effect on substantia nigra reticulata neurons in comparison to haloperidol.
Asunto(s)
Antipsicóticos/farmacología , Clozapina/farmacología , Antagonistas de Dopamina/farmacología , Haloperidol/farmacología , Risperidona/farmacología , Sustancia Negra/efectos de los fármacos , Animales , Antipsicóticos/administración & dosificación , Ganglios Basales/citología , Ganglios Basales/efectos de los fármacos , Ganglios Basales/metabolismo , Clozapina/administración & dosificación , Antagonistas de Dopamina/administración & dosificación , Relación Dosis-Respuesta a Droga , Electrofisiología , Haloperidol/administración & dosificación , Inyecciones Intravenosas , Masculino , Neuronas/citología , Neuronas/efectos de los fármacos , Neuronas/patología , Ratas , Ratas Wistar , Receptores de Dopamina D2/efectos de los fármacos , Receptores de Dopamina D2/metabolismo , Reticulocitos/citología , Reticulocitos/efectos de los fármacos , Reticulocitos/metabolismo , Risperidona/administración & dosificación , Antagonistas de la Serotonina/administración & dosificación , Antagonistas de la Serotonina/farmacología , Sustancia Negra/metabolismoRESUMEN
Dopamine (DA) released from dendrites of substantia nigra dopaminergic neurons potentially is in a position to modulate basal ganglia outputs from the substantia nigra pars reticulata (SNR) via stimulation of D1 receptors on the terminals of striatonigral afferents. The effects of endogenous DA release in the SNR were examined in rats using behavioral activation, multiunit activity of SNR neurons, and cortical EEG pattern as dependent measures. Unilateral infusion of amphetamine (AMPH) into SNR (10 micrograms/0.5 microliter; 5 min) produced a short-lasting behavioral activation that was blocked by coinfusion of the D1 DA receptor antagonist SCH 23390 (0.5 micrograms). Multiunit recordings of SNR neurons in anesthetized rats showed that AMPH, infused as above, produced a rapid decrease in SNR activity. This decrease was maximal (approximately 90%) during the first 10 min postinfusion, followed by a gradual return to baseline levels. Coinfusion of SCH 23390 blocked the AMPH-induced decrease in SNR activity, although by itself this drug produced a 40% decrease in activity. Cortical EEG acquired during the SNR infusions/recordings showed a short-duration change in pattern immediately after AMPH infusion. A relative shift in power from the lowest frequency interval determined (0.8-2.7 Hz) to the next higher frequency interval (2.7-6.8 Hz) was observed which could be prevented by coinfusion of SCH 23390. Thus, dendritically released DA can inhibit the activity of SNR neurons via local stimulation of D1 receptors. This effect is associated with a brief behavioral activation and EEG desynchronization.
Asunto(s)
Anfetamina/farmacología , Conducta Animal/efectos de los fármacos , Dendritas/efectos de los fármacos , Dopaminérgicos/farmacología , Receptores de Dopamina D1/agonistas , Sustancia Negra/efectos de los fármacos , Vías Aferentes/efectos de los fármacos , Animales , Conducta Animal/fisiología , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Dendritas/metabolismo , Electroencefalografía , Masculino , Terminaciones Nerviosas/efectos de los fármacos , Terminaciones Nerviosas/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de Dopamina D1/fisiología , Sustancia Negra/metabolismo , Tálamo/efectos de los fármacos , Tálamo/metabolismoRESUMEN
The release of dopamine (DA) from tuberoinfundibular (TIDA) neurons during prolactin (PRL) surge and nonsurge periods and the effects of the thyrotropin-releasing hormone (TRH) analogue CG 3703 on DA and PRL secretion were studied in awake pseudopregnant (PSP) rats by simultaneous measurement of extracellular DA levels in the mediobasal hypothalamus (MBH) by means of microdialysis and of plasma PRL concentrations by radioimmunoassay of PRL in blood sampled from a permanent heart cannula. Since basal DA levels were low, the experiments were performed under local infusion of the reuptake inhibitor nomifensine (5 mumol/l), which increased extracellular DA levels 5-fold around the probe, but did not affect the occurrence of the nocturnal PRL surge on day 7-8 of PSP. Under nomifensine conditions, during the interphase (18.00-1.00 h) plasma PRL levels were low (< 50 ng/ml), while the DA release from TIDA neurons was elevated (approximately 250%) relative to the DA values measured during the phase when the nocturnal PRL surge occurred (100%; 1.00-12.00 h; plasma PRL levels were elevated to approximately 300 ng/ml). Thus, semicircadian rhythms were detected both for DA and PRL, which were broadly reciprocal in timing. The TRH analogue CG 3703 (100 and 500 micrograms/animal i.v.), when administered at 00.00 h, dose-dependently increased extracellular DA levels (to 300 and 500% of pretreatment values, respectively) and postponed the PRL surge in a corresponding manner (for approximately 2 and 3 h, respectively). Thus, in addition to its PRL-releasing effects, TRH can also suppress the PRL secretion by stimulating the release of DA from TIDA neurons, thereby increasing the inhibitor DAergic tone on lactotrophs. During the interphase, when DA levels were relatively elevated, administration of the DA blocking agent HA 966 (100 mg/kg body weight i.p.) at 20.00 h resulted in a short-lasting decrease in extracellular DA levels (to approximately 60% of pretreatment values for 30 min) accompanied by an immediate, short-lasting increase in PRL levels (to 400 ng/ml for approximately 1 h). Administration of CG 3703 (500 micrograms/animal i.v.) in combination with HA 966 (100 mg/kg body weight i.p.) at 20.00 h prevented the decrease in DA levels and the rise in plasma PRL values. Thus, the TRH analogue and HA 966 counteracted each other regarding the DAergic system, which again illustrates the stimulatory effect of the TRH analogue on the release of DA from TIDA neurons. Moreover, our results suggest that the interphase and the phase during which the nocturnal PRL surge occurs under the condition of PSP differ with regard to the DAergic inhibition of the PRL secretion; during the interphase the DAergic inhibitory tone prevents the rise in PRL secretion, while during the nocturnal PRL surge period another factor in addition to a decrease in DA levels appears necessary to increase plasma PRL levels.
Asunto(s)
Ganglios Basales/fisiología , Ritmo Circadiano/fisiología , Dopamina/metabolismo , Hipotálamo/fisiología , Prolactina/metabolismo , Seudoembarazo/fisiopatología , Hormona Liberadora de Tirotropina/farmacología , Ácido 3,4-Dihidroxifenilacético/metabolismo , Animales , Femenino , Microdiálisis , Nomifensina/farmacología , Prolactina/sangre , Ratas , Ratas Wistar , Factores de TiempoRESUMEN
The gamma-aminobutyric acid (GABA)-ergic system in the substantia nigra reticulata (SNR) was challenged by local infusion of various receptor-specific agents to obtain additional information on the physiological significance of extracellular GABA levels as measured by microdialysis in awake rats. Notwithstanding in vitro results, basal extracellular GABA levels were not affected by local infusion of the GABA-A agonist muscimol or by infusion of the GABA-B agonist baclofen. Upon a dopaminergic challenge, the D2 agonist LY 171555 was equally ineffective, but the D1 agonist induced an increase in extracellular GABA levels, which persisted in the presence of tetrodotoxin (TTX). Using excitatory amino acids, kainic acid was ineffective in modulating GABA levels, whereas N-methyl-D-aspartate induced an increase in extracellular GABA levels, again persisting when co-infused with TTX. The functional significance of TTX-independent changes in extracellular GABA levels is discussed.
Asunto(s)
Estimulantes del Sistema Nervioso Central/farmacología , Espacio Extracelular/metabolismo , Sustancia Negra/metabolismo , Ácido gamma-Aminobutírico/metabolismo , Animales , Ganglios Basales/efectos de los fármacos , Ganglios Basales/metabolismo , Agonistas de Dopamina/farmacología , Espacio Extracelular/efectos de los fármacos , GABAérgicos/farmacología , Masculino , Microdiálisis , Ratas , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/metabolismo , Sustancia Negra/efectos de los fármacosRESUMEN
To determine the functional presence of dopamine (DA) autoreceptors on tuberoinfundibular dopamine (TIDA)-ergic neurons in awake rats, a microdialysis probe was implanted into the mediobasal hypothalamus (MBH). In the presence of the re-uptake inhibitor nomifensine, which increased DA levels to 350% of basal values, systemic administration of the non-selective D1/D2 antagonist haloperiol induced an immediate increase in DA and DOPAC levels to 145% of pretreatment values. However, neither local infusion of the selective D2 antagonist sulpiride nor of the D1 antagonist SCH 23390 affected the nomifensine-elevated extracellular DA or DOPAC levels in the MBH. Systemic administration of the D2 antagonist raclopride equally did not affect the nomifensine-elevated DA release in the MBH. Upon basal extracellular DA levels (without nomifensine), local infusion of the D2 agonist (-)N-0437 equally did not affect the DA or DOPAC levels in the MBH. Furthermore, the increase in DA levels induced by haloperidol could not be antagonized by the D1 agonist CY 208-243. Therefore, the present study does not provide support for the concept of functional autoreceptors located on TIDA neurons regulating the release of DA. Possibly, the effect of haloperidol was non-DA-ergic in character.
Asunto(s)
Hipotálamo Medio/química , Receptores Dopaminérgicos/análisis , Ácido 3,4-Dihidroxifenilacético/análisis , Animales , Benzazepinas/farmacología , Estado de Conciencia , Antagonistas de Dopamina/farmacología , Haloperidol/farmacología , Masculino , Microdiálisis , Nomifensina/farmacología , Racloprida , Ratas , Ratas Wistar , Salicilamidas/farmacología , Sulpirida/farmacologíaRESUMEN
The effects of the anti-epileptic drugs valproic acid and gamma-vinyl-GABA (vigabatrin) on the extracellular content of GABA was determined by microdialysis. Probes were implanted in the substantia nigra reticulata (SNR) of rats. It was found that gamma-vinyl-GABA (1000 mg/kg) induced a 4-6-fold increase in the extracellular content of GABA. This increase lasted for at least 72 h. PTZ-induced convulsions were partly antagonized by the GVG treatment. The increase of extracellular GABA after gamma-vinyl-GABA was not affected by infusion of tetrodotoxin. In contrast valproic acid (200 mg/kg), although effective in preventing pentylenetetrazol (PTZ)-induced convulsions, did not affect extracellular GABA in the SNR. PTZ-induced convulsions did not modify extracellular GABA, neither in control rats nor in valproic acid or gamma-vinyl-GABA pretreated animals. The results do not support the idea that extracellular GABA in the SNR plays a significant role in anti-convulsive treatment. However, the present data can also be interpreted that extracellular GABA, as sampled by microdialysis, is not a reliable marker for GABA release.