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1.
Summary The stereospecific blockade by raclopride and FLB472 (the R enantiomer of raclopride) of the specific in vivo binding of [ 3H]-spiperone, [ 3H]-N,N-propylnorapomorphine (NPA) and [ 3H]-raclopride was studied in seven brain regions (e.g., caudate nucleus, olfactory tubercle, septum, hippocampus, frontal cortex, substantia nigra, pituitary gland) of the male albino rat. The binding of all three ligands was dose-dependently blocked by raclopride and FLB472. The blockade by FLB 472 occurred at doses 50–100 times higher than that obtained by raclopride. The maximal blockade by raclopride of [ 3H]-spiperone binding differed between brain areas. Thus, the largest blockade was obtained in the substantia nigra (95%), septum (90%), caudate nucleus (60%) and olfactory tubercle (60%), while the blockade of [ 3H]-spiperone binding in the frontal cortex and pituitary gland did not exceed 30% and 50%, respectively. In contrast to [ 3H]-spiperone, the in vivo binding of [ 3H]-NPA and [ 3H]-raclopride was prevented by 90–100% in all brain areas examined. Taken together, the present findings indicate that the in vivo binding of three radioactive ligands to a central dopamine D-2 receptor can be stereoselectively blocked by the enantiomers of raclopride. The findings suggest that, under in vivo conditions, [ 3H]-raclopride and [ 3H]-NPA may label a closely related receptor site. However only some of the [ 3H]-spiperone binding sites may be identical to the [ 3H]-raclopride binding sites. The findings indicate furthermore that the relative overlap of D-2 sites shared by [ 3H]-spiperone and [ 3H]-raclopride may vary between brain regions.Raclopride is identical to ()-(S)-3,5,dichloro-N-(1-ethyl-2-pyrrolidinyl)methyl-6-methoxysalicylamide tartrate [FLA870()]. The (R) enantiomer of this compound will in the present paper be referred to as FLB472. 相似文献
2.
This study tested the hypothesis that blockade of D-1 dopamine receptors in the nucleus accumbens shell, central nucleus of the amygdala or dorsal striatum by intracerebral microinjection of the dopamine antagonist SCH 23390 produces an attenuation of the effects of self-administered cocaine. Microinjection of SCH 23390 (0–4.0 μg total dose) into any of the three brain regions dose-dependently increased the rate of cocaine self-administration, consistent with a partial attenuation of the effects of cocaine under these conditions (0.25 mg cocaine i.v.; fixed-ratio 5 timeout 20 s). The regional rank order potency of SCH 23390 was accumbens > amygdala > striatum, striatal injections being equipotent with subcutaneous administration. Moreover, SCH 23390 produced rapid effects on cocaine self-administration only when injected into the accumbens or amygdala. The time course of this regional selectivity was consistent with the rate of diffusion of SCH 23390 from the site of injection as measured by quantitative autoradiography, demonstrating that the regional selectivity of intracerebral injections of SCH 23390 is time-dependent. These results support a role for D-1 dopamine receptors in the nucleus accumbens and amygdala in the effects of self-administered cocaine, and suggest that D-1 receptors in certain portions of the ‘extended amygdala’ may be an important substrate for the reinforcing actions of cocaine. 相似文献
3.
1. The effects of acute administration of SCH 23390 (0.05 and 0.25 mg/kg s.c.), a dopamirie D-1 receptor antagonist having also a moderate serotonin-S 2 (5-HT-2) receptor blocking activity, and ritanserin (0.5 mg/kg), a specific 5-HT-2 antagonist, on dopamine (DA) and serotonin (5-HT) turnover were investigated in dopaminergic (nucleus caudatus, nucleus accumbens, substantia nigra, A10 area) and serotonergic (nucleus raphe dorsalis and nucleus raphe medialis) rat brain nuclei. 2. Acute SCH 23390 (both doses) increased the metabolism of DA and tended to augment the rate of DA synthesis (accumulation of DOPA after inhibition of aromatic acid decarboxylase) in the nucleus accumbens, but not in the nucleus caudatus. In addition, SCH 23390 had a moderate effect on DA metabolism in substantia nigra. SCH 23390 did not alter the turnover of 5-HT in any of the nuclei studied. 3. Acute administration of ritanserin did not modify 5-HT or DA turnover in any of the nuclei studied. 4. In conclusion, these results suggest that acute SCH 23390 administration preferentially activates the mesolimbic DA system. The lack of effect of ritanserin on DA or 5-HT turnover in nigrostriatal and mesolimbic DAergic areas suggests that under basal conditions the blockade of 5-HT2 receptors do not change monoamine metabolism in these areas. The role of 5-HT-2 blockade in the actions of SCH 23390 on DA turnover appears thus to be of a minor importance. 相似文献
4.
The effects of bilateral intracranial injections of the D-1 dopamine receptor antagonist SCH 23390 HCl (0, 0.8, 1.6, 3.2, and 6.4 μg total bilateral dose) administered into the dorsolateral bed nucleus of the stria terminalis (dlBNST) immediately prior to a 3 h intravenous cocaine self-administration session were examined. In addition, anatomical control injections of the most effective dose of SCH 23390 HCl (6.4 μg) were made either 1.5 mm dorsal to the dlBNST or into the lateral ventricle. Injections directly into the dlBNST, but not those dorsal to the dlBNST or into the lateral ventricle, significantly increased the rate of cocaine self-administration within the first 20 min of the self-administration session, consistent with a partial attenuation of the reinforcing effects of cocaine under a fixed-ratio schedule of reinforcement (0.25 mg cocaine iv; fixed-ratio 5, timeout 20 s). Injections into all three sites increased cocaine self-administration across the entire 3 h session. These results suggest a role for D-1 dopamine receptors in the dlBNST in the reinforcing properties of self-administered cocaine, and also support the hypothesis that D-1 dopamine receptors in the ‘extended amygdala' may play a significant role in cocaine self-administration. 相似文献
5.
Summary The binding of 3H-SCH 23390 to membranes from rat and mouse brain tissue has been investigated. The binding was saturable and reached equilibrium after 60 minutes. Nonspecific binding was low. Association and dissociation rates were Mg ++-sensitive. In almost all respects the binding of 3H-SCH 23390 was comparable to the binding of 3H-piflutixol and 3H-cis(Z)-flupentixol.The density of binding sites in striatum was greater than in limbic structures which in turn was greater than in frontal cortex. The density of binding sites in these structures were comparable with those of 3H-piflutixol and 3H-cis(Z)-flupenthixol, 2–3 times higher than the D-2-receptor density. Whereas an increase was seen in 3H-spiperone binding after unilateral 6-OHDA lesion no changes were seen in 3H-SCH 23390 binding. The binding was decreased approximately 72% 3 weeks after unilateral kainic acid lesion whereas that of 3H-spiperone was only decreased 56%. Finally, the affinities of neuroleptics to the 3H-SCH 23390-binding sites correlated to the affinities to 3H-piflutixol-binding sites and to the effects on DA-sensitive adenylate cyclase.Agonist competition curves were shallow and the data best fit a two-site model composed of a high and a low affinity component.Thus, 3H-SCH 23390 is regarded as a highly selective ligand for brain dopamine D-1 receptors in vitro. 相似文献
6.
Summary Mice were pretreated with reserpine plus -methyl-p-tyrosine (10 mg/ kg plus 200 mg/kg). One hour later they were administered the selective dopamine D-2 agonist bromocriptine or vehicle. Three hours after the bromocriptine, mice were challenged with the selective D-1 agonist SKF 38393, and locomotor activity was measured each 5 min for three hours. Neither bromocriptine nor SKF 38393 produced significant stimulation. The combination, however, produced a dose-dependent and coordinated increase in activity. If the bromocriptine was given only one hour before the SKF 38393 challenge ( i.e., three hours after the reserpine plus -methyl-p-tyrosine), no interaction was seen. In naive mice, when SKF 38393 and bromocriptine were administered together, the locomotor response to bromocriptine was quantitatively and qualitatively altered. The initial depressant response to bromocriptine was shortened, producing a more rapid onset of the stimulant response. In one experiment, the maximal activity induced by bromocriptine was increased by SKF 38393. The ability of SKF 38393 to alter the locomotor stimulant effect of bromocriptine in naive mice was blocked by their pretreatment with the selective D-1 antagonist, SCH 23390. The data indicate that the locomotor stimulant effects of bromocriptine are modulated by D1 receptors. 相似文献
7.
Summary The substituted benzamide drug [ 3H]-raclopride (Köhler et al., 1985) was used to label dopamine D-2 receptors within the individual lobes of the pituitary gland as well as in the brain of male rats in vivo. The in vivo [ 3H]-raclopride binding was found to be saturable, reversible and of high specificity. Between 5–30% of the binding was non-specific at saturating concentrations dependent upon the lobe of the pituitary gland as well as of the brain region (e.g., caudate nucleus and olfactory tubercle) studied. Saturation analyses revealed B max-values of 12.9±1.6 and 2.2±0.9pmol·g –1 wet weight in the intermediate and anterior lobes, respectively with respective K D values of 6.5±4.6 and 7.3±2.4 nmol·kg –1. Quantitative autoradiographic studies using a single concentration of [ 3H]-raclopride showed a similar relationship with regard to binding densities in the different lobes, and showed, in addition, that the posterior lobe contained the lowest number of specific [ 3H]-raclopride binding sites. The binding capacities and affinities of binding were 12.9±1.7 and 9.2±2.8 respectively in the caudate nucleus and 6.1±0.7 and 9.3±2.7 respectively in the olfactory tubercle.The pharmacological analysis revealed that (S)sulpiride, remoxipride and raclopride were 10 to 125 times more potent than their corresponding isomers [(R)sulpridie, FLA 731(–), and FLB 472, respectively] in blocking the in vivo [ 3H]raclopride binding in the pituitary gland as well as in brain. The in vivo potency of different D-2 antagonists in preventing the [ 3H]-raclopride binding in the anterior and intermediate lobes was: spiperone > domperidone > raclopride > (S)sulpiride > remoxipride. The D-1 selective antagonist SCH 23390 did not block the in vivo binding of [ 3H]-raclopride neither in the pituitary lobes nor in the brain. In agreement with these findings the D-2 agonists N,N-propylnorapomorphine and quinpirole (LY 171555) but not the D-1 agonist SKF 38393-A blocked the specific in vivo [ 3H]-raclopride binding in the pituitary gland as well as in the brain. Comparisons between the relative potencies of different drugs in blocking pituitary and brain D-2 receptors in vivo showed that some drugs, including sulpiride and domperidone, were more potent in the pituitary gland than in the brain, while remoxipride and raclopride were equipotent in the two areas. The D-2 agonists tested appeared to be slightly more potent in the brain than in the pituitary gland. 相似文献
8.
The effects of cyclic AMP (cAMP)-related compounds on in vivo [(3)H]SCH 23390 binding to striatal dopamine D(1) receptors were investigated using autoradiography in order to clarify the possible regulation of the cAMP-dependent mechanisms in the in vivo ligand-receptor bindings in the living brain. Intrastriatal infusion of the cAMP analogue, N6,2'-O-dibutyryl-cyclic AMP (db-cAMP; 5, 25 and 100 nmol/side) produced a dose-dependent increase of in vivo [(3)H]SCH 23390 binding in conscious rats. This increasing effect of [(3)H]SCH 23390 binding completely disappeared by 6 h after the infusion of db-cAMP. A similar increase of in vivo [(3)H]SCH 23390 binding to striatal D(1) receptors was also observed by intrastriatal injection of 8-bromo-cyclic AMP (8Br-cAMP, 100 nmol/side). Pretreatment with Rp-cyclic AMP triethylamine (Rp-cAMPS, 100 nmol/side), an inhibitor of the cAMP-dependent protein kinase (PKA), completely blocked the increasing effect of [(3)H]SCH 23390 binding induced by db-cAMP. In contrast, in vitro [(3)H]SCH 23390 binding was not significantly altered by intrastriatal infusion of db-cAMP, which indicated that the maximum number of binding sites (B(max)) for D(1) receptors was not changed. The kinetic analysis employed the graphical method indicated that a db-cAMP-induced increase of in vivo [(3)H]SCH 23390 binding was mainly due to an increase in the bimolecular association rate constant (k(on)). These results strongly indicate that the PKA-mediated phosphorylation may play a pivotal role in the regulating the in vivo [(3)H]SCH 23390 dopamine D(1) receptor binding in intact rat brain. 相似文献
9.
Summary The effects of 30 dopamine (DA) antagonists, including 4 as stereoisomeric pairs, on circling behaviour induced by the D-1 agonist SKF 38393 and the D-2 agonist pergolide in rats with unilateral 6-hydroxy-DA lesions have been studied. SKF 38393-induced circling was selectively blocked by the specific D-1 antagonists SCH 23390 and SKF 83566, and was furthermore blocked by other DA antagonists with potencies correlating to their affinities to D-1 receptors labelled by 3H-SCH 23390 in vitro. Pergolide-antagonistic potencies in contrast correlated to affinities to D-2 receptors labelled by 3H-spiperone in vitro. Pergolide-induced circling was selectively blocked by the specific D-2 antagonists in the benzamide series. No interaction between D-1 and D-2 antagonists was observed in combination experiments with SCH 23390 and YM 09151-2 in both circling models.Among other reference neurotransmitter antagonists acting on - and -adrenoceptors, histamine, serotonin and muscarinic receptors, only the
1-adrenoceptor antagonist prazosin was effective in high doses. In contrast, the
2- and -adrenoceptor agonists clonidine and clenbuterol as well as the muscarinic agonist RS 86 inhibited circling induced by SKF 38393 as well as pergolide. The 5-HT 1A agonist 8-OHDPAT inhibited pergolide-induced circling only.It is concluded that these two behavioural models are selective in vivo measures of relative D-1 and D-2 receptor activity of DA antagonists. 相似文献
10.
Dopamine (DA) D 1 receptors are distributed in the nucleus accumbens and the amygdala, two regions of the mesocorticolimbic DA system known to be activated by aversive environmental stimuli. The objective of the present study was to determine the contribution of D 1 receptors in these brain regions to the expression of a fear-motivated behavior, notably, potentiated startle in rats. Injection of the DA D 1 receptor antagonist SCH 23390 into the amygdala blocked the ability of a conditioned light stimulus previously paired with footshock to enhance acoustic startle amplitudes. Bilateral intracerebral administration of SCH 23390 into the nucleus accumbens had no effect on fear-potentiated startle. The observed opposing effects of amygdaloid DA D 1 receptor antagonism on fear expression, along with earlier research demonstrating the involvement of ventral tegmental area (VTA) DA neurons on fear-potentiated startle, suggest a role for mesoamygdaloid activity in conditioned excitatory fear reactions. 相似文献
11.
Summary. To assess the role of dopamine receptors in the genesis of dyskinesia, we have used quantitative autoradiography to determine the effect of chronic l-dopa administration on dopamine D-1 (using [ 3H]SCH 23390), D-2 (using [ 3H]spiperone) and D-3 (using [ 3H]7-OH-DPAT) receptor binding levels in the striatum of dyskinetic or non-dyskinetic monkeys. Total and subregional striatal analysis showed no difference in D-1, D-2 or D-3 receptor binding in the caudate and putamen between monkeys receiving high dose l-dopa treatment with marked dyskinesia and those without dyskinesia compared to untreated animals. It thus appears unlikely that changes in dopamine receptor expression are a primary cause of l-dopa induced dyskinesia. Rather, a functional dissociation of D-2 receptor coupling to co-expressed enkephalin/adenosine-2a receptor activity in the striato-GPe indirect pathway may be more important in the development or expression of l-dopa-induced involuntary movements. Received July 3, 2000; accepted March 13, 2001 相似文献
12.
In this study, we examined the effect of the acute and chronic administration of WAY-405, a selective 5-HT(1A) receptor antagonist, on the number and firing pattern of spontaneously active substantia nigra pars compacta (A9) and ventral tegmental area (A10) dopamine (DA) neurons in anesthetized rats. This was accomplished using in vivo, extracellular single unit recording. The i.v. administration of WAY-405 (5-640 microg/kg) did not significantly alter the basal firing rate or pattern of spontaneously active A9 and A10 DA neurons. A single injection of 10 microg/kg of WAY-405 decreased the number of spontaneously active A10 DA neurons and the 100 microg/kg dose significantly decreased the number of spontaneously active A9 and A10 DA neurons compared to vehicle-treated animals. A single injection of 1, 10, or 100 microg/kg of WAY-405 significantly decreased the degree of bursting of A10 DA neurons. In contrast, 1 microg/kg i.p. of WAY-405 significantly increased the percent of A9 DA neurons exhibiting a bursting pattern. The repeated administration of 10 or 100 microg/kg i.p. of WAY-405 (21 days) significantly decreased the number of spontaneously active DA neurons in both the A9 and A10 compared to vehicle-treated animals and this decrease was not reversed by i.v. (+)-apomorphine. The repeated administration of WAY-405 significantly altered the firing pattern of DA neurons, particularly those in the A10 area. Overall, these results indicate that the antagonism of the 5-HT(1A) receptor significantly alters the activity of midbrain DA neurons in anesthetized rats. 相似文献
13.
The regional distribution of D 1 dopamine (DA) receptors in the rat brain has been studied by quantitative autoradiography using the specific D 1 antagonist [ 3H]SCH 23390 as a ligand. The binding of [ 3H]SCH 23390 to striatal sections was saturable, stereospecific, reversible and of high affinity ( Kd = 2.05nM); it occurred at single population of sites and possessed the pharmacological features of the D 1 DA receptor. The highest densities of [ 3H]SCH 23390 binding sites were found in the caudate-putamen, olfactory tubercle, nucleus accumbens and substantia nigra (especially in the pars compacta). High densities were also observed in the nucleus interstitialis striae terminalis, the anterior olfactory nucleus, the entopeduncular nucleus, the subthalamic nucleus, the claustrum and the amygdalohippocampal area. An intermediate labelling was found in the anteromedial and suprarhinal DA terminal fields of the cerebral cortex, the basolateral, medial and lateral amygdaloid nuclei, the endopiriform nucleus, the primary olfactory cortex, the globus pallidus, the superior colliculus (especially the superficial layer), the nucleus amygdaloideus corticalis and the dorsal hippocampus (molecular layer of the CA 1 and dentate gyrus). In the anteromedial and suprarhinal cortices, [ 3H]SCH 23390 binding was more concentrated in layers V and VI. Moderate levels of [ 3H]SCH 23390 were found in the thalamus, hypothalamus, the habenula, the ventral tegmental area, the posterior cingulate and entorhinal cortices, the supragenual dopamine terminal system and the cerebellum (molecular layer). This regional distribution of [ 3H]SCH 23390 closely correlated (except for the cerebellum) with the reported distribution of dopaminergic terminals. The topographical distribution of [ 3H]SCH 23390 has also been studied in detail in striatal subregions. The density of D 1 receptors was much greater in the ventrolateral sector and medial margin of the striatum than in the ventromedial and dorsolateral sectors. A rostrocaudal decrease in the densities of D 1 sites was also found along the rostrocaudal axis of the caudate-putamen. These lateral to medial and anteroposterior gradients overlapped with the density of the dopaminergic afferents. 相似文献
14.
This study examined the effects of both systemic and intraaccumbens administration of SCH-23390 in rats on dopamine D1 receptor occupancy and on locomotor activity produced by intraaccumbens infusion of cocaine. In experiment 1, rats received SCH-23390 (0–1 mg/kg, IP) 15 minutes prior to intraaccumbens infusion of cocaine (0 or 100 μg/side). In experiment 2, rats received coinfusion of SCH-23390 (0–1 μg/side) and cocaine (0 or 100 μg/side) into the nucleus accumbens (NAc). After behavioral testing, receptors occupied by SCH-23390 were quantified by injecting animals with their respective dose of SCH-23390, followed by a systemic injection of the irreversible antagonist N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ). Receptors occupied by SCH-23390, and therefore protected from EEDQ-induced inactivation, were quantified from autoradiograms of sections labeled with 3H-SCH-23390. Systemic administration of SCH-23390 dose-dependently (0.1–1.0 mg/kg) reversed cocaine-induced locomotion and occupied 72–100% of D1-like receptors in the anterior NAc. D1 receptor occupancy following systemic administration of SCH-23390 was evident as an inverted U-shaped, dose-dependent change, with the greatest occupancy observed at the intermediate dose of 0.3 mg/kg. Intraaccumbens infusion of SCH-23390 did not alter cocaine-induced locomotor activity despite occupying 40–60% of D1-like receptors in the anterior NAc core and shell. The findings that systemic, but not intraaccumbens, administration of SCH-23390 potently reversed locomotion produced by intraaccumbens cocaine infusion suggest that stimulation of D1 receptors in regions other than the NAc is involved in locomotion produced by intraaccumbens infusion of cocaine, and that stimulation of D1 receptors in the NAc is not necessary for this behavior. Synapse 30:194–204, 1998. © 1998 Wiley-Liss, Inc. 相似文献
15.
This study examined the effect of the acute and repeated per os (p.o.) administration of the selective 5-HT(6) receptor antagonist SB-271046, on the number, as well as the firing pattern of spontaneously active dopamine (DA) neurons in the rat substantia nigra pars compacta (SNC) and ventral tegmental area (VTA) in anesthetized male Sprague-Dawley rats. This was accomplished using the technique of extracellular in vivo electrophysiology. A single p.o. administration of either 1, 3, or 10 mg/kg of SB-271046 did not significantly alter the number of spontaneously active SNC DA neurons per stereotaxic electrode tract compared to vehicle-treated animals. The acute administration of either 1 or 3 mg/kg of SB-271046 did not significantly alter the number of spontaneously active VTA DA neurons. In contrast, a significant decrease in the number of spontaneously active VTA DA neurons was observed after a single administration of 10 mg/kg of SB-271046 compared to vehicle-treated animals. The acute p.o. administration of SB-271046 significantly altered the firing pattern parameters of all (bursting + nonbursting DA neurons) DA neurons, particularly those in the VTA, compared to vehicle-treated animals. The repeated p.o. administration (once per day for 21 days) of 1, 3, or 10 mg/kg of SB-271046 did not significantly alter the number of spontaneously active VTA DA neurons compared to vehicle-treated animals. The repeated administration of 3 or 10 mg/kg of SB-271046 significantly increased the number of spontaneously active SNC DA neurons compared to vehicle controls. Overall, the repeated administration of SB-271046 had relatively little effect on the firing pattern of midbrain DA neurons. The results obtained following the chronic administration of SB-271046 show that this compound has a profile different from that of typical or atypical antipsychotic drugs in this model. Clinical studies are required to understand what role 5-HT(6) receptor blockade might eventually play in the treatment of schizophrenia. 相似文献
16.
The present study demonstrated the age-related changes in the striatal dopamine D1 receptor binding and its related cAMP second-messenger system in the living brains of conscious young (6.4 +/- 1.8 years old) and aged (19.5 +/- 3.3 years old) monkeys (Macaca mulatta) using positron emission tomography (PET). For quantitative analysis of D1 receptors, [11C]SCH23390 was used and phosphodiesterase type-IV (PDE-IV) activity, as an index of cAMP system, was estimated by two scans with R- and S-[11C]rolipram. Significant age-related decreases in D1 receptor binding were observed in the striatum and frontal cortex. Analysis of uptake of R- and S-[11C]rolipram indicated age-related decreases in PDE-IV activity showing 22.0 and 25.2% decreases in the striatum and frontal cortex, respectively, while no significant changes were observed in the cerebellum. With systemic preadministration of the dopamine D1 receptor antagonist SCH23390 (0.2, 0.6, and 2 mg/kg), the PDE-IV activities in the striatum and frontal cortex were dose-dependently suppressed in both age groups. However, the degree of suppression by SCH23390 was more marked in young than in aged monkeys. These results demonstrate that the striatal cAMP second-messenger system activity as well as its functional response to dopamine D1 antagonist showed age-related impairment in the brain. 相似文献
17.
The present study evaluated the effects of methamphetamine and scopolamine on the striatal dopamine D(1) receptor binding, measured by [(11)C]SCH23390, and D(1) receptor-coupled cAMP messenger system, determined as phosphodiesterase type-IV (PDE-IV) activity, were evaluated in the brains of conscious monkeys using positron emission tomography (PET) with microdialysis. When methamphetamine (0.1, 0.3, and 1 mg/kg) or scopolamine (0.01, 0.03, and 0.1 mg/kg) was systemically administered, [(11)C]SCH23390 binding to D(1) receptors was not affected. With administration of methamphetamine, the striatal PDE-IV activity, as measured with R-[(11)C]rolipram (active form) and S-[(11)C]rolipram (inactive form), was dose-dependently facilitated with enhanced dopamine level in the striatal ECF. Administration of scopolamine also induced facilitated PDE-IV activity without any apparent changes in the ECF dopamine. These facilitations of PDE-IV activity were abolished by preadministration of SCH23390, but not by raclopride. These results demonstrate that, as evaluated by PDE-IV activity, the inhibition of muscarinic cholinergic receptors actually facilitated dopamine neuronal signal transduction through D(1) receptors, as observed previously on D(2) receptors with no apparent increase in the striatal ECF dopamine level, but the enhanced dopamine transmission could not detected by [(11)C]SCH23390. 相似文献
18.
We have previously shown that Fawn-Hooded (FH) rats reared in isolation display an anxiety-like phenotype and an enhanced acquisition of ethanol seeking behaviour. Furthermore, antalarmin, a selective corticotrophin-releasing factor type 1 (CRF1) receptor antagonist, reduces isolation-induced acquisition and maintenance of volitional ethanol consumption in this strain. The aim of this study was to investigate the ability of CRF1 receptor antagonism by antalarmin to impact upon brain chemistry in both isolated and group-housed FH rats. To achieve this, FH rats were reared, from weaning, in either group-housed or isolation-housed conditions and at 12 weeks of age were treated with antalarmin (20 mg/kg, i.p; n = 10 per group) or vehicle (1 mL/kg, i.p; n = 10 per group) bi-daily for ten consecutive days before being killed and their brains removed for neurochemical analyses. Autoradiography and in situ hybridization was employed to analyse changes in the dopaminergic and neurotrophin systems. Isolation rearing increased dopamine D2 receptor density in the central amygdala and nucleus accumbens, an effect reversed by antalarmin treatment. Conversely, treatment with antalarmin had no impact upon the isolation-induced alterations of the mRNA encoding brain-derived neurotrophic factor or the TrkB receptor. Collectively, these findings demonstrate that multiple signalling systems are susceptible to modulation by social isolation and that antalarmin can reverse some, but not all, isolation-induced alterations in brain chemistry. 相似文献
19.
Whereas structurally dissimilar D(1) antagonists competing for [(3)H]-SCH23390 binding recognize primarily one site in striatum, two distinct affinity states are observed in both amygdala and hippocampus. The binding profile of SCH23390 is similar in both of these regions, with the high affinity site (K(D) approximately 0.4 nM) consistent with D(1)/D(5) receptors. The appearance of the low affinity site (K(D) approximately 300 nM) is dependent upon the absence of MgCl(2), but independent of D(1) expression (i.e., still present in D(1) knockout mice). Although the density of high affinity state receptor is lower in hippocampus or amygdala of D(1) knockout mice, some residual binding remains, consistent with the known expression of D(5) receptors in these regions. Remarkably, in hippocampus, the affinity of the low affinity site is shifted rightward in the presence of the D(2) antagonist domperidone and is largely absent in the hippocampus of D(2) knockout animals. Additionally, this site is also shifted rightward in the presence of the A(2A) ligands SCH58261, CSC, or NECA, or in the absence of A(2A) receptors. The affinity of SCH23390 for this low affinity site is greater than seen for SCH23390 binding to D(2) receptors in heterologous expression systems, consistent with the hypothesis that both D(2) and A(2A) receptors are involved in the low affinity binding site. Therefore, we suggest that the heteromerization of D(2) and A(2A) receptors reported previously in vitro also may occur in the brain of both rats and mice. 相似文献
20.
Summary. With in vivo microvoltammetry, the dopamine (DA) receptor antagonists, clozapine (D 4/D 2), haloperidol (D 2) and the selective D 4 antagonist, PNU-101387G, were evaluated for their effects on DA and serotonin (5-HT) release within A 10 neuronal terminal fields [mesocortical, prefrontal cortex (PFC), mesolimbic, nucleus accumbens, (NAcc)] and within A 9 neuronal terminal fields [nigrostriatal, caudate putamen (CPU)], in chloral hydrate anesthetized rats. Clozapine, which also has 5-HT 2 receptor antagonist properties, significantly (p < 0.001) increased DA release within A 10 terminal fields, PFC and NAcc; DA release was not increased by clozapine within A 9 terminals, CPU. Serotonin release was significantly (p < 0.001) increased by clozapine within A 10 and A 9 terminal fields. Haloperidol significantly (p < 0.001) increased DA release within PFC, dramatically and significantly (p < 0.001) increased DA release
within CPU, but not within NAcc; haloperidol had a small but statistically significant (p < 0.05) increase on 5-HT release
within PFC [only at the highest dose studied (2.5 mg/kg)] and within CPU [only at the lowest dose studied 1.0 mg/kg) (p <
0.05)]. The selective D 4 antagonist, PNU-101387G dramatically and significantly (p < 0.001) increased DA release within PFC, modestly, but significantly (p < 0.001) increased
DA release within CPU, did not alter DA release within NAcc at the lowest dose studied (1.0 mg/kg) and significantly (p <
0.05) decreased DA release within NAcc at the highest dose studied (1.0 mg/kg). The selective D 4 antagonist did not affect 5-HT release within either A 10 or A 9 terminal fields. The present data are discussed in terms of the neurochemistry, antipsychotic activity, and side effect profiles
of clozapine and haloperidol, in order to provide comparative profiles for a selective D 4 antagonist, PNU-101387G.
Received January 13, 1998; accepted April 27, 1998 相似文献
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