共查询到20条相似文献,搜索用时 0 毫秒
1.
Susan J. Brown Rammy Gill John L. Evenden Susan D. Iversen Peter J. Richardson 《Psychopharmacology》1991,103(1):78-82
The effect of the purine agonist N-ethylcarboxamido-adenosine (NECA) on apomorphine-induced rotation was investigated in rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal pathway. Intrastriatal administration of NECA on the denervated side caused a dose-dependent inhibition of contralateral rotation. This inhibition was prevented by prior intrastriatal injection of theophylline. The adenosine A1 receptor antagonist 8-cyclopentyltheophylline was ineffective at concentrations which block this receptor, but effective in preventing the action of NECA at concentrations which block the adenosine A2 receptor. In the absence of apomorphine, NECA had no effect on behaviour. It is concluded that A2 receptor activation counteracts apomorphine effects in the striatum. Since the A2 receptor may be localized to striatal cholinergic neurones, the possible role of these neurones in purine-induced behaviours is discussed. 相似文献
2.
Corsi C Pinna A Gianfriddo M Melani A Morelli M Pedata F 《European journal of pharmacology》2003,464(1):33-38
The objective of the work was to study, by in vivo microdialysis, the effect of the adenosine A(2A) receptor antagonist 7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine (SCH 58261) on glutamate outflow in the striata of unilateral 6-hydroxydopamine-infused rats. Two vertical microdialysis probes were implanted bilaterally in both the denervated striatum and in the intact striatum. Glutamate concentrations in the dialysate were determined by high-performance liquid chromatography (HPLC). Infusion of the adenosine A(2A) receptor antagonist SCH 58261 (50 nM), through the microdialysis fiber, significantly increased glutamate outflow from the denervated striatum while it decreased glutamate outflow from the intact striatum. The opposite effects of SCH 58261 on glutamate outflow in the intact and 6-hydroxydopamine-lesioned striatum might be attributed to blockade of striatal adenosine A(2A) receptors located on either striatal indirect output pathways or glutamatergic terminals. These results may be relevant to our understanding of the mechanism of action of adenosine A(2A) receptor antagonists in Parkinson's disease. 相似文献
3.
Claude Oberlander Claude Dumont Jacques R. Boissier 《European journal of pharmacology》1980,62(1):107-110
The curve describing the time course of apomorphine-induced circling behaviour in rats with a 6-hydroxy-dopamine-induced lesion of the nigrostriatal dopamine (DA) pathway was studied with a microcomputerized rotometer. Up to a 2-week interval after lesioning, the contralateral circling response was a single bell-shaped curve but this gradually became a double-peaked curve after 4–5 months. At this time bell-shaped curve was, however, restored by haloperidol pretreatment. It is concluded that the response of striatal DA receptors was modified either by the lesion of another neuronal system and/or that the absence of DA nerve endings induced changes in the striatal DA receptor itself. 相似文献
4.
The effects of the adenosine A(2A) receptor agonist 2-p-(2-carboxyethyl)phenethyl-amino-5'-N-ethylcarboxamidoadenosine (CGS 21680) on currents mediated by excitatory amino acid receptors were examined in rat striatal brain slices. In a Mg(2+)-free superfusion medium, CGS 21680 decreased the amplitude of excitatory postsynaptic currents (EPSCs) in about 70% of striatal neurons. The inhibitory effect of CGS 21680 disappeared both in the presence of the adenosine A(2A) receptor antagonist 8-(3-chlorostyryl) caffeine and the NMDA receptor antagonist 2-amino-5-phosphonopentanoic acid (AP-5). NMDA-induced currents were also depressed by CGS 21680 in a subset of striatal cells, whereas alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)-induced currents were not affected. The results suggest that adenosine A(2A) receptor agonists inhibit the NMDA component of the EPSC. 相似文献
5.
Antagonistic cannabinoid CB1/dopamine D2 receptor interactions in striatal CB1/D2 heteromers. A combined neurochemical and behavioral analysis 总被引:1,自引:0,他引:1
Marcellino D Carriba P Filip M Borgkvist A Frankowska M Bellido I Tanganelli S Müller CE Fisone G Lluis C Agnati LF Franco R Fuxe K 《Neuropharmacology》2008,54(5):815-823
In vitro results show the ability of the CB(1) receptor agonist CP 55,940 to reduce the affinity of D(2) receptor agonist binding sites in both the dorsal and ventral striatum including the nucleus accumbens shell. This antagonistic modulation of D(2) receptor agonist affinity was found to remain and even be enhanced after G-protein activation by Gpp(NH)p. Using the FRET technique in living HEK-293T cells, the formation of CB(1)-D(2) receptor heteromers, independent of receptor occupancy, was demonstrated. These data thereby indicate that the antagonistic intramembrane CB(1)/D(2) receptor-receptor interactions may occur in CB(1)/D(2) formed heteromers. Antagonistic CB(1)/D(2) interactions were also discovered at the behavioral level through an analysis of quinpirole-induced locomotor hyperactivity in rats. The CB(1) receptor agonist CP 55,940 at a dose that did not change basal locomotion was able to block quinpirole-induced increases in locomotor activity. In addition, not only the CB(1) receptor antagonist rimonobant but also the specific A(2A) receptor antagonist MSX-3 blocked the inhibitory effect of CB(1) receptor agonist on D(2)-like receptor agonist-induced hyperlocomotion. Taken together, these results give evidence for the existence of antagonistic CB(1)/D(2) receptor-receptor interactions within CB(1)/D(2) heteromers in which A(2A) receptors may also participate. 相似文献
6.
Wirkner K Gerevich Z Krause T Günther A Köles L Schneider D Nörenberg W Illes P 《Neuropharmacology》2004,46(7):994-1007
The function of adenosine A(2A) receptors, localized at the enkephalin-containing GABAergic medium spiny neurons of the striatum, has been discussed controversially. Here we show that, in the absence of external Mg(2+), the adenosine A(2A) receptor agonist CGS 21680 postsynaptically depressed the NMDA, but not the non-NMDA (AMPA/kainate) receptor-mediated fraction of the electrically evoked EPSCs in a subpopulation of striatal neurons. Current responses to locally applied NMDA but not AMPA were also inhibited by CGS 21680. However, in the presence of external Mg(2+), the inhibition by CGS 21680 of the GABA(A) receptor-mediated IPSCs led to a depression of the EPSC/IPSC complexes. The current response to the locally applied GABA(A) receptor agonist muscimol was unaltered by CGS 21680. Whereas, the frequency of spontaneous (s)IPSCs was inhibited by CGS 21680, their amplitude was not changed. Hence, it is suggested that under these conditions the release rather than the postsynaptic effect of GABA was affected by CGS 21680. In conclusion, under Mg(2+)-free conditions, CGS 21680 appeared to postsynaptically inhibit the NMDA receptor-mediated component of the EPSC, while in the presence of external Mg(2+) this effect turned into a presynaptic inhibition of the GABA(A) receptor-mediated IPSC. 相似文献
7.
《Expert opinion on therapeutic patents》2013,23(4):489-501
Adenosine, a naturally-occurring nucleoside, modulates a variety of physiological and pathophysiological processes. The effects of adenosine are mediated via a family of cell surface G-protein-coupled receptors designated into four subtypes, A1, A2A, A2B and A3. The adenosine receptors have widespread tissue distribution and are often co-expressed in the same cell type. Research on adenosine receptors over the past few decades has resulted in the molecular cloning of the four subtypes from multiple species, significant progress in identifying selective agonists and antagonists and an increased understanding of the particular roles adenosine receptor subtypes play in physiological processes. This knowledge has continued to fuel considerable interest in pursuing adenosine receptors as therapeutic targets. For example, adenosine receptor agonists have been proposed for the treatment of heart arrhythmias, inflammatory diseases and in diagnosing coronary artery disease. In general, adenosine receptor agonists are derivatives of the physiological agonist, adenosine. The development of adenosine receptor agonists has been limited by an essential requirement for retention of the ribose moiety for agonist activity. Despite this restriction, significant progress has been made in the identification of potent and selective adenosine receptor agonists, some of which have entered clinical trials. 相似文献
8.
Vanattou-Saïfoudine N Gossen A Harkin A;Neuropsychopharmacology Research Group 《European journal of pharmacology》2011,(1):759-228
Co-administration of caffeine profoundly enhances the acute toxicity of 3,4 methylenedioxymethamphetamine (MDMA) in rats. The aim of this study was to determine the ability of caffeine to impact upon MDMA-induced dopamine release in superfused brain tissue slices as a contributing factor to this drug interaction. MDMA (100 and 300 μM) induced a dose-dependent increase in dopamine release in striatal and hypothalamic tissue slices preloaded with [3H] dopamine (1 μM). Caffeine (100 μM) also induced dopamine release in the striatum and hypothalamus, albeit to a much lesser extent than MDMA. When striatal tissue slices were superfused with MDMA (30 μM) in combination with caffeine (30 μM), caffeine enhanced MDMA-induced dopamine release, provoking a greater response than that obtained following either caffeine or MDMA applications alone. The synergistic effects in the striatum were not observed in hypothalamic slices. As adenosine A1 receptors are, one of the main pharmacological targets of caffeine, which are known to play an important role in the regulation of dopamine release, their role in the modulation of MDMA-induced dopamine release was investigated. 1 μM 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), a specific A1 antagonist, like caffeine, enhanced MDMA-induced dopamine release from striatal slices while 1 μM 2,chloro-N(6)-cyclopentyladenosine (CCPA), a selective adenosine A1 receptor agonist, attenuated this. Treatment with either SCH 58261, a selective A2A receptor antagonist, or rolipram, a selective PDE-4 inhibitor, failed to reproduce a caffeine-like effect on MDMA-induced dopamine release. These results suggest that caffeine regulates MDMA-induced dopamine release in striatal tissue slices, via inhibition of adenosine A1 receptors. 相似文献
9.
James K. Rowlett Norman W. Pedigo Jr. Michael T. Bardo 《Pharmacology, biochemistry, and behavior》1991,40(4)
Systemic injection of the D1 dopamine receptor antagonist SCH 23390 produces catalepsy that is of lesser magnitude in neonatal than in adult rats. The present experiments were conducted in order to determine if SCH 23390 would produce catalepsy in neonatal rats following intrastriatal injection and if the ontogenetic pattern of catalepsy induced by intrastriatal SCH 23390 would be similar to the pattern observed with systemic injections. Rat pups (11 or 28 days of age) were microinjected unilaterally with SCH 23390 (0.2, 1, 5 or 10 μg) and tested for catalepsy using the forepow-on-horizontal-bar test. The results demonstrated that robust catalepsy occurred at both ages following intrastriatal injection and that catalepsy induced by 5 μg SCH 23390 was of lesser magnitude in 11-day-olds than in 28-day-olds. A separate study assessed the distribution of [3H]SCH 23390 (5 μg) following intrastriatal injection in 28-day-olds. Results of the distribution study indicated that [3H]SCH 23390 was localized primarily within the striatum. Taken together, these results suggest that the striatal mechanisms for catalepsy produced by D1 receptor blockade are present, but not fully mature, in preweanling rat pups. 相似文献
10.
Like the dopamine agonist apomorphine, the methylxanthines caffeine, theophylline and theobromine produced dose-dependent contralateral rotation in rats with unilateral 6-hydroxydopamine denervation, a response considered to be dependent upon dopamine receptors rendered supersensitive. This response was also observed after the injection of the substances into the denervated striatum. Indeed, intrastriatal administration of caffeine into the dopamine denervated striatum produced, dose-dependently (1.0–50.0 g/l), contralateral rotation. However, while apomorphine produced ipsilateral rotation in rats with unilateral striatal kainic acid lesions, a response considered to be dependent upon normosensitive dopamine receptors, neither caffeine nor theophylline produced rotational responses. As for apomorphine, the rotational behaviour elicited by caffeine (15.0 mg/kg SC) and theophylline (25.0 mg/kg SC) was inhibited by the dopamine antagonistscis-(Z)flupentixol, haloperidol and sulpiride. Nevertheless, despite the fact thatcis-(Z)flupentixol was the most potent inhibitor of the caffeine response, no more than 50% inhibition was produced with doses as high as 1.0–10.0 mg/kg SC ofcis-(Z)flupentixol. Pretreatment with alpha methyl-p-tyrosine inhibited the rotational response produced by caffeine in 6-OHDA-lesioned animals, but did not significantly modify the apomorphine response. Furthermore, the benzodiazepine diazepam produced a dose-dependent inhibition of the caffeine rotation, but again, the apomorphine response, although qualitatively modified, was not significantly inhibited. 相似文献
11.
The influence of the selective adenosine A(2A) receptor antagonist ZM 241385 on exogenous l-DOPA-derived dopamine (DA) release in intact and dopamine-denervated rats was studied using an in vivo microdialysis in freely moving animals. Local infusion of l-DOPA (2.5 microM) produced a marked increase in striatal extracellular DA level in intact and malonate-lesioned rats. Intrastriatal perfusion of ZM 241385 (50-100 microM) had no effect on basal extracellular DA level, but enhanced dose-dependently the l-DOPA-induced DA release in intact and malonate-lesioned animals. A non-selective adenosine A(2A) receptor antagonist DMPX (100 microM), similarly to ZM 241385, accelerated conversion of l-DOPA in intact and malonate-denervated rats. This effect was not produced by the adenosine A(1) receptor antagonist, CPX (10-50 microM). However, ZM 241385 did not affect the l-DOPA-induced DA release in rats pretreated with reserpine (5 mg/kg i.p.) and alpha-methyl-p-tyrosine (AMPT, 300 mg/kg i.p.). Obtained results indicate that blockade of striatal adenosine A(2A) receptors increases the l-DOPA-derived DA release possibly by indirect mechanism exerted on DA terminals, an effect dependent on striatal tyrosine hydroxylase activity. Selective antagonists of adenosine A(2A) receptors may exert a beneficial effect at early stages of Parkinson's disease by enhancing the therapeutic efficacy of l-DOPA applied exogenously. 相似文献
12.
Sergi Ferré Robert Schwarcz Xi Ming Li Per Snaprud Sven Ove Ögren Kjell Fuxe 《Psychopharmacology》1994,116(3):279-284
Stimulation of adenosine A2 receptors (with the selective adenosine A2 agonist CGS 21680) in rat striatal membrane preparations, produces a decrease in both the affinity of D2 receptors and the transduction of the signal from the D2 receptor to the G protein. This intramembrane A2-D2 interaction might be responsible for the behavioural depressant effects of adenosine agonists and for the behavioural stimulant effects of adenosine antagonists such as caffeine and theophylline. Dopamine denervation induces an increase in the intramembrane A2-D2 interaction, which may underlie the observed higher sensitivity to the behavioural effects induced by adenosine antagonists found in these animals. The present study was designed to examine if chronic treatment with haloperidol, which also produces dopamine receptor supersensitivity, is also associated with an increase in the intramembrane A2-D2 interaction in the neostriatum and with a higher sensitivity to the behavioural effects induced by adenosine antagonists. The data showed that: (i) haloperidol pretreatment causes a higher binding of the D2 antagonist [3H] raclopride in striatal membrane preparations due to an increase in the number of D2 receptors without changes in their affinity for the antagonist (increase in Bmax without changes in kd); (ii) GCS 21680 decreases the affinity of dopamine for the D2 receptor, by increasing the equilibrium dissociation constants of high (Kh) and low affinity (K1) dopamine D2 binding sites and increases the proportion of high affinity binding sites (Rh); (iii) a low dose of CGS 21680 (3 nM), which is ineffective in membrane preparations from neostriatum of nontreated animals, is effective in membranes from the striatum of haloperidol-pretreated animals; (iv) the nonselective adenosine antagonist theophylline (20 mg/kg SC) causes a higher motor activation in rats pretreated with haloperidol. The possible relevance of these results for the pathophysiology and treatment of tardive dyskinesias is discussed. 相似文献
13.
We examined modulation of [(3)H]GABA uptake in slices of the rat globus pallidus because stimulation of adenosine A(2A) receptors increases extracellular GABA in this structure. Pharmacological analysis showed that GAT-1 is the main transporter present in these slices. Both adenosine and the A(2A) agonist CGS 21680 reduced GABA uptake. Antagonist ZM 241385 prevented these effects. Agents that increase protein kinase A activity like forskolin and 8-bromo-cAMP also inhibited GABA uptake. The inhibition of uptake produced by these substances and by CGS 21680 was prevented by the protein kinase A blocker H-89. The protein phosphatase blocker okadaic acid reduced uptake; this effect and the response to CGS 21680 were not additive. The effective concentrations of adenosine (EC(50)=15.2microM) are within the range measured in the interstitial fluid under some physiological conditions. Thus, inhibition of uptake may be important in increasing interstitial GABA during endogenous adenosine release. 相似文献
14.
A reduction in airway beta-adrenoceptor density has been reported in cystic fibrosis lung but the mechanism underlying this defect remains unclear. In this study, we have investigated whether the decrease in beta2-adrenoceptor associates with altered G protein-coupled receptor kinase (GRK) levels. We assessed GRK activity by rhodopsin phosphorylation, and beta2-adrenoceptor and GRK at the mRNA and protein levels by Northern and Western blotting in peripheral lung samples from normal donors and patients with cystic fibrosis. GRK activity was significantly increased in peripheral cystic fibrosis lung with parallel increases in GRK2/5 mRNAs and protein expression. Functionally, isoproterenol-stimulated adenylyl cyclase activity was also diminished by 65% in cystic fibrosis lung homogenates. These data suggest that the increase in GRK activity may be one of the mechanisms underlying alterations in the coupling between beta2-adrenoceptor and adenylyl cyclase via G-protein and may thus contribute to the downregulation of beta2-adrenoceptor in cystic fibrosis lung. 相似文献
15.
Bilkei-Gorzo A Abo-Salem OM Hayallah AM Michel K Müller CE Zimmer A 《Naunyn-Schmiedeberg's archives of pharmacology》2008,377(1):65-76
In this study, we examined the effects of systemic and local administration of the subtype-selective adenosine receptor antagonists
PSB-36, PSB-1115, MSX-3, and PSB-10 on inflammation and inflammatory hyperalgesia. Pharmacological blockade of adenosine receptor
subtypes after systemic application of antagonists generally led to a decreased edema formation after formalin injection and,
with the exception of A3 receptor antagonism, also after the carrageenan injection. The selective A2B receptor antagonist PSB-1115 showed a biphasic, dose-dependent effect in the carrageenan test, increasing edema formation
at lower doses and reducing it at a high dose. A1 and A2B antagonists diminished pain-related behaviors in the first phase of the formalin test, while the second, inflammatory phase
was attenuated by A2B and A3 antagonists. The A2B antagonist was particularly potent in reducing inflammatory pain dose-dependently reaching the maximum effect at a low dose
of 3 mg/kg. Inflammatory hyperalgesia was totally eliminated by the A2A antagonist MSX-3 at a dose of 10 mg/kg. In contrast to the A1 antagonist, the selective antagonists of A2A, A2B, and A3 receptors were also active upon local administration. Our results demonstrate that the blockade of adenosine receptor subtypes
can decrease the magnitude of inflammatory responses. Selective A2A antagonists may be useful for the treatment of inflammatory hyperalgesia, while A2B antagonists have potential as analgesic drugs for the treatment of inflammatory pain. 相似文献
16.
El Yacoubi M Ledent C Parmentier M Costentin J Vaugeois JM 《European journal of pharmacology》2005,519(3):290-291
Adenosine A(2A) receptor knockout mice (A(2A)R KO) were compared to wild-type controls (A(2A)R WT) in a caffeine intake paradigm. When mice had ad libitum access to caffeine (0.3 g/l) and water in a two-bottle paradigm for 12 consecutive days, adenosine A(2A)R KO mice drank less caffeinated solution, demonstrating a reduced appetite for caffeine as compared to adenosine A(2A)R WT mice. These data reveal an important role for the adenosine A(2A) receptor in the appetitive properties of caffeine. 相似文献
17.
A. Conti A. Monopoli M. Gamba P. A. Borea E. Ongini 《Naunyn-Schmiedeberg's archives of pharmacology》1993,348(1):108-112
Summary We investigated the negative chronotropic and vasodilating properties of new selective A1 and A2 adenosine agonists such as 2-chloro-N6-cyclopentyladenosine (CCPA) and 2-hexynyl-5-N-ethyl-carboxamidoadenosine (2-hexynyl-NECA) as compared with reference adenosine analogues. The potency of these compounds on heart rate was assessed in the rat atrial preparation and their activity on the vascular tone was determined in both rat aorta and bovine coronary artery. CCPA was found to be the most potent At agonist of those currently available in producing negative chronotropic effects (EC50 = 8.2 nM). The A1 antagonist 8-cyclopentyl-1,3-dipropyl-xanthine (DPCPX) blocked CCPA activity in a dose-dependent manner. There was also a significant correlation between its biological effect and the affinity for A1 receptors as measured in the rat brain by [3H]-N6-cyclohexyladenosine (3[H]-CHA) binding. The A2 selective agonist 2-hexynyl-NECA showed vasodilating properties comparable with those observed with the reference compounds, CGS 21680 and NECA. EC50 values were 596 and 569 nM in rat aorta and bovine coronary artery, respectively. Moreover, the rank order of potency was similar in the two vascular districts examined, suggesting that the rat aorta is a useful model for studying the effects of adenosine derivatives on vascular tone. In addition, the potency of the compounds in inducing vasodilation was found to be correlated with their affinity for A2 receptors as measured in the rat striatum by 3[H]-CGS 21680 binding.These data further support that A1 receptors are involved in depressing cardiac activity and A2 receptors in inducing vasorelaxation.Correspondence to A. Conti at the above address 相似文献
18.
P. Simon B. Guardiola J. Bizot-Espiard P. Schiavi J. Costentin 《Psychopharmacology》1992,108(1-2):47-50
The new compound (+) S-20499, an amino chromane derivative (8[-4[N-(5-methoxychromane-3yl)N-propyl]aminobutyl] azaspiro[4–5] décane-7,9 dione), is a high affinity full 5-HT1A agonist. We have investigated its effects on dopaminergic transmission. (+) S-20499 displayed a 10–8 M affinity for D2 dopamine (DA) receptors, 100 fold lower than for 5-HT1A receptors. The hypothermic effect of the drug was reversed by haloperidol in mice, suggesting that it behaves as a direct dopamine agonist. However, increasing doses of (+) S-20499 induced neither yawning nor penile erections, which constitute characteristic responses of direct DA agonists administered at low doses. In addition, (+) S-20499 prevented the apomorphine (100 µg/kg SC) induced yawning and penile erections. This inhibition appears to result from the stimulation of 5-HT1A receptors since it is an effect shared by both buspirone (from 5 mg/kg) and 8-OH-DPAT (from 0.10 mg/kg). In addition, when rats are treated with the 5-HT1A receptor antagonist tertatolol (2–5 mg/kg; SC), increasing doses of (+) S-20499 elicit the expected yawns and penile erections. It is concluded that the 5-HT1A agonist property opposes to that of D2 dopamine receptor stimulation with regard to yawning and penile erections. 相似文献
19.
The adenosine-receptor modulation of noradrenaline release was compared in prostatic and epididymal portions of rat vas deferens. In both portions, tritium overflow elicited by electrical stimulation (100 pulses/8 Hz) was reduced by the adenosine A(1) receptor agonist, N(6)-cyclopentyladenosine, and enhanced by the nonselective receptor agonist, 5'-N-ethylcarboxamidoadenosine, in the presence of the adenosine A(1) receptor antagonist, 1,3-dipropyl-8-cyclopentyl-1,3-dipropylxanthine (DPCPX; 20 and 100 nM). The adenosine A(2A) receptor agonist, 2-p-(2-carboxyethyl)phenethyl-amino-5'-N-ethylcarboxamidoadenosine, increased tritium overflow, but only in the epididymal portion. The enhancement caused by NECA was prevented by the adenosine A(2A) receptor antagonist, 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo-[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM 241385; 20 nM), in the epididymal and by the adenosine A(2B) receptor antagonist, alloxazine (1 microM), in the prostatic portion. Inhibition of adenosine uptake enhanced tritium overflow in both portions, an effect blocked by ZM 241385 in the epididymal and by alloxazine in the prostatic portion. The results indicate that adenosine exerts an adenosine A(1) receptor-mediated inhibition, in both portions, and facilitation mediated by adenosine A(2A) receptors in the epididymal and by A(2B) receptors in the prostatic portion. 相似文献
20.
Ferrada C Ferré S Casadó V Cortés A Justinova Z Barnes C Canela EI Goldberg SR Leurs R Lluis C Franco R 《Neuropharmacology》2008,55(2):190-197
The striatum contains a high density of histamine H(3) receptors, but their role in striatal function is poorly understood. Previous studies have demonstrated antagonistic interactions between striatal H(3) and dopamine D(1) receptors at the biochemical level, while contradictory results have been reported about interactions between striatal H(3) and dopamine D(2) receptors. In this study, by using reserpinized mice, we demonstrate the existence of behaviorally significant antagonistic postsynaptic interactions between H(3) and D(1) and also between H(3) and dopamine D(2) receptors. The selective H(3) receptor agonist imetit inhibited, while the H(3) receptor antagonist thioperamide potentiated locomotor activation induced by either the D(1) receptor agonist SKF 38393 or the D(2) receptor agonist quinpirole. High scores of locomotor activity were obtained with H(3) receptor blockade plus D(1) and D(2) receptor co-activation, i.e., when thioperamide was co-administered with both SKF 38393 and quinpirole. Radioligand binding experiments in striatal membrane preparations showed the existence of a strong and selective H(3)-D(2) receptor interaction at the membrane level. In agonist/antagonist competition experiments, stimulation of H(3) receptors with several H(3) receptor agonists significantly decreased the affinity of D(2) receptors for the agonist. This kind of intramembrane receptor-receptor interactions are a common biochemical property of receptor heteromers. In fact, by using Bioluminescence Resonance Energy Transfer techniques in co-transfected HEK-293 cells, H(3) (but not H(4)) receptors were found to form heteromers with D(2) receptors. This study demonstrates an important role of postsynaptic H(3) receptors in the modulation of dopaminergic transmission by means of a negative modulation of D(2) receptor function. 相似文献