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1.
The effects of the dopamin D1 antagonist SCH23390 and the D2 antagonist sulpiride on the rewarding effects of opioid receptor agonists were examined in mice. Both [d-Pen2, Pen5]enkephalin (DPDPE, 1–15 nmol, ICV), a selective 1 opioid receptor agonist, and [d-Ala2]deltorphin II (DELT, 0.5–5 nmol, ICV), a selective 2 opioid receptor agonist, produced a dose-dependent place preference in mice. The DPDPE (15 nmol, ICV)-induced place preference was abolished by BNTX (0.5 mg/kg, SC), a 1 opioid receptor antagonist, but not by NTB (0.5 mg/kg, SC), a 2 opioid receptor antagonist. In contrast, the DELT (5 nmol, ICV)-induced place preference was antagonized by NTB, but not BNTX. Pretreatment with SCH23390 (3 µg/kg, SC) abolished the DPDPE-induced place preference, but not affect the DELT-induced place preference. Moreover, pretreatment with sulpiride (40 mg/kg, SC) did not modify the place preference induced by DPDPE or DELT. In the present study, we found that the activation of both central 1 and 2 opioid receptors produced rewarding effects. Furthermore, these results suggest that the rewarding effects of 1 opioid receptor agonist may be produced through activation of the central dopaminergic system, especially dopamine D1 receptors, whereas the rewarding effects of 2 opioid receptor agonists may be produced by some other mechanism(s). 相似文献
2.
Kieran F. Rooney Roisin A. Armstrong Robert D. E. Sewell 《Naunyn-Schmiedeberg's archives of pharmacology》1991,343(5):458-462
Summary The effects of acutely administered opioid receptor agonists sufentanil, U50,488H and [d-Ala2, d-Leu5]-enkephalin (DADL) were observed upon dopamine D1 and D2 binding site density in the striatum of the rat. In addition, the functional implications of opioid-induced changes in dopamine receptor sensitivity were studied using the behavioural profile elicited by apomorphine in the rat. The -agonist sufentanil (1 or 20 Erg/kg, i. p.), the -agonist U50,488H (10 mg/kg, i. p.) and DADL (1 g/animal, i. c. v.) all significantly elevated D2 but not D1 binding site density in rat striatum. Pretreatment with sufentanil (1 g/kg, i. p.) induced an elevation in apomorphine-induced sterotyped behaviour, but attenuated locomotor activity. Following administration of U50,488H (10 mg/kg, i. p.), both the degree of stereotypy and the intensity of the locomotor activity were enhanced. Contralateral rotation was observed in animals pretreated with DADL (1 g/animal, i. c. v.) following challenge with apomorphine. It is concluded that the opioid agonists studied induce a significant elevation in functional D2 sites to the exclusion of D1 sites. However, the precise mechanism by which this effect is elicited remains to be established.
Send offprint requests to R. D. E. Sewell at the above address 相似文献
3.
Vladimir Dolezall Rolf Jackisch Georg Hertting Clemens Allgaier 《Naunyn-Schmiedeberg's archives of pharmacology》1992,345(1):16-20
Summary The possible involvement of dopamine D1 receptors in the regulation of acetylcholine release in the rabbit caudate nucleus was investigated. Caudate slices, preincubated with [3H]choline, were superfused continuously and subjected to electrical field stimulation with only a single pulse. In agreement with the view that the release of acetylcholine evoked by a single electrical pulse is not influenced by endogenous transmitters, atropine and domperidone failed to icnrease the evoked release of [3H]acetylcholine, whereas oxotremorine and quinpirole caused a concentration-dependent inhibition of transmitter release. Neither the dopamine D1 receptor antagonist SCH 23390 nor the Dt agonist SKF 38393 in a concentration range of 0.01–1 mol/l changed the evoked [3H]acetylcholine release. The inhibitory effect of the dopamine D2 receptor agonist quinpirole was virtually abolished in the presence of 0.1 mol/l domperidone and diminished in the presence of 1 mol/l SCH 23390. It remained unchanged in the presence of 1 mol/l SKF 38393. It is concluded that the inhibition of acetylcholine release by dopamine is mediated exclusively via presynaptic dopamine D2 receptors and that the antagonistic effect of SCH 23390 on the inhibition of acetylcholine release by quinpirole is due to its interaction with dopamine D2 rather than D1 receptors located on cholinergic nerve terminals.
Send offprint requests to C. Allgaier at the above address 相似文献
4.
Machiko Matsumoto Mitsuhiro Yoshioka Hiroko Togashi Toshiya Ikeda Hideya Saito 《Naunyn-Schmiedeberg's archives of pharmacology》1996,353(6):621-629
The functional regulation by dopamine (DA) receptors of serotonin (5-HT) release from the rat hippocampus was investigated by use of in vivo microdialysis. Dialysate 5-HT levels were reduced by co-perfusion of 10 M tetrodotoxin (TTX) and were elicited by K+ (60 and 120 mM) stimulation in a concentration-dependent manner. Local perfusion (10 M) and peripheral administration (20 mg/kg, i.p.) of fluoxetine produced increases in 5-HT levels. These results indicate that the spontaneous 5-HT levels in the rat hippocampus can be used as indices of neuronal origin from the serotonergic nerve terminals. The nonselective dopamine (DA) receptor agonist apomorphine (1, 10 and 100 M), when perfused through the probe over a period of 40 min, increased 5-HT release in a concentration-dependent manner. Apomorphine-induced (100 M) increases in 5-HT release was abolished by pretreatment with the selective D2 receptor antagonist, S(–)-sulphide (1 and 10 M), but not prevented by pretreatment with the selective D1 receptor antagonist, R(+)-SCH-23390 (R(+)-7-chloro-8-hydroxy-3-methyl-l-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine) (1 M). S(–)-Sulpiride and R(+)-SCH-23390 by themselves did not alter the spontaneous 5-HT levels. The 5-HT release was elevated by perfusion of the selective DA reuptake inhibitor GBR 12909 (1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-[3-phenylpropyl]piperazine)(1, 10 and 100 M), indicating the possibility of not only exogenous but also endogenous DA-mediated facilitatory effects on 5-HT release in vivo. The 5-HT release was also elevated by perfused (±)-PPHT ((±)-2-(N-phenylethyl-N-propyl)-amino-5-hydroxytetralin)(1, 10 and 100 M), the selective D2 receptor agonist, in a concentration-dependent manner. On the other hand, (±)-PPHT (100 M) failed to increase 5-HT release in catecholamine (CA)-lesioned rats pretreated with 6-hydroxydopamine (6-OHDA)(200 g/rat, i.c.v.). The (±)-PPHT-induced (100 M) increase in 5-HT release was prevented not only by pretreatment with 10 M S(–)-sulphide but also by pretreatment with the 2-adrenoceptor antagonist idazoxan (10 M). These findings suggest that the functional regulation of 5-HT release via D2 receptors exists in the rat hippocampus. Furthermore our results indicate that the facilitatory effect of 5-HT release via D2 receptors may be mediated indirectly by noradrenergic neurons, but not mediated directly through D2 receptors located on serotonergic nerve terminals. 相似文献
5.
Fluphenazine-N-mustard (FNM) has been shown to irreversibly block dopaminergic receptor sites and inhibit certain dopaminergically-mediated behaviors. In this study we measured whether FNM has any differential effects on D1 and D2 dopaminergic events. Accordingly, we examined the relative effects of FNM on rotational behavior induced by SKF 38393 (D1 agonist) and Ly 171555 (D2 agonist) in mice with unilateral, 6-hydroxydopamine-induced lesions of the striatum and the effects of FNM on the binding of [3H]Sch 23390 (D1 ligand) and [3H]spiroperidol (D2 ligand) to mouse striatal membranes. FNM inhibited rotational behavior induced by Ly 171555 at doses 10-fold lower than those required to block rotations induced by SKF 38393 (ID50 values: Ly 171555=1.8 mole/kg, IP; SKF 38393=16 mole/kg, IP). The inhibitory effect of high doses of FNM (20 mole/kg) on rotational behavior was overcome by increasing the dose of SKF 38393 and apomorphine, a nonselective dopaminergic agonist. By contrast, the inhibitory effect of FNM was not overcome by Ly 171555, even when given in doses more than 100 times its ED50. Using striatal homogenates in vitro, FNM inhibited the specific binding of [3H]spiroperidol at concentrations about 10-fold lower than those required to inhibit the binding of [3H]Sch 23390 (IC50 values: [3H]spiroperidol=90 nM; [3H]Sch 23390=840 nM). Considerably higher concentrations of FNM were needed to irreversibly inhibit calmodulin activity in striatal homogenates (IC50=10 M). In vivo, FNM inhibited the binding of [3H]spiroperidol measured ex vivo (ID50=4 mole/kg), but did not inhibit the binding of [3H]Sch 23390, even when given in doses as high as 100 mole/kg. These studies indicate that FNM was approximately 10 times more potent at inhibiting D2-than D1-mediated behavior and at displacing D2 versus D1 ligands and suggest that FNM may be useful for studying and differentiating D2- and D1-mediated events. 相似文献
6.
Egon Werle Theo Lenz Günther Strobel Helmut Weicker 《Naunyn-Schmiedeberg's archives of pharmacology》1988,338(1):28-34
Summary The binding properties of 3- and 4-O-sulfoconjugated dopamine (DA-3-0-S, DA-4-0-S) as well as 3-O-methylated dopamine (MT) to rat striatal dopamine D2 receptors were investigated. 3H-spiperone was used as a radioligand in the binding studies. In saturation binding experiments (+)butaclamol, which has been reported to bind to dopaminergic D2 and serotoninergic 5HT2 receptors, was used in conjunction with ketanserin and sulpiride, which preferentially label 5HT2 and D2 receptors, respectively, in order to discriminate between 3H-spiperone binding to D2 and to 5HT2 receptors. Under our particular membrane preparation and assay conditions, 3H-spiperone binds to D2 and 5HT2 receptors with a maximal binding capacity (B
max) of 340 fmol/mg protein in proportions of about 75%:25% with similar dissociation constants K
D (35 pmol/l; 43 pmol/l). This result was verified by the biphasic competition curve of ketanserin, which revealed about 20% high (K
D = 24 nmol/l) and 80% low (K
D = 420 nmol/l) affinity binding sites corresponding to 5HT2 and D2 receptors, respectively. Therefore, all further competition experiments at a tracer concentration of 50 pmol/l were performed in the presence of 0.1 mol/l ketanserin to mask the 5HT2 receptors. DA competition curves were best fitted assuming two binding sites, with high (K
H = 0.12 mol/l) and low (KL = 18 mol/l) affinity, present in a ratio of 3:1. The high affinity binding sites were interconvertible by 100 mol/l guanyl-5-yl imidodiphosphate [Gpp(NH)p], resulting in a homogenous affinity state of DA receptors (K
D = 2.8 mol/l). Competition experiments with various compounds confirmed the binding of 3H-spiperone to D2 receptors. DA-3-O-S, DA-4-O-S, and MT were more than 5,000-, more than 10,000-, and 530-fold less potent in competing for 3H-spiperone binding when compared with DA at the high affinity binding site which mediates biological effects. Therefore, it is concluded that these DA metabolites are biologically ineffective at central D2 receptors.
Send offprint requests to E. Werle at the above address 相似文献
7.
Based on previous own EEG-studies and behavioural studies of other authors, it has been claimed recently that D1 receptors are involved in addictive properties of drugs. It seemed, therefore, of interest to study whether nicotine produces D1-characteristic EEG alterations in rats. EEG was recorded in non-anesthetized, freely moving rats, transmitted telemetrically and underwent power spectral analysis.Nicotine (0.1, 0.2, 0.4 mg/kg s.c.) produced a desynchronization in the EEG and a decrease of power in all of the frequency bands (, , 1, 2, 1) except in 2. With regard to behaviour, an increase of locomotor activity and some discontinuous sniffing was manifest. The effect of nicotine (0.2 mg/kg) was not antagonized by blockade of dopamine D1 receptors by SCH 23390 (0.1 mg/kg s.c., 30 min before nicotine), although this drug by itself increased the power in most of the frequency bands. Prazosine (0.2 mg/kg i.p.), a selective antagonist at 1 adrenoceptors, by itself increased the power in all of the frequency bands, but also failed to antagonize the effects of nicotine (0.2 mg/kg). In contrast, the blocker of nicotinic cholinoceptors mecamylamine (1 mg/kg i.p.) was effective in antagonizing the action of nicotine on the EEG.The results suggest that in nicotine-mediated desynchronization and decrease of power in the EEG, the activation of dopamine D1 or 1 adrenoceptors is not involved.
Correspondence to: K. Kuschinsky at the above address 相似文献
8.
Eric N. Juberg Kenneth P. Minneman Peter W. Abel 《Naunyn-Schmiedeberg's archives of pharmacology》1985,330(3):193-202
Summary The properties of
1- and
2-adrenoceptors in right and left atria of rat heart, and their roles in mediating chronotropic and inotropic responses to-adrenoceptor agonists were examined. [125I](-)-pindolol (125IPIN) bound saturably and specifically to a single class of high affinity sites in homogenates of both right and left atria. Thek
1's for association in right and left atria were 6.5×109 l/mol-min and 2.3×109 l/mol-min respectively, while thek
–1's for dissociation were 0.20 min–1 and 0.17 min–1. The kinetically determinedK
D's were 75 pmol/l in right and 30 pmol/l in left atria and were similar to the equilibriumK
D's determined from Scatchard analysis of saturation isotherms of specific125IPIN binding. Inhibition of125IPIN binding by-adrenoceptor antagonists was stereoselective and the order of potency was timolol > 1-propranolol > d-propranolol > sotalol. Inhibition by
1- and
2-adrenoceptor subtype selective antagonists yielded flat displacement curves with low Hill coefficients. Nonlinear regression analysis of displacement by
1-selective (practolol, atenolol and metoprolol) and
2-selective (ICI 118,551) antagonists gave estimates of the proportion of
1- and
2-adrenoceptors present in rat atria. Right atria contained 67±4.2%
2-adrenoceptors and 33±4.2%
2-adrenoceptor, while left atria contained 67±2.8%
1- and 33±2.8%
2-adrenoceptors. Increases in the rate of spontaneously beating right atria and the force of electrically driven left atria caused by-adrenoceptor agonists were also measured. pA2 values for non-subtype selective-adrenoceptor antagonists in inhibiting isoprenaline-induced increases in rate and force were highly correlated withK
D values determined for specific125IPIN binding. pA2 values for
1- and
2-selective antagonists in inhibiting isoprenaline-induced increases in rate and force correlated well with the pK
D values of these drugs in binding to
1-adrenoceptors, but not with the pK
D values in binding to
2-adrenoceptors. Dose-response curves for stimulation of both rate and force by the
2-selective agonists procaterol and zinterol were shifted to a much greater extent by selective blockade of
1-adrenoceptors with metoprolol than by selective blockade of
2-adrenoceptors with ICI 118,551, suggesting that these compounds caused their effects by activating
1-adrenoceptors. These results suggest that
1- and
2-adrenoceptors coexist in both left and right atria of rat heart in approximately a 21 ratio, however only
1-adrenoceptors mediate the chronotropic and inotropic effects of-adrenoceptor agonists.Supported by a grant from the American Heart Association — Georgia Affiliate 相似文献
9.
R. Jackisch H. Hotz C. Allgaier G. Hertting 《Naunyn-Schmiedeberg's archives of pharmacology》1994,349(3):250-258
Slices of the rabbit caudate nucleus, preincubated with [3H]dopamine and subjected to electrical field stimulation, were used (1) to investigate the involvement of G-proteins in the signal transduction of presynaptic D2 (auto)receptors and -opioid receptors on dopaminergic axon terminals in this tissue and (2) to study a possible mutual interaction of these two presynaptic receptors. Pretreatment of the slices with either pertussis toxin (8 g/ml; 18 h), or N-ethylmaleimide (30 M, 30 min) significantly reduced the inhibitory effects of both the D2 agonist quinpirole and the -opioid receptor agonist U-50488H on the [3H]overflow evoked by 36 pulses (2 ms, 24 mA, 0.3 Hz), suggesting the coupling of both receptors to G-proteins.Experiments designed to study possible interactions of these two presynaptic receptors were carried out under stimulation conditions (only 1 pulse), which strongly diminish interference of endogenous transmitters released in the tissue with modulatory effects of exogenous drugs. For instance, due to the presence of endogenous dopamine, quinpirole was much less potent during 36-pulse-than during 1-pulse field stimulation, whereas the D2 antagonist domperidone was almost without effect in the latter case. Using the 1-pulse stimulation paradigm, the concentration/response curve of quinpirole was unaffected in the presence of the halfmaximal inhibitory concentration of U-50,488 H (0.1 M). On the other hand, also quinpirole at its halfmaximal inhibitory concentration (0.1 M), hardly affected the concentration/response curve of U-50,488 H: only high concentrations of U-50,488 H (above 1 M) seemed to be slightly less effective in the presence than in the absence of the D2 agonist. U-50,488 H, at these high concentrations, was also less potent under 36-pulse than under 1-pulse stimulation conditions. From these findings, we conclude that there is only a limited interaction between presynaptic D2 autoreceptors and -opioid receptors on dopaminergic axon terminals in the rabbit caudate nucleus, despite they are both coupled to PTX/NEM-sensitive G-proteins.
Correspondence to: R. Jackisch at the above address 相似文献
10.
Background The role of dopamine D3/D2 receptors in the control of locomotion is poorly understood.Objectives To examine the influence of selective antagonists at D3 or D2 receptors on locomotion in rats, alone and in interaction with the preferential D3 versus D2 receptor agonist, PD128,907.Methods Affinities of ligands at rat D2 and cloned, human hD3, hD2S, hD2L and hD4 sites were determined by standard procedures. Locomotion was monitored automatically in rats pre-habituated for 30 min to an open-field environment. Extracellular levels of dopamine (DA) were determined by dialysis in the nucleus accumbens and striatum. Drugs were given acutely via the systemic route.Results PD128,907, which preferentially recognised D3 versus D2 sites, biphasically reduced and enhanced locomotion at low (0.01–0.63 mg/kg) and high (2.5–10 mg/kg) doses, respectively. L741,626 and S23199, which behaved as preferential D2 versus D3 receptor antagonists, enhanced the reduction in locomotion evoked by the low dose of PD128,907, blocked the increase provoked by the high dose and suppressed spontaneous locomotion alone. Analogous findings were obtained with haloperidol and raclopride which showed equilibrated affinity at D2 and D3 receptors. UH232 and AJ76, which showed a mild preference for D3 versus D2 sites, did not modify the effect of a low dose of PD128,907, slightly enhanced the hyperlocomotion elicited by the high dose and exerted little influence on locomotion alone. S14297 and U99194, which acted as preferential D3 versus D2 receptor antagonists, abolished the reduction in locomotion elicited by a low dose of PD128,907, potentiated the induction of locomotion by a high dose, and failed to influence locomotion alone. The actions of S14297 were stereoselective inasmuch as they were mimicked by the racemic form, S11566, but not by the inactive enantiomer, S17777. In contrast to S14297, S11566 and U99194, however, S33084, SB269,652, GR218,231 and N-[-4-[-(1-naphtyl)piperazine-1-yl]butyl] anthracene-2-carboxamide (NGB-1), highly selective D3 versus D2 receptor antagonists, were inactive under all conditions. PD128,907 (0.01–10.0 mg/kg) suppressed dialysate levels of DA in the nucleus accumbens and striatum, actions blocked by L741,626 and haloperidol, yet unaffected by S14297 and S33084.Conclusions The facilitatory influence of a high dose of PD128,907 upon locomotion is mediated by postsynaptic D2 receptors and, possibly, countered by their D3 counterparts. Correspondingly, selective blockade of D2 but not of D3 receptors alone suppresses motor function. The reduction in locomotion provoked by a low dose of PD128,907 may be mediated by D2 autoreceptors, but a role of postsynaptic D3 receptors cannot be excluded. Finally, mechanisms underlying the contrasting influence of chemically diverse D3 receptor antagonists upon locomotion remain to be elucidated. 相似文献
11.
Summary The potent dopamine receptor antagonist [3H]-spiroperidol was used to label binding sites in a membrane fraction derived from rabbit mesenteric artery which had characteristics expected for dopamine receptors. The binding was of high affinity with an equilibrium dissociation constant (KD) of 13.1 nM; it was saturable with 110 fmol of [3H]-spiroperidol bound/mg protein at maximal occupancy of the sites. Binding at 37° C was rapid and readily reversible with rate constants of 0.0154 nM–1 min–1 and 0.114 min–1 for forward and reverse reaction, respectively. Dopamine receptor antagonists were about 100–200 times more potent than -adrenolytic drugs in competing for the [3H]-spiroperidol binding sites and dopamine was much more potent than (–)-noradrenaline, adrenaline, (–)-isoprenaline, clonidine or serotonin. It is concluded that in a membrane fraction of the rabbit mesenteric artery there exist binding sites for [3H]-spiroperidol indistinguishable from dopamine receptors. Thus the present results support the view that in vascular smooth muscle there exist specific dopamine receptors.This work was supported by the Deutsche Forschungsgemeinschaft 相似文献
12.
Régine Ramdine Anne-Marie Galzin Salomon Z. Langer 《Naunyn-Schmiedeberg's archives of pharmacology》1989,340(4):386-395
Summary In superfused rat hypothalamic slices prelabelled with [3H]-noradrenaline, the 2-adrenoceptor agonist UK 14304 inhibited in a concentration-dependent manner the electrically-evoked release of tritium. This inhibition was antagonized by the 2-adrenoceptor blocking agent idazoxan, which by itself increased the electrically-evoked tritium overflow. Exposure to forskolin, an adenylate cyclase activator, increased the electrically-evoked release of [3H]-noradrenaline. In the presence of forskolin (1 mol/l), both the inhibitory effect of UK 14304 and the increasing effect of idazoxan on the electrically-evoked release of [3H]-noradrenaline were less pronounced than in the absence of the adenylate cyclase activator. Exposure to forskolin and to the phosphodiesterase inhibitor 3-isobutyl-l-methylxanthine shifted to the right the concentration-effect curve for UK 14304 in a similar manner as that observed in the presence of forskolin alone. Exposure to phorbol-12,13-dibutyrate (0.01–10 mol/l), a drug which activates protein kinase C, increased the electrically-evoked release of [3H]-noradrenaline. In the presence of phorbol-12,13-dibutyrate (0.1 and 1 mol/l), the concentration effect curve for UK 14304 on tritium overflow was significantly shifted to the right. The increasing effect of idazoxan on tritium overflow was significantly less pronounced in the presence of 1 mol/l phorbol-12,13-dibutyrate.In superfused rat hypothalamic slices prelabelled with [3H]-5-hydroxytryptamine, the 2-adrenoceptor agonist UK 14304 significantly inhibited the electrically-evoked release of tritium. Exposure to forskolin increased in a concentration-dependent manner [3H]-5-hydroxytryptamine overflow, but did not modify the UK 14304-mediated inhibition. Exposure to 3-isobutyl-1-methylxanthine enhanced the electrically-evoked release of [3H]-5-hydroxytryptamine. In the presence of both forskolin (1 mol/l) and 3-isobutyl-l-methylxanthine (1 mmol/l), the concentration-response curve for UK 14304 was significantly shifted to the right. Exposure to phorbol-12,13-dibutyrate (0.01–10 mol/l) enhanced in a concentration-dependent manner the electrically-evoked overflow of [3H]-5-hydroxytryptamine. In the presence of phorbol-12,13-dibutyrate (0.1 and 1 mol/l), UK 14304 was significantly less potent to inhibit tritium release than in the absence of the protein kinase C activator.It is concluded that both cyclic AMP and phosphoinositide turnover are involved in the modulation of noradrenaline and 5-hydroxytryptamine release by presynaptic 2-adrenoceptors in rat hypothalamic slices. However, these interactions do not represent definitive proof for a cause-effect relationship for the second messengers mediating the 2-adrenoceptor induced inhibition of transmitter release either as autoreceptor or as heteroreceptor.Send offprint requests to S. Z. Langer at the above address 相似文献
13.
Anne-Ulrike Trendelenburg Klaus Starke Norbert Limberger 《Naunyn-Schmiedeberg's archives of pharmacology》1994,350(5):473-481
2-Adrenoceptors modulating the release of dopamine were identified and characterized in slices of the head of the rabbit caudate nucleus. Release of endogenous dopamine was measured by fast cyclic voltammetry as the increase in the extracellular concentration of dopamine elicited by electrical stimulation. The electrochemical signal was identified as dopamine by means of the oxidation potential, the voltammogram and the fact that the signal was not changed by desipramine, which inhibits the high affinity uptake of noradrenaline, but was greatly increased by nomifensine, which in addition inhibits the high affinity uptake of dopamine.Stimulation by 6 pulses/100 Hz increased the extracellular concentration of dopamine by about 85 nM. The selective 2-adrenoceptor agonist 5-bromo-6-(2-imidazolin-2-ylamino)-quinoxaline (UK 14,304) reduced this release with an EC50 of 173 nM and by maximally 75%. The 2-adrenoceptor agonists clonidine and oxymetazoline only tended to cause a decrease. Six drugs, including oxymetazoline, were tested as antagonists against UK 14,304. Their order of antagonist potency (pKD values in brackets) was rauwolscine (8.0) > oxymetazoline (7.5) > 2-(2,6-dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxane (WB 4101; 7.3) > phentolamine (7.1) > corynanthine (5.1) prazosin (< 6). Given alone, the antagonists did not change the release of dopamine elicited by 6 pulses/100 Hz, and the same was true for the dopamine receptor antagonist sulpiride. When caudate slices were stimulated by 10 pulses/1 Hz, sulpiride increased the release of dopamine. Desipramine and rauwolscine, in contrast, again caused no change.It is concluded that dopaminergic axons in the rabbit caudate nucleus possess release-inhibiting 2-adrenoceptors. The antagonist affinities indicate that they belong to the 2A subtype. In this, they agree with all presynaptic 2-autoreceptors studied so far in rabbits as well as with the 2-heteroreceptors modulating the release of serotonin in rabbit brain cortex, suggesting that at least the majority of presynaptic 2-adrenoceptors in the rabbit are 2A. The agonist sensitivity of the caudate presynaptic 2-adrenoceptors is low in comparison with cerebrocortical presynaptic 2-autoreceptors, possibly due to absence of a receptor reserve.
Correspondence to: N. Limberger at the above address 相似文献
14.
Summary Fast cyclic voltammetry has been used to measure electrically evoked dopamine overflow from slices of rat nucleus accumbens in vitro. The substance detected was shown voltammetrically and biochemically to be dopamine of neuronal origin. Enough dopamine was released by a single electrical pulse to be easily detectable, and under these conditions there was no auto-inhibition by the endogenous transmitter (as demonstrated by the failure of dopamine antagonists to increase the amount released). There was no significant inhibition, or enhancement, of release by agonists at the following receptor types: dopamine D1, 5-hydroxytryptamine, cholinoceptors, 1-, 2-, -adrenoceptors, cholecystokinin or neurotensin receptors. However, the dopamine D2 receptor agonist, quinpirole, was capable of totally inhibiting the release; this effect was concentration-dependently antagonized by the D2 antagonists haloperidol, sulpiride, metoclopramide and clozapine, with potencies which corresponded to their affinities for D2 receptors in striatal tissue. The results show that the presynaptic receptors on dopaminergic nerve terminals are of the D2 type and apparently identical to those in the corpus striatum. 相似文献
15.
Frankle WG Gil R Hackett E Mawlawi O Zea-Ponce Y Zhu Z Kochan LD Cangiano C Slifstein M Gorman JM Laruelle M Abi-Dargham A 《Psychopharmacology》2004,175(4):473-480
Rationale To examine the D2 occupancy of two commonly used antipsychotic medications and relate this to the D2 occupancy by endogenous dopamine in schizophrenia.Objectives The aim of this study is to compare the occupancy of striatal D2 receptors by the atypical antipsychotic medications risperidone and olanzapine at fixed dosages and to estimate the effect on D2 occupancy by dopamine as a result of these treatments.Methods Seven patients with schizophrenia taking risperidone 6 mg/day and nine patients with schizophrenia taking olanzapine 10 mg/day underwent an [123I]IBZM SPECT scan after 3 weeks of treatment. The specific to non-specific equilibrium partition coefficient (V3) after bolus plus constant infusion of the tracer was calculated as [(striatal activity)/(cerebellar activity)]–1. D2 receptor occupancy was calculated by comparing V3 measured in treated patients to an age-corrected V3 value derived from a group of untreated patients with schizophrenia, previously published, according to the following formula: OCC=1–(V3 treated/V3 drug free).Results V3 was significantly lower in risperidone treated patients compared with olanzapine treated patients (0.23±0.06 versus 0.34±0.08, P=0.01), which translated to a significantly larger occupancy in schizophrenic patients treated with risperidone compared to olanzapine (69±8% versus 55±11%, P=0.01). Data from our previous study were used to calculate the occupancy of striatal D2 receptors by antipsychotic medications required to reduce the occupancy of these receptors by endogenous dopamine to control values. In medication-free patients with schizophrenia, the occupancy of striatal D2 receptors by endogenous dopamine is estimated at 15.8%. In healthy controls, the occupancy of striatal D2 receptors by dopamine is estimated at 8.8%. In order to reduce the dopamine occupancy of striatal D2 receptors in patients with schizophrenia to control values, 48% receptor occupancy by antipsychotic medications is required.Conclusions These data indicate that the dosage of these medications, found to be effective in the treatment of schizophrenia, reduces DA stimulation of D2 receptors to levels slightly lower than those found in unmedicated healthy subjects. 相似文献
16.
Esa R. Korpi Garry Wong Hartmut Lüddens 《Naunyn-Schmiedeberg's archives of pharmacology》1995,352(4):365-373
Clozapine, an atypical neuroleptic, functionally antagonizes the -aminobutyric acid-induced chloride uptake via the main central inhibitory receptor, -aminobutyric acid type A (GABAA) receptor, in brain vesicles. GABAA antagonism by micromolar concentrations of clozapine is more efficient in rat cerebrocortical and hippocampal membranes than in cerebellar membranes, as evidenced by clozapine reversal GABA-inhibition of [35S]t-butylbicyclophosphorothionate ([35S]TBPS) binding. A typical neuroleptic, haloperidol, failed to antagonize GABA in any of these brain regions, while the specific GABAA antagonist 2-(3-carboxy-2,3-propyl)-3-amino-6-p-methoxyphenylpyrazinium bromide (SR 95531) was efficient in all three brain regions. Clozapine action on [35S]TBPS binding was unaffected by the benzodiazepine receptor antagonist flumazenil. Clozapine inhibited the binding of [3H]muscimol and [3H]SR 95531 to the GABA recognition site, but this effect only partially correlated with the regional differences in and the potency of clozapine antagonism of GABA-inhibition of [35S]TBPS binding, suggesting that also other than GABA sites may mediate clozapine actions. Autoradiography of [35S]TBPS binding revealed GABA antagonism by clozapine in most brain regions. Main exceptions were cerebellar granule cell and molecular layers, olfactory bulb external plexiform and glomerular layers and primary olfactory cortex, where clozapine antagonized GABA inhibition less than average, and lateral hypothalamic and preoptic areas where its antagonism was greater than average. Recombinant 622 receptors, the predominant 6 subunit-containing receptor subtype in cerebellar granule cells, failed to show GABA antagonism by clozapine up to 100 M. In contrast, recombinant 122 receptors, forming the predominant receptor subtype in the brain, were clozapine sensitive. Recombinant 622 and 632 receptors resulted in clozapine-insensitive receptors, whereas 612 receptors were clozapine sensitive. The efficacy of clozapine to antagonize GABA in 1x2 receptors decreased in the order of 112>122>132. The results indicate that clozapine antagonizes the function of most GABAA receptor subtypes, and that the interaction is determined by the interaction of the and subunit variants. GABA antagonism is a unique property of clozapine, not shared by haloperidol, which might be involved in the pharmacological mechanism for the increased seizure susceptibility associated with clozapine treatment. 相似文献
17.
Human cerebral cortical synaptosomes were used to determine the 5-hydroxytryptamine (5-HT) receptor subtype to which the inhibitory presynaptic 5-HT autoreceptor belongs. The synaptosomes preincubated with [3H]5-HT were superfused and tritium overflow was stimulated by high K+. The K+-evoked tritium overflow, which was Ca2+-dependent but tetrodotoxin-resistant, was concentration-dependently inhibited by the nonselective 5-HTlD1D/1D receptor agonist, 5-carboxamidotryptamine. Ketanserin at a concentration which should block the 5-HT1D but not the 5-HT1D receptor failed to antagonize the inhibitory effect of 5-carboxamidotryptamine. In contrast, the non-selective 5-HT1D/1D receptor antagonist, methiothepin, at a concentration which should block both the 5-HT1D and the 5-HT1D receptor abolished the effect of 5-carboxamidotryptamine. It is concluded that the presynaptic 5-HT autoreceptor, which has previously been classified as 5-HT1D, belongs to the 5-HT1D subtype. 相似文献
18.
Ludwig Funk Anne-Ulrike Trendelenburg Norbert Limberger Klaus Klaus 《Naunyn-Schmiedeberg's archives of pharmacology》1995,352(1):58-66
The study was designed to classify in terms of 2A, 2B, 2C and 2D the presynaptic 2-autoreceptors, as well as the 2-receptors modulating the release of acetylcholine, in the myenteric plexus-longitudinal muscle (MPLM) preparation of the guinea-pig ileum. A set of antagonists was chosen that was able to discriminate between the four subtypes. Small pieces of the MPLM preparation were preincubated with 3H-noradrenaline or 3H-choline and then superfused and stimulated electrically.The stimulation periods used (3H-noradrenaline: 3 trains of 20 pulses, 50 Hz, train interval 60 s; 3H-choline: single trains of 30 pulses, 0.2 Hz) did not lead to 2-autoinhibition or inhibition of 3H-acetylcholine release by endogenous noradrenaline. The 2-selective agonist 5-bromo6-(2-imidazolin-2-ylamino)-quinoxaline (UK 14,304) reduced the evoked overflow of tritium in both 3H-noradrenaline and 3H-choline experiments. Most (3H-noradrenaline) or all (3H-choline) of the 10 antagonists shifted the concentration-inhibition curves of UK 14,304 to the right. pKd values of the antagonists were calculated from the shifts. pKd values from 3H-noradrenaline experiments correlated with pKd values from 3H-choline experiments (r = 0.981).It is concluded that 2-autoreceptors and 2-heteroreceptors modulating the release of acetylcholine in the MPLM preparation are of the same subtype. Comparison with antagonist affinities for prototypic native 2 binding sites, binding sites in cells transfected with 2 subtype genes, and previously classified presynaptic 2-adrenoceptors — all taken from the literature — indicates that both are 2D. The results are consonant with the hypothesis that at least the majority of 2-autoreceptors belong to the 2A/D branch of the 2-adrenoceptor tree, across mammalian or at least across rodent and lagomorph species. The same may hold true for 2-adrenoceptors on non-noradrenergic neurones. 相似文献
19.
P. M. Beart C. J. Cook M. Cincotta D. J. de Vries P. Tepper D. Dijkstra A. S. Horn 《Naunyn-Schmiedeberg's archives of pharmacology》1987,336(5):487-493
Summary The affinity of a series of N,N-disubstituted 2-aminotetralins for the rat striatal D2 dopamine receptor labelled by [3H]spiperone has been determined. Displacement data for the more potent 2-aminotetralins were better described by a model where the compounds competed for [3H]spiperone at two sites. The high affinity component accounted for approximately 80% of the total sites. Displacement curves for all 2-aminotetralins were shifted to the right by 100 M guanosine-5-triphosphate; a result attributable to the redistribution of 13–47% of the sites to a low affinity form. These data are consistent with the N,N-disubstituted 2-aminotetralins being agonists at the D2 dopamine receptor. In particular, the affinities of the 5-hydroxy-2-aminotetralins were as high as those of traditional dopamine agonists.
Send offprint requests to P. M. Beart 相似文献
20.
R. Jackisch S. Moll T. J. Feuerstein G. Hertting 《Naunyn-Schmiedeberg's archives of pharmacology》1985,330(2):105-113
Summary
3H-Noradrenaline release in the rabbit hippocampus and its possible modulation via presynaptic dopamine receptors was studied. Hippocampal slices were preincubated with 3H-noradrenaline, continuously superfused in the presence of cocaine (30 mol/l) and subjected to electrical field stimulation. The electrically evoked tritium over-flow from the slices was reduced by 0.1 and 1 mol/l dopamine and apomorphine, but significantly enhanced by 10 mol/l apomorphine or by 0.1 and 1 mol/l bromocriptine. If the 2-adrenoceptor antagonist yohimbine (0.1 mol/l) was present throughout superfusion, the inhibitory effects of dopamine and apomorphine were more pronounced and even 10 mol/l apomorphine and 1 mol/l bromocriptine inhibited noradrenaline release. Qualitatively similar observations were made in the presence of another 2-antagonist, idazoxane (0.1 mol/l). In the presence of the D2-receptor antagonist domperidone (0.1 mol/l) the inhibitory effects of dopamine were almost abolished, whereas both apomorphine (>1 mol/l) and bromocriptine (>0.01 mol/l) greatly facilitated noradrenaline release. The D2-receptor agonist LY 171555 (0.1 and 1 mol/l) significantly reduced the evoked noradrenaline release whereas the D1-selective agonist SK & F 38393 was ineffective at similar concentrations. The effects of LY 171555 were abolished in the presence of domperidone (0.1 mol/l) but remained unchanged in the presence of yohimbine or idazoxane (0.1 mol/l, each).At 1 mol/l the D2-receptor antagonists domperidone and (-)sulpiride significantly increased the evoked noradrenaline release by about 10%. However, at this concentration, domperidone (but not (-)sulpiride) affected also basal tritium outflow. Bulbocapnine and the preferential D1-receptor antagonists SCH 23390 enhanced the evoked noradrenaline release already at 0.1 mol/l. Their marked facilitatory effects (50 to 60% increase at 1 mol/l) were reduced in the presence of idazoxane (0.1 mol/l) and almost abolished in the presence of 0.1 mol/l yohimbine, whereas the increase due to 1 mol/l (-)sulpiride persisted under these conditions.The evoked tritium efflux from rabbit hippocampal slices preincubated with 3H-serotonin was not affected by dopamine receptor agonists.From our results we conclude that hippocampal noradrenaline, but not serotonin release, is modulated via D2-dopamine receptors. In addition, our results provide evidence for more or less pronounced 2-adrenoceptor agonistic properties of dopamine and 2-adrenoceptor antagonistic properties of apomorphine, bromocriptine, SCH 23390 and bulbocapnine in this noradrenaline release model from CNS tissue. 相似文献