Changes in soluble calmodulin following activation of dopamine receptors in rat striatal slices.

Various molecular forms of cyclic nucleotide phosphodiesterase (PDE) are present in the striatum of rats. While Ca²⁺ by itself cannot modulate striatal PDE, this ion is essential for the activation of striatal PDE by calmodulin (CaM). Incubation of striatal slices with apomorphine (10^?7 M) for 30 min increased the total CaM content of the supernatant fraction. Also the amount of CaM associated with PDE was increased and the K_m of PDE for cAMP was lowered. A shorter incubation with dopamine or apomorphine (10 min) failed to increase CaM and to lower the K_m of PDE.Haloperidol (10^?7 M), a dopamine receptor antagonist, prevented the change in the kinetic profile of PDE elicited by dopamine (2 × 10^?7M). Transection of the nigra-striatal fibre bundle by itself did not change the kinetic profile of striatal PDE, but in slices prepared from deafferented striata, a 30 min activation of dopamine receptors still elicited a decrease in the K_m of PDE for cAMP. These findings suggest that following a persistent stimulation of dopamine receptors, the CaM content increases in the cytosol because it is mobilized from a pool located in post-synaptic membranes. This mobilization of CaM regulates PDE; thus, regulation of PDE through a translocation of CaM may participate in reducing the functional output of dopamine receptors following persistent stimulation.     

Differential influence of D1 and D2 dopamine receptors on acute opiate withdrawal in guinea-pig isolated ileum

1. The effects exerted by D₁ and D₂ dopamine agonists and antagonists on the acute opiate withdrawal induced by μ- and κ-receptor agonists were investigated in vitro.
2. Following a 4 min in vitro exposure to morphine (moderately selective μ-agonist), [D-Ala², Me-Phe⁴, Gly-ol⁵]enkephalin (DAMGO, highly selective μ-agonist) or U-50488H (highly selective κ-agonist) the guinea-pig isolated ileum exhibited a strong contracture after the addition of naloxone.
3. The non-selective dopamine receptor antagonist haloperidol when added before or after the opioid agonists, was able dose-dependently to prevent or to reverse the naloxone-induced contracture after exposure to μ- (morphine and DAMGO) and κ- (U-50488H) opioid agonists. The non-selective dopamine receptor agonist, apomorphine, was able to exert the same effects only at the highest concentration used.
4. The selective D₂ dopamine receptor antagonist, sulpiride, was also able to reduce dose-dependently both μ- and κ-opioid withdrawal, whereas the D₁-receptor selective antagonist SCH 23390 did not affect either μ- or κ-opioid withdrawal.
5. Bromocriptine, a D₂ selective dopamine receptor agonist was able to increase significantly, and in a concentration-dependent manner, the naloxone-induced contracture by μ- and κ-opioid agonists, whereas SKF 38393, a D₁ selective dopamine receptor agonist, increased only the withdrawal after morphine or U50-488H.
6. Our data indicate that both D₁ and D₂ dopamine agonists and antagonists are able to influence opiate withdrawal in vitro, suggesting an important functional interaction between the dopaminergic system and opioid withdrawal at both the μ- and κ-receptor level.
7. Furthermore, the ability of sulpiride to block strongly opiate withdrawal when compared to SCH 23390, as well as the effect of bromocriptine to increase opiate withdrawal suggest that D₂ dopamine receptors may be primarily involved in the control of opiate withdrawal.

     

激动多巴胺受体抑制大鼠纹状体脑片Ca^2＋—钙调蛋白依赖性蛋白激酶Ⅱ活性

目的：研究缺氧时纹状体多巴胺能神经毒性的机制。方法：采用大鼠纹状体脑片体外培养模型。以底物磷酸化^32P-掺入法测定Ca^2 -钙调蛋白依赖性蛋白激酶Ⅱ（CCDPKⅡ）的活性。结果：缺氧30min,纹状体脑片CCDPKⅡ活性降低75％,慢性利血平化使得缺氧诱导的酶活性降低程度减轻,与对照组相比大约降低40％。外源性多巴胺显著降低纹状体脑片CCDPKⅡ活性。去除胞外Ca^2 后,多巴胺诱导的酶活性降低作用被削弱。阿扑吗啡（非特异性多巴胺受体激动剂）、SKF38393（特异性D1样受体激动剂）和喹吡罗（特异性D2样受体动剂）均可显著降低CCDPKⅡ的活性。Sch-23390(特异性D1样受体拮抗剂）和吗丁啉（特异性D2样受体拮抗剂）均可拮抗多巴胺所诱导的酶活性的抑制作用。结论：多巴胺参与缺氧诱导的纹状体CCDPKⅡ活性抑制,其作用机制与D1样和D2样受体的激活以及胞外Ca^2 的内流有关,从而导致多巴胺介导的纹状体神经损伤。     

Evidence for central selective dopamine receptor stimulation in the mediation of nomifensine-induced hyperalgesia and the effects of opiate antagonists

The hyperalgesic effects of nomifensine were studied using a modified tail immersion test in mice. Intracerebroventricular injection of the peripherally acting dopamine antagonist domperidone totally antagonized nomifensine-induced hyperalgesia but this blockade was not evident after peripheral administration of domperidone suggesting mediation of hyperalgesia at a central location. The dopamine antagonist cis-flupenthixol and also bromocriptine shifted the nomifensine-induced hyperalgesia dose-response curve to the right, whereas sulpiride had no antagonistic effect. These results are discussed in relation to the D-1 and D-2 classification of dopamine receptors, and their putative agonists and antagonists. Naloxone produced a blockade of nomifensine-induced hyperatgesia, but another opiate antagonist MR 1452, though inherently hyperalgesic, did not modify the hyperalgesia produced by nomifensine. These findings do not rule out the participation of an opiate receptor in the mechanism of opiate antagonist blockade of nomifensine-induced hyperalgesia. However, they may suggest that MR 1452-induced hyperalgesia depends on a different mechanism from that of induced by nomifensine since they were not synergistic.     

A pharmacological study of dopaminergic receptors in planaria

The dopaminergic receptors of planaria have been studied with pharmacological and biochemical criteria. Dopamine D₁ selective agonists (CY 208243 (10 μg/ml) and SKF 38393 (10 μg/ml)) induced in planaria typical screw-like hyperkinesias, that were inhibited by a D₁ antagonist (SCH 23390 (10 μg/ml)), but not by a D₂ antagonist (sulpiride (1000 μg/ml)). Dopamine D₂ selective agonists (PHNO (5 μg/ml), lisuride (5 μg/ml)) on the contrary induced a typical “C” like curling, that was inhibited by pretreatment with D₂ selective blocking agents, but not by D₁ selective blocking agents. With agonists with a D₁ /D₂ mixed action (apomorphine 60 μg/ml) or with amphetamine (100 μg/ml), the D₁ type movements appeared to be more evident.

Dopamine D₁-selective agonists, mixed action agonists or D₂-selective agonists, all induced a significant increase in levels of cAMP, that was prevented by pretreatment with the specific DA blocking agent.     

锰对大鼠脑纹状体多巴胺受体的毒作用

大鼠每日ip15或30mg/kg硫酸锰,连续10d。末次染毒后24h,体重、脑重和纹状体重均未见变化。30mg/kg组,DNA,RNA降低,蛋白质/DNA比值明显增加;电镜下DA神经元个别线粒体肿胀。锰增加[~3H]spiperone与脑纹状体DA受体的特异性结合,同时亦看到染毒大鼠纹状体和突触中锰含量升高,提示脑纹状体DA受体功能状态与其锰含量变化有关。锰的中枢神经毒性表现来源于DA神经功能的损害。     

Effect of dopamine D-1 and D-2 receptor selective drugs on dopamine release and metabolism in rat striatum in vivo

Summary The effect of the dopamine (DA) D-1 agonist SKF 38393, the D-2 agonist LY 171555 and the mixed D-1/D-2 agonist apomorphine on striatal DA release and metabolism was tested in vivo using an intracerebral dialysis method in halothane-anaesthetized rats. The specificity of responses to these agonists was tested using the selective DA antagonists SCH 23390 (D-1) and sulpiride (D-2).Both LY 171555, 0.01 mg/kg, and SKF 38393, 10 mg/kg, reduced levels of DA in striatal perfusates. Neither SCH 23390, 0.5 and 5 mg/kg, nor sulpiride, 10 mg/kg, affected levels of DA in striatal perfusates, but 250 mg/kg sulpiride caused a DA increase. The decrease of DA levels induced by LY 171555 (0.01 mg/kg) was prevented by pretreatment with sulpiride (10 mg/kg) but not SCH 23390 (0.5 mg/kg). In comparison, pretreatment with SCH 23390 (0.5 mg/kg) completely inhibited the reduction of DA induced by SKF 38393 (10 mg/kg) while sulpiride (10 mg/kg) was without effect. Apomorphine (0.05 mg/kg) also decreased DA in striatal perfusates and this action was partially inhibited by both SCH 23390 (0.5 mg/kg) and sulpiride (10 mg/kg).Levels of the DA metabolite DOPAC in striatal perfusates also significantly decreased following LY 171555 (0.01 mg/kg) and apomorphine (0.05 mg/kg) but not SKF 38393 (10 mg/kg). The antagonist SCH 23390, in a dose, 0.5 mg/kg, that alone did not increase levels of DOPAC, inhibited the reduction of DOPAC induced by both LY 171555 and apomorphine. Sulpiride, 10 mg/kg, caused a marked increase in striatal DOPAC and this was not affected by a subsequent injection of LY 171555, SKF 38393 or apomorphine.We conclude from these data that DA release in rat striatum is autoregulated by independent D-1 and D-2 receptor-linked mechanisms. In contrast, the level of DA metabolism is controlled by a D-2 receptor-coupled mechanism which can be influenced by the D-1 receptor. This study provides further evidence that DA release and DA synthesis/metabolism are able to change independent of each other.     

四氢原小檗碱类对小牛纹状体D_1和D_2多巴胺受体结合的特性(英文)

目的:研究四氢原小檗碱类(THPB)对脑内多巴胺受体D_1和D_2亚型的结合特性,并阐明它们之间的构效关系.方法:放射配位体测定结合双位点模型分析.结果:4个THPB与D_1受体以R_H和R_L双位点结合,它们在C_2和C_9或C_2和C_(10)位有两个羟基,另外11个THPB与D_1受体以单位点结合.对于D_2受体,11个被检测的化合物均以单位点结合,其中,在C_2位有羟基的THPB亲和力最强.结论:在C_2和C_9或C_2和C_(10)位有双羟基的THPB具有D_1受体激动剂的内在活性,其它THPB则无此活性.11个THPB均为D_2受体拮抗剂.     

Comparison between radiolabelled and endogenous dopamine release from rat striatal slices: effects of electrical field stimulation and regulation by D2-autoreceptors

Summary Direct comparisons have been made between the release of radiolabelled and endogenous dopamine from superfused rat striatal slices prelabelled with ³H-dopamine. Both spontaneous release and release evoked by electrical field stimulation (3 Hz, 2 min) were measured using a high-sensitivity HPLC system with electrochemical (coulometric) detection, plus scintillation counting of chromatographically separated superfusate fractions. Two periods of electrical stimulation released similar amounts of endogenous dopamine, but the second stimulation released much less ³H-dopamine than did the first, although the levels of spontaneous release immediately before the two stimuli were similar. Substantial increases in endogenous 3,4-dihydroxy phenyl acetic acid (DOPAC) release but only minor increases in ³H-DOPAC release occurred following the two stimuli. The dopamine agonist pergolide (1 M) reduced the electrically-stimulated release of both ³H-dopamine and endogenous dopamine to a similar extent, whilst the D₂-selective antagonist sulpiride (1 M) produced large increases in both ³H-dopamine and endogenous dopamine electrically-stimulated release. In addition, spontaneous release of both ³H-dopamine and endogenous dopamine were decreased by pergolide and increased by sulpiride. Co-addition of sulpiride and pergolide produced lesser increases than those seen with sulpiride alone. These studies indicate that, despite major differences between ³H-dopamine and endogenous dopamine release in response to various stimuli, their regulation by D₂-autoreceptors appears similar; a novel finding being the modulation of spontaneous ³H-dopamine release by autoreceptors. This suggests that these autoreceptors do not selectively affect any specific intracellular pool contributing to dopamine release under these conditions, though it should be noted that the prelabelling process itself may alter the intracellular sources of subsequent release.This work was supported by Medical Research Council Send offprint requests to S. R. Nahorski at the above address     

Dopamine receptors modulating [H]acetylcholine release in slices of the cat caudate: Effects of (−)-N-(2-chloroethyl)-norapomorphine

(−)-N-(2-Chloroethyl)-norapomorphine ((−)-NCA) inhibited in a concentration-dependent manner the electrically evoked [³H]acetylcholine release in slices of cat caudate. The inhibition by (−)-NCA was reversible and antagonized by the benzamide neuroleptic S-sulpiride. Although (−)-NCA is an irreversible antagonist at some behaviorally relevant postsynaptic dopamine receptors, its effect as an agonist on dopamine receptors modulating [³H]acetylcholine release strongly resembles its action on presynaptic dopamine autoreceptors modulating [³H]dopamine release. Our results suggest that the dopamine receptor modulating [³H]acetylcholine release may not be an appropriate in vitro model for those behaviorally relevant postsynaptic dopamine receptors which are antagonized by (−)-NCA. It is more likely that it conforms to the characteristics of presynaptic release-modulating dopamine autoreceptors. The agonistic action of (−)-NCA at presynaptic dopamine receptors, in contrast to the irreversible antagonism of some postsynaptic dopamine receptors by (−)-NCA, should be interpreted with caution. Evidence is presented which suggests that (−)-NCA breaks down in solution into (−)-N-(2-hydroxylethyl)-norapomorphine ((−)-NHA). Since (−)-NHA is an agonist at presynaptic dopamine receptors, this physicochemical breakdown product may be partly responsible for the apparent agonistic properties of (−)-NCA under our in vitro conditions.     

Both agonists and antagonists of the strychnine-insensitive glycine site of N-methyl-D-aspartate receptors modulate polysynaptic excitations in slices of mouse olfactory cortex

Summary In this study, it is reported that bath application of D-serine and, to a lesser extent glycine, potentiated polysynaptic but not monosynaptic excitations evoked in slices of mouse olfactory cortex perfused with solution containing Mg²⁺ (1 mmol/l), picrotoxin and strychnine (both 25 μmol/l). Effects were largely confined to the longer latency components of the field potentials and occurred at amino acid concentrations of between 0.01 and 1 mmol/l. The effects of D-serine and glycine were antagonized by 7-chlorokynurenate and indole-2-carboxylate, antagonists of the glycine regulatory site of the N-methyl-D-aspartate (NMDA) receptor complex. D-Serine (glycine not tested) also potentiated, and 7-chlorokynurenate partially inhibited the longer latency components of the polysynaptic field potentials evoked in slices perfused in the absence of picrotoxin and strychnine. However, neither D-serine nor glycine potentiated responses evoked by the bath application of NMDA. It is concluded that under the present experimental conditions, the glycine regulatory sites of those NMDA receptor involved in the mediation of polysynaptic excitations in the mouse olfactory cortex are not saturated with endogenous glycine.     

多巴胺D_2/血管紧张素AT_1嵌合受体:D_2受体第三细胞内环影响受体与配基结合以及与G蛋白偶联的特性(英文)

目的:研究受体第三细胞内环(IL_3)的长度对受体与配基结合及与G蛋白偶联特性的影响.方法:用目前已知的G蛋白偶联受体中IL_3最短的血管紧张素Ⅱ AT_1受体的IL_3替换野生型D_2受体较长的IL_3,组成D_2/AT,嵌合受体.结果:与野生型D_2受体相比,D_2/AT_1嵌合受体与拮抗剂的亲和性均降低,与激动剂的亲和性有的增高,有的降低.嵌合受体失去与G蛋白偶联的能力,也不能产生磷酸肌醇水解.结论:受体的IL_3对受体配基结合位点和空间构象有一定影响;受体与G蛋白的偶联不仅与IL_3有关,而且还受非IL_3区域的影响,而IL_3的长度是决定这两方面影响的因素之一.     

Morphine and nigrostriatal function in the rat and mouse: The role of nigral and striatal opiate receptors

Using local injections of drugs and hemisection experiments, a comparison was made of the actions of morphine on the dopaminergic nigrostriatal system of the rat and mouse. In the rat, morphine appeared to act exclusively at presynaptic opiate receptors on dopaminergic nerve endings in the striatum. Activation of these receptors resulted in enhanced dopamine synthesis but with no associated increase in dopamine release. In the mouse, morphine acted at the level of the substantia nigra to enhance both striatal dopamine synthesis and release. The exact localization of these receptors in the substantia nigra remains to be determined.     

GABA_B受体的最新进展:从药理学到分子生物学(英文)

Bicuculline-insensitive receptors for the inhibitory neurotransmitter γ-aminobutyric acid (GABA), GABAB receptors, are a distinct subclass of receptors that mediate depression of synaptic transmission and contribute to neu-ronal inhibition. When activated, these receptors reduce transmission at excitatory and inhibitory synapses, as a result of an increase in K conductance, or a decrease in voltage-dependent Ca2 currents. They are also linked to G-proteins, or intracellular effector systems in a very complex manner. The recent development of highly specific and potent agonists and antagonists for these receptors has led to a much better understanding of their physiology and pharmacology, including their heterogeneity, as well as their molecular biology. Over the past year, expression and cloning studies have contributed to major advances in characterizing GABAB receptor structure, with the discovery of the amino acid sequences of GABABRla/R1b splice variants and GABABR2 receptors. These isoforms are     

Rapid heterologous desensitization of antinociceptive activity between mu or delta opioid receptors and chemokine receptors in rats

Previous studies have shown pretreatment with chemokines CCL5/RANTES (100 ng) or CXCL12/SDF-1alpha (100 ng) injected into the periaqueductal grey (PAG) region of the brain, 30 min before the mu opioid agonist DAMGO (400 ng), blocked the antinociception induced by DAMGO in the in vivo cold water tail-flick (CWT) antinociceptive test in rats. In the present experiments, we tested whether the action of other agonists at mu and delta opioid receptors is blocked when CCL5/RANTES or CXCL12/SDF-1alpha is administered into the PAG 30 min before, or co-administered with, opioid agonists in the CWT assay. The results showed that: (1) CXCL12/SDF-1alpha (100 ng, PAG) or CCL5/RANTES (100 ng, PAG), given 30 min before the opioid agonist morphine, or selective delta opioid receptor agonist DPDPE, blocked the antinociceptive effect of these drugs; (2) CXCL12/SDF-1alpha (100 ng, PAG) or CCL5/RANTES (100 ng, PAG), injected at the same time as DAMGO or DPDPE, significantly reduced the antinociceptive effect induced by these drugs. These results demonstrate that the heterologous desensitization is rapid between the mu or delta opioid receptors and either CCL5/RANTES receptor CCR5 or CXCL12/SDF-1alpha receptor CXCR4 in vivo, but the effect is greater if the chemokine is administered before the opioid.     

Evidence for the sensitivity of operant timing behaviour to stimulation of D1 dopamine receptors

Rationale Temporal differentiation of operant behaviour is sensitive to dopaminergic manipulations. Previous studies using the fixed-interval peak procedure implicated D₂-like dopamine receptors in these effects. However, recent findings suggest that d-amphetamine alters timing performance on the free-operant psychophysical procedure via D₁-like receptors. It is not known whether this effect of d-amphetamine is mimicked by direct D₁-like receptor stimulation. Objective The effects of a D₁-like receptor agonist 6-chloro-2,3,4,5-tetrahydro-1-phenyl-1H-3-benzazepine (SKF-81297) on performance on the free-operant psychophysical procedure and the interaction between SKF-81297 and a D₁-like receptor antagonist 8-bromo-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin-7-ol (SKF-83566) and a D₂-like receptor antagonist haloperidol, were examined. Materials and methods Rats were trained to respond on two levers (A and B) under a free-operant psychophysical schedule, in which sucrose reinforcement was provided intermittently for responding on A during the first half and on B during the second half of 50-s trials. Logistic psychometric functions were fitted to the relative response rate data (percent responding on B [%B] vs time from trial onset [t]) under each treatment condition, and quantitative indices of timing (T₅₀ [value of t corresponding to %B = 50] and the Weber fraction [(T₇₅-T₂₅)/2T₅₀; T₂₅ and T₇₅ are values of t corresponding to %B = 25 and %B = 75] were compared among treatments. Results SKF-81297 (0.8 mg kg⁻¹) reduced T₅₀; this effect was antagonized by SKF-83566 (0.03 mg kg⁻¹) but not by haloperidol (0.05, 0.1 mg kg⁻¹). Conclusions Stimulation of D₁-like dopamine receptors affects performance in the free-operant psychophysical procedure.     

Control of the release of newly synthetized 3H-5-hydroxytryptamine by nicotinic and muscarinic receptors in rat hypothalamic slices

Summary The effects of various cholinergic agonists and antagonists on the spontaneous release of newly synthetized ³H-5-HT were examined in rat hypothalamic slices. ³H-5-HT was measured in incubating medium at the end of a 30 min incubation carried out with l-³H-tryptophan in the presence of the various durgs tested. ACh (10^–5 M) in the presence of eserine (2×10^–4 M), and carbachol (10^–5 M) stimulated the release of ³H-5-HT. In contrast, oxotremorine (10^–5 M) reduced the ³H-amine release. The effect of carbachol was blocked by two nicotinic blockers, mecamylamine (10^–6 M) and d-tubocurarine (10^–6 M). It was not reduced by the muscarinic antagonists, atropine (10^–6 M) and scopolamine (10^–6 M). In fact, each of two antagonists added alone to the incubating medium enhanced ³H-5-HT release. The scopolamine (10^–6 M) stimulating effect on ³H-5-HT release was suppressed by d-tubocurarine (10^–6 M). Finally, the inhibiting effect of oxotremorine on ³H-5-HT release was not prevented by d-tubocurarine (10^–6 M) but was in the presence of atropine (10^–6 M) or scopolamine (10^–6 M).In the concentrations used in the release study, the cholinergic agonists and antagonists had no effect on the total formation of ³H-5-HT and ³H-5-HIAA from l-³H-tryptophan and on the accumulation of l-³H-tryptophan in tissues. In these concentrations, except for eserine, they did not affect the uptake of exogenous ³H-5-HT in hypothalamic synaptosomes (P₂ fraction).These results suggest that cholinergic receptors of the muscarinic and nicotinic type are involved in the control of ³H-5-HT release; since the stimulation of the muscarinic and nicotonic cholinergic receptors resulted in an inhibition and an activation of ³H-5-HT release, respectively. As in the case of peripheral noradrenergic and central dopaminergic neurons the cholinergic receptors could be localized on serotoninergic terminals.     

Effect of cerebral ischemia on dopamine receptors and uptake sites in the gerbil hippocampus

Dopamine D₁ and D₂ receptors and uptake sites were studied in the gerbil hippocampus, parietal cortex and thalamus 1 h to 7 days after 10 min of cerebral ischemia using the occlusion of bilateral common carotid arteries. [³H]SCH23390 ([N-methyl-³H]R[+]-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-7-ol-benzazepine) and [³H]mazindol were used as markers of dopamine D₁ receptors and uptake sites, respectively. [³H]Nemonapride was used to label dopamine D₂ receptors. No obvious alteration in [³H]SCH23390 and [³H]mazindol binding was found in the hippocampus up to 48 h after ischemia. These bindings showed a significant reduction in the hippocampus after 7 days of recirculation. In contrast, [³H]nemonapride binding was unaffected in the hippocampus during the recirculation periods. The parietal cortex and thalamus also exhibited no significant changes in [³H]SCH23390, [³H]nemonapride and [³H]mazindol binding after ischemia. MAP2 (microtubule-associated protein 2) immunoreactivity was unchanged in all regions up to 48 h after ischemia. Thereafter, a marked loss of MAP2-immunoreactive neurons was observed in the hippocampal CA1 and CA3 neurons 7 days after recirculation. These findings were consistent with histological observations with cresyl violet staining. Our results demonstrate that dopamine D₁ receptors and dopamine uptake sites in the hippocampus are susceptible to cerebral ischemia, whereas dopamine D₂ receptors in this region are particularly resistant. Furthermore, these findings suggest that dopamine transmission may not be major factor in producing ischemic hippocampal damage.     

Electrically induced release of endogenous noradrenaline and dopamine from brain slices: pseudo-one-pulse stimulation utilized to study presynaptic autoinhibition

Summary Slices of rat hypothalamus (noradrenaline experiments) or rabbit caudate nucleus (dopamine experiments) were prepared, superfused, and field-stimulated using series of monophasic rectangular pulses. Noradrenaline, dopamine and the main dopamine metabolite, dihydroxyphenylacetic acetic acid (DOPAC), were determined using HPLC with electrochemical detection. Electrical stimulation was performed using the following protocols: 1) 4 pulses delivered at 100 Hz; this type of stimulation is referred to as pseudo-one-pulse stimulation (POP); its short duration of only 32 ms does not allow the development of autoinhibition; 2) 2 bursts of 4 pulses at 100 Hz, delivered 1 s apart (2-POP-stimulation); 3) 8 pulses at 1 Hz (dopamine experiments only); 4) 36 pulses at 3 Hz. Noradrenaline experiments. The ₂-adrenoceptor antagonist yohimbine (1 mol/l) did not enhance noradrenaline overflow following POP stimulation, but enhanced the overflow following 2-POP-stimulation by about 50% and that following 36-pulse-stimulation by almost 100%. Dopamine experiments. The D₂-dopamine receptor antagonist sulpiride (3 mol/l) facilitated the overflow of dopamine elicited with 2-POP-stimulation (66%), 8 pulses/1 Hz (92%), and 36 pulses/3 Hz (140%). It did not significantly facilitate the overflow of dopamine following POP-stimulation (19%). The overflow of DOPAC was not, or only slightly, increased by electrical stimulation, and its spontaneous outflow was more than three times higher than that of dopamine. Furthermore, the electrically induced overflow of dopamine did not exceed the outflow of DOPAC at any of the stimulation conditions employed.The results of the present study bear out important claims of the autoreceptor theory and confirm the data obtained in previous experiments using labelled transmitters. Correspondence to E. A. Singer at the above address     

5-HT3 receptor antagonists inhibit the response of kappa opioid receptors in the morphine-induced Straub tail [corrected

We used the morphine-induced Straub tail to examine the actions of a 5-HT₃ receptor antagonist and κ opioid receptor agonist. The κ opioid receptor agonist, U-50,488H (4–16 mg/kg i.p.), produced a dose-related inhibition of the tail elevation induced by morphine (10 mg/kg s.c.) in ICR male mice. ICS-205-930 (3 and 10 mg/kg i.p.) and zacopride (0.3 and 1 mg/kg i.p.), 5-HT₃ receptor antagonists, attenuated the inhibitory effect of U-50,488H in a dose-dependent manner. ICS-205-930 and zacopride did not inhibit the morphine-induced Straub tail. These observations suggest that the actions of κ opioid receptors may be modulated by 5-HT³ receptors in the morphine-induced Straub tail.