Antagonistic Effects of OPC-14597, a Novel Antipsychotic Drug,on Quinpirole- and (–)-Sulpiride-induced Changes in Evoked Dopamine Release in Rat Striatal Slices

The effects of a newly synthesized quinolinone derivative, 7-{4-(4-(2,3-dichlorophenyl)-1-piperazinyl) butoxy}-3,4-dihydro-2-(1H)-quinolinone (OPC-14597), a novel antipsychotic drug, on electrically evoked dopamine release in rat striatal slices were investigated. OPC-14597 (0.1–10 μm) had no effect on the dopamine release evoked in the striatal slices. The decrease induced by quinpirole, a dopamine receptor agonist, in evoked dopamine release was attenuated by supervision with OPC-14597 (1 and 10 μm) which by itself had no effect on evoked dopamine release. The increase induced by (–)-sulpiride, a dopamine receptor antagonist, in evoked dopamine release was, moreover, also attenuated by 1 and 10 μm OPC-14597. These findings indicate that OPC-14597 antagonizes both dopamine agonist- and antagonist-induced changes in evoked dopamine release in striatal slices in rats.     

Differential Effects of Dopamine Antagonists on Evoked Dopamine Release from Slices of Striatum and Nucleus Accumbens in Rats

The effects of dopamine-receptor antagonists on electrically-evoked dopamine release were compared in the nucleus accumbens and striatal slices of rats. (-)-Sulpiride induced a concentration-dependent increase in the evoked dopamine release from both regions, the increase in the nucleus accumbens being significantly greater than that in the striatum. Clozapine also increased evoked dopamine release from the nucleus accumbens, but not from the striatum. The haloperidol-induced increase in evoked dopamine release from the nucleus accumbens was less than that from the striatum. These findings indicate that, in terms of dopamine transmission, (-)-sulpiride and clozapine, but not haloperidol, predominantly affect the nucleus accumbens rather than the striatum. We have previously reported that the contribution of D₃ receptors to the regulation of dopamine release from dopamine nerve terminals is much greater in the nucleus accumbens than that in the striatum. (-)-Sulpiride and clozapine have relatively higher affinity for D₃ receptors than does haloperidol. The regional differences in responsiveness of dopamine release to dopamine antagonists could be due to the different affinities to D₂ or D₃ receptors of the dopamine antagonists.     

Differential action of (+)-amphetamine on electrically evoked dopamine overflow in rat brain slices containing corpus striatum and nucleus accumbens.

1. The effects of (+)-amphetamine on electrically evoked dopamine overflow were examined in the rat brain slice containing either anterior caudate putamen (aCPu) or nucleus accumbens (NAc), by fast cyclic voltammetry. 2. (+)-Amphetamine (1 microM) caused a time-dependent increase in the extracellular concentration of dopamine ([dopamine]ex) due to displacement of dopamine from terminal sites. After a 40 min superfusion, [dopamine]ex in the aCPu was 0.617 +/- 0.117 microM and in the NAc was 0.270 +/- 0.04 microM. Pretreatment with (-)-sulpiride (1 microM) did not affect this action of (+)-amphetamine. 3. (+)-Amphetamine (1 microM) exhibited a complex and time-dependent effect on electrically stimulated dopamine overflow, evoked by 1p, 4p/10 Hz and 20p/20 Hz. 4. In the aCPu, (+)-amphetamine (1 microM) resulted in attenuation of dopamine overflow due to 1p and 4p/10 Hz but potentiation of dopamine overflow to 20p/20 Hz. (-)-Sulpiride (1 microM) prior to (+)-amphetamine (1 microM) reversed the attenuation of dopamine overflow evoked by 1p and 4p/10 Hz but had no significant effect on dopamine overflow evoked by 20p/20 Hz. 5. (+)-Amphetamine (1 microM) potentiated dopamine overflow in the NAc to all three stimuli. (-)-Sulpiride (1 microM) prior to (+)-amphetamine (1 microM), resulted initially, in a further potentiation of overflow, followed by a time-dependent attenuation of dopamine overflow to all three stimuli. 6. t1/2, the rate of removal of [dopamine]ex following electrical stimulation was not significantly different in the aCPu and NAc for any of the stimulation conditions.(ABSTRACT TRUNCATED AT 250 WORDS)     

Phenoxybenzamine blocks dopamine autoreceptors irreversibly: Implications for multiple dopamine receptor hypotheses

Phenoxybenzamine in μM concentrations increased the electrically evoked overflow of recently taken up [³H]dopamine from superfused slices of cat caudate nucleus, an effect which is also observed for dopamine receptor antagonists. The magnitude of the increase in electrically evoked [³H]dopamine release caused by 1 μM phenoxybenzamine was equal to that elicited by maximally effective concentrations of the specific dopamine receptor antagonist, S-sulpiride. Phenoxybenzamine (1 μM) completely antagonized the inhibition of [³H]dopamine release caused by the dopamine receptor agonist pergolide (10 nM). The α-adrenoceptor antagonist phentolamine (1 μM) had no effect on the electrically evoked overflow of [³H]dopamine, ruling out the possibility that the effect of phenoxybenzamine could be attributed to α-adrenoceptor blockade. A 20 min exposure to 1 μM phenoxybenzamine increased the electrically evoked [³H]dopamine overflow even after the tissue had been washed for two and a half hours. When the caudate slices were exposed for 30 min to the reversible dopamine receptor antagonist S-sulpiride (1 μM) and washed for two and a half hours, no similar increase in stimulation-evoked [³H]dopamine overflow was observed. When sulpiride (1 μM) was present during the exposure to phenoxybenzamine (1 μM), no increase in electrically evoked [³H]dopamine overflow was observed after the washout period. Thus phenoxybenzamine at 1 μM appears to block irreversibly the dopamine autoreceptor in the caudate nucleus. Phenoxybenzamine has been previously reported to block irreversibly dopamine-stimulated adenylate cyclase (D₁) and neuroleptic receptor binding (D₂). The present demonstration that phenoxybenzamine also blocks the dopamine autoreceptor irreversibly thus supports the view that all currently well-established dopamine receptors are sensitive to phenoxybenzamine.     

Stereoselectivity of presynaptic autoreceptors modulating dopamine release

The effects of the (R)- and (S)-enantiomers of sulpiride and butaclamol were studied on the spontaneous and field stimulation-evoked release of total radioactivity from slices of rabbit caudate nucleus prelabelled with [3H]dopamine. (S)-Sulpiride in concentrations ranging from 0.01--1 microM enhanced the electrically evoked release of [3H]dopamine while (R)-sulpiride was 10 times less potent than (S)-sulpiride. Exposure to (S)-butaclamol (0.01--1 microM) but not to (R)-butaclamol (0.1--10 microM) enhanced the field-stimulated release of [3H]dopamine. The facilitatory effects of (S)- and (R)-sulpiride and (S)-butaclamol on the stimulated release of the labelled neurotransmitter were observed under conditions in which these drugs did not modify the spontaneous outflow of radioactivity. Only the active enantiomers of sulpiride and butaclamol antagonized the inhibition by apomorphine (1 microM) of the stimulated release of [3H]dopamine. Our results indicate that the presynaptic inhibitory dopamine autoreceptors modulating the stimulation-evoked release of [3H]dopamine in the caudate nucleus are, like the classical postsynaptic dopamine receptors, chemically stereoselective.     

Acetylcholine release in rat nucleus accumbens is regulated through dopamine D2-receptors

Summary Experiments in slices of rat nucleus accumbens were carried out in order to investigate whether the release of acetylcholine in this tissue is modulated through dopamine receptors. The slices were preincubated with ³H-choline and then superfused and stimulated electrically twice for 2 min each at a frequency of 3 Hz.The electrically evoked overflow of tritium averaged 2.9–3.9% of the tritium content of the tissue in the various groups. The D₂-selective agonist quinpirole (0.01–1 mol/l) reduced the evoked overflow of tritium by maximally 56%, an effect antagonized by the D₂-selective antagonist (–)-sulpiride (1 mol/l). The D₁-selective agonist 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine (SKF 38393) caused a slight decrease only at the high concentration of 10 mol/l. (–)-Sulpiride (0.1–10 mol/l) moderately increased the evoked overflow of tritium when given alone. The dopamine uptake inhibitor nomifensine (10 mol/l) caused a decrease, and in its presence the increase produced by (–)-sulpiride became much more marked, amounting to maximally 149%. (+)-Sulpiride (0.1–1 mol/l) failed to change the evoked overflow of tritium in the presence of nomifensine. The dopamine-releasing agent (±)-amphetamine (1 mol/l) also reduced the evoked overflow, an effect abolished by (–)-sulpiride. Finally, bretylium (1 mmol/l), which blocks the release of dopamine, increased the evoked overflow. (–)-Sulpiride (1 mol/l) lost its facilitatory effect in slices treated with bretylium.We conclude that the release of acetylcholine in rat nucleus accumbens, like its release in the nucleus caudatusputamen, is modulated through dopamine D₂-receptors. The receptors are activated by endogenous dopamine under the conditions of these experiments. Send offprint requests to K. Starke at the above address     

Presynaptic regulation of the electrically evoked release of endogenous dopamine from the isolated neurointermediate lobe or isolated neural lobe of the rat pituitary gland in vitro

Summary Isolated neurointermediate lobes (NILs) or isolated neural lobes (NLs) of the rat pituitary gland were incubated in Krebs-HEPES solution which contained pargyline and the dopamine uptake inhibitor GBR 12921. The release of endogenous dopamine was determined by HPLC with electrochemical detection. Electrical stimulation of the pituitary stalk induced a frequency-dependent release of dopamine.The release of dopamine from the combined NIL evoked by stimulation at 15 Hz was increased by 130% in the presence of the dopamine D2 receptor antagonist, (–)-sulpiride; the (+)-enantiomer of sulpiride had virtually no effect. When the stimulation frequency was 3 Hz (–)-sulpiride caused an increase in dopamine release by 230%. A similar increase was observed in the presence of domperidone, another dopamine D2 receptor antagonist.The dopamine receptor agonists, apomorphine and quinpirole, had no significant effects on the evoked release of dopamine indicating that under the present incubation conditions endogenous dopamine may have been maximally activating the autoinhibition. However, in the presence of 1 mol/l (–)-sulpiride, apomorphine as well as quinpirole reduced the evoked release of dopamine in a concentration-dependent manner.The dopamine D1 receptor selective antagonist, SCH 23390, had no effect on the evoked release of dopamine at a concentration of 1 mol/1. Only at a concentration of 10 mol/l did SCH 23390 cause a small increase in dopamine release; this effect was, however, abolished in the presence of 1 mol/1(–)-sulpiride.In the presence of 1 mol/l (–)-sulpiride neither clonidine, yohimbine, 5-methoxytryptamine nor metitepine significantly affected the release of dopamine from the NIL evoked by stimulation at 3 Hz.In the NL, the release of dopamine is inhibited by endogenous opioids. For this reason, naloxone 1 or 10 mol/1 was present in the experiments on isolated NLs. Domperidone and (–)-sulpiride, but not (+)-sulpiride, increased the release of dopamine from the NL evoked by electrical stimulation at 15 Hz by about 90%. SCH 23390 caused a significant increase in dopamine release at 10 mol/l, but not at 1 mol/lIn conclusion, the release of endogenous dopamine from the neurons terminating in the intermediate and neural lobe of the pituitary gland is inhibited via dopamine receptors of the D2 type.Abbreviations DOPAC dihydroxyphenylacetic acid - 5-HT 5-hydroxytryptamine - HPLC high performance liquid chromatography - IL intermediate lobe - NIL neurointermediate lobe - NL neurallobe Send offprint requests to K. Racké at the above address     

Potentiation by cadmium ion of ATP-evoked dopamine release in rat phaeochromocytoma cells.

1. The effects of cadmium ion (Cd2+) on release of dopamine and on an inward current evoked by extracellular ATP were investigated in rat phaeochromocytoma PC12 cells. 2. Cd2+ (100 microM-3 mM) potentiated the dopamine release evoked by 30 microM ATP from the cells. Cd2+ (100 microM) shifted the concentration-response curve of ATP-evoked dopamine release to the left without affecting the maximal response. 3. Suramin (30 microM) completely abolished the dopamine release evoked by 30 microM ATP but only partially inhibited the release evoked by 100 microM ATP consistent with its role as a competitive antagonist. The response evoked by 30 microM ATP in the presence of Cd2+ (300 microM) was comparable to that observed with 100 microM ATP alone; however, only the former was almost completely inhibited by suramin. 4. Cd2+ (100 microM) potentiated an inward current activated by 30 microM ATP alone. A higher concentration of Cd2+ (300 microM) had a smaller effect on amplitude potentiation but significantly prolonged the duration of the current. 5. The time-course of the ATP-evoked dopamine release was investigated using a real-time monitoring system for dopamine release. Although Cd2+ (300 microM) had little effect on the time-course of activation the ATP-evoked dopamine release, it produced a long-lasting dopamine release which slowly returned to the baseline. 6. Taken together, these observations suggest that Cd2+ enhances ATP-evoked dopamine release by affecting P2-purinoceptor/channels. The enhancement may be attributed to a Cd(2+)-dependent increase in sensitivity to ATP.     

Yohimbine affects the evoked overflow of neurotransmitters from rat brain slices by more than one mechanism

Both yohimbine (0.1–10 μm) and phentolamine (10 μm) increased the tritium overflow evoked by electrical stimulation (3Hz, 2 ms, 18 mA for 120s every 20 min) of rat brain cortex slices previously incubated with [³H](?)-noradrenaline. At their maximally effective concentrations, neither of these compounds produced an effect which was fully maintained over the 1 h of the experiment, but the decline in effect of yohimbine (1.25 μM) was more marked, falling sharply to reach, after 1 h, 25% of the effect observed after 20 min, whereas phentolamine only declined to 60% of the effect after 20 min. In rat brain cortex slices previously incubated with [³H]5-hydroxytryptamine ([³H]5-HT), the tritium overflow evoked by electrical stimulation (3 Hz, 2 ms, 40 mA for 120 s) was increased by yohimbine (0.1–1 μM) and phentolamine (0.1–10 μM), but a higher concentration of yohimbine (10 μM) decreased evoked overflow below the levels seen in the absence of either drug. It is concluded that, at concentrations effective in inhibiting the presynaptic α-adrenoceptor-mediated mechanisms controlling transmitter release in rat brain slices, a non-a-adrenoceptor-mediated, possible local anaesthetic, action of yohimbine contributes to the overall effect of this drug on transmitter overflow.     

Biphasic actions of L-DOPA on the release of endogenous noradrenaline and dopamine from rat hypothalamic slices.

Effects of L-DOPA on the release of endogenous noradrenaline and dopamine from rat hypothalamic slices evoked by electrical field stimulation at 5 Hz were investigated in the absence and presence of p-bromobenzyloxyamine (NSD-1055), a DOPA-decarboxylase inhibitor. In the absence of NSD-1055, L-DOPA produced a facilitation of impulse-evoked release of noradrenaline at 0.1 microM but not at 1 and 10 microM, and had no effect on the spontaneous release. On the other hand, L-DOPA 0.1 to 10 microM dose-dependently increased the spontaneous release of dopamine and the highest concentration only increased the evoked release and tissue content of dopamine. In the presence of NSD-1055 10 microM, the increase in the spontaneous release of dopamine was prevented and L-DOPA produced biphasic regulatory effects on the evoked release of noradrenaline and dopamine, a facilitation at 0.1 microM and an inhibition at 1 microM. The facilitation was antagonized by (-)-propranolol 0.1 microM, but not by the (+)-isomer, whereas the inhibition was antagonized by S-sulpiride 1 nM, but not by the R-isomer. In conclusion, L-DOPA appears to produce biphasic actions on the release of endogenous noradrenaline and dopamine from rat hypothalamic slices, not through its conversion to dopamine but through presynaptic regulatory mechanisms, an inhibition via dopamine receptors at a micromolar concentration and a facilitation via beta-adrenoceptors at the lower concentration.     

Prejunctional α2-adrenoreceptors modulate the stimulated release of noradrenaline in isolated follicle strips from bovine ovaries

1 Strips from the follicle wall of bovine ovaries were incubated in Krebs-Ringer solution containing ³H-noradrenaline for measurement of transmitter liberation during electrical field stimulation (5 Hz frequency, 1 ms pulse duration, 10 V between the electrodes). The effects of noradrenaline as well as selective α-adrenoreceptor agonists and antagonists were studied on the electrically induced efflux of radioactivity. 2 Noradrenaline (1 μM) inhibited the stimulated release of radioactivity. The α₂-adrenoreceptor agonist, oxymetazoline, significantly reduced the release of radioactivity in concentrations as low as 0.01 μM. The α1-adrenoreceptor agonist, phenylephrine (0.01–1 μm), was without significant effect. 3 Phentolamine (0.01–1 μm) and the selective α₂-adrenoreceptor antagonist, idazoxan (0.01–1 μm) significantly enhanced the electrically evoked release. The α₁-adrenoreceptor antagonist, prazosin (0.01–1 μm), was without effect. Idazoxan (0.1 μm) reversed the inhibitory effect of oxymetazoline (0.1 μm). 4 It is concluded that administration of noradrenaline or the α₂-adrenoreceptor agonists reduces the release of labelled noradrenaline by acting on prejunctional α₂-adrenoreceptors in the noradrenergic nerves distributed in the wall of the bovine ovarian follicle. This is one of several prejunctional receptor mechanisms that modulate the activity of the sympathetic nerves innervating the smooth musculature of the follicle wall.     

Sympathomimetic Actions of Methylenedioxymethamphetamine in Rat and Rabbit Isolated Cardiovascular Tissues

Abstract— The aim of this study was to investigate the actions of methylenedioxymethamphetamine (MDMA) in several isolated cardiovascular tissues. In spontaneously beating rat atria, concentration-dependent positive chronotropic responses to MDMA and amphetamine were blocked by the neuronaluptake inhibitor desipramine (1 μm ) and the β-adrenoceptor antagonist propranolol (1 μm ). In atria incubated with [³H]noradrenaline to label transmitter stores, 10 μm MDMA and 1 μm amphetamine increased the resting outflow of radioactivity, while 1 μm desipramine had no effect on resting outflow. The MDMA- and amphetamine-induced release of radioactivity were blocked by 1 μm desipramine. MDMA, amphetamine and desipramine each enhanced the electrical stimulation-induced (2 Hz, 30-s train) release of radioactivity; the enhancing effects of MDMA and amphetamine were blocked by 1 μm desipramine. In rat isolated perfused hearts, MDMA (1 and 10 μm ) increased heart rate by a similar amount to the increase caused by noradrenaline (10 and 50 Nm ). MDMA also induced dysrhythmias in 7 out of 11 rat isolated perfused heart preparations. In rabbit isolated perfused and superfused ear arteries preloaded with [³H]noradrenaline, MDMA increased the resting release of radioactivity by 230 ± 18% (n = 6) of control resting release; the increase was accompanied by a rise in perfusion pressure of 17 ± 7 mmHg (n = 6). MDMA also facilitated the vasoconstrictor responses to noradrenaline (3–9 ng) and perivascular nerve stimulation (1–5 Hz, 10-s train). MDMA-induced vasoconstriction and the facilitation of vasoconstrictor responses to noradrenaline and electrical stimulation were blocked by 1 μm desipramine. These results suggest that MDMA has similar sympathomimetic activity to amphetamine on cardiovascular tissues. The sympathomimetic actions of MDMA could account for the cardiovascular side-effects associated with its use.     

Effects of phencyclidine on synaptosomal dopamine continuously appearing from phenylalanine: Sensitivity to reserpine

In the present study some effects of phencyclidine on synaptosomal (P₂) synthesis and release of labelled dopamine, continuously appearing from [¹⁴C]phenylalanine, were investigated in vitro. Also examined was the sensitivity of such effects of phencyclidine to reserpine, acting either in vitro or in vivo. Synaptosomal (P₂) preparations from rat caudate nuclei were incubated with the drugs added at various concentrations in the presence of [¹⁴C]phenylalanine substrate. The particulates were quickly separated from the medium after incubation and the separated fractions were analyzed for labelled dopamine and the synaptosomal uptake of [¹⁴C]phenylalanine. Of the total labelled dopamine formed, the fraction that was present in the medium was determined and taken as a measure of the spontaneous or basal release and its enhancement by any drug addition. Phencyclidine (3.1–36.4 μM) stimulated both the total (medium plus particulates) formation and the synaptosomal release of labelled dopamine, while reserpine (0.09–1.80 μM) inhibited the formation and enhanced the release. A coaddition of reserpine (0.09–1.80 μM) and phencyclidine to the incubation medium blocked the stimulating effect of the latter drug on the labelled dopamine synthesis; the same experiments revealed furthermore, an inhibitory effect of phencyclidine (0.91–36.4 μM) on the synthesis, an effect that was additive to the inhibition due to reserpine alone. The enhancing effect of phencyclidine on labelled dopamine release was however maintained in the presence of reserpine. Phencyclidine (0.22–36.4 μM) also inhibited the formation of labelled dopamine and enhanced its release when the P₂ fraction was prepared from reserpine-pretreated rats (5.0 and 2.5 mg/kg, i.p., at 24 and 2 hr before the experiment). Reserpine (1.80 μM) itself, added in vitro to the same P₂ preparation, was without any significant effect. The phencyclidine congener Ketamine, with or without reserpine, had little effect either on the synthesis or the release. In none of the incubations did the addition of drugs affect the synaptosomal uptake of labelled phenylalanine.     

SR 48968, A Novel Non-peptide Tachykinin NK-2-Receptor Antagonist,Selectively Inhibits the Non-Cholinergically Mediated Neurogenic Contraction of Guinea-pig Isolated Bronchial Muscle

Abstract— We have examined the actions of SR 48968 ((S)-N-methyl-N-[4-(4-acetylamino-4-phenyl piperidino)-2-(3,4-dichlorophenyl)butyl]benzamide), a novel non-peptide tachykinin NK-2-receptor antagonist, on the response evoked by electrical field stimulation or by acetylcholine and neurokinin A on guinea-pig isolated airway smooth muscle. Electrical field stimulation (1–32 Hz, 0·3 ms, 30 V for 20 s) evoked a biphasic response in a frequency-dependent manner, consisting of a cholinergically-mediated fast contraction followed by a non-adrenergically-mediated relaxation in tracheal muscle and by a noncholinergically-mediated slow contraction in bronchial muscle. SR 48968 (0·01–1 μm ) caused a concentration-dependent inhibition of non-cholinergically mediated contraction of bronchial muscle, without significant influence on cholinergically and non-adrenergically-mediated responses. Submaximal contractions of tracheal and bronchial muscles evoked by exogenous neurokinin A (10–300 Nm ) were markedly inhibited by SR 48968 (0·1–1 μm ), but those by exogenous acetylcholine (1–3 μm ) were slightly inhibited by the antagonist. The results indicate that in guinea-pig isolated bronchial muscle, SR 48968 selectively inhibited non-cholinergically mediated neurogenic contraction via antagonism of NK-2 receptors.     

Pharmacology: Ouabain-induced Increase in Dopamine Release from Mouse Striatal Slices is Antagonized by Riluzole

We have examined the effects of riluzole, a neuroprotective drug which stabilizes voltage-dependent sodium channels in their inactivated state and inhibits the release of glutamate in-vivo and in-vitro, on the release of newly taken up [³H]dopamine induced by ouabain, a potent and selective inhibitor of Na⁺/K⁺-ATPase in mouse striatal slices in-vitro. Riluzole potently (IC50 (concentration resulting in 50% inhibition) = 0.9±0.3 μM) and dose-dependently antagonized ouabain-stimulated [³H]dopamine release, the effect being observed at low concentrations. Tetrodotoxin (1 μM) and nomifensine (10 μM) also abolished ouabain-induced [³H]dopamine release. Blockade of glutamate receptors with dizocilpine (1 μM) and 6-(1H-imidazol-1-yl)-7-nitro-2,3(1H,4H)-quinoxalinedione (YM-90K; 10 μM), alone or in combination, was without effect. Incubation of striatal slices with 50 μM La³⁺, which blocks voltage-dependent calcium channels, did not inhibit [³H]dopamine release induced by ouabain. The potent effects of riluzole observed in this model are probably related to its ability to block voltage-dependent sodium channels. The consequences of this activity are critically discussed in relation to the protective action of riluzole previously reported in various models of Parkinson's disease and other neurodegenerative disorders.     

Behavioural effects of dibutyryl cyclic 3',5' AMP, noradrenaline and cyclic 3',5' AMP in rats

It was shown that dibutyryl cyclic AMP (DAMP) injected intraventricularly in doses of 100–200 μg in rats causes the increase of locomotor and exploratory activity and convulsions, depending on the dose. DAMP increased excitatory behavioural effects of noradrenaline (NA) injected intraventricularly in doses of 10 or 50 μg. NA in a dose of 200 μg abolished convulsions evoked by DAMP. Cyclic AMP (cAMP) injected intraventricularly in doses of 100–400 μg had no effect on the rat's behaviour. Pretreatment of rats with dimethylsulphoxide and with theophylline caused in some animals behavioural phenomena after injection of cAMP, similar to the behavioural symptoms evoked by DAMP.     

Effect of neurotensin and its fragments neurotensin-(1-6) and neurotensin-(8-13) on dopamine release from cat striatum

At low concentrations, neurotensin (10(-9) M) enhanced electrically evoked release of dopamine. At higher concentrations, neurotensin (10(-7) M) also enhanced basal release of dopamine. The carboxy-terminal sequence of neurotensin-(8-13) was fully active and enhanced both electrically evoked and basal release. In contrast, the amino-terminal fragment neurotensin-(1-6) did not enhance electrically evoked release of dopamine even at high concentrations (10(-6) M). However, it retained the ability to enhance basal dopamine release. Combination of different doses of apomorphine with a subthreshold (10(-10) M) and submaximal concentrations (10(-9) M) of neurotensin gave clear additive effects. It is concluded that in the cat striatum neurotensin stimulates dopamine release by a direct effect on its own neurotensin receptor, and does not modulate the sensitivity of presynaptic dopamine autoreceptors. Furthermore, it is suggested that there exist at least two types of neurotensin receptors in the cat striatum. One type stimulates evoked dopamine release and another influences basal release of dopamine.     

Dopamine D2 receptor mediated presynaptic inhibition of striatopallidal GABA(A) IPSCs in vitro.

The modulation of GABA release within the globus pallidus (GP) by dopamine was studied using whole-cell patch clamp recordings from visually identified neurones. In sagittal slices, single shock electrical stimulation in the striatum evoked GABA(A) inhibitory postsynaptic currents (IPSCs), which were inhibited by dopamine in a dose-dependent manner (0.3-30 microM) with an IC(50) value of 0.7 microM. The inhibition was accompanied by an increase in paired pulse facilitation, indicative of a presynaptic effect. In coronal slices, stimulation within the GP adjacent to the recording site evoked GABA(A) IPSCs which were relatively unaffected by dopamine indicating the lack of modulation of GABA release from terminals of local GP axon collaterals. No consistent changes in holding current, membrane potential, firing rate or the frequency of spontaneous IPSCs was observed.Tetrodotoxin-resistant miniature (m)IPSCs were recorded in chloride-loaded cells. Dopamine (3-30 microM) reduced the frequency of mIPSCs, but was without effect on mIPSC amplitude, confirming a presynaptic effect. The addition of the "D2 like" agonist quinpirole (3 microM), but not the "D1 like" agonist SKF 38393 (10 microM), mimicked these effects. The "D2 like" antagonist sulpiride (10 microM), while having no effect alone, blocked the action of dopamine. In contrast the dopamine D4 selective antagonist L745, 870 (1 microM) or D1 antagonist SCH 23390 (10 microM) were without effect.These results indicate that dopamine acts on presynaptic D2 receptors on striatopallidal terminals to reduce the release of GABA in the GP. Attenuation of this mechanism following the depletion of dopamine may contribute to the changes in GP neuronal activity observed in animal models of Parkinson's disease.     

Inhibition of evoked dopamine release by monopropionylcadaverine in vitro

A naturally occurring diamine, cadaverine, and one of its acyl derivatives, monopropionylcadaverine, were tested for their effects on the in vitro release of endogenous dopamine from slices of the rat neostriatum. Dopamine release was allowed to occur spontaneously and was evoked by elevating the potassium concentration in the incubation medium or by electric field stimulation. Monopropionylcadaverine had no effect on spontaneous release of dopamine and little effect on potassium-evoked release of dopamine, but at concentrations as low as 10^?8 M in the medium it significantly depressed the electrically induced dopamine release.     

Functional innervation of the biliary sphincter of the guinea‐pig revealed by anti‐autonomic drugs

1 The roles of excitatory and inhibitory intrinsic motor nerves on contractions reflexly evoked by wall distension were investigated in the isolated sphincter of Oddi of the guinea‐pig (SO‐GP).
2 Distension of the terminal bile duct for 30–60 s time periods increased the frequency of contractions from about 2 to 12 min?1 (n=16).
3 Hexamethonium (HEX; 300 μm ) largely prevented the distension‐evoked increase in contraction frequency (4.5 min?1, n=8) as did atropine (ATR; 1 μm ) (0.8 min?1, n=6), while tetrodotoxin (TTX; 1 μm ) blocked the contractions triggered during distension.
4 L‐nitroarginine (L ‐NA; 100 μm ) significantly increased the frequency of contractions during and in the absence distension while apamin (APAM; 0.5 μm ) significantly increased their frequency and doubled their mean amplitude during distension.
5 These results suggest that distension activates excitatory cholinergic motor nerves to increase the frequency of contractions in the SO‐GP. These actions are modulated by the concomitant activation of intrinsic nitrergic and non‐nitrergic inhibitory motor nerves.