Hypotheses on the role of cytokines in peptic ulcer disease

BACKGROUND: A novel gastric pentadecapeptide, BPC 157, has been shown to attenuate different lesions (i.e., gastrointestinal tract, liver, pancreas, somatosensory neurons). This suggests an interaction with the dopamine system. When used alone, BPC 157 does not affect gross behavior or induce stereotypy. METHODS: We first investigated the effect of pentadecapeptide BPC 157 on stereotypy and acoustic startle response in rats, given as either a prophylactic (10 micrograms/kg i.p.) or therapeutic (10 ng/kg i.p.) regimen, with the dopamine indirect agonist amphetamine (10 mg/kg i.p.). RESULTS: There was a marked attenuation of stereotypic behavior and acoustic startle response. When the medication was given at the time of maximum amphetamine-induced excitability, there was a reversal of this behavior. A further focus was on the effect of this pentadecapeptide on increased climbing behavior in mice pretreated with the dopamine antagonist haloperidol (5.0 mg/kg i.p.), and subsequently treated with amphetamine (20 mg/kg i.p. challenge 1, 2, 4, and 10 days after haloperidol pretreatment). This protocol is usually used for the study of behavioral supersensitivity to the amphetamine stimulating effect. CONCLUSIONS: An almost complete reversal was noted when pentadecapeptide was coadministered with haloperidol. Together, these data provide compelling evidence for the interaction of pentadecapeptide BPC 157 with the dopamine system.     

Apparent thermodynamic parameters of ligand binding to the cloned rat mu-opioid receptor

This study examined the involvement of spinal dopamine D2 receptors in the cardiovascular effects induced by intravenous administration of the selective dopamine D2 receptor agonist quinpirole, as has been previously reported for the hypotensive action of systemic bromocriptine. In normotensive pentobartitone-anaesthetised rats, intravenous injection of quinpirole (25 to 1000 microg/kg) decreased mean aortic pressure and heart rate in a dose-related manner. The intravenous (0.5 mg/kg) or intrathecal (40 microg/rat at T9-T10) pretreatment with domperidone, a dopamine D2 receptor antagonist that does not cross the blood-brain barrier, significantly reduced the maximal hypotensive and bradycardic responses to intravenous quinpirole (1000 microg/kg). In contrast, the latter effects were fully abolished either by intravenous metoclopramide (5 mg/kg) or combined pretreatment with intravenous and intrathecal domperidone. In addition, when injected intrathecally at the T9-T10 level of the spinal cord, quinpirole (7.7 to 61.4 microg/rat) also produced dose-dependent depressor and bradycardic effects which could be blocked by intrathecal, but not intravenous, domperidone pretreatment. This suggests that, in anaesthetised normotensive rats, the hypotensive and bradycardic responses to intravenous quinpirole are fully mediated by dopamine D2 receptors, some of which are located in the peripheral circulation and some of which are located within the spinal cord. The latter finding is novel, suggesting that partial spinal mediation may not be peculiar to bromocriptine, as was previously thought. Rather, partial spinal mediation may be common to most dopamine D2 receptor agonists.     

Adrenergic activation confers cardioprotection mediated by adenosine, but is not required for ischemic preconditioning

BACKGROUND: The aim of this study was to determine whether (1) adrenergic activation is cardioprotective, (2) adrenergic cardioprotection occurs via adenosine receptor activation, and (3) ischemic preconditioning requires alpha-adrenergic activation. METHODS: Anesthetised open chest rabbits underwent 30 min coronary occlusion and 3 h reperfusion. Ischemic preconditioning was elicited with 5 min coronary occlusion and 10 min reperfusion. Activation of adrenergic receptors with endogenous norepinephrine was achieved with tyramine (0.28 mg/kg/min intravenously for 5 min). Adenosine receptors were blocked with 8-p-sulfophenyl theophylline (10 mg/kg intravenously), alpha 1-adrenergic receptors were selectively blocked with prazosin (0.1 mg/kg intravenously), and alpha-adrenergic receptors were blocked with phentolamine (4 mg/kg intravenously). RESULTS: Ischemic preconditioning reduced risk-adjusted infarct volume by 79% (P < 0.0005). This protection was attenuated by adenosine receptor blockade. Tyramine infusion resulted in a 1305% change from baseline plasma norepinephrine concentration (P < or = 0.01), and reduced infarct volume by 55% (P = 0.01). Adenosine receptor blockade abolished this protection. Blockade of alpha 1-adrenergic receptors with prazosin failed to abolish ischemic preconditioning (79 versus 89% reduction in infarct volume, without and with prazosin, respectively). Similarly, non-selective blockade of alpha-adrenergic receptors also failed to abolish ischemic preconditioning (79 versus 57% reduction without and with phentolamine, respectively). CONCLUSIONS: We conclude that the cardioprotection of ischemic preconditioning and alpha-adrenergic activation both involve adenosine, but ischemic preconditioning does not require alpha-adrenergic activation.     

Pentadecapeptide BPC 157 positively affects both non-steroidal anti-inflammatory agent-induced gastrointestinal lesions and adjuvant arthritis in rats

Besides a superior protection of the pentadecapeptide BPC 157 (an essential fragment of an organoprotective gastric juice peptide BPC) against different gastrointestinal and liver lesions, an acute anti-inflammatory and analgetic activity was also noted. Consequently, its effect on chronic inflammation lesions, such as adjuvant arthritis, and non-steroidal anti-inflammatory agents (NSAIAs)-induced gastrointestinal lesions was simultaneously studied in rats. In gastrointestinal lesions (indomethacin (30 mg/kg s.c.), aspirin (400 mg/kg i.g.) and diclofenac (125 mg/kg i.p.) studies, BPC 157 (10 micrograms or 10 ng/kg i.p.) was regularly given simultaneously and/or 1 h prior to drug application (indomethacin). In the adjuvant arthritis (tail-application of 0.2 mL of Freund's adjuvant) studies (14 days, 30 days, 1 year) BPC 157 (10 micrograms or 10 ng/kg i.p.), it was given as a single application (at 1 h either before or following the application of Freund's adjuvant) or in a once daily regimen (0-14th day, 14-30th day, 14th day-1 year). Given with the investigated NSAIAs, BPC 157 consistently reduced the otherwise prominent lesions in the stomach of the control rats, as well as the lesions in the small intestine in the indomethacin groups. In the adjuvant arthritis studies, the lesion's development seems to be considerably reduced after single pentadecapeptide medication, and even more attenuated in rats daily treated with BPC 157. As a therapy of already established adjuvant arthritis, its salutary effect consistently appeared already after 2 weeks of medication and it could be clearly seen also after 1 year of application. Taking together all these results, the data likely point to a special anti-inflammatory and mucosal integrity protective effect.     

Role of beta-adrenoceptors in gastric mucosal integrity and gastroprotection induced by epidermal growth factor

The central and peripheral adrenergic systems are involved in the regulation of gastric secretion but little is known about the role of alpha- and beta-adrenoceptors in gastroprotection. In this study, acute gastric lesions were produced by an intragastric (i.g.) application of 100% ethanol and gastric blood flow (GBF) was determined by H2-gas clearance technique in rats with or without i.g. or intraperitoneal (i.p.) administration of alpha- or beta-adrenoceptor agonists or antagonists. Phenylephrine, alpha1-adrenergic agonist, and clonidine, alpha2-agonist, significantly augmented the ethanol-induced lesions while decreasing the GBF and these effects were reversed by the blockade of alpha1-adrenoceptors with prazosin and alpha2-adrenoceptors with yohimbine. In contrast, isoproterenol (ISO) (0.01-10 mg/kg i.g.), beta-adrenoceptor agonist, reduced dose-dependently ethanol-induced mucosal injury and this effect was accompanied by an elevation of the GBF similarly as after epidermal growth factor (EGF) (100 microg/kg x h s.c.) or after classic protective agent, 16,16-dimethyl-PGE2 (PGE2) (10 microg/kg i.g.). The pretreatment with beta-antagonist, propranolol, diminished the protective and hyperemic effects of ISO and EGF but failed to affect those induced by PGE2. Suppression of nitric oxide (NO) synthase activity by L-NAME or sensory denervation with capsaicin attenuated significantly the ISO- and EGF-induced gastroprotection and elevation of GBF, whereas the inhibition of PG biosynthesis by indomethacin remained without any significant effect. Adrenal medullectomy or chemical sympathectomy by 6-hydroxydopamine by itself failed to influence significantly the ethanol-induced damage but completely abolished the protective and hyperemic effects of EGF being without any influence on those induced by PGE2. ISO combined with EGF, restored the protective and hyperemic effects of this peptide in medullectomized rats. We conclude that (1) local activation of beta-adrenoceptors by ISO affords protection and elevation of GBF, both these effects being mediated by arginine-NO pathway and sensory nerves and (2) sympathetic system and adrenal medulla contribute to the protective and hyperemic activity of EGF.     

A new gastric juice peptide, BPC. An overview of the stomach-stress-organoprotection hypothesis and beneficial effects of BPC

The possibility that the stomach, affected by general stress, might initiate a counter-response has not until recently been considered in theories of stress. We suggest that the stomach, as the most sensitive part of the gastrointestinal tract and the largest neuroendocrine organ in the body, is crucial for the initiation of a full stress response against all noxious stress pathology. The end result would be a strong protection of all organs invaded by 'stress'. Consistent with this assumption, this coping response is best explained in terms of 'organoprotection'. Endogenous organoprotectors (eg prostaglandins, somatostatin, dopamine) are proposed as mediators. Such an endogenous counteraction could even be afforded by their suitable application. A new gastric juice peptide, M(r) 40,000, named BPC, was recently isolated. Herein, a 15 amino acid fragment (BPC 157), thought to be essential for its activity, has been fully characterized and investigated. As has been demonstrated for many organoprotective agents using different models of various tissue lesions, despite the poorly understood final mechanism, practically all organ systems appear to benefit from BPC activity. These effects have been achieved in many species using very low dosages (mostly microgram and ng/kg range) after ip, ig, and intramucosal (local) application. The effect was apparent already after one application. Long lasting activity was also demonstrated. BPC was highly effective when applied simultaneously with noxious agents or in already pathological, as well as chronical, conditions. Therefore, it seems that BPC treatment does not share any of the so far known limitations for 'conventional organoprotectors'. No influence on different basal parameters and no toxicity were observed. These findings provide a breakthrough in stress theory. BPC, as a possible endogenous free radical scavenger and organoprotection mediator, could be a useful prototype of a new class of drugs, organoprotective agents.     

Surface structure of human mucin using X-ray photoelectron spectroscopy

The stimulating effect of antiparkinsonian drugs, talipexole and bromocriptine, on the striatal postsynaptic dopamine receptors were studied by measuring contralateral rotational behavior in rats. The nigro-striatal dopamine system of rats was degenerated by unilateral injection of 6-hydroxydopamine (6-OHDA, 8 micrograms/rat) into substantia nigra. By subcutaneous administration, talipexole at 0.16 mg/kg and bromocriptine at 10.24 mg/kg induced significantly increased rotational behavior to the contralateral direction to the lesioned side. The onset of the effect was 30 min for talipexole and 90 min for bromocriptine. By intragastric administration, talipexole at 0.4 mg/kg and bromocriptine at 20.48 mg/kg significantly increased the rotational behavior, and the onset of the effect was 60 min for talipexole and 180 min for bromocriptine. Rotational behavior induced by talipexole was suppressed by a D2 antagonist, sulpiride (40 mg/kg, s.c.), but not by a D1 antagonist, SCH23390 (1 mg/kg, s.c.). In contrast, rotational behavior induced by bromocriptine was suppressed by both sulpiride and SCH23390. These results indicated that when the nigrostriatal dopaminergic functions are disrupted, talipexole stimulates the striatal postsynaptic dopamine receptors at much lower doses than bromocriptine. Also it was indicated that the stimulating effect of talipexole is solely mediated by dopamine D2 receptors, whereas the effect of bromocriptine is mediated by both D1 and D2 receptors.     

A comparative genetic analysis of the role of the brain dopaminergic systems in the regulation of behavioral elements in the "open field" test in DBA/2J and C57BL/6J mice

The effects of intraperitoneal injections of sulpiride (10 mg/kg), bromocriptine (5 mg/kg), and alaptide (1 mg/kg) on the behavior of male C57BL/6J (C57BL) and DBA/2J (DBA) mice in the open-field test were studied. In this test, C57BL mice exhibited a significantly higher horizontal locomotor activity than DBA mice, whereas DBA mice moved in place substantially longer than C57BL mice. Dopaminergic agents had different effects on the open-field behavior in different mouse strains. Alaptide increased horizontal locomotor activity in DBA, but not in C57BL mice; all the three agents decreased the duration of movement in place in DBA but not in C57BL mice; bromocriptine suppressed vertical locomotor activity and the act of looking into holes in C57BL but not in DBA mice. Thus, interstrain differences in dopaminergic functions were demonstrated. The revealed strain-specific characteristics largely contribute to the determination of open-field behavior in the studied mouse strains.     

Histoautoradiography of the DNA in trophoblast giant cells of the mouse placenta. A contribution to the problem of metabolic DNA

In the cat anterior tibialis muscle preparation dopamine produces a decrease on indirectly evoked twitch contraction when it is administered intraarterially but not on intravenous injection. Edrophonium (0.3 mg/kg) exerts only a brief antagonism to the dopamine-induced inhibition. The phenothiazine derivative, chlorpromazine (CPZ, 400 mug/kg) which possesses both alpha and dopaminergic blocking properties significantly reduces the action of dopamine on skeletal muscle. However, phentolamine (1 mg/kg), an alpha adrenergic blocker is without effect, possibly indicating that the dopaminergic blocking characteristic of CPZ is responsible for decreasing the action of dopamine. A more selective dopaminergic blocking agent, pimozide (100 and 200 mug/kg) is an effective antagonist to the paralysis caused by dopamine on the anterior tibialis muscle. The results of this investigation suggests the possibility that a dopaminergic receptor may be present in or on skeletal muscle.     

Effects of dopamine and domperidone on ventilatory sensitivity to hypoxia after 8 h of isocapnic hypoxia

Acclimatization to altitude involves an increase in the acute hypoxic ventilatory response (AHVR). Because low-dose dopamine decreases AHVR and domperidone increases AHVR, the increase in AHVR at altitude may be generated by a decrease in peripheral dopaminergic activity. The AHVR of nine subjects was determined with and without a prior period of 8 h of isocapnic hypoxia under each of three pharmacological conditions: 1) control, with no drug administered; 2) dopamine (3 microg. min-1. kg-1); and 3) domperidone (Motilin, 40 mg). AHVR increased after hypoxia (P 相似文献   

Characterization of the expression and steroid hormone control of sialomucin complex in the rat uterus: implications for uterine receptivity

Oxidative stress, a process in which neurotoxic oxygen free radicals cause dopaminergic neuronal degeneration, has been implicated in the degenerative process in Parkinson's disease. Glutamate-induced neurotoxicity is a model of oxidative stress. We demonstrated that preincubation with D2-type dopamine agonists bromocriptine and quinpirole provides neuroprotection against glutamate-induced neurotoxicity in cultured rat mesencephalic neurons. Simultaneous administration of D2 agonists, however, did not provide neuroprotection. The protective effects were dependent on the duration of preincubation and were blocked by a D2 antagonist and a protein synthesis inhibitor. Furthermore, preincubation with D2 agonists provided neuroprotection against toxicity induced by calcium overload and exposure to superoxide anions. Confocal microscopic analysis, using 2,7-dichlorofluorescin diacetate, revealed that bromocriptine preincubation suppressed the action of radicals on neurons. These findings indicate that dopamine D2 agonists provide protection mediated not only by the inhibition of dopamine turnover but also via D2-type dopamine receptor stimulation and the subsequent synthesis of proteins that scavenge free radicals.     

Activation of beta3-adrenoceptors by exogenous dopamine to lower glucose uptake into rat adipocytes

The effect of dopamine hydrochloride on beta3-adrenoceptors was studied in isolated adipocytes of Wistar rats using uptake of [14C]-deoxy-D-glucose (2-DG) as the indicator. Dopamine induced a concentration-dependent decrease of 2-DG uptake into adipocytes in a manner which was not modified by haloperidol at concentrations sufficient to block dopaminergic receptors. Failure of blockade was also observed in samples receiving the pretreatment with a mixture of SCH23390 and domperidone, the dopaminergic antagonists. Absence of dopaminergic receptors in rat white adipocytes was further supported by the findings that dopaminergic agonists did not modify the glucose uptake and the negative response to receptor antibodies in immunoblotting analysis. Pindolol and propranolol reversed this inhibition of dopamine in a concentration-dependent manner. However, this action of dopamine was not affected by prazosin at concentrations sufficient to block alpha-adrenoceptors. Effect of dopamine was reduced in the presence of Rp-cyclic AMPS triethylamine, the membrane-permeable antagonist of cyclic AMP (cAMP), indicating the mediation of cAMP in this inhibition. Direct effect of exogenous dopamine on beta3-adrenoceptors was identified using the antibody for beta3-adrenoceptors that reversed the inhibition of dopamine. These results suggest that dopamine can activate beta3-adrenoceptors to lower glucose uptake into rat white adipocytes which lack dopaminergic receptors.     

Dopamine receptors and dopaminergic nerves in the vas deferens of the rat

Phentolamine antagonized competitively the effects of noradrenaline (pA2 = 7.1), dopamine (pA2 = 8.0) and tyramine (pA2 = 8.2). Haloperidol had a pA2 value of 7.3 against dopamine and 6.5 against noradrenaline. Apomorphine antagonized competitively dopamine (pA 2 = 4.8) and tyramine (pA2 = 5.1) and noncompetitively antagonized noradrenaline (pD'2 = 3.6). From these data it is concluded that these antagonists interact with dopamine receptors and alpha-adrenergic receptors. Apomorphine (10-4 M) attenuated the maximal response to dopamine and field stimulation, whereas the same concentration of apomorphine potentiated the maximal response to noradrenaline. Assuming that tyramine and field stimulation release the naturally occurring neurohumoral transmitter from adrenergic nerve endings, it is concluded that dopamine is the physiologically functional neurohumoral transmitter in the rat vas deferens which, when released, stimulates specific dopamine receptors.     

Antinociceptive effects of ketamine-opioid combinations in the mouse tail flick test

In rats kept at an ambient temperature of 22 degrees C, centrally and peripherally administered sauvagine induces a dose-dependent hypothermia. To clarify the regulatory mechanisms and to ascertain which neurotransmitter systems mediate sauvagine-induced hypothermia, we administered sauvagine intracerebroventricularly and subcutaneously in rats pretreated with antagonists of muscarinic receptors (atropine), opiate receptors (naloxone), alpha-adrenoceptors (phentolamine, yohimbine and prazosin), beta-adrenoceptors (propranolol) and dopamine receptors (haloperidol and spiperone). Systemic pretreatment of rats with atropine, naloxone, prazosin and propranolol left sauvagine-induced hypothermia unaltered. Pretreatment with phentolamine (4 mg/kg, s.c.), a non-selective alpha-adrenoceptor antagonist, and yohimbine (3 mg/kg, s.c.), a selective alpha 2-adrenoceptor antagonist, enhanced the hypothermic action of sauvagine. Pretreatment with haloperidol (2 mg/kg, s.c.), a non-selective dopamine receptor antagonist, and spiperone (80 micrograms/kg, s.c.), a selective dopamine D2 receptor antagonist, significantly reduced the temperature fall induced by centrally (4 micrograms/rat) and peripherally (20 micrograms/kg) administered sauvagine. Thus, sauvagine-induced hypothermia appears not to be mediated by interactions with cholinergic, endogenous opiate or noradrenergic systems, but rather D2 dopaminergic pathways alone are involved in the inhibitory effect of sauvagine on body temperature in the rat.     

Inhibitory effect of octopamine on the release of endogenous acetylcholine from isolated myenteric synaptosomes of guinea-pig

1. The effect of octopamine on the release of endogenous acetylcholine (ACh) from isolated ileal synaptosomal preparations of guinea-pigs was examined using high pressure liquid chromatography with electrochemical detection. Release of ACh was induced by substance P or by depolarization with high potassium (50 mmol/L) in medium containing atropine, propranolol and naloxone. 2. Octopamine produced a dose-dependent inhibition of substance P-induced ACh release. A similar inhibitory action of octopamine was found in the samples depolarized by high potassium as a reference. 3. The action of octopamine was not reversed by the dopamine receptor antagonists either for the DA-2 subtype, domperidone, or for the DA-1 subtype, SCH23390, or by haloperidol. However, idazoxan and yohimbine antagonized this octopamine-induced inhibition at concentrations sufficient to abolish the action of clonidine. 4. Failure of guanethidine or nomifensine to inhibit octopamine ruled out mediation by noradrenergic neurotransmitters. 5. Octopamine decreased the influx of [45Ca] stimulated by substance P into synaptosomal preparations and this was reversed by idazoxan or yohimbine at concentrations sufficient to block the action of clonidine. 6. Pertussis toxin abolished the inhibitory action of octopamine at a dose high enough to block the action of clonidine. 7. These results indicate that octopamine suppresses the influx of calcium ions into cholinergic nerve terminals of ileal synaptosomes of guinea-pigs via an activation of alpha 2-adrenoceptors coupled with a pertussis toxin-sensitive GTP-binding protein which results in a decrease of ACh release.     

Scavenging effects of dopamine agonists on nitric oxide radicals

It has recently been considered that free radicals are closely involved in the pathogenesis of Parkinson's disease (PD), and the level of nitric oxide radical (.NO), one of the free radicals, is reported to increase in PD brain. In the present study, we established a direct detection system for .NO in an in vitro .NO-generating system using 3-(2-hydroxy-1-methylethyl-2-nitrosohydrazino)-N-methyl-1-propa namine as an .NO donor and 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide (carboxy-PTIO) by electron spin resonance (ESR) spectrometry and examined the quenching effects of the dopamine agonists pergolide and bromocriptine on the amount of.NO generated. .NO appeared to be scavenged by pergolide and, to a lesser extent, by bromocriptine. In the competition assay, the 50% inhibitory concentration values for pergolide and bromocriptine were estimated to be approximately 23 and 200 microM, respectively. It was previously reported that in vivo treatment of pergolide and bromocriptine completely protected against the decrease in levels of striatal dopamine and its metabolites in the 6-hydroxydopamine-injected mouse. Considering these findings, pergolide and probably bromocriptine may also protect against dysfunction of dopaminergic neurons because of its multiple effects; not only does it stimulate the presynaptic autoreceptors, but it also directly scavenges .NO radicals and hence protects against .NO-related cytotoxicity. This ESR spectrometry method using carboxy-PTIO may be useful for screening other drugs that can quench .NO.     

5-Hydroxytryptamine induces forestomach hypomotility in sheep through 5-HT4 receptors

The effects evoked by 5-hydroxytryptamine (5-HT; serotonin) on forestomach myoelectric activity were investigated in conscious sheep. Myoelectric signals were recorded with electrodes chronically implanted in the reticulum, rumen (dorsal sac) and omasal body, and were analysed by a computer-based method. The 5-HT receptors and the neuronal pathways involved in these actions were studied. The intravenous (i.v.) infusion of 5-HT (8 micrograms kg-1 min-1 for 5 min) evoked an inhibition of activity of the whole forestomach. Methiothepin, injected i.v. at 0.1 mg kg-1, inhibited rumen secondary contractions and omasum activity. However, forestomach activity remained unchanged after the administration of 0.2 mg kg-1 of ketanserin, ondansetron, tropisetron, GR-113808, phentolamine, propranolol, domperidone and naloxone. Atropine (0.2 mg kg-1), hexamethonium (2 mg kg-1) or haloperidol (0.1 mg kg-1) abolished rumen secondary cycles and inhibited omasum activity. In addition, atropine also suppressed primary cycles. GR-113808 blocked all 5-HT-induced effects. Furthermore, atropine or hexamethonium prevented the 5-HT-evoked inhibition of reticulorumen primary cycles. In contrast, the remaining antagonists did not alter the 5-HT-evoked forestomach hypomotility. In conclusion, 5-HT induces inhibition of forestomach myoelectric activity through 5-HT4 receptors, these actions being mediated by cholinergic neural pathways involving muscarinic and nicotinic receptors. However, adrenergic, dopaminergic or opiate pathways are not implicated.     

A heroin-, but not a cocaine-expecting, self-administration state preferentially alters endogenous brain peptides

The effects of L-type voltage-dependent Ca2+ channel blockers on apomorphine, bromocriptine and morphine-induced changes in locomotor activity were examined in mice. Apomorphine (4 mg/kg) and morphine (20 mg/kg) produced locomotor stimulation. Bromocriptine (8 mg/kg) produced a biphasic effect on motor behaviour, an early depressant phase, followed by locomotor stimulation. Amlodipine (2.5 mg/kg), nicardipine (10 mg/kg), diltiazem (10 mg/kg) and verapamil (10 mg/kg), which by itself did not affect locomotor activity, inhibited the stimulant phase of bromocriptine without altering the depressant phase, while they did not affect apomorphine- and morphine-induced locomotor stimulation. Apomorphine, bromocriptine and morphine-induced locomotor stimulation was decreased by SCH 23390 (R-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7- ol) (0.05 mg/kg) or haloperidol (0.1 mg/kg). These results indicate that L-type voltage-dependent Ca2+ channels are involved in the motor stimulant effect of bromocriptine, but not in apomorphine- and morphine-induced locomotor stimulation. The effects of Ca2+ channel blockers on the dopaminergic system appears not to be directly related to dopamine receptor blockade.     

Effect of coadministration of glutamate receptor antagonists and dopaminergic agonists on locomotion in monoamine-depleted rats

Combinations of dopaminergic agonists with glutamate receptor antagonists have been suggested to be a possible alternative treatment of Parkinson's disease. To gain further insights into this possibility, the antagonist of the competitive AMPA-type glutamate receptor NBQX and the ion-channel blocker of the NMDA glutamate receptor (+)-MK-801 in combination with the dopamine D1 receptor agonists: SKF 38393, SKF 82958 and dihydrexidine; the dopamine D2 receptor agonist bromocriptine and the dopamine-precursor L-DOPA were tested in rats pretreated with reserpine and alpha-methyl-p-tyrosine. MK-801 on its own induced locomotor behaviour and potentiated the antiakinetic effects of dihydrexidine and L-DOPA but not of the other dopamine agonists tested. NBQX neither on its own nor coadministered with the dopamine agonists tested had an antiakinetic effect. These results indicate that agents, blocking the ion-channel of the NMDA receptor, might be useful adjuvants to some but not all dopaminomimetics in therapy of Parkinson's disease. The same does not seem to be true for the AMPA-antagonist NBQX.     

Histochemistry in rat brain and spinal cord with an antibody directed at the cholecystokininA receptor

The role of D2/D3 receptors in striatum was electrophysiologically examined in vitro in chloralose-anesthetized rats. In addition, in vitro patch clamp method with rat brain slices was followed. Stimulations of the substantia nigra pars compacta (SN) in vivo elicited spike generation which was inhibited by microiontophoretically applied domperidone, a D2 antagonist. These domperidone-sensitive neurons were activated by microiontophoretic application of D2 agonists such as talipexole, quinpirole and bromocriptine as well as the D2 agonist, 7-OH-DPAT. They were also excited by either intravenous injection of bromocriptine or talipexole in a dose-dependent manner. Furthermore, the SN-induced increases in neuronal firing were blocked during microiontophoretic application of domperidone. In patch clamp whole-cell recording large-sized cells, identified visually under Ramanosky microscope, were depolarized with repetitive firing on bath application of talipexole and 7-OH-DPAT at a current clamp mode. Talipexole-induced depolarization in the large-sized cell was similarly observed in the presence of TTX and high Mg2+ in Ca(2+)-free physiological solution. In contrast, the medium-sized cells were hyperpolarized on bath application of talipexole without being affected by 7-OH-DPAT. These findings suggest that the large-sized cells, which were presumably cholinergic interneurons, are activated by dopamine derived from the SN via D2 and/or D3 receptors, while the medium-sized cells are inhibited by dopamine via D2 receptors.