Dopamine receptor D1 agonist inhibits glioblastoma via calpain­mediated ER stress and mitochondrial dysfunction.

Recent studies have reported the important roles of dopamine receptors in the early development and progression of glioblastoma (GBM). The present research aimed to explore the antineoplastic effect and intrinsic pathways of action of dopamine receptor D1 agonist SKF83959 on GBM cells. Flow cytometric analysis revealed a significant level of apoptotic cell death under SKF83959 treatment. SKF83959 administration increased intracellular calcium levels and oxidative stress through the phospholipase C/inositol trisphosphate pathway. The downstream calpains were activated and dysregulated by the increased calcium levels. The mitochondrial membrane potential­dependent staining assay revealed decreased mitochondrial transmembrane potential in GBM cells under SKF83959 treatment. The mitochondrial/cytosolic fraction and western blotting further demonstrated mitochondrial dysfunction and endoplasmic reticulum stress, followed by apoptosis. The calpain inhibitor, calpastatin, significantly reversed the increase in mitochondrial injury and endoplasmic reticulum stress and eventually ameliorated GBM cell apoptosis during SKF83959 treatment. Finally, the in vivo inhibitory efficacy of SKF83959 was verified in GBM xenograft models. In addition, immunohistochemistry and western blotting both revealed increased expression of calpains in xenograft GBM tissues. These results suggested a potential therapeutic target for human GBM treatment regarding calpain expression and activity regulation.

SKF83959 Has Protective Effects in the Scopolamine Model of Dementia.

Patients with Alzheimer's disease (AD) always have cognitive impairments. In this study we investigated whether 6-chloro-7,8-dihydroxy-3-methyl-1-(3-methylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine (SKF83959) has improvements on cognitive dysfunction. The scopolamine model of dementia was used to investigate the anti-amnesic activities of SKF83959, and then, Western blotting and pharmacological inhibitor were used to assay the anti-amnesic mechanisms of SKF83959. It was found that SKF83959 administration significantly improved the scopolamine-induced memory impairments in the passive avoidance task, Y-maze test, and Morris water maze task. Moreover, SKF83959 treatment significantly antagonized the down-regulating effects of scopolamine on brain-derived neurotrophic factor (BDNF) signaling cascade in the hippocampus, but not cortex. Importantly, the usage of K252a, a selective inhibitor of tyrosine kinase B (TrkB), significantly attenuated the protective effects of SKF83959 in the scopolamine model. Collectively, this study shows that SKF83959 has beneficial effects in the scopolamine model of dementia by modulation of hippocampal BDNF signaling, implying a novel and potential therapeutic agent for treating dementia in AD.

The atypical dopamine receptor agonist SKF 83959 enhances hippocampal and prefrontal cortical neuronal network activity in a rat model of cognitive dysfunction.

Deficits in neuronal network synchrony in hippocampus and prefrontal cortex have been widely demonstrated in disorders of cognitive dysfunction, including schizophrenia and Alzheimer's disease. The atypical dopamine agonist SKF 83959 has been shown to increase brain-derived neurotrophic factor signalling and suppress activity of glycogen synthase kinase-3 in PFC, two processes important to learning and memory. The purpose of this study was to therefore evaluate the impact of SKF 83959 on oscillatory deficits in methylazoxymethanol acetate (MAM) rat model of schizophrenia. To achieve this, local field potentials were recorded simultaneously from the hippocampus and prefrontal cortex of anesthetized rats at 15 and 90 min following both acute and repeated administration of SKF 83959 (0.4 mg/kg). In MAM rats, but not controls, repeated SKF 83959 treatment increased signal amplitude in hippocampus and enhanced the spectral power of low frequency delta and theta oscillations in this region. In PFC, SKF 83959 increased delta, theta and gamma spectral power. Increased HIP-PFC theta coherence was also evident following acute and repeated SKF 83959. In apparent contradiction to these oscillatory effects, in MAM rats, SKF 83959 inhibited spatial learning and induced a significant increase in thigmotactic behaviour. These findings have uncovered a previously unknown role for SKF 83959 in the positive regulation of hippocampal-prefrontal cortical oscillatory network activity. As SKF 83959 is known to have affinity for a number of receptors, delineating the receptor mechanisms that mediate the positive drug effects on neuronal oscillations could have significant future implications in disorders associated with cognitive dysfunction.

Influence of SKF38393 on changes of gene profile in rat prefrontal cortex during chronic paradoxical sleep deprivation.

Chronic paradoxical sleep deprivation (CSD) can induce dramatic physiological and neurofunctional changes in rats, including decreased body weight, reduced learning and memory, and declined locomotor function. SKF38393, a dopamine D1 receptor agonist, can reverse the above damages. However, the mechanism of CSD syndrome and reversal role of SKF38393 remains largely unexplained. To preliminarily elucidate the mechanism of the neural dysfunction caused by CSD, in the present study we use gene chips to examine the expression profile of more than 28,000 transcripts in the prefrontal cortex (PFC). Rats were sleep deprived by modified multi-platform method for 3 weeks. Totally 59 transcripts showed differential expressions in CSD group in contrast to controls; they included transcripts coding for caffeine metabolism, circadian rhythm, drug metabolism and some amino acid metabolism pathway. Among the 59 transcripts, 39 increased their expression and 20 decreased. Two transcripts can be specifically reversed with SKF38393, one of them is Homer1, which is related to 20 functional classifications and coding for Glutamatergic synapse pathway. Our findings in the present study indicate that long-term sleep deprivation may trigger the changes of some certain functions and pathways in the PFC, and lead to the dysfunction of this advanced neuron, and the activation of D1 receptor by SKF38393 might ameliorate these changes via modulation of some transcripts such as Homer1, which is involved in the Ca(2+) pathway and MAPK pathway related to Glutamatergic synapse pathway.

Allosteric modulation of sigma-1 receptors elicits anti-seizure activities.

BACKGROUND AND PURPOSE: Application of orthosteric sigma-1 receptor agonists as anti-seizure drugs has been hindered by questionable efficacy and potential adverse effects. Here, we have investigated the anti-seizure effects of the novel and potent allosteric modulator of sigma-1 receptors, SKF83959 and its derivative SOMCL-668 (3-methyl-phenyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol). EXPERIMENTAL APPROACH: The anti-seizure effects of SKF83959 were investigated in three mouse models, maximal electroshock seizures, pentylenetetrazole-induced convulsions and kainic acid-induced 'status epilepticus'. Also, in rats, the cortical epileptiform activity induced by topical application of picrotoxin was recorded in electrocorticograms. In rat hippocampal brain slices, effects of the drugs on the high potassium-evoked epileptiform local field potentials were studied. Anti-seizure activities of SOMCL-668, a newly developed sigma-1 receptor selective allosteric modulator, were also investigated. KEY RESULTS: SKF83959 (20, 40 mg·kg(-1) ) exhibited anti -seizure actitity in the three mouse models and reduced the cortical epileptiform activity without alteration of spontaneous motor activity and motor coordination. These effects were blocked by the sigma-1 receptor antagonist BD1047, but not the dopamine D1 receptor antagonist SCH23390. SKF83959 alone did not directly inhibit the epileptiform firing of CA3 neurons induced by high potassium in hippocampal slices, but did potentiate inhibition by the orthosteric sigma-1 receptor agonist SKF10047. Lastly, a selective sigma-1 receptor allosteric modulator SOMCL-668, which does not bind to dopamine receptors, exerted similar anti-seizure activities. CONCLUSIONS AND IMPLICATIONS: SKF83959 and SOMCL-668 displayed anti-seizure activities, indicating that allosteric modulation of sigma-1 receptors may provide a novel approach for discovering new anti-seizure drugs.

D1 receptor agonist improves sleep-wake parameters in experimental parkinsonism.

Both excessive daytime sleepiness (EDS) and rapid eye movement (REM) sleep deregulation are part of Parkinson's disease (PD) non-motor symptoms and may complicate dopamine replacement therapy. We report here that dopamine agonists act differentially on sleep architecture in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine macaque monkey. Continuous sleep and wake electroencephalographic monitoring revealed no effect of the selective dopamine D2 receptor agonist quinpirole on EDS, whereas the selective dopamine D1 receptor agonist SKF38393 efficiently alleviated EDS and restored REM sleep to baseline values. The present results question the relevance of abandoning D1 receptor agonist treatment in PD as it might actually improve sleep-related disorders.

SKF83959 is a novel triple reuptake inhibitor that elicits anti-depressant activity.

AIM: SKF83959 (3-methyl-6-chloro-7,8-hydroxy-1-(3-methylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine) is an atypical dopamine receptor-1 (D1 receptor) agonist, which exhibits many D1 receptor-independent effects. In the present work, we examined the effects of SKF83959 on monoaminergic transporters in vitro and its anti-depressant activity in vivo. METHODS: Human serotonin transporter (SERT), norepinephrine transporters (NET) or dopamine transporters (DAT) were stably expressed in CHO cells. The uptake kinetics of SERT, NET, and DAT were examined using [(3)H]-serotonin, [(3)H]-norepinephrine or [(3)H]-dopamine, respectively. A triple reuptake inhibitor DOV21947 was used as the positive control. Tail suspension test and forced swimming test were conducted in mice. SKF83959 or DOV21947 (2-8 mg/kg) were intraperitoneally injected 30 min before the tests. RESULTS: SKF83959 was a competitive inhibitor of SERT (K(i)=1.43±0.45 µmol/L), but a noncompetitive inhibitor of NET (K(i)=0.60±0.07 µmol/L) and DAT (K(i)=9.01±0.80 µmol/L). In contrast, DOV21947 was a competitive inhibitor of SERT (K(i)=0.89±0.24 µmol/L) and DAT (K(i)=1.47±0.31 µmol/L) and a noncompetitive inhibitor of NET (K(i)=0.18±0.04 µmol/L). In mice, both SKF83959 and DOV21947 elicited anti-depressant activity in a dose-dependent manner. CONCLUSION: SKF83959 functions as a novel triple reuptake inhibitor in vitro and exerts anti-depressant effects in vivo.

D(1)-like receptor activation improves PCP-induced cognitive deficits in animal models: Implications for mechanisms of improved cognitive function in schizophrenia.

Phencyclidine (PCP) produces cognitive deficits of relevance to schizophrenia in animal models. The aim was to investigate the efficacy of the D(1)-like receptor agonist, SKF-38393, to improve PCP-induced deficits in the novel object recognition (NOR) and operant reversal learning (RL) tasks. Rats received either sub-chronic PCP (2 mg/kg) or vehicle for 7 days, followed by a 7-day washout. Rats were either tested in NOR or the RL tasks. In NOR, vehicle rats successfully discriminated between novel and familiar objects, an effect abolished in PCP-treated rats. SKF-38393 (6 mg/kg) significantly ameliorated the PCP-induced deficit (P<0.01) an effect significantly antagonised by SCH-23390 (0.05 mg/kg), a D(1)-like receptor antagonist (P<0.01). In the RL task sub-chronic PCP significantly reduced performance in the reversal phase (P<0.001); SKF-38393 (6.0 mg/kg) improved this PCP-induced deficit, an effect antagonised by SCH-23390 (P<0.05). These results suggest a role for D(1)-like receptors in improvement of cognitive function in paradigms of relevance to schizophrenia.

Hypothalamic neuropeptide Y (NPY) and the attenuation of hyperphagia in streptozotocin diabetic rats treated with dopamine D1/D2 agonists.

1. Dopamine is an appetite suppressant, while neuropeptide Y (NPY), an appetite stimulant in the brain, is reported to be involved in anorectic action induced by a combined administration of D1/D2 agonists in normal rats. In diabetic rats, however, these factors have not been studied. 2. Rats (including normal, diabetic and insulin-treated diabetic rats) were given daily injections of saline or D1/D2 agonists for 6 days. Changes in food intake and hypothalamic NPY content of these rats were assessed and compared. 3. The D1/D2 agonist-induced anorectic responses were altered in diabetic rats compared to normal rats treated similarly. Both the anorectic response on the first day of dosing and the tolerant response on the subsequent days were attenuated. 4. This alteration was independent of the neuroendocrine disturbance on feeding behavior since the basic pattern of food intake during the time course of a 24-h day/night cycle was similar in normal and diabetic rats; the decrease of food intake following drug treatment was only shown at the initial interval of 0-6 h in both groups of rats. 5. However, this alteration coincided with changes in NPY content following D1/D2 coadministration. The replacement of insulin in diabetic rats could normalize both NPY content and D1/D2 agonist-induced anorexia. 6. It is demonstrated that the response of D1/D2 agonist-induced appetite suppression is attenuated in diabetic rats compared to normal rats and that elevated hypothalamic NPY content may contribute to this alteration.

Attenuation of morphine withdrawal signs by a D1 receptor agonist in the locus coeruleus of rats.

In the present study, the effects of intra-locus coeruleus injection of a dopamine D(1) receptor agonist (SKF38393) on naloxone-induced withdrawal signs of morphine-dependent rats were examined. Twenty different withdrawal signs were assessed. The total withdrawal score was calculated and used as an index of withdrawal intensity for comparison. The D(1) agonist and antagonist were injected 15 and 30 min prior to expression of naloxone-induced withdrawal signs, respectively. SKF38393 (2 and 4 microg/site) decreased while SCH23390 (a D(1) antagonist) had no effect on the total withdrawal score. On the other hand, SCH23390 (25 ng/site) reversed the SKF38393 effect. It may be concluded that activation of dopamine D(1) receptors in the locus coeruleus attenuates naloxone-induced withdrawal.

Effects of chronic administration of the D1 receptor partial agonist SKF 77434 on cocaine self-administration in rhesus monkeys.

RATIONALE: Dopamine D1 receptor partial agonists have been proposed as candidate medications for the treatment of cocaine dependence. However, there currently is scant information regarding how chronic exposure to D1 agonists may modify behavioral effects of cocaine and, especially, whether tolerance develops to their effects on cocaine self-administration. OBJECTIVE: The present studies were conducted to evaluate the effects of chronic treatment with the D1 receptor partial agonist SKF 77434 on IV cocaine self-administration in rhesus monkeys. METHODS: A protocol was developed to rapidly evaluate the effects of chronic drug exposure on extinction behavior, threshold dose of self-administered cocaine, and the dose-effect function for cocaine self-administration behavior. Monkeys performed in daily sessions of IV cocaine self-administration under a fixed-ratio schedule of reinforcement and food presentation under either a fixed-ratio or fixed-interval schedule of reinforcement. When both types of performance were stable, chronic exposure to SKF 77434 followed with month-long regimens of IV treatment with each of two or three dosages. RESULTS: The effects of SKF 77434 were dose-related. Exposure to 1.0 mg/kg per day of SKF 77434 yielded a moderate and persistent rightward shift in the descending portion of the dose-effect function for cocaine self-administration but did not alter the threshold dose and did not disrupt either extinction behavior or food-maintained performance. An increase in dosage to 3.2-5.6 mg/kg per day displaced the dose-effect function for cocaine self-administration downward from its prechronic position, altered threshold dose values, and disrupted food-maintained performance. CONCLUSIONS: Chronic treatment with D1 receptor partial agonists produced dose-dependent effects on cocaine self-administration that may be relevant to their further evaluation as candidate medications for the treatment of cocaine dependence.

Bromocriptine/SKF38393 treatment ameliorates dyslipidemia in ob/ob mice.

Our previous studies have shown that the dopaminergic D1 receptor agonist SKF38393 (SKF) plus the D2 receptor agonist bromocriptine (BC) act synergistically to reduce obesity in obese C57BL/6J (ob/ob) mice. The present study investigated the effects of this combination on dyslipidemia in ob/ob mice. Female ob/ob mice were treated daily with vehicle or SKF (20 mg/kg body weight [BW]) plus BC (16 mg/kg BW [BC/SKF]) for 14 days. The animals were then used for the characterization of plasma lipoprotein profiles, hepatic triacylglycerol synthesis and secretion, adipocyte lipolysis, adipose and muscle lipoprotein lipase (LPL) activity, and muscle triglyceride (TG) content. The treatment significantly reduced plasma glucose 54%, TG 41%, cholesterol 21%, phospholipid 20%, and free fatty acid (FFA) 36% (P < .01). Hepatic triacylglycerol synthesis was 55% lower in treated mice versus control mice (P < .01). The cell size of isolated adipocytes was significantly reduced (41%) by treatment. LPL activity was increased in soleus skeletal muscle (25%, P < .05) but was sharply reduced in adipose tissue (91%, P < .01) in treated versus control mice. The TG content of hindlimb muscle was about 49% lower in treated versus control mice (P < .05). The basal and isoproterenol-stimulated lipolytic rate was decreased (approximately 53%) in adipocytes from treated animals compared with the control (P < .01). In conclusion, BC/SKF normalized the hypertriglyceridemia likely via its simultaneous antilipogenic action in liver tissue and antilipolytic action in adipose tissue. Decreased plasma flux of FFA partially contributed to the reduced hepatic lipogenesis, plasma very-low-density lipoprotein (VLDL)-TG, and TG in skeletal muscle. The above-described effects of BC/SKF treatment are largely independent of its effect to normalize hyperphagia in ob/ob mice.

Biochemical mechanisms responsible for the attenuation of diabetic and obese conditions in ob/ob mice treated with dopaminergic agonists.

OBJECTIVE: We previously reported that a two week treatment with SKF 38393 (SKF, a dopamine D1 receptor agonist), plus bromocriptine (BC, a dopamine D2 receptor agonist) acted synergistically to normalize hyperphagia, body fat, hyperglycaemia and hyperlipidaemia in ob/ob mice. The present study further investigates the biochemical mechanisms triggered by this drug treatment. DESIGN: Six week old female C57BL/6J ob/ob mice were divided into three groups and treated for two weeks with either BC and SKF, vehicle (control), or vehicle and pair fed to match the drug-treated group's daily food intake. RESULTS: BC/SKF treatment reduced food consumption by 55%, and treated mice weighed less than either pair fed or ad libitum fed controls after two weeks of treatment. Moreover, oxygen consumption was increased by 2.4-fold and the respiratory quotient (RQ) decreased from 1.23 to 0.96 (indicating a reduction in de novo lipogenesis) by drug treatment relative to ad libitum fed controls, but these parameters were unaffected by pair feeding control mice. The treatment also reduced blood glucose and free fatty acids (FFA) relative to pair fed and ad libitum fed controls. BC/SKF treatment (but not pair feeding) concurrently reduced lipolysis, lipogenic enzyme activities and hepatic gluconeogenic enzyme activities. Treatment also increased hepatic concentrations of glycogen and xylulose-5-phosphate (X-5-P), a key stimulator of glycolysis. Finally, BC/SKF, but not pair feeding, reduced the circulating concentrations of thyroxine and corticosterone, two hormones known to increase lipolysis, lipogenesis and hyperglycaemia. Drug treatment also increased serum dehydroepiandrosterone (DHEA) sulfate concentrations, an inhibitor of body fat store accumulation. CONCLUSION: These findings demonstrate that BC/SKF treatment not only normalizes hyperphagia of ob/ob mice, but also redirects several metabolic and endocrine activities, independent of its effects on feeding to improve the obese-diabetic syndrome in ob/ob mice.

Interaction between midazolam-induced anterograde amnesia and memory enhancement by treatments given hours later in hippocampus, entorrhinal cortex or posterior parietal cortex.

Rats were bilaterally implanted with indwelling cannulae in the CA1 region of the dorsal hippocampus, the entorrhinal cortex or the posterior parietal cortex. After recovery from surgery, they were trained in a one-trial step-down inhibitory avoidance task using a 0.3 mA footshock. The animals received i.p. 15 min before training either saline (1 ml/kg) or midazolam (1 mg/kg). Three hours after training they received, through the cannulae, infusions of saline, norepinephrine (0.3 microg/side), SKF38393 (7.5 microg/side), or 8-Br-cAMP (1.25 microg/side) into the brain regions mentioned. Animals were tested for retention 24 h after the training session. Midazolam produced anterograde amnesia, and the post-training treatments (with the exception of SKF38393 given into the entorrhinal cortex) caused retrograde memory facilitation. The amnestic effect of midazolam and the facilitatory effect of the treatments given into the brain cancelled each other out. Therefore, the mechanisms triggered by midazolam can interact with others in areas involved in memory processing several hours after their onset.

Bromocriptine/SKF38393 treatment ameliorates obesity and associated metabolic dysfunctions in obese (ob/ob) mice.

It has been postulated that dopaminergic activities comprise a major functional component of a central regulatory system for metabolism which can be manipulated by dopamine modulating drugs. The present study is aimed at delineating the role and importance of pharmacological dopaminergic activation in the regulation of metabolism during obesity and diabetes. We treated C57BL/6J ob/ob mice for 2 weeks with bromocriptine (dopamine D2 agonist), SKF38393 (dopamine D1 agonist), both drugs combined or vehicle and monitored the effects of such treatment on body composition, food consumption, and serum metabolites. Bromocriptine and SKF38393 individually produced moderate improvements in obesity, hyperglycemia, and hyperinsulinemia. However, a combination of bromocriptine plus SKF38393 resulted in major reductions in body weight (7.5 g), body fat (40%), food consumption (42%), and serum concentrations of glucose (59%), triglyceride (37%), free fatty acid (45%) and insulin (49%) while increasing protein mass (8%). These results indicate that regulatory components of metabolism in the ob/ob mouse are modulated by and/or are comprised of dopaminergic activities. Importantly, dopaminergic D1/D2 receptor coactivation maximizes this dopaminergic response (i.e., improvement of metabolic abnormalities) in these mice.

Amphetamine-induced locomotor stereotypy in rats is reduced by a D1 but not a D2 antagonist.

Amphetamine produces locomotor stereotypy (repetitive routes of locomotion) in an open field. In this research we tested the ability of the D1 antagonist SKF 83566 and the D2 antagonist sulpiride to block the locomotor stereotypy produced by 2 mg/kg amphetamine. SKF 83566 decreased amphetamine-induced locomotor stereotypy; sulpiride had no consistent effect on amphetamine-induced locomotor stereotypy. There was no evidence that either antagonist potentiated the effect of the other.

Gastric and duodenal anti-ulcer activity of SKF 38393, a dopamine D1-receptor agonist in rats.

The effect of SKF 38393 (1-phenyl-7,8-diol-2,3,4,5-tetrahydro-1H-3-benzazepine), a specific dopamine D1-receptor agonist, was studied on pylorus-ligation and water immersion plus restraint stress-induced gastric ulcers, and cysteamine-induced duodenal ulcers in rats. Repeated administration of SKF 38393 (5 and 10 mg kg-1, p.o.) for six days was found to be effective in the prevention of gastric ulceration induced by water immersion plus restraint stress in rats. In 19-h pylorus-ligated rats, repeated treatment with SKF 38393 showed a significant reduction in the number and severity of ulcers. SKF 38393 did not alter the total gastric-mucosal carbohydrates:protein ratio; however, the gastric content volume and the free and total acidity were significantly reduced. In cysteamine-induced duodenal ulcers, the treatment with SKF 38393 for 6 days prevented the duodenal lesions. Our data suggests the involvement of dopamine D1 receptors in the anti-ulcer activity of SKF 38393, which could be largely attributed to its anti-secretory effect. Its anti-ulcer activity against water immersion plus restraint, also points towards a central mode of action, but its failure to alter the carbohydrate:protein ratio rules out any protective effect through the strengthening of the gastric mucosal barrier.

Dopamine receptor agonist reduces ethanol self-administration in the ethanol-preferring C57BL/6J inbred mouse.

This report experimentally examined whether the genetically determined low nigrostriatal/mesolimbic dopaminergic activity in the C57BL/6J (herein referred to as C57) inbred mouse mediated the congenital high risk for ethanol abuse (ethanol consumption and ethanol preference) in this model. C57 mice pretreated with dopamine D1 receptor agonist ((+)-SKF-38393) or dopamine D2 receptor agonist (bromocriptine) to augment synaptic dopamine availability exhibited marked 76% and 38% reductions in voluntary ethanol intake in comparison to untreated controls. Dopamine receptor agonist administration resulted in changes in dopamine D1 and D2 receptor mRNA in the cell bodies and dopamine D1 and D2 receptor densities principally in the afferent targets of nigrostriatal/mesolimbic dopamine neurons. Dopamine receptor agonists promoted a decrease of striatal dopamine D1 and D2 receptor densities and corresponding down-regulation of olfactory tubercle dopamine D1 and D2 receptor mRNA abundance. Dopamine receptor agonist-induced increases in forebrain dopaminergic activity was compensated with increased dopamine D2 receptor density and correspondingly higher dopamine D2 receptor mRNA content in the brain stem. When bromocriptine was administered to ethanol-sensitized mice, it was ineffective in reducing voluntary ethanol abuse. In these mice, treatment with the dopamine D2 receptor antagonist haloperidol led to a 28% reduction in the absolute amount of ethanol consumed, but not in voluntary ethanol preference. These data indicated that nigrostriatal/mesolimbic dopamine D1-D2 receptor mechanism(s) mediating the potential for becoming high ethanol drinking on exposure to ethanol are distinct from factors mediating voluntary ethanol drinking after sensitization to ethanol. These data constitute direct evidence supporting a dopamine hypothesis for ethanol abuse in the genetically ethanol-preferring C57 mouse.

Hemodynamic profile of intravenous fenoldopam in patients with hypertensive crisis.

Fenoldopam, a newly developed intravenous dopaminergic DA1 receptor agonist, was used in an open, prospective study for blood pressure control in 12 patients presenting with hypertensive crisis. At a dose of 0.2-0.5 microgram kg-1 min-1 fenoldopam decreased systolic blood pressure from 209 +/- 13 to 151 +/- 17 mmHg and diastolic blood pressure from 114 +/- 10 to 78 +/- 10 mmHg. Blood pressure was controlled in all 12 patients within 5-50 min. In none of the patients did rebound hypertension occur upon termination of the study medication, nor was any adverse event reported. Major hemodynamic changes induced by fenoldopam were a decrease in total peripheral resistance from 1853 +/- 611 to 1193 +/- 368 and in pulmonary vascular resistance from 252 +/- 170 to 180 +/- 74 dyne s-1 cm-5. In patients with high left ventricular filling pressure at study pulmonary capillary wedge pressure decreased while the stroke volume index and mixed venous oxygen saturation increased under fenoldopam. Thus, fenoldopam appears to be a rapid-acting, well-tolerated, and highly effective intravenous substance for the treatment of severe hypertension.

Dopamine DA1 receptor activation reduces experimentally-induced gastritis in rats.

1. A selective dopamine DA1 receptor agonist, SKF38393, reduced the severity of experimentally-induced gastritis in rats. 2. This is the first such demonstration with a dopamine DA1 receptor agonist. 3. When considered together with other reported actions of D1/DA1 receptor agonists, these data confirm a significant gastroprotective role for dopamine.