Primate trace amine receptor 1 modulation by the dopamine transporter

Recently identified trace amine receptors are potential direct targets for drugs of abuse, including amphetamine and 3,4-methylenedioxymethamphetamine (MDMA). We cloned full-length rhesus monkey trace amine receptor 1 (rhTA(1)) that was 96% homologous to human TA(1). The trace amines tyramine and beta-phenylethylamine (PEA) and the monoamine transporter substrates (+/-)-amphetamine and (+/-)-MDMA stimulated cAMP accumulation in rhTA(1)-expressing cell lines, as measured by a cAMP response element-luciferase assay. Cocaine did not stimulate cAMP accumulation in rhTA(1) cells, but it blocked [(3)H]PEA transport mediated by the dopamine transporter. Cotransfection with the human dopamine transporter enhanced PEA-, amphetamine-, and MDMA-mediated rhTA(1) receptor activation, but it diminished tyramine activation of rhTA(1). Because TA(1) (EGFP-rhTA(1) chimera) was largely intracellular, conceivably the dopamine transporter can facilitate access of specific agonists to intracellular TA(1). rhTA(1) mRNA expression was detected in rhesus monkey substantia nigra, implying that TA(1) may be colocalized with the dopamine transporter in dopamine neurons. In summary, primate TA(1) receptors are direct targets of trace amines, amphetamine, and MDMA. These receptors could also be indirect targets of amphetamine, MDMA, and cocaine through modification of monoamine transporter function. Conceivably, rhTA(1) receptors may be located on pre- or postsynaptic membranes. Interference with the carrier function of monoamine transporters with a consequent rise of extracellular levels of trace amines could activate these receptors. The cloning of a highly homologous TA(1) from rhesus monkey and demonstration that rhTA(1) receptors are activated by drugs of abuse, indicate that nonhuman primates may serve to model physiological and pharmacological TA(1)-mediated responses in humans.     

Procainamide in vivo modulates suppressor T lymphocyte activity

Autoantibodies to histone and denatured DNA have been found in 80% of patients treated with procainamide. Of these 10 to 20% will eventually develop a Systemic Lupus Erythematosus-like syndrome. Although the mechanism by which procainamide exerts its effect is unknown, in vitro studies suggest that procainamide may inhibit suppressor T cell activity. We have studied the immune function of 18 patients receiving a two hour infusion of procainamide during transvenous catheter electrophysiologic studies. There was no difference between pre and post infusion samples with respect to T and B cell mitogenesis or pokeweed mitogen-induced immunoglobulin secretion. However, in seventeen of eighteen patients, there was a marked decrease in Concanavalin A-inducible suppressor cell activity. This decrease appeared to be related to the amount of procainamide infused as high dose samples showed less suppressor activity than low dose samples. Thus the data show that procainamide, when given in vivo, leads to a rapid and dose dependent decrease in suppressor cell activity.     

Regional brain abnormalities in norepinephrine uptake and dopamine beta-hydroxylase activity in the genetically epilepsy-prone rat

Two markers for noradrenergic neurons: 1) desmethylimipramine sensitive norepinephrine (NE) uptake and 2) dopamine beta-hydroxylase activity were compared in various brain regions of normal and genetically epilepsy-prone rats (GEPR). These studies were designed to characterize further the nature of the noradrenergic deficit in GEPRs, which has been described as a reduction in steady-state NE levels. The high affinity (desmethylimipramine-sensitive) uptake of 3H-NE into crude synaptosomes was found to be significantly reduced in widespread areas of the GEPR forebrain including cortex, hippocampus, amygdala and hypothalamus. GEPRs also displayed a reduced uptake of 3H-NE in synaptosomes from the inferior colliculus, a structure that has been implicated in the audiogenic seizure, but other regions of the brain stem (reticular formation, cochlear nucleus, cerebellum) failed to reveal abnormalities in NE uptake. Reductions in dopamine beta-hydroxylase activity seemed to parallel the reductions in NE uptake regionally (except for the caudate nucleus), and both deficits (uptake and dopamine beta-hydroxylase) were similar in magnitude to the decrements in steady-state NE levels reported previously. The present findings therefore support the concept that there is a reduction in the number of noradrenergic terminals in most structures receiving noradrenergic innervations in the GEPR brain.     

Studies of the biogenic amine transporters. 12. Identification of novel partial inhibitors of amphetamine-induced dopamine release

Previous studies identified partial inhibitors and allosteric modulators of 5-hydroxytryptamine ([5-amino-3-(3,4-dichlorophenyl)-1,2-dihydropyrido[3,4-b]pyrazin-7-yl]carbamic acid ethyl ester [SoRI-6238], 4-(2-[bis(4-fluorophenyl)methoxy]ethyl)-1-(2-trifluoromethyl-benzyl)-piperidine [TB-1-099]) and dopamine transporters N-(diphenylmethyl)-2-phenyl-4-quinazolinamine, [SoRI-9804]). We report here the identification of three novel allosteric modulators of the dopamine transporter [N-(2,2-diphenylethyl)-2-phenyl-4-quinazolinamine [SoRI-20040], N-(3,3-diphenylpropyl)-2-phenyl-4-quinazolinamine [SoRI-20041], and [4-amino-6-[(diphenylmethyl)amino]-5-nitro-2-pyridinyl]carbamic acid ethyl ester [SoRI-2827]]. Membranes were prepared from human embryonic kidney cells expressing the cloned human dopamine transporter (hDAT). [(125)I]3beta-(4'-Iodophenyl)tropan-2beta-carboxylic acid methyl ester ([(125)I]RTI-55) binding and other assays followed published procedures. SoRI-20040, SoRI-20041, and SoRI-2827 partially inhibited [(125)I]RTI-55 binding, with EC(50) values ranging from approximately 1.4 to 3 microM and E(max) values decreasing as the [(125)I]RTI-55 concentrations increased. All three compounds decreased the [(125)I]RTI-55 B(max) value and increased the apparent K(d) value in a manner well described by a sigmoid dose-response curve. In dissociation rate experiments, SoRI-20040 (10 microM) and SoRI-20041 (10 microM), but not SoRI-2827 (10 microM), slowed the dissociation of [(125)I]RTI-55 from hDAT by approximately 30%. Using rat brain synaptosomes, all three agents partially inhibited [(3)H]dopamine uptake, with EC(50) values ranging from 1.8 to 3.1 microM and decreased the V(max) value in a dose-dependent manner. SoRI-9804 and SoRI-20040 partially inhibited amphetamine-induced dopamine transporter-mediated release of [(3)H]1-methyl-4-phenylpyridinium ion from rat caudate synaptosomes in a dose-dependent manner. Viewed collectively, we report several compounds that allosterically modulate hDAT binding and function, and we identify novel partial inhibitors of amphetamine-induced dopamine release.     

Ghrelin modulates the activity and synaptic input organization of midbrain dopamine neurons while promoting appetite

The gut hormone ghrelin targets the brain to promote food intake and adiposity. The ghrelin receptor growth hormone secretagogue 1 receptor (GHSR) is present in hypothalamic centers controlling energy metabolism as well as in the ventral tegmental area (VTA), a region important for motivational aspects of multiple behaviors, including feeding. Here we show that in mice and rats, ghrelin bound to neurons of the VTA, where it triggered increased dopamine neuronal activity, synapse formation, and dopamine turnover in the nucleus accumbens in a GHSR-dependent manner. Direct VTA administration of ghrelin also triggered feeding, while intra-VTA delivery of a selective GHSR antagonist blocked the orexigenic effect of circulating ghrelin and blunted rebound feeding following fasting. In addition, ghrelin- and GHSR-deficient mice showed attenuated feeding responses to restricted feeding schedules. Taken together, these data suggest that the mesolimbic reward circuitry is targeted by peripheral ghrelin to influence physiological mechanisms related to feeding.     

Carcinoembryonic antigen-related cell adhesion molecule 1 modulates vascular remodeling in vitro and in vivo

Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), a cellular adhesion molecule of the Ig superfamily, is associated with early stages of angiogenesis. In vitro, CEACAM1 regulates proliferation, migration, and differentiation of murine endothelial cells. To prove that CEACAM1 is functionally involved in the regulation of vascular remodeling in vivo, we analyzed 2 different genetic models: in Ceacam1-/- mice, the Ceacam1 gene was deleted systemically, and in CEACAM1(endo+) mice, CEACAM1 was overexpressed under the control of the endothelial cell-specific promoter of the Tie2 receptor tyrosine kinase. In Matrigel plug assays, Ceacam1-/- mice failed to establish new capillaries whereas in CEACAM1(endo+) mice the implants were vascularized extensively. After induction of hind limb ischemia by femoral artery ligation, Ceacam1-/- mice showed significantly reduced growth of arterioles and collateral blood flow compared with their WT littermates. In agreement with a causal role of CEACAM1 in vascular remodeling, CEACAM1(endo+) mice exhibited an increase in revascularization and collateral blood flow after arterial occlusion. Our findings indicate that CEACAM1 expression is important for the establishment of newly formed vessels in vivo. Hence CEACAM1 could be a future target for therapeutic manipulation of angiogenesis in disease.     

Citrulline increases cholesterol efflux from macrophages in vitro and ex vivo via ATP-binding cassette transporters

Reverse cholesterol transport (RCT) is a mechanism critical to the anti-atherogenic property of HDL. Although citrulline contributes to the amelioration of atherosclerosis via endothelial nitric oxide production, it remains unclear whether it affects RCT. This study was undertaken to clarify the effects of citrulline on expressions of specific transporters such as ATP binding cassette transporters (ABC)A1 and ABCG1, and the cholesterol efflux from macrophages to apolipoprotein (apo) A-I or HDL in vitro and ex vivo. Citrulline increased ABCA1 and ABCG1 mRNA and protein levels in THP-1 macrophages, translating into enhanced apoA-I- and HDL-mediated cholesterol efflux. In the human crossover study, 8 healthy male volunteers (age 30–49 years) consumed either 3.2 g/day citrulline or placebo for 1 week. Citrulline consumption brought about significant increases in plasma levels of citrulline and arginine. Supporting the in vitro data, monocyte-derived macrophages (MDM) differentiated under autologous post-citrulline sera demonstrated enhancement of both apoA-I- and HDL-mediated cholesterol efflux through increased ABCA1 and ABCG1 expressions, compared to MDM differentiated under pre-citrulline sera. However, the placebo did not modulate these parameters. Therefore, in addition to improving endothelium function, citrulline might have an anti-atherogenic property by increasing RCT of HDL.     

Neurotensin-induced dopamine release in vivo and in vitro from substantia nigra and nucleus caudate

We compared the dopamine (DA) releasing effects of neurotensin (NT) from cell bodies (substantia nigra) and nerve terminals (nucleus caudate). In rats implanted with push-pull cannula, NT induced DA release from substantia nigra and nucleus caudate. NT was more potent in releasing DA from the substantia nigra than from the nucleus caudate (EC50%, 1.1 microM in substantia nigra and 9.8 microM in nucleus caudate). In vitro, in superfused rabbit brain slices, NT enhanced the depolarization-evoked release of DA and exerted a direct releasing effect. The latter was greater in the substantia nigra, and the former in the nucleus caudate. The direct releasing effect of NT was not inhibited, but enhanced by nomifensine (3 microM). Sulpiride, a D2 DA receptor antagonist, failed to modify NT-induced DA release; in addition, NT did not affect the inhibition of DA and acetylcholine release produced by LY-171555, a D2 DA agonist. In both the substantia nigra and the nucleus caudate, desensitization to the releasing effect of NT was observed, either after 2.5, 5, or 10 min of exposure to the peptide. A synergistic interaction on DA release was observed between NT and potassium (K+), and between NT and electrical stimulation. Greater synergism was observed with high extracellular K+. Pretreatment of striatal slices with 15 mM K+ produced a 9-fold enhancement of NT-induced DA release. When K+ (25 mM, 2 min) was given together with NT there was a 2- to 3-fold increase in DA release compared to the release evoked by K+ in the absence of NT.(ABSTRACT TRUNCATED AT 250 WORDS)     

Carfecillin: antibacterial activity in vitro and in vivo.

Carfecillin, the alpha-phenyl ester of carbenicillin, hydrolyses rapidly in the presence of serum or body tissues to liberate carbenicillin but hydrolysis is less rapid in aqueous solution. The activity of carfecillin in antibacterial tests in vitro depends upon the extent of hydrolysis to carbenicillin, and in conventional serial dilution tests carfecillin shows an antibacterial spectrum generally similar to that of carbenicillin due to extensive hydrolysis. However, in tests in which the extent of hydrolysis is reduced, carfecillin displays lesser activity than carbenicillin against gram-negative bacilli and greater activity against gram-positive cocci. In the presence of serum carfecillin is hydrolysed rapidly to carbenicillin and the activity shown is solely that of carbenicillin. Unlike carbenicillin, carfecillin is well absorbed in mice after oral administration, producing significant carbenicillin blood concentrations and the compound is as effective by the oral route in the treatment of various experimental mouse infections as is parenteral carbenicillin.     

Saperconazole: in vitro and in vivo anticandidal activity.

The in vitro activity of saperconazole against eight candidal species (81 strains) was determined and compared with fluconazole, Sch 39304 and amphotericin B. Using brain heart infusion broth with an inoculum of 10(4) CFU/ml, the MIC ranges (micrograms/ml) of saperconazole were: less than or equal to 0.015- greater than 32 for Candida albicans, less than or equal to 0.015-16 for C. tropicalis, less than or equal to 0.015-32 for C. glabrata, less than or equal to 0.015-32 for C. parapsilosis, less than or equal to 0.015-0.12 for C. guilliermondii and less than or equal to 0.015-0.06 for C. krusei. Saperconazole was the most active agent tested against Candida species. Saperconazole and 5-fluorocytosine combinations showed synergistic interactions against Candida species, and no antagonistic interaction was demonstrated. In a rat vaginal candidiasis infection model, saperconazole and fluconazole were equipotent producing 75-100% cures at levels of 0.016-0.25%, respectively, when dosed intravaginally. After single oral dosing, saperconazole was 5-fold more potent than fluconazole with an ED50 value of 0.53 mg/kg. These data demonstrate that saperconazole is effective in a rat vaginal candidiasis infection either with a single oral dose or by intravaginal treatment.     

In vitro and in vivo study on the antioxidant activity of dexrazoxane

Objectives

The iron chelator dexrazoxane has been shown to significantly reduce anthracycline-induced cardiac toxicity in several randomized controlled studies. Aim of the present study was to assess the in vitro and in vivo antioxidant effects of dexrazoxane.

Methods

The in vitro antioxidant activity of dexrazoxane as its total oxyradical scavenging capacity (TOSC) was assessed and compared to that of some classic antioxidants such as reduced glutathione (GSH), uric acid and trolox. The plasma antioxidant activity of 20 newly-diagnosed non-Hodgkin lymphoma (NHL) patients scheduled to receive anthracycline-containing chemotherapy (ProMECE-CytaBOM) was also evaluated. Results were expressed as TOSC units.

Results

Dexrazoxane exhibited an in vitro scavenging capacity towards hydroxyl radicals 320% higher than that of GSH (p < 0.00001), 20% higher than that of uric acid (p < 0.001), and 100% higher than that of trolox (p < 0.001). In the clinical study, ProMECE-CytaBOM infusion significantly reduced plasma TOSC in NHL patients (p = 0.0001). Dexrazoxane supplementation was able to restore plasma antioxidant activity in two hours from the end of the ProMECE-CytaBOM infusion.

Conclusions

Dexrazoxane has in vitro antioxidant capacity. In vivo, it is able to reduce the epirubicin-induced free radical production. The intrinsic antioxidant effect of this compound could explain the reduction of the anthracyclines-induced toxicity in those patients treated with dexrazoxane supplementation.     

In vitro and in vivo anti-inflammatory activity of the new glucocorticoid ciclesonide

The glucocorticoid ciclesonide is the 2'R-epimer of 2'-cyclohexyl-11beta-hydroxy-21-isobutyryloxy-16bH-dioxolo[5',4':16,17]pregna-1,4-diene-3,20-dione. The active metabolite desisobutyryl-ciclesonide (des-CIC) is derived from ciclesonide by esterase cleavage of isobutyrate at the C21 position. The relative binding affinities at the rat glucocorticoid receptor were dexamethasone, 100; ciclesonide, 12; des-CIC, 1212; and budesonide, 905. Des-CIC potently inhibited the activation of murine and human lymphocytes in a series of different in vitro systems. With the exception of concanavalin A-stimulated rat spleen cells, des-CIC was more potent than the parent compound. Des-CIC compared well with budesonide in all in vitro systems. Furthermore, the respective 2'S-epimers were always significantly less potent than the 2'R-epimers. In vivo, ciclesonide (intratracheal administration), des-CIC, and budesonide inhibited antigen-induced accumulation of eosinophils, protein, and tumor necrosis factor-alpha into the bronchoalveolar lavage fluid of ovalbumin-sensitized and -challenged Brown Norway rats with an ED(50) value ranging from 0.4 to 1.3 mg/kg, indicating similar potency, which suggests in vivo activation of the parent compound. Ciclesonide and budesonide inhibited the bradykinin-induced protein leakage into the rat trachea. In the rat cotton pellet model, ciclesonide inhibited granuloma formation (ED(50):= of 2 microg/pellet), whereas budesonide and des-CIC were 15- and 20-fold less active; thymus involution was induced with an ED(50) of 303, 279, and 154 microg/pellet, respectively. When applied orally to rats for 28 days, ciclesonide showed low potency in reducing weight of thymus and adrenals, suggesting low oral bioavailability. The in vivo data on ciclesonide highlight its effective local action and a reduced potential for side effects.     

A comparison between classes of drugs having phencyclidine-like behavioral properties on dopamine efflux in vitro and dopamine metabolism in vivo

Phencyclidine [(l-phenylcyclohexyl) piperidine] (PCP) is known to increase the basal efflux of striatal dopamine (DA) in vitro and to enhance haloperidol (HAL)-induced striatal DA metabolism in vivo. This study compared these activities of PCP to several representatives of the arylcyloalkylamine, benzomorphan and substituted dioxolane classes whose behavioral similarities to PCP have been well studied. The affinity of these drugs for the PCP/sigma opiate receptor also was estimated by determining the concentration of these drugs required to inhibit the specific binding of 10 nM [3H]PCP to rat cortical membranes by 50%. Of the arylcycloalkylamines tested on the basal efflux of [3H]DA, we found the rank-order effectiveness to be as follows: PCP greater than 1-[l-(napthyl)cyclohexyl]piperidine HCl (m-amino-PCP) greater than ketamine greater than or equal to 1-[l-(m-nitrophenyl)cyclohexyl]piperidine HCl (m-nitro-PCP) greater than N-ethyl-l-phencyclohexylamine (PCE). However, in vivo we found that PCP, m-amino-PCP and PCE significantly elevated HAL-induced DA metabolism, whereas ketamine and m-nitro-PCP were without effect. Although each of the benzomorphans tested [N-allylnormetazocine (NANM) and ethylketocyclazocine (EKC)] slightly enhanced the basal efflux of [3H]DA from striatal slices, concentrations of 10 to 30 microM were required to elicit the same magnitude of [3H]DA release caused by 3 microM PCP. Quantitatively similar responses were produced by the substituted dioxolanes tested (etoxadrol, dexoxadrol and levoxadrol). Neither (+)-NANM, (-)-NANM, (+/-)-NANM, etoxadrol nor dexoxadrol had any effect on HAL-induced DA metabolism. On the other hand, both levoxadrol and EKC significantly decreased the ratio of HVA/DA after HAL administration.(ABSTRACT TRUNCATED AT 250 WORDS)     

Rhesus monkey trace amine-associated receptor 1 signaling: enhancement by monoamine transporters and attenuation by the D2 autoreceptor in vitro

Trace amine-associated receptor 1 (TAAR1) is a G protein-coupled receptor that directly responds to endogenous monoamines as well as amphetamine-related psychostimulants, including methamphetamine. In the present study, we demonstrate TAAR1 mRNA and protein expression in rhesus monkey brain regions associated with monoaminergic systems, variable cellular distribution of TAAR1 in rhesus monkey brain, and TAAR1 coexpression with the dopamine transporter (DAT) in a subset of dopamine neurons in both rhesus monkey and mouse substantia nigra. On this basis, we evaluated rhesus monkey TAAR1 activation by different compounds and its functional relation with monoamine transporters and the dopamine D2 receptor (D2) short isoform (D2s) autoreceptor in vitro using a cAMP response element-luciferase assay. TAAR1 activation by monoamines and amphetamine-related compounds was greatly enhanced by coexpression of dopamine, norepinephrine, or serotonin transporters, and the activation enhancement was blocked by monoamine transporter inhibitors. This enhancement did not occur in control experiments in which the dopamine D1 receptor (D1) was substituted for TAAR1. Furthermore, activation of TAAR1 by dopamine was completely inhibited by D2s when coexpressed with TAAR1, and this inhibition was blocked by the D2 antagonist raclopride. Last, dopamine activation of TAAR1 could induce c-FOS-luciferase expression but only in the presence of DAT, whereas dopamine activation of D1 resulted in equivalent c-FOS expression in the presence or absence of DAT. Together, these data reveal a broad agonist spectrum for TAAR1, a functional relation of TAAR1 with monoamine transporters and D2s, and a mechanism by which D2 receptor drugs can influence brain monoaminergic function and have efficacy through affecting TAAR1 signaling.     

Mouse locomotor activity: an in vivo test for dopamine autoreceptor activation

A pharmacologic test is described for assessing selective dopamine (DA) autoreceptor activation using locomotor activity (LMA) of the mouse as the dependent variable. In this test, three criteria must be satisfied to indicate selectivity for the DA autoreceptor. First, a dose-related fall in LMA, taken as a measure of DA autoreceptor activation, should be produced by the putative autoreceptor agonist. Second, to demonstrate a DA system is involved, the reduction in LMA should be blocked by a DA receptor antagonist. Finally, the test compound should produce no LMA-stimulating (i.e., postsynaptic DA receptor agonist) effects over prolonged periods of observation. Using these criteria, 15 DA agonists were evaluated for DA autoreceptor selectivity. Four agents satisfied all criteria as selective DA autoreceptor agonists: CF 25-397, N-n-3-propyl-3- hydroxyphenylpiperidine , 6,7-dihydroxy-2- dimethylaminotetralin (TL-99) and 2-amino-6,7- dibenzoyloxy -1,2,3,4- tetrahydronapthalene . Seven DA agonists produced U-shaped dose-response curves indicative of activity at both the autoreceptor and postsynaptic DA receptor. These agents were: apomorphine, n-propylnorapomorphine, pergolide, RU 24213, RU 24926, (-)-6-ethyl-9-oxaergoline and lisuride. SKF 38393 failed to exert any significant effect on the LMA of the mouse. Both lergotrile and bromocriptine produced dose-related falls in LMA, but both caused a rebound increase in LMA before their durations of action were terminated. Although 3,4-dihydroxyphenylamino-2-imidazoline did produce a dose-related fall in LMA, the inhibition produced by 3,4-dihydroxyphenylamino-2-imidazoline was not reduced by sulpiride, suggesting a nondopaminergic action for 3,4-dihydroxyphenylamino-2-imidazoline.(ABSTRACT TRUNCATED AT 250 WORDS)     

Amphipathic DNA polymers exhibit antiherpetic activity in vitro and in vivo

Phosphorothioated oligonucleotides have a sequence-independent antiviral activity as amphipathic polymers (APs). The activity of these agents against herpesvirus infections in vitro and in vivo was investigated. The previously established sequence-independent, phosphorothioation-dependent antiviral activity of APs was confirmed in vitro by showing that a variety of equivalently sized homo- and heteropolymeric AP sequences were similarly active against herpes simplex virus type 1 (HSV-1) infection in vitro compared to the 40mer degenerate parent compound (REP 9), while the absence of phosphorothioation resulted in the loss of antiviral activity. In addition, REP 9 demonstrated in vitro activity against a broad spectrum of other herpesviruses: HSV-2 (50% effective concentration [EC(50)], 0.02 to 0.06 microM), human cytomegalovirus (EC(50), 0.02 to 0.13 microM), varicella zoster virus (EC(50), <0.02 microM), Epstein-Barr virus (EC(50), 14.7 microM) and human herpesvirus types 6A/B (EC(50), 2.9 to 10.2 microM). The murine microbicide model of genital HSV-2 was then used to evaluate in vivo activity. REP 9 (275 mg/ml) protected 75% of animals from disease and infection when provided 5 or 30 min prior to vaginal challenge. When an acid-stable analog (REP 9C) was used, 75% of mice were protected when treated with 240 mg/ml 5 min prior to infection (P < 0.001), while a lower dose (100 mg/ml) protected 100% of the mice (P < 0.001). The acid stable REP 9C formulation also provided protection at 30 min (83%, P < 0.001) and 60 min (50%, P = 0.07) against disease. These observations suggest that APs may have microbicidal activity and potential as broad-spectrum antiherpetic agents and represent a novel class of agents that should be studied further.     

D-1 and D-2 dopamine receptor blockade: interactive effects in vitro and in vivo

Haloperidol, at low concentrations that block D-2 dopamine (DA) receptors but not D-1 DA receptors (less than 10 microM), potentiated the enhancement of adenylate cyclase activity produced by the D-1 agonist SKF 38393. Low concentrations of haloperidol (less than or equal to 5 microM) also potentiated the K+-evoked release of [3H]acetylcholine from superfused striatal tissue slices. Both of these effects of haloperidol were blocked by nanomolar concentrations of SCH 23390, a D-1 receptor antagonist. In addition, SCH 23390 reduced the ability of haloperidol to antagonize the inhibition of [3H]acetylcholine release produced by the DA agonist apomorphine. By itself, SCH 23390 did not alter either basal adenylate cyclase activity or the K+-evoked release of [3H]acetylcholine. These findings suggest that SCH 23390 can attenuate in vitro responses to D-2 receptor blockade. Likewise, in vivo, very low doses (less than 1 microgram/kg) of SCH 23390 reduced the ability of haloperidol to elevate striatal DA metabolite concentrations and plasma prolactin concentrations. Thus, D-1 receptor blockade may attenuate the effects of D-2 DA receptor blockade both in vitro and in vivo.     

Comparison of the cerebral effects of dopamine and norepinephrine in severely head-injured patients

OBJECTIVE: To compare the cerebral effects of dopamine and norepinephrine after severe head injury. DESIGN: Prospective, clinical study. SETTING: Surgical intensive care unit in a university hospital. PATIENTS: Nineteen patients with severe head-injuries already requiring vasopressor therapy. Group 1: patients receiving dopamine (n = 9); group 2: patients receiving norepinephrine (n = 10). INTERVENTION: Vasopressor therapy was switched from dopamine to norepinephrine in group 1 and from norepinephrine to dopamine in group 2, maintaining the same mean arterial pressure (MAP). MEASUREMENTS AND RESULTS: MAP, intracranial pressure (ICP), jugular venous oxygen saturation (SjvO2), transcranial Doppler mean velocity in the middle cerebral artery (Vm), and transoesophagal Doppler aortic output (AO) were evaluated under dopamine and norepinephrine. Means for each group were compared with the paired Student's t-test. For the same MAP, ICP was significantly higher with dopamine than norepinephrine in both groups (respectively, group 1: 26 +/- 11 vs 23 +/- 11 mmHg, P < 0.005; group 2: 39 +/- 13 vs 31 +/- 9 mmHg, P < 0.005). SjvO2, Vm, and AO did not change significantly between treatments. The ICP variation between treatments was not correlated with the variation of any other measured parameter. The ICP variation between treatments was significantly higher in group 2 than group 1, which could be explained by autoregulation mechanisms. CONCLUSIONS: For the same MAP, ICP was significantly higher with dopamine than norepinephrine with no argument supporting an increase of cerebral blood flow.