Neuropeptides: Animal behaviour and human psychopathology

Summary Animal studies have demonstrated that neuropeptides modulate nervous system functions. It has been postulated that disturbances in neuropeptide systems may be aetiological factors in psychiatric and neurological disorders. Neuropeptides related to ACTH/MSH, including ORG 2766, increase motivation and attention and facilitate recovery processes after nerve damage. These peptides may be effective during the early stage of dementia. Vasopressin and related peptides improve memory processes in animals and humans. In addition, these peptides influence social behaviour, mood and addictive behaviour. The non-opioid content/tk77wk711g68650m/xxlarge947.gif" alt="gamma" align="MIDDLE" BORDER="0">-type endorphins have neurolepticlike activities in animals and antipsychotic effects in a category of schizophrenic patients. Peptides related to CCK have also been found to be effective in these patients. Some neuropeptides, e.g. TRH and PLG, have been reported to exert antidepressant effects. Further research may eventually produce neuropeptides with therapeutic action in psychiatric and neurological diseases.Parts of this article were presented on the occasion of the inauguration ceremony of the Department of Psychiatry of the University of Mainz on April 2 and 3, 1987     

β-Methyl-15-p-iodophenylpentadecanoic acid metabolism and kinetics in the isolated rat heart

The use of 15-p-iodophenyl-content/n1660k166543322t/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-methyl-pentadecanoic acid (content/n1660k166543322t/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">Me-IPPA) as an indicator of long chain fatty acid (LCFA) utilization in nuclear medicine studies was evaluated in the isolated, perfused, working rat heart. Time courses of radioctivity (residue curves) were obtained following bolus injections of both content/n1660k166543322t/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">Me-IPPA and its straight chain counterpart 15-p-iodophenyl-pentadecanoic acid (IPPA). IPPA kinetics clearly indicated flow independent impairment of fatty acid oxidation caused by the carnitine palmitoyltransferase I inhibitor 2[5(4-chlorophenyl)pentyl]oxirane-2-carboxylate (POCA). In contrast, content/n1660k166543322t/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">Me-IPPA kinetics were insenstive to changes in fatty acid oxidation rate and net utilization of long chain fatty acid. Analysis of radiolabeled species in coronary effluent and heart homogenates showed the methylated fatty acid to be readily incorporated into complex lipids but a poor substrate for oxidation. POCA did not significatly alter metabolism of the tracer, suggesting that the tracer is poorly metabolized beyond content/n1660k166543322t/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">Me-IPPA-CoA in the oxidative pathway.     

The reduction of water intake in rats caused by a low dose of apomorphine is unaltered by α-methyl-p-tyrosine: are autoreceptors not involved?

Summary Low doses of the dopamine (DA) agonist apomorphine (APO) induces a behavioural syndrome characterized by reduced spontaneous activity, reduced food and water intake and induction of yawning and penile erections. Traditionally these effects of APO have been considered to be caused by a preferential stimulation of DA autoreceptors, causing a decreased amount of transmitter at the postsynaptic receptors. If this is so, it could be hypothesized that 1) the same behavioural effects should be obtained if DA transmission is decreased by some other means, for example by synthesis inhibition, and that 2) the response to APO should be altered if DA transmission is already lowered.It was found that high doses of content/w8x5867877j7152h/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0">-methyl-p-tyrosine (content/w8x5867877j7152h/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0">-MPT; 50–200 mg/ kg) did not reduce water intake in thirsty rats, which low doses of APO do. It was further found that pretreatment with content/w8x5867877j7152h/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0">-MPT did not alter the response to APO. These results are difficult to reconcile with the DA autoreceptor hypothesis claiming that behavioural effects of low doses of APO are caused by a decreased release of DA. An alternative interpretation is that low doses of APO stimulates a certain population of sensitive postsynaptic D-2 receptors.     

In comparison: 1.064 μm-1.318 μm Nd-YAG continuous wave lasers. In vitro and in vivo experiments for endoscopic tumour therapy in the gastrointestinal tract

In in vitro and animal experiments the tissue effects of the 1.318content/h063n57j384h2719/xxlarge956.gif" alt="mgr" align="MIDDLE" BORDER="0">m Nd-YAG laser were compared to those of the standard 1.064content/h063n57j384h2719/xxlarge956.gif" alt="mgr" align="MIDDLE" BORDER="0">m Nd-YAG laser in order to evaluate the advantages of the new wavelength with a ten times higher absorption in water for gastroenterological tumour treatment. Under irradiation parameters related to clinical endoscopic practice, the laser of the wavelength 1.318content/h063n57j384h2719/xxlarge956.gif" alt="mgr" align="MIDDLE" BORDER="0">m needs for both vaporization and coagulation significantly less energy than the 1.064content/h063n57j384h2719/xxlarge956.gif" alt="mgr" align="MIDDLE" BORDER="0">m laser. Since vaporization at 1.318content/h063n57j384h2719/xxlarge956.gif" alt="mgr" align="MIDDLE" BORDER="0">m is always accompanied by a higher coagulation effect compared to 1.064content/h063n57j384h2719/xxlarge956.gif" alt="mgr" align="MIDDLE" BORDER="0">m the risk of late necrosis and resulting perforation appears to be increased.     

Preponderance of β- over α-adrenoceptors in mediating the positive inotropic effect of phenylephrine in the ferret ventricular myocardium

Summary [³H]prazosin bound to the membrane fraction derived from the ferret ventricular muscle with high affinity in a saturable manner (K _d = 0.25 nmol/l and B _max = 27 fmol/mg protein in the right ventricle). [³H]CGP-12177, a content/q36337836672084r/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-adrenoceptor ligand, bound to the membrane fraction with a _{K d} value of 0.29 nmol/l and a B _max of 42 fmol/mg protein. In the isolated ferret papillary muscle driven at 1 Hz at 37°C, phenylephrine elicited a concentration-dependent positive intropic effect. The maximal effect of phenylephrine was comparable to that of isoprenaline. Prazosin (0.3 content/q36337836672084r/xxlarge956.gif" alt="mgr" align="MIDDLE" BORDER="0">ol/l) shifted the concentration-response curve for phenylephrine slightly but significantly to the right, the maximal response being unaffected. In contrast, bupranolol (0.3 gmol/l) shifted the curve for phenylephrine markedly downwards: the maximal response was depressed significantly to 40% and the curve became less steep. In the presence of prazosin and bupranolol the curve was shifted to the right, being essentially parallel to the control curve. These results indicate that in the ferret ventricular myocardium both content/q36337836672084r/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0">- and content/q36337836672084r/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-adrenoceptors mediate the positive inotropic effect of phenylephrine. The extent of contribution of the two classes of adrenoceptor is quite different from that in other mammalian species. In the ferret heart, content/q36337836672084r/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-adrenoceptors predominate over content/q36337836672084r/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0">-adrenoceptors in mediating the positive inotropic effect of phenylephrine, although the number of content/q36337836672084r/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-adrenoceptors is not especially high when compared with other species. Send offprint requests to M. Endoh at the above address     

Hepatic,intestinal and renal transport of 1-naphthol-β-d-glucuronide in mutant rats with hereditary-conjugated hyperbilirubinemia

Summary Recently, a mutant rat strain was described with a genetic defect for the biliary excretion of organic anions (TR^– rats). To determine the possible heterogeneity of the transport systems in liver, intestine and kidney we investigated the transport of the anion 1-naphthol-content/mu3160048322n7m0/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-d-glucuronide (1-NG) in isolated vascularly perfused organ preparations of the rat liver, intestine and kidney of both Wistar rats and TR^– rats. 1-NG was administered as such (liver and kidney experiments) or formed intracellularly from 1-naphthol (1-N) (liver and gut experiments). Independent of the type of exposure to 1-NG, the biliary excretion was considerably impaired in TR^– rats. In the intestine the total appearance and the vascular/luminal distribution pattern of 1-NG were not significantly different from the values in control rats. Furthermore, no significant disturbance was found with respect to the renal clearance of 1-NG in the TR^– rat when compared with the Wistar rat. Thus, the genetic defect in the TR^– rat is restricted to an impaired hepatobiliary excretion of 1-NG and does not affect the excretory systems of the intestine and kidney. These results suggest that the excretion of 1-NG by the liver, intestine and kidney involves distinct organ-specific transport systems.     

Involvement of adenylate cyclase and protein kinase C in the α2-adrenoceptor-mediated inhibition of noradrenaline and 5-hydroxytryptamine release in rat hypothalamic slices

Summary In superfused rat hypothalamic slices prelabelled with [³H]-noradrenaline, the content/n18hv44l823xv6x7/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0">₂-adrenoceptor agonist UK 14304 inhibited in a concentration-dependent manner the electrically-evoked release of tritium. This inhibition was antagonized by the content/n18hv44l823xv6x7/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0">₂-adrenoceptor blocking agent idazoxan, which by itself increased the electrically-evoked tritium overflow. Exposure to forskolin, an adenylate cyclase activator, increased the electrically-evoked release of [³H]-noradrenaline. In the presence of forskolin (1 content/n18hv44l823xv6x7/xxlarge956.gif" alt="mgr" align="MIDDLE" BORDER="0">mol/l), both the inhibitory effect of UK 14304 and the increasing effect of idazoxan on the electrically-evoked release of [³H]-noradrenaline were less pronounced than in the absence of the adenylate cyclase activator. Exposure to forskolin and to the phosphodiesterase inhibitor 3-isobutyl-l-methylxanthine shifted to the right the concentration-effect curve for UK 14304 in a similar manner as that observed in the presence of forskolin alone. Exposure to phorbol-12,13-dibutyrate (0.01–10 content/n18hv44l823xv6x7/xxlarge956.gif" alt="mgr" align="MIDDLE" BORDER="0">mol/l), a drug which activates protein kinase C, increased the electrically-evoked release of [³H]-noradrenaline. In the presence of phorbol-12,13-dibutyrate (0.1 and 1 content/n18hv44l823xv6x7/xxlarge956.gif" alt="mgr" align="MIDDLE" BORDER="0">mol/l), the concentration effect curve for UK 14304 on tritium overflow was significantly shifted to the right. The increasing effect of idazoxan on tritium overflow was significantly less pronounced in the presence of 1 content/n18hv44l823xv6x7/xxlarge956.gif" alt="mgr" align="MIDDLE" BORDER="0">mol/l phorbol-12,13-dibutyrate.In superfused rat hypothalamic slices prelabelled with [³H]-5-hydroxytryptamine, the content/n18hv44l823xv6x7/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0">₂-adrenoceptor agonist UK 14304 significantly inhibited the electrically-evoked release of tritium. Exposure to forskolin increased in a concentration-dependent manner [³H]-5-hydroxytryptamine overflow, but did not modify the UK 14304-mediated inhibition. Exposure to 3-isobutyl-1-methylxanthine enhanced the electrically-evoked release of [³H]-5-hydroxytryptamine. In the presence of both forskolin (1 content/n18hv44l823xv6x7/xxlarge956.gif" alt="mgr" align="MIDDLE" BORDER="0">mol/l) and 3-isobutyl-l-methylxanthine (1 mmol/l), the concentration-response curve for UK 14304 was significantly shifted to the right. Exposure to phorbol-12,13-dibutyrate (0.01–10 content/n18hv44l823xv6x7/xxlarge956.gif" alt="mgr" align="MIDDLE" BORDER="0">mol/l) enhanced in a concentration-dependent manner the electrically-evoked overflow of [³H]-5-hydroxytryptamine. In the presence of phorbol-12,13-dibutyrate (0.1 and 1 content/n18hv44l823xv6x7/xxlarge956.gif" alt="mgr" align="MIDDLE" BORDER="0">mol/l), UK 14304 was significantly less potent to inhibit tritium release than in the absence of the protein kinase C activator.It is concluded that both cyclic AMP and phosphoinositide turnover are involved in the modulation of noradrenaline and 5-hydroxytryptamine release by presynaptic content/n18hv44l823xv6x7/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0">₂-adrenoceptors in rat hypothalamic slices. However, these interactions do not represent definitive proof for a cause-effect relationship for the second messengers mediating the content/n18hv44l823xv6x7/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0">₂-adrenoceptor induced inhibition of transmitter release either as autoreceptor or as heteroreceptor.Send offprint requests to S. Z. Langer at the above address     

Uptake inhibitors do not change the effect of imidazoline α2-adrenoceptor agonists on transmitter release evoked by single pulse stimulation in mouse vas deferens

Summary The present study was undertaken to compare the presynaptic interaction of neuronal noradrenaline uptake inhibitors with imidazoline and phenylethylamine content/g353177366487428/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0">₂adrenoceptor agonists under two different conditions: at low and high noradrenaline concentrations in the biophase.Isolated mouse vasa deferentia were stimulated with trains of 7 pulses given at 0.2 Hz and the inhibition by the content/g353177366487428/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0">₂-adrenoceptor agonists clonidine, content/g353177366487428/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0">-methylnoradrenaline, and UK-14,304 of twitch responses was measured in the absence and in the presence of either cocaine (12 content/g353177366487428/xxlarge956.gif" alt="mgr" align="MIDDLE" BORDER="0">mol/l) or desipramine (40 nmol/l). The effects were determined for the first (equivalent to single pulse stimulation) and the last stimulus of each train. Both uptake inhibitors antagonized the presynaptic inhibitory effects of imidazolines (clonidine and UK-14,304) on the last twitch; the effects on the first twitch remained unchanged. In contrast, the uptake inhibitors potentiated the inhibitory effect of the phenylethylamine (content/g353177366487428/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0">-methylnoradrenaline) on both the first and the last twitches.These results support the view that the concentration of noradrenaline in the biophase plays a decisive role in the inhibition by a₂-adrenoceptor agonists of the electrically evoked release of noradrenaline. Agonists that are not substrates of neuronal uptake (i.e., clonidine, UK-14,304) become less effective when noradrenaline is present in the biophase while substrates of neuronal uptake (i. e., content/g353177366487428/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0">-methylnoradrenaline) do not. The results argue against the hypothesis that uptake inhibitors interact directly with presynaptic content/g353177366487428/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0">₂-adrenoceptors or act at some link between uptake and receptor sites. Send offprint requests to S. Guimarães at the above address     

Phase I study of 4′-deoxydoxorubicin (esorubicin) in children with malignant solid tumors

Summary 4content/mx0j786714087943/xxlarge8242.gif" alt="prime" align="BASELINE" BORDER="0"> -Deoxydoxorubicin was given to 15 patients with drug-resistant pediatric malignant solid tumors with the objectives of determining the maximum tolerated dosage and dose-limiting toxicity. Maximum tolerated dosage was 36 mg/m₂ given IV once every 3 weeks. Dose limiting toxicity was myelosuppression, which was severe and prolonged. Therapeutic benefits were not observed for these patients.     

2-deoxy-D-glucose inhibits the antitumor effects of α-difluoromethylornithine on the growth of colon cancer in vivo

Summary The glycolytic inhibitor, 2-deoxy-D-glucose (2-DG), has been shown to inhibit the growth of certain cancers. content/rj26m2127062h541/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0">-Difluoromethylornithine (DFMO) is an irreversible inhibitor of ornithine decarboxylase (ODC), the ratelimiting enzyme in polyamine biosynthesis. DFMO has been shown to inhibit cancer growth in a number of models. The present study was designed to investigate the effects of 2-DG alone and combined with DFMO on MC-26 mouse colon adenocarcinoma tumors growing in vivo. Twenty-eight male Balb/c mice were inoculated with 250,000 MC-26 cells, and then randomized into four groups of 7 each: group I served as control; group II received DFMO (3% in drinking water); group III received 2-DG (500 mg/kg/d IP); group IV received a combination of 2-DG and DFMO. Treatment began 5 days after tumor cell inoculation. MC-26 tumor area was reduced 73% by DFMO compared to a 24% reduction caused by 2-DG. The tumor weight was reduced 80% by DFMO and 52% by 2-DG. The tumor contents of DNA, RNA, and protein were significantly reduced by DFMO but not 2-DG. The tumor concentration of the polyamines putrescine and spermidine were reduced by DFMO alone or combined with 2-DG while spermine levels remained unchanged. 2-DG alone did not alter polyamine levels. These results indicate that both 2-DG and DFMO, when added as single agents, inhibit tumor growth. However, the addition of 2-DG to the DFMO regimen inhibited the antitumor effects of DFMO. Survival studies performed on MC-26 cells in vitro corroborated the antagonisms between DFMO and 2-DG that were shown in vivo.Dr. Upp was awarded a fellowship grant from the American Cancer Society Texas Division.