Acute effects of selective serotonin reuptake inhibitors on neuroleptic-induced catalepsy in mice

Depression found in Parkinson disease (PD) usually responds to selective serotonin reuptake inhibitors (SSRIs). Drugs that modify experimental neuroleptic catalepsy (NC) might affect extrapyramidal symptoms in PD. Therefore, the effects of SSRIs on NC were tested in mice, 26-36 g, separated by sex. Catalepsy was induced with haloperidol (H; 1 mg/kg, ip) and measured at 30-min intervals using a bar test. An SSRI (sertraline, ST; paroxetine, PX; fluoxetine) or vehicle (C) was injected ip 30 min before H. Dunnett's test was used for comparison of means. ST (1-5 mg/kg) or PX (1-5 mg/kg) attenuated NC, with a similar inhibition found in both sexes (5 mg/kg, 180 min: ST - males: 124 ± 10 vs 714 ± 15 s in C; females: 116 ± 10 vs 718 ± 6 s in C; PX - males: 106 ± 10 vs 714 ± 14 s in C; females: 102 ± 10 vs 715 ± 14 s in C). At 0.3 mg/kg, neither of these drugs affected NC. Fluoxetine (1-25 mg/kg) also inhibited catalepsy, although the effect was not dose-dependent; no differences were observed between males and females (5 mg/kg, 180 min: males, 185 ± 14 vs 712 ± 14 s in C; females, 169 ± 10 vs 710 ± 19 s in C). For these SSRIs, maximal inhibition of NC was obtained with 5 mg/kg, 180 min after H. These results are consistent with the hypothesis that serotonergic mechanisms modulate nigrostriatal transmission, and suggest that SSRIs are possibly safe in depressive PD patients.

Solid-state reference and ion-selective electrodes : towards portable potentiometric sensing

Potentiometric sensors are very attractive tools for chemical analysis because of their simplicity, low power consumption and low cost. They are extensively used in clinical diagnostics and in environmental monitoring. Modern applications of both fields require improvements in the conventional construction and in the performance of the potentiometric sensors, as the trends are towards portable, on-site diagnostics and autonomous sensing in remote locations. The aim of this PhD work was to improve some of the sensor properties that currently hamper the implementation of the potentiometric sensors in modern applications. The first part of the work was concentrated on the development of a solid-state reference electrode (RE) compatible with already existing solid-contact ion-selective electrodes (ISE), both of which are needed for all-solid-state potentiometric sensing systems. A poly(vinyl chloride) membrane doped with a moderately lipophilic salt, tetrabutylammonium-tetrabutylborate (TBA-TBB), was found to show a satisfactory stability of potential in sample solutions with different concentrations. Its response time was nevertheless slow, as it required several minutes to reach the equilibrium. The TBA-TBB membrane RE worked well together with solid-state ISEs in several different situations and on different substrates enabling a miniature design. Solid contacts (SC) that mediate the ion-to-electron transduction are crucial components of well-functioning potentiometric sensors. This transduction process converting the ionic conduction of an ion-selective membrane to the electronic conduction in the circuit was studied with the help of electrochemical impedance spectroscopy (EIS). The solid contacts studied were (i) the conducting polymer (CP) poly(3,4-ethylienedioxythiophene) (PEDOT) and (ii) a carbon cloth having a high surface area. The PEDOT films were doped with a large immobile anion poly(styrene sulfonate) (PSS-) or with a small mobile anion Cl-. As could be expected, the studied PEDOT solid-contact mediated the ion-toelectron transduction more efficiently than the bare glassy carbon substrate, onto which they were electropolymerized, while the impedance of the PEDOT films depended on the mobility of the doping ion and on the ions in the electrolyte. The carbon cloth was found to be an even more effective ion-to-electron transducer than the PEDOT films and it also proved to work as a combined electrical conductor and solid contact when covered with an ion-selective membrane or with a TBA-TBB-based reference membrane. The last part of the work was focused on improving the reproducibility and the potential stability of the SC-ISEs, a problem that culminates to the stability of the standard potential E°. It was proven that the E° of a SC-ISE with a conducting polymer as a solid contact could be adjusted by reducing or oxidizing the CP solid contact by applying current pulses or a potential to it, as the redox state of the CP solid-contact influences the overall potential of the ISE. The slope and thus the analytical performance of the SC-ISEs were retained despite the adjustment of the E°. The shortcircuiting of the SC-ISE with a conventional large-capacitance RE was found to be a feasible instrument-free method to control the E°. With this method, the driving force for the oxidation/reduction of the CP was the potential difference between the RE and the SC-ISE, and the position of the adjusted potential could be controlled by choosing a suitable concentration for the short-circuiting electrolyte. The piece-to-piece reproducibility of the adjusted potential was promising, and the day-today reproducibility for a specific sensor was excellent. The instrumentfree approach to control the E° is very attractive considering practical applications.

The selective and non-selective cyclooxygenase inhibitors valdecoxib and piroxicam induce the same postoperative analgesia and control of trismus and swelling after lower third molar removal

We compared the clinical efficacy of orally administered valdecoxib and piroxicam for the prevention of pain, trismus and swelling after removal of horizontally and totally intrabony impacted lower third molars. Twenty-five patients were scheduled to undergo removal of symmetrically positioned lower third molars in two separate appointments. Valdecoxib (40 mg) or piroxicam (20 mg) was administered in a double-blind, randomized and crossed manner for 4 days after the surgical procedures. Objective and subjective parameters were recorded for comparison of postoperative courses. Both agents were effective for postoperative pain relief (N = 19). There was a similar mouth opening at suture removal compared with the preoperative values (86.14 ± 4.36 and 93.12 ± 3.70% of the initial measure for valdecoxib and piroxicam, respectively; ANOVA). There was no significant difference regarding the total amount of rescue medication taken by the patients treated with valdecoxib or piroxicam (173.08 ± 91.21 and 461.54 ± 199.85 mg, respectively; Wilcoxon test). There were no significant differences concerning the swelling observed on the second postoperative day compared to baseline measures (6.15 ± 1.84 and 8.46 ± 2.04 mm for valdecoxib and piroxicam, respectively; ANOVA) or on the seventh postoperative day (1.69 ± 1.61 and 2.23 ± 2.09 mm for valdecoxib and piroxicam, respectively; ANOVA). The cyclooxygenase-2 selective inhibitor valdecoxib is as effective as the non-selective cyclooxygenase inhibitor piroxicam for pain, trismus and swelling control after removal of horizontally and totally intrabony impacted lower third molars.

Comparison of the neurobiological effects of attribution retraining group therapy with those of selective serotonin reuptake inhibitors

The aim of this study was to compare the effectiveness of attribution retraining group therapy (ARGT) with selective serotonin reuptake inhibitors (SSRIs) in the treatment of major depressive disorder (MDD), generalized anxiety disorder (GAD), and obsessive-compulsive disorder (OCD). Subjects were sequentially recruited and randomized into two groups, one receiving ARGT (n = 63) and the other SSRIs (n = 66) for 8 weeks. Fifty-four ARGT outpatients with MDD (n = 19), GAD (n = 19), and OCD (n = 16) and 55 SSRI outpatients with MDD (n = 19), GAD (n = 19), and OCD (n = 17) completed the study. All subjects were assessed using the Hamilton Depression Scale and Hamilton Anxiety Scale before and after treatment. The 10-item Yale-Brown Obsessive Compulsive Scale was employed only for OCD subjects. Plasma levels of serotonin, norepinephrine, cortisol, and adrenocorticotropic hormone were also measured at baseline and 8 weeks after completion of treatment. Symptom scores were significantly reduced (P < 0.001) in both the ARGT and SSRI groups at the end of treatment. However, MDD, GAD and OCD patients in the ARGT group had significantly lower plasma cortisol concentrations compared to baseline (P < 0.05), whereas MDD and OCD patients receiving SSRIs showed significantly increased plasma levels of serotonin (P < 0.05). These findings suggest that ARGT may modulate plasma cortisol levels and affect the hypothalamus-pituitary-adrenal axis as opposed to SSRIs, which may up-regulate plasma serotonin levels via a different pathway to produce an overall improvement in the clinical condition of the patients.

Cellular and molecular studies of the effects of a selective COX-2 inhibitor celecoxib in the cardiac cell line H9c2 and their correlation with death mechanisms

Cardiovascular disease is one of the leading causes of death worldwide, and evidence indicates a correlation between the inflammatory process and cardiac dysfunction. Selective inhibitors of cyclooxygenase-2 (COX-2) enzyme are not recommended for long-term use because of potentially severe side effects to the heart. Considering this and the frequent prescribing of commercial celecoxib, the present study analyzed cellular and molecular effects of 1 and 10 µM celecoxib in a cell culture model. After a 24-h incubation, celecoxib reduced cell viability in a dose-dependent manner as also demonstrated in MTT assays. Furthermore, reverse transcription-polymerase chain reaction analysis showed that the drug modulated the expression level of genes related to death pathways, and Western blot analyses demonstrated a modulatory effect of the drug on COX-2 protein levels in cardiac cells. In addition, the results demonstrated a downregulation of prostaglandin E2 production by the cardiac cells incubated with celecoxib, in a dose-specific manner. These results are consistent with the decrease in cell viability and the presence of necrotic processes shown by Fourier transform infrared analysis, suggesting a direct correlation of prostanoids in cellular homeostasis and survival.

Effects of acute administration of selective serotonin reuptake inhibitors on sympathetic nerve activity

Serotonergic mechanisms have an important function in the central control of circulation. Here, the acute effects of three selective serotonin (5-HT) reuptake inhibitors (SSRIs) on autonomic and cardiorespiratory variables were measured in rats. Although SSRIs require 2-3 weeks to achieve their full antidepressant effects, it has been shown that they cause an immediate inhibition of 5-HT reuptake. Seventy male Wistar rats were anesthetized with urethane and instrumented to record blood pressure, heart rate, renal sympathetic nerve activity (RSNA), and respiratory frequency. At lower doses, the acute cardiovascular effects of fluoxetine, paroxetine and sertraline administered intravenously were insignificant and variable. At middle and higher doses, a general pattern was observed, with significant reductions in sympathetic nerve activity. At 10 min, fluoxetine (3 and 10 mg/kg) reduced RSNA by -33±4.7 and -31±5.4%, respectively, without changes in blood pressure; 3 and 10 mg/kg paroxetine reduced RSNA by -35±5.4 and -31±5.5%, respectively, with an increase in blood pressure +26.3±2.5; 3 mg/kg sertraline reduced RSNA by -59.4±8.6%, without changes in blood pressure. Sympathoinhibition began 5 min after injection and lasted approximately 30 min. For fluoxetine and sertraline, but not paroxetine, there was a reduction in heart rate that was nearly parallel to the sympathoinhibition. The effect of these drugs on the other variables was insignificant. In conclusion, acute peripheral administration of SSRIs caused early autonomic cardiovascular effects, particularly sympathoinhibition, as measured by RSNA. Although a peripheral action cannot be ruled out, such effects are presumably mostly central.

Dynamic expression of desmin, α-SMA and TGF-β1 during hepatic fibrogenesis induced by selective bile duct ligation in young rats

We previously described a selective bile duct ligation model to elucidate the process of hepatic fibrogenesis in children with biliary atresia or intrahepatic biliary stenosis. Using this model, we identified changes in the expression of alpha smooth muscle actin (α-SMA) both in the obstructed parenchyma and in the hepatic parenchyma adjacent to the obstruction. However, the expression profiles of desmin and TGF-β1, molecules known to be involved in hepatic fibrogenesis, were unchanged when analyzed by semiquantitative polymerase chain reaction (RT-PCR). Thus, the molecular mechanisms involved in the modulation of liver fibrosis in this experimental model are not fully understood. This study aimed to evaluate the molecular changes in an experimental model of selective bile duct ligation and to compare the gene expression changes observed in RT-PCR and in real-time quantitative PCR (qRT‐PCR). Twenty-eight Wistar rats of both sexes and weaning age (21-23 days old) were used. The rats were separated into groups that were assessed 7 or 60 days after selective biliary duct ligation. The expression of desmin, α-SMA and TGF-β1 was examined in tissue from hepatic parenchyma with biliary obstruction (BO) and in hepatic parenchyma without biliary obstruction (WBO), using RT-PCR and qRT‐PCR. The results obtained in this study using these two methods were significantly different. The BO parenchyma had a more severe fibrogenic reaction, with increased α-SMA and TGF-β1 expression after 7 days. The WBO parenchyma presented a later, fibrotic response, with increased desmin expression 7 days after surgery and increased α-SMA 60 days after surgery. The qRT‐PCR technique was more sensitive to expression changes than the semiquantitative method.

Cell cycle synchronization and BrdU incorporation as a tool to study the possible selective elimination of ErbB1 gene in the micronuclei in A549 cells

Lung cancer often exhibits molecular changes, such as the overexpression of the ErbB1 gene that encodes epidermal growth factor receptor (EGFR). ErbB1 amplification and mutation are associated with tumor aggressiveness and low response to therapy. The aim of the present study was to design a schedule to synchronize the cell cycle of A549 cell line (a non-small cell lung cancer) and to analyze the possible association between the micronuclei (MNs) and the extrusion of ErbB1 gene extra-copies. After double blocking, by the process of fetal bovine serum deprivation and vincristine treatment, MNs formation was monitored with 5-bromo-2-deoxyuridine (BrdU) incorporation, which is an S-phase marker. Statistical analyses allowed us to infer that MNs may arise both in mitosis as well as in interphase. The MNs were able to replicate their DNA and this process seemed to be non-synchronous with the main cell nuclei. The presence of ErbB1 gene in the MNs was evaluated by fluorescent in situ hybridization (FISH). ErbB1 sequences were detected in the MNs, but a relation between the MNs formation and extrusion of amplified ErbB1could not be established. The present study sought to elucidate the meaning of MNs formation and its association with the elimination of oncogenes or other amplified sequences from the tumor cells.

Effect of selective β-adrenoceptor blockade and surgical resection of the celiac-superior mesenteric ganglion complex on delayed liquid gastric emptying induced by dipyrone, 4-aminoantipyrine, and antipyrine in rats

There is evidence for participation of peripheral β-adrenoceptors in delayed liquid gastric emptying (GE) induced in rats by dipyrone (Dp), 4-aminoantipyrine (AA), and antipyrine (At). The present study aimed to determine whether β-adrenoceptors are involved in delayed GE induced by phenylpyrazole derivatives and the role of the prevertebral sympathetic nervous system in this condition. Male Wistar rats weighing 220-280 g were used in the study. In the first experiment rats were intravenously pretreated with vehicle (V), atenolol 30 mg/kg (ATE, β1-adrenergic antagonist), or butoxamine 25 mg/kg (BUT, β2-adrenergic antagonist). In the second experiment, rats were pretreated with V or SR59230A 2 mg/kg (SRA, β3-adrenergic antagonist). In the third experiment, rats were subjected to surgical resection of the celiac-superior mesenteric ganglion complex or to sham surgery. The groups were intravenously treated with saline (S), 240 µmol/kg Dp, AA, or At, 15 min after pretreatment with the antagonists or V and nine days after surgery. GE was determined 10 min later by measuring the percentage of gastric retention (%GR) of saline labeled with phenol red 10 min after gavage. The %GR (means±SE, n=6) values indicated that BUT abolished the effect of Dp (BUT+Dp vs V+Dp: 35.0%±5.1% vs 56.4%±2.7%) and At (BUT+At vs V+At: 33.5%±4.7% vs 52.9%±2.6%) on GE, and significantly reduced (P<0.05) the effect of AA (BUT+AA vs V+AA: 48.0%±5.0% vs 65.2%±3.8%). ATE, SRA, and sympathectomy did not modify the effects of treatments. These results suggest that β2-adrenoceptor activation occurred in delayed liquid gastric emptying induced by the phenylpyrazole derivatives dipyrone, 4-aminoantipyrine, and antipyrine. Additionally, the released neurotransmitter did not originate in the celiac-superior mesenteric ganglion complex.

Effect of blanching time on selective mineral elements extraction from the spinach substitute (Tetragonia expansa) commonly used in Brazil

The true spinach (Spinacia oleracea) does not grow well in warm climates and for that reason is not commercialized in Brazil. Instead, a spinach substitute (Tetragonia expansa), originally from New Zealand, is widely used in the country. There is scant information on the mineral profile and none on the soluble mineral fraction of this vegetable. The solubility of a mineral is one of the important factors for its absorption. For this reason, the calcium, magnesium, iron, manganese, copper, zinc, potassium, and sodium soluble fractions in the raw spinach substitute were determined and the effect of blanching times on the solubility of these minerals was investigated. Blanching times of 1, 5, and 15 minutes were employed. The magnesium, manganese, potassium, and sodium soluble fractions increased sizably with shorter blanching time. Longer blanching time (15 minutes) caused large losses of minerals. The soluble mineral fractions can contribute poorly to diet in terms of potassium, magnesium, manganese, and zinc. The spinach substitute cannot be considered a dietary source of calcium, iron and copper due to the insolubility of these minerals in the vegetable, possibly caused by the large oxalate content.

The role of metal ions in selective and sustainable processes

Sustainability and recycling are core values in today’s industrial operations. New materials, products and processes need to be designed in such a way as to consume fewer of the diminishing resources we have available and to put as little strain on the environment as possible. An integral part of this is cleaning and recycling. New processes are to be designed to improve the efficiency in this aspect. Wastewater, including municipal wastewaters, is treated in several steps including chemical and mechanical cleaning of waters. Well-cleaned water can be recycled and reused. Clean water for everyone is one of the greatest challenges we are facing today. Ferric sulphate, made by oxidation from ferrous sulphate, is used in water purification. The oxidation of ferrous sulphate, FeSO4, to ferric sulphate in acidic aqueous solutions of H2SO4 over finely dispersed active carbon particles was studied in a vigorously stirred batch reactor. Molecular oxygen was used as the oxidation agent and several catalysts were screened: active carbon, active carbon impregnated with Pt, Rh, Pd and Ru. Both active carbon and noble metal-active carbon catalysts enhanced the oxidation rate considerably. The order of the noble metals according to the effect was: Pt >> Rh > Pd, Ru. By the use of catalysts, the production capacities of existing oxidation units can be considerably increased. Good coagulants have a high charge on a long polymer chain effectively capturing dirty particles of the opposite charge. Analysis of the reaction product indicated that it is possible to obtain polymeric iron-based products with good coagulation properties. Systematic kinetic experiments were carried out at the temperature and pressure ranges of 60B100°C and 4B10 bar, respectively. The results revealed that both non-catalytic and catalytic oxidation of Fe2+ to Fe3+ take place simultaneously. The experimental data were fitted to rate equations, which were based on a plausible reaction mechanism: adsorption of dissolved oxygen on active carbon, electron transfer from Fe2+ ions to adsorbed oxygen and formation of surface hydroxyls. A comparison of the Fe2+ concentrations predicted by the kinetic model with the experimentally observed concentrations indicated that the mechanistic rate equations were able to describe the intrinsic oxidation kinetics of Fe2+ over active carbon and active carbon-noble metal catalysts. Engineering aspects were closely considered and effort was directed to utilizing existing equipment in the production of the new coagulant. Ferrous sulphate can be catalytically oxidized to produce a novel long-chained polymeric iron-based flocculent in an easy and affordable way in existing facilities. The results can be used for modelling the reactors and for scale-up. Ferric iron (Fe3+) was successfully applied for the dissolution of sphalerite. Sphalerite contains indium, gallium and germanium, among others, and the application can promote their recovery. The understanding of the reduction process of ferric to ferrous iron can be used to develop further the understanding of the dissolution mechanisms and oxidation of ferrous sulphate. Indium, gallium and germanium face an ever-increasing demand in the electronics industry, among others. The supply is, however, very limited. The fact that most part of the material is obtained through secondary production means that real production quota depends on the primary material production. This also sets the pricing. The primary production material is in most cases zinc and aluminium. Recycling of scrap material and the utilization of industrial waste, containing indium, gallium and geranium, is a necessity without real options. As a part of this study plausible methods for the recovery of indium, gallium and germanium have been studied. The results were encouraging and provided information about the precipitation of these valuables from highly acidic solutions. Indium and gallium were separated from acidic sulphuric acid solutions by precipitation with basic sulphates such as alunite or they were precipitated as basic sulphates of their own as galliunite and indiunite. Germanium may precipitate as a basic sulphate of a mixed composition. The precipitation is rapid and the selectivity is good. When the solutions contain both indium and gallium then the results show that gallium should be separated before indium to achieve a better selectivity. Germanium was separated from highly acidic sulphuric acid solutions containing other metals as well by precipitating with tannic acid. This is a highly selective method. According to the study other commonly found metals in the solution do not affect germanium precipitation. The reduction of ferric iron to ferrous, the precipitation of indium, gallium and germanium, and the dissolution of the raw materials are strongly depending on temperature and pH. The temperature and pH effect were studied and which contributed to the understanding and design of the different process steps. Increased temperature and reduced pH improve the reduction rate. Finally, the gained understanding in the studied areas can be employed to develop better industrial processes not only on a large scale but also increasingly on a smaller scale. The small amounts of indium, gallium and germanium may favour smaller and more locally bound recovery.

The Role of Sleep in the Selective Reconsolidation of Declarative Memories

While sleep has been shown to be involved in memory consolidation and the selective enhancement of newly acquired memories of future relevance (Wilhelm, et al., 2011), limited research has investigated the role of sleep or future relevance in processes of memory reconsolidation. The current research employed a list-method directed forgetting procedure in which participants learned two lists of syllable pairs on Night 1 and received directed forgetting instructions on Night 2. On Night 2, one group (Labile; n = 15) received a memory reactivation treatment consisting of reminders designed to return memories of the learned lists to a labile state. A second group (Stable, n = 16) received similar reminders designed to leave memories of the learned lists in their stable state. No differences in forgetting were found across the two lists or groups. However, a negative correlation between frontal delta (1 – 4 Hz) electroencephalographic (EEG) power during Early Stage 2 non-rapid eye movement (NREM) sleep and forgetting of to-beremembered material was found exclusively in the Labile group (r = -.61, p < .05). Further, central theta (4 – 8 Hz ) EEG power during rapid eye movement (REM) sleep was found to correlate with directed forgetting exclusively in the Labile group (r = .81, p < .001) and total forgetting in the Stable group (r = .50, p < .05). These observed relationships support the proposed hypothesis suggesting that sleep processes are involved in the reconsolidation of labile memories, and that this reconsolidation may be selective for memories of future relevance. A role for sleep in the beneficial reprocessing of memories through the selective reconsolidation of labile memories in NREM sleep and the weakening of memories in REM sleep is discussed.

Cell-selective modulation of the Drosophila neuromuscular system by a neuropeptide

Neuropeptides can modulate physiological properties of neurons in a cell-specific manner. The present work examines whether a neuropeptide can also modulate muscle tissue in a cell-specific manner, using identified muscle cells in third instar larvae of fruit flies. DPKQDFMRFa, a modulatory peptide in the fruit fly Drosophila melanogaster, has been shown to enhance transmitter release from motor neurons and to elicit contractions by a direct effect on muscle cells. We report that DPKQDFMRFa causes a nifedipine-sensitive drop in input resistance in some muscle cells (6 and 7) but not others (12 and 13). The peptide also increased the amplitude of nerve-evoked contractions and compound excitatory junctional potentials (EJPs) to a greater degree in muscle cells 6 and 7 than 12 and 13. Knocking down FMRFa receptor (FR) expression separately in nerve and muscle indicate that both presynaptic and postsynaptic FR expression contributed to the enhanced contractions, but EJP enhancement was due mainly to presynaptic expression. Muscle-ablation showed that DPKQDFMRFa induced contractions and enhanced nerve-evoked contractions more strongly in muscle cells 6 and 7 than cells 12 and 13. In situ hybridization indicated that FR expression was significantly greater in muscle cells 6 and 7 than 12 and 13. Taken together, these results indicate that DPKQDFMRFa can elicit cell-selective effects on muscle fibres. The ability of neuropeptides to work in a cell-selective manner on neurons and muscle cells may help explain why so many peptides are encoded in invertebrate and vertebrate genomes.

Cell-selective modulation of the neuromuscular system in Drosophila

The capacity for all living cells to sense and interact with their environment is a necessity for life. In highly evolved, eukaryotic species, like humans, signalling mechanisms are necessary to regulate the function and survival of all cells in the organism. Synchronizing systemic signalling systems at the cellular, organ and whole-organism level is a formidable task, and for most species requires a large number of signalling molecules and their receptors. One of the major types of signalling molecules used throughout the animal kingdom are modulatory substances (e.x. hormones and peptides). Modulators can act as chemical transmitters, facilitating communication at chemical synapses. There are hundreds of circulating modulators within the mammalian system, but the reason for so many remains a mystery. Recent work with the fruit fly, Drosophila melanogaster demonstrated the capacity for peptides to modulate synaptic transmission in a neuron-specific manner, suggesting that peptides are not simply redundant, but rather may have highly specific roles. Thus, the diversity of peptides may reflect cell-specific functions. The main objective of my doctoral thesis was to examine the extent to which neuromodulator substances and their receptors modulate synaptic transmission at a cell-specific level using D. melanogaster. Using three different modulatory substances, i) octopamine - a biogenic amine released from motor neuron terminals, ii) DPKQDFMRFa - a neuropeptide secreted into circulation, and iii) Proctolin - a pentapeptide released both from motor neuron terminals and into circulation, I was able to investigate not only the capacity of these various substances to work in a cell-selective manner, but also examine the different mechanisms of action and how modulatory substances work in concert to execute systemic functionality . The results support the idea that modulatory substances act in a circuit-selective manner in the central nervous system and in the periphery in order to coordinate and synchronize physiologically and behaviourally relevant outputs. The findings contribute as to why the nervous system encodes so many modulatory substances.