Zebrafish as an Animal Model in Cannabinoid Research.

Cannabinoids are active substances present in plants of the Cannabis genus. Both the Food and Drug Administration (FDA) and European Medicines Agency (EMA) have approved several medicinal products containing natural cannabinoids or their synthetic derivatives for the treatment of drug-resistant epilepsy, nausea and vomiting associated with cancer chemotherapy, anorexia in AIDS patients, and the alleviation of symptoms in patients with multiple sclerosis. In fact, cannabinoids constitute a broad group of molecules with a possible therapeutic potential that could be used in the management of much more diseases than mentioned above; therefore, multiple preclinical and clinical studies on cannabinoids have been carried out in recent years. Danio rerio (zebrafish) is an animal model that has gained more attention lately due to its numerous advantages, including easy and fast reproduction, the significant similarity of the zebrafish genome to the human one, simplicity of genetic modifications, and body transparency during the early stages of development. A number of studies have confirmed the usefulness of this model in toxicological research, experiments related to the impact of early life exposure to xenobiotics, modeling various diseases, and screening tests to detect active substances with promising biological activity. The present paper focuses on the current knowledge of the endocannabinoid system in the zebrafish model, and it summarizes the results and observations from studies investigating the pharmacological effects of natural and synthetic cannabinoids that were carried out in Danio rerio. The presented data support the notion that the zebrafish model is a suitable animal model for use in cannabinoid research.

Changes in Physicochemical and Bioactive Properties of Quince (Cydonia oblonga Mill.) and Its Products.

Quince (Cydonia oblonga Miller) is a plant that is commonly cultivated around the world, known for centuries for its valuable nutritional and healing properties. Although quince fruit are extremely aromatic, due to their high hardness and sour, astringent, and bitter taste, they are not suitable for direct consumption in an unprocessed form. However, they are an important raw material in fruit processing, e.g., in the production of jams, jellies, and juices. Quince fruits fall under the category of temperate fruits, so their shelf life can be predicted. Considering that technological processing affects not only the organoleptic properties and shelf life but also the functional properties of fruits, the aim of this research was to determine the impact of various types of technological treatments on the physicochemical and bioactive properties of quince fruit. In fresh, boiled, and fried fruits and in freshly squeezed quince fruit juice, basic parameters, such as the content of dry matter, moisture, soluble solids (°Brix), pH, total acidity, water activity, and color parameters (L*a*b*) were determined. The content of key bioactive ingredients, i.e., tannins, carotenoids, flavonoids, phenolic acids, and total polyphenols, was also determined, as well as the antioxidant activity of raw and technologically processed (cooked, fried, and squeezed) quince fruits. The conducted research showed that fresh quince fruit and processed quince products can be a very good source of bioactive ingredients in the diet, such as tannins (3.64 ± 0.06 mg/100 g in fresh fruit; from 2.22 ± 0.02 mg/100 g to 5.59 ± 0.15 g/100 g in products), carotenoids (44.98 ± 0.18 mg/100 g in fresh fruit; from 141.88 ± 0.62 mg/100 g to 166.12 ± 0.62 mg/100 g in products), and polyphenolic compounds (246.98 ± 6.76 mg GAE/100 g in fresh fruit; from 364.53 ± 3.76 mg/100 g to 674.21 ± 4.49 mg/100 g in products). Quince fruit and quince products are also characterized by high antioxidant properties (452.41 ± 6.50 µM TEAC/100 g in fresh fruit; 520.78 ± 8.56 µM TEAC/100 g to 916.16 ± 6.55 µM TEAC/100 g in products). The choice of appropriate technological processing for the quince fruit may allow producers to obtain high-quality fruit preserves and act a starting point for the development of functional products with the addition of quince fruit in its various forms, with high health-promoting values and a wide range of applications in both the food and pharmaceutical industries.

Effects of Selen on the Antidepressant-like Activity of Agents Affecting the Adenosinergic Neurotransmission.

The main goal of this study was to determine the antidepressant-like potential of the co-administration of sodium selenite (Se) and the selective adenosine A1 and A2A antagonists DPCPX and istradefylline (IST), respectively, in mice despair tests. Biochemical studies were performed to elucidate the action mechanisms of the investigated treatment strategies. The results confirmed that, when administered by itself, Se exerts an antidepressant-like effect in the FST and TST and that this activity is dose-dependent. Further experiments demonstrated that Se (0.25 mg/kg) significantly enhanced the activity of mice in both tests when co-administered with DPCPX (1 mg/kg) and IST (0.5 mg/kg) at doses which would be ineffective if administered individually. Our research revealed that neither DPCPX, IST, nor Se or combinations of the tested substances induced significant changes in the brain-derived neurotrophic factor (BDNF) levels in mice serum vs. the NaCl-treated group. However, we observed a decrease in the mRNA level of antioxidant defense enzymes. Molecular studies also showed changes in the expression of the Slc6a15, Comt, and Adora1 genes, particularly after exposure to the combination of Se and DPCPX, which indicates a beneficial effect and may help to explain the key mechanism of the antidepressant effect. The combination of Se with substances attenuating adenosine neurotransmission may become a new therapeutic strategy for patients with depression.

The Sensory Quality and the Physical Properties of Functional Green Tea-Infused Yoghurt with Inulin.

The purpose of this study was to investigate the influence of the addition of inulin (3%, 6% and 9%) to green tea-infused set type yoghurt on its sensory quality and physical properties. Yogurts were made by combining green tea with milk and inulin and inoculated with freeze-dried starter cultures YO-122. Incubation was conducted at 43 °C for approximately 4.5 h until a pH value of 4.5-4.6 was achieved. For the prepared yoghurts, a panel of experts (n = 10) was selected, characterized 35 attributes and conducted a sensory quality assessment of these yoghurts using the Quantitative Descriptive Profile method. Additionally, instrumental analyses such as yield stress, adhesiveness, firmness, physical stability and color parameters were also carried out. The use of green tea infusion increased the perception of green tea flavor, bitterness, astringency, dark color of the yoghurt and the existing whey, which worsened the overall sensory quality of the yoghurt. The addition of inulin (9%) to the green tea yoghurt, increased the perception of sweet, peach flavor and aroma and improved the firmness of the yoghurt while reducing the perception of sour taste, which improved the sensory quality of the yoghurt. Both inulin and green tea affected the physical properties of the yoghurts, causing an increase in the yield stress (43%, and 20%, respectively) and deteriorated the stability of the yoghurts. Green tea affected the color of the yoghurts, causing the lightness to decrease. The L* parameter decreased from 89.80 for the control sample to 84.42 for the green tea infused yoghurt. The use of infused green tea in yoghurt production makes it necessary to use ingredients that will neutralize its adverse effects on sensory quality and physical parameters of yoghurt, and such an additive can be prebiotic fiber-inulin at a concentration of 9%.

Zebrafish as an Animal Model for Testing Agents with Antidepressant Potential.

Depression is a serious mental disease that, according to statistics, affects 320 million people worldwide. Additionally, a current situation related to the COVID-19 pandemic has led to a significant deterioration of mental health in people around the world. So far, rodents have been treated as basic animal models used in studies on this disease, but in recent years, Danio rerio has emerged as a new organism that might serve well in preclinical experiments. Zebrafish have a lot of advantages, such as a quick reproductive cycle, transparent body during the early developmental stages, high genetic and physiological homology to humans, and low costs of maintenance. Here, we discuss the potential of the zebrafish model to be used in behavioral studies focused on testing agents with antidepressant potential.

The Sensory Quality and the Textural Properties of Functional Oolong Tea-Infused Set Type Yoghurt with Inulin.

Set type yoghurts are characterised by a semi-solid texture, which is created during the fermentation process. The tea infusion in this type of yoghurt production can influence the quality of the final product. Therefore, the aim of the experiment was to evaluate the influence of the addition of 3, 6 and 9% inulin to oolong tea-infused yoghurts on the sensory quality. It has been evaluated by trained experts using a Quantitative Descriptive Profile analysis and by consumers using hedonic scaling, as well as on instrumentally evaluated features such as texture, stability and visual parameters. The addition of oolong tea to yoghurt resulted in positive changes in the perception of sweet, peach and nectar odours and flavours, and also creaminess, as well as negative changes in the presence of a bitter taste, the whey presence and a colour intensification towards dark cream (p ≤ 0.05). The addition of inulin to the tested oolong tea yogurts caused a decrease in the whey presence and brightened the yoghurt's colour (6% and 9%, p ≤ 0.05, respectively), as well as an improved creaminess and an increase in the sweet taste of the yoghurt. It was also observed that the addition of oolong tea deteriorated the instrumentally evaluated texture of the set yoghurts, while inulin at a higher concentration (9%, p ≤ 0.05) increased the firmness and adhesiveness. Moreover, the addition of inulin also had a positive effect on the yoghurt's stability. The addition of inulin to oolong tea-infused set yoghurts may be valuable both as a source of prebiotic fibre in functional products and as a factor improving the quality of these products.

The Interaction of Selective A1 and A2A Adenosine Receptor Antagonists with Magnesium and Zinc Ions in Mice: Behavioural, Biochemical and Molecular Studies.

The purpose of the study was to investigate whether the co-administration of Mg2+ and Zn2+ with selective A1 and A2A receptor antagonists might be an interesting antidepressant strategy. Forced swim, tail suspension, and spontaneous locomotor motility tests in mice were performed. Further, biochemical and molecular studies were conducted. The obtained results indicate the interaction of DPCPX and istradefylline with Mg2+ and Zn2+ manifested in an antidepressant-like effect. The reduction of the BDNF serum level after co-administration of DPCPX and istradefylline with Mg2+ and Zn2+ was noted. Additionally, Mg2+ or Zn2+, both alone and in combination with DPCPX or istradefylline, causes changes in Adora1 expression, DPCPX or istradefylline co-administered with Zn2+ increases Slc6a15 expression as compared to a single-drug treatment, co-administration of tested agents does not have a more favourable effect on Comt expression. Moreover, the changes obtained in Ogg1, MsrA, Nrf2 expression show that DPCPX-Mg2+, DPCPX-Zn2+, istradefylline-Mg2+ and istradefylline-Zn2+ co-treatment may have greater antioxidant capacity benefits than administration of DPCPX and istradefylline alone. It seems plausible that a combination of selective A1 as well as an A2A receptor antagonist and magnesium or zinc may be a new antidepressant therapeutic strategy.

Trends of Using Sensory Evaluation in New Product Development in the Food Industry in Countries That Belong to the EIT Regional Innovation Scheme.

Sensory evaluation plays an important role in New Product Development (NPD) in food industry. In the present study, the current trends of using sensory evaluation in NPD in the food industry in countries that belong to EIT Regional Innovation Scheme (RIS) were identified. The research was conducted in the first quarter of 2020. Computer assisted self-interviewing (CASI) technique for survey data collection was used. The sample included 122 respondents representing RIS countries that are the EU Member States and European Horizon 2020 Associated Countries that are classified as modest and moderate innovators according to European Innovation Scoreboard. The analysis presented in the paper allowed to describe the methods of sensory evaluation that can be used to support NPD in the food industry, identify the trends of using sensory evaluation in NPD in the food industry companies in RIS countries. The research results showed that almost 70% of companies apply sensory evaluation methods in NPD. The larger the company, the more often the methods of sensory evaluation are used in NPDs. Almost 60% of companies employing 51-100, 101-1000 and more than 5000 people, respectively declare the use of expert (analytical) test. However, regardless of size, most companies prefer consumer (affective) test to expert tests. Based on the results, it seems that the potential of usage sensory evaluation methods is not yet fully exploited in the food industry.

Assessment of Chokeberry Powders Quality Obtained Using an Innovative Fluidized-Bed Jet Milling and Drying Method with Pre-Drying Compared with Convection Drying.

There is a need and great interest among food producers in obtaining powders from fruit and vegetables of both high nutritional value and sensory qualities superior to those hitherto obtained by convection drying (CD) and spray drying methods and cheaper to prepare than the sublimation method. This study is focused on whether powders can be obtained from fruit berries with a sticky structure, using the chokeberry (Aronia melanocarpa) as a test example, by a combined fluidized-bed jet milling and drying (FBJD) of pre-dried fruit by CD to an adequate water activity (aw). The pre-drying step reduced sticking between fruit particles during the simultaneous drying and grinding processes of the FBJD method in order to obtain powders of desired granulation. Three different pre-drying temperatures of 50, 60, and 70 °C were tested for levels of microorganisms in chokeberries at a water activity of 0.4. Vitamin C content and antioxidant properties were also examined along with polyphenol separation. Fruit pre-dried at 60-70 °C had significantly higher vitamin C and polyphenolic content and greater antioxidant properties than those pre-dried at 50 °C. Further studies were thus undertaken on powders pre-dried at 70 °C in which antioxidant properties, vitamin C, and polyphenols content were also compared with CD obtained powders. The FBJD method combined with CD pre-drying proved superior to just using the CD method, where powders had a greater preservation of vitamin C at 84% (CD powders 35%), a 12% higher total polyphenol content, and a 10% higher antioxidant activity. The test method also uses a much shorter drying time than the CD method, because the grinding of the hard-textured material takes only few minutes.

The in vitro efficacy of eye drops containing a bacteriophage solution specific for Staphylococcus spp. isolated from dogs with bacterial conjunctivitis.

BACKGROUND: The purpose of the study was to evaluate the in vitro antibacterial effect of experimental eye drops with bacteriophages in elimination of Staphylococcus spp. isolated from dogs with bacterial conjunctivitis.. The bacterial material was collected from dogs with independent clinical signs of bacterial conjunctivitis. Staphylococcus spp. were identified by phenotypic and genotypic methods (MALDI-TOF MS mass spectrometry). Antibiotic resistance was determined by the disc-diffusion method. Phage activity (Plaque forming units, PFU) was determined on double-layer agar plates. Phages with lytic titres > 108 PFU were used to prepare eye drops. The stability of the antibacterial titre was evaluated for preparations stored in sealed bottles as well as after opening and reclosing. RESULTS: The tests confirmed the occurrence of Staphylococcus spp. strains as etiological agents of bacterial conjunctivitis in dogs. A high percentage of strains were resistant to more than three antibiotics. The experimental phage eye drops used in the study exhibited 100% efficacy in vitro against the tested Staphylococcus isolates. Particularly noteworthy is the long duration of activity and constant antibacterial lytic titre of ≥108 PFU/mL of two eye drop solutions, nos. 7 and 12, after the bottle had been opened (21 days) and after hermetically sealed packaging (28 days) at 4-8 °C. CONCLUSIONS: The results represent the first stage of research and require continuation in vivo. If positive effects are obtained in animals, the results can be used in applied research in humans and animals.

Functional Tea-Infused Set Yoghurt Development by Evaluation of Sensory Quality and Textural Properties.

In the present study, the potential to design natural tea-infused set yoghurt was investigated. Three types of tea (Camellia sinensis): black, green and oolong tea as well as lemon balm (Melissa officinalis L.) were used to produce set yoghurt. The sensory quality (using Quantitative Descriptive Profile analysis and consumer hedonic test) and texture analysis, yield stress, physical stability and colour analysis were assessed to describe the profile of the yoghurt and influence of quality attributes of the product on the consumer acceptability of infused yoghurts in comparison with plain yoghurt. Among the analyzed plant additives for yoghurt, addition of 2% oolong tea to the yoghurt allows a functional food to be obtained with satisfactory texture and sensory properties, accepted by consumers at the same level as for control yoghurt. Both types of yoghurt were also characterised by high consumer willingness to buy, which confirms the legitimacy of using oolong tea as a natural, functional yoghurt additive that improves the sensory quality of the product. The high overall quality of yoghurt with oolong tea in comparison to other plant extracts was associated with the intensive peach flavour and odour, nectar and sweet odour and flavour, and the highest creaminess and thickness. That was confirmed by principal component analysis (PCA) where the overall sensory quality of yoghurts was mainly positively correlated with peach flavour and odour, sweet odour and yoghurt odour, while it was negatively correlated with herbs flavor and odour, and green tea flavour and odour. The sensory profile confirmed no differences in textural profile between plain yoghurt and the tea-infused one measured in the mouth, which corresponds to the result of textural properties such as firmness and adhesiveness.

Correction to: Long-term vigabatrin treatment modifies pentylenetetrazole-induced seizures in mice: focused on GABA brain concentration.

The article Long-term vigabatrin treatment modifies pentylenetetrazole-induced seizures in mice: focused on GABA brain concentration.

Influence of the endocannabinoid system on the antidepressant activity of bupropion and moclobemide in the behavioural tests in mice.

BACKGROUND: Though there are several classes of antidepressant drugs available on the pharmaceutical market, depression that affects globally over 320 million people is still undertreated. Scientists have made attempts to develop novel therapeutical strategies to maximize effectiveness of therapy and minimize undesired reactions. One of the ideas is use of either dual-action agents or combined administration of two substances that affect diverse neurotransmissions. Thus, we investigated whether the selected CB receptor ligands (oleamide, AM251, JWH133, and AM630) can have an impact on the activity of bupropion and moclobemide. Bupropion belongs to the dual acting drugs, whereas moclobemide is an inhibitor of monoamine oxidase. METHODS: The mice forced swim test and the tail suspension test were applied in order to determine the potential antidepressant-like activity, whereas the HPLC method was used in order to assess the brain concentrations of the tested antidepressants. RESULTS: An intraperitoneal injection of sub-effective doses of oleamide (5 mg/kg), AM251 (0.25 mg/kg), and AM630 (0.25 mg/kg) increased activity of bupropion (10 mg/kg) in both behavioural tests. Effects of moclobemide (1.5 mg/kg) were potentiated only by AM251. These results were not influenced by the hypo- or hyperlocomotion of animals. CONCLUSION: The outcomes of the present study revealed that particularly activation or inhibition of the CB1 receptor function may augment the antidepressant activity of bupropion, whereas only inhibition of the CB1 receptor function manages to increase activity of moclobemide. Most probably, an interplay between CB receptor ligands and bupropion or moclobemide takes place at the cellular level.

Long-term vigabatrin treatment modifies pentylenetetrazole-induced seizures in mice: focused on GABA brain concentration.

BACKGROUND: The goal of our study was to examine the long-term effect of vigabatrin (VGB), a γ-aminobutyric acid aminotransferase (GABA-AT) inhibitor on clonazepam (CLO), ethosuximide (ETX) and valproate (VPA) anticonvulsive activity against pentylenetetrazole (PTZ)-induced seizures in mice. METHODS: VGB was administered for 3 and 7 days. Convulsions were evoked by PTZ at its CD97 (99 mg/kg). The influence of CLO, ETX and VPA alone or in combination with VGB on motor performance and long-term memory was analyzed. γ-aminobutyric acid (GABA) concentration in mice brain and plasma as well as glutamate decarboxylase (GAD) activity was measured. RESULTS: After 3 days of treatment, VGB in doses up to 500 mg/kg increased PTZ-induced seizure threshold, whereas after 7 days VGB (at the dose of 125 mg/kg) inhibited clonic seizures in experimental mice. 7 days of VGB administration did not change the protective effect of CLO, ETX and VPA against PTZ-induced seizures. 7 days of VGB treatment at a subthreshold dose of 75 mg/kg decreased TD50 of ETX and CLO in the chimney test, but did not affect TD50 value for VPA. 7 days of VGB administration in combination with AEDs did not affect long-term memory in mice. VGB after 3 days or 7 days of administration increased brain GABA concentration. GAD activity was decreased after 3 and 7 days of VGB administration. CONCLUSIONS: The presented results confirm anticonvulsive activity of VGB through GABA metabolism alteration and suggest care when combining VGB with ETX or CLO in the therapy.

Influence of the CB1 and CB2 cannabinoid receptor ligands on the activity of atypical antidepressant drugs in the behavioural tests in mice.

Available data support the notion that cannabinoids, whose therapeutic value is limited due to severe adverse reactions, could be beneficial as adjunctive agents in the management of mood disorders. Polytherapy, which is superior to monotherapy in the terms of effectiveness, usually requires lower doses of the individual components. Therefore, the main objective of our study was to determine whether administration of cannabinoid (CB) receptor ligands would enhance the antidepressant activity of atypical antidepressant drugs, i.e. agomelatine and tianeptine. To evaluate the antidepressant-like potential of the tested combinations, the mouse forced swim test (FST) and the tail suspension test (TST) were used. The HPLC method was applied to assess the brain levels of agomelatine and tianeptine. Both behavioural tests demonstrated that per se an ineffective intraperitoneal dose of oleamide (CB1 receptor agonist, 5 mg/kg) potentiated the anti-immobility activity of tianeptine (15 mg/kg), whereas AM251 (CB1 receptor inverse agonist/antagonist, 0.25 mg/kg) enhanced the antidepressant effects of tianeptine and agomelatine (20 mg/kg). Intraperitoneal co-administration of per se inactive doses of AM630 (CB2 receptor inverse agonist/antagonist) and agomelatine or tianeptine significantly reduced the immobility time of animals only in the FST. CB receptor ligands did not affect the brain levels of the tested atypical antidepressants. In summary, the outcomes of the present study showed that activation and inhibition of CB1 receptors as well as inhibition of CB2 receptors may increase the antidepressant activity of tianeptine, whereas only inhibition of CB1 and CB2 receptors has a potential to augment the antidepressant activity of agomelatine.

Agomelatine and tianeptine antidepressant activity in mice behavioral despair tests is enhanced by DMPX, a selective adenosine A2A receptor antagonist, but not DPCPX, a selective adenosine A1 receptor antagonist.

BACKGROUND: Adenosine, an endogenous nucleoside, modulates the release of monoamines, e.g., noradrenaline, serotonin, and dopamine in the brain. Both nonselective and selective stimulation of adenosine receptors produce symptoms of depression in some animal models. Therefore, the main objective of our study was to assess the influence of a selective adenosine A1 receptor antagonist (DPCPX) and a selective adenosine A2A receptor antagonist (DMPX) on the activity of agomelatine and tianeptine. METHODS: The forced swim test (FST) and tail suspension test (TST) were performed to assess the effects of DPCPX and DMPX on the antidepressant-like activity of agomelatine and tianeptine. Drug serum and brain levels were analyzed using HPLC. RESULTS: Co-administration of agomelatine (20 mg/kg) or tianeptine (15 mg/kg) with DMPX (3 mg/kg), but not with DPCPX (1 mg/kg), significantly reduced the immobility time both in the FST and TST in mice. These effects were not associated with an enhancement in animals' spontaneous locomotor activity. The observed changes in the mouse behavior after concomitant injection of DMPX and the tested antidepressant agents were associated with elevated brain concentration of agomelatine and tianeptine. CONCLUSION: Our study shows a synergistic action of the selective A2A receptor antagonist and the studied antidepressant drugs, and a lack of such interaction in the case of the selective A1 receptor antagonist. The interaction between DMPX and agomelatine/tianeptine at least partly occurs in the pharmacokinetic phase. A combination of a selective A2A receptor antagonist and an antidepressant may be a new strategy for treating depression.

Influence of salbutamol on the anticonvulsant potency of the antiepileptic drugs in the maximal electroshock-induced seizures in mice.

BACKGROUND: ß2-Adrenergic receptor agonists are widely used agents in the treatment of asthma or preterm labor. Since prevalence of asthma was shown to be higher in patients with epilepsy and modulation of noradrenergic system activity may modify epilepsy course, the aim of the present study was to examine the effect of salbutamol (SALB), one of the most commonly used ß2-adrenergic receptor agonist on the anticonvulsant potency of four classical antiepileptic drugs (AEDs): valproate (VPA), carbamazepine (CBZ), phenytoin (DPH) and phenobarbital (PB) in mice subjected to the maximal electroshock (MES)-induced seizures. METHODS: Seizures were caused by a current delivered through ear-clip electrodes. The influence of AEDs and SALB on animals' motor coordination and memory processes was also evaluated. RESULTS: Single SALB injection did not change, whereas 7 days SALB administration decreased seizure threshold in the MES-induced seizures in mice. Moreover, SALB injected ip for 1 day and for 7 days lowered the antiepileptic activity of PB in the MES-induced seizures in mice, but did not change the effect of other analyzed AEDs: VPA, CBZ or DPH. Butoxamine, a selective ß2-adrenergic receptor antagonist, reversed SALB influence on the activity of PB. SALB given alone or in combination with the tested AEDs did not affect animals' motor performance and memory after both single and 7 days administration. CONCLUSIONS: Presented results show that SALB may decrease the antiepileptic efficacy of PB. A special caution is advised to patients with epilepsy receiving ß2-adrenergic receptors agonists in the pharmacotherapy of pulmonary and obstetrical disorders.

Antidepressant-Like Activity of Typical Antidepressant Drugs in the Forced Swim Test and Tail Suspension Test in Mice Is Augmented by DMPX, an Adenosine A2A Receptor Antagonist.

Unsatisfactory therapeutic effects of currently used antidepressants force to search for new pharmacological treatment strategies. Recent research points to the relationship between depressive disorders and the adenosinergic system. Therefore, the main goal of our studies was to evaluate the effects of DMPX (3 mg/kg, i.p.), which possesses selectivity for adenosine A2A receptors versus A1 receptors, on the activity of imipramine (15 mg/kg, i.p.), escitalopram (2.5 mg/kg, i.p.), and reboxetine (2 mg/kg, i.p.) given in subtherapeutic doses. The studies carried out using the forced swim and tail suspension tests in mice showed that DMPX at a dose of 6 and 12 mg/kg exerts antidepressant-like effect and does not affect the locomotor activity. Co-administration of DMPX at a dose of 3 mg/kg with the studied antidepressant drugs caused the reduction of immobility time in both behavioral tests. The observed effect was not associated with an increase in the locomotor activity. To evaluate whether the observed effects were due to a pharmacokinetic/pharmacodynamic interaction, the levels of the antidepressants in blood and brain were measured using high-performance liquid chromatography. It can be assumed that the interaction between DMPX and imipramine was exclusively pharmacodynamic in nature, whereas an increased antidepressant activity of escitalopram and reboxetine was at least partly related to its pharmacokinetic interaction with DMPX.

DPCPX, a selective adenosine A1 receptor antagonist, enhances the antidepressant-like effects of imipramine, escitalopram, and reboxetine in mice behavioral tests.

The main goal of the present study was to evaluate the influence of the adenosine A1 receptor (A1R) antagonist - DPCPX - on depressive-like behavior in mice, as well as the effect of DPCPX on the activity of imipramine, escitalopram, and reboxetine, each at non-effective doses. The influence of DPCPX on behavior and its influence on the activity of selected antidepressants was evaluated in the forced swim test (FST) and the tail suspension test (TST) in mice. Locomotor activity was measured to verify and exclude false-positive data obtained in the FST and TST. Moreover, serum and brain concentrations of tested antidepressants were determined using HPLC. DPCPX, at doses of 2 and 4 mg/kg, exhibited antidepressant activity in the FST and TST, which was not related to changes in the spontaneous locomotor activity. Co-administration of DPCPX with imipramine, escitalopram, or reboxetine, each at non-active doses, significantly reduced the immobilization period in the FST and TST in mice, which was not due to the increase in locomotor activity. Both antagonists of 5-HT receptors (WAY 100635 and ritanserin) completely antagonized the effect elicited by DPCPX in the behavioral tests. Results of assessment of the nature of the interaction between DPCPX and test drugs show that in the case of DPCPX and imipramine or reboxetine, there were pharmacodynamic interactions, whereas the DPCPX-escitalopram interaction is at least partially pharmacokinetic in nature. Presented outcomes indicate that an inhibition of A1Rs and an increase of monoaminergic transduction in the CNS may offer a novel strategy for the development of antidepressant drugs.

Withdrawal of caffeine after its chronic administration modifies the antidepressant-like activity of atypical antidepressants in mice. Changes in cortical expression of Comt, Slc6a15 and Adora1 genes.

RATIONALE: Depressed patients often present increased consumption of caffeine. OBJECTIVES: We aimed to investigate the effects of chronic treatment with caffeine (5 mg/kg, twice daily for 14 days) on the activity of single, ineffective doses of agomelatine (20 mg/kg) or mianserin (10 mg/kg) given on day 15 alone or simultaneously with caffeine. METHODS: We used the forced swim test (FST), tail suspension test (TST), and locomotor activity test in mice and quantitative real-time PCR analysis of the selected genes in the cerebral cortex (Cx). RESULTS: There were no changes in the immobility time between mice that received saline and caffeine for 14 days. Administration of agomelatine or mianserin on day 15 did not produce an antidepressant-like effect, but such effect was observed after administration of agomelatine or mianserin simultaneously with caffeine on day 15, in both mice that received saline and caffeine for 14 days. In mice treated with caffeine for 14 days, joint administration of agomelatine or mianserin and caffeine on day 15 decreased solute carrier family 6, member 15 (Slc6a15), messenger RNA (mRNA) level in the Cx, compared to the group which received only the respective antidepressant on this day. Moreover, in mice treated with caffeine for 14 days, joint administration of mianserin and caffeine on day 15 decreased adenosine A1 receptor (Adora1) and catechol-O-methyltransferase (Comt) mRNA level in the Cx, compared to the group which received mianserin without caffeine on this day. CONCLUSIONS: Withdrawal of caffeine after its chronic intake can modify the activity of antidepressants. Adora1, Slc6a15, and Comt may be involved in the antidepressant-like effect observed after joint administration of caffeine and mianserin or agomelatine, following chronic treatment with caffeine.