Esketamine Inhibits Cocaine-Seeking Behaviour Subsequent to Various Abstinence Conditions in Rats.

BACKGROUND: Cocaine use disorder (CUD) is a relapsing brain disease caused by a chronic drug intake that involves neural mechanisms and psychological processes, including depression. Preclinical and clinical studies have demonstrated the promise of pharmacological drugs in controlling the reinstatement of cocaine by targeting the N-methyl-D-aspartate (NMDA) receptor. Recent evidence has revealed that esketamine, a (S) enantiomer of ketamine, shows a high affinity to NMDA receptors and has been used in clinical trials to treat moderate-to-severe depression. METHODS: In the present paper, we investigated the effects of esketamine in regulating cocaine-seeking behaviour induced through the use of cocaine (10 mg/kg) or the cocaine-associated conditioned cue after a short (10 days)-lasting period of drug abstinence with extinction training, home cage or enrichment environment conditions in male rats. Furthermore, we investigated the acute effects of esketamine on locomotor activity in drug-naïve animals. RESULTS: Esketamine (2.5-10 mg/kg) administered peripherally attenuated the reinstatement induced with cocaine priming or the drug-associated conditioned cue after different conditions of abstinence. CONCLUSIONS: These results seem to support esketamine as a candidate for the pharmacological management of cocaine-seeking and relapse prevention; however, further preclinical and clinical research is needed to better clarify esketamine's actions in CUD.

Maternal monosaccharide diets evoke cognitive, locomotor, and emotional disturbances in adolescent and young adult offspring rats.

Anxiety and depression are the most common mental disorders affecting people worldwide. Recent studies have highlighted that a maternal high-sugar diet (HSD) could be a risk factor for neurobehavioural dysregulations, including mood disorders. Increased consumption of added sugar in food such as refined fructose/glucose can increase the risk of metabolic disorders and impact susceptibility to mental disorders. Furthermore, a few papers have reported disabilities in learning and memory among offspring after maternal HSD, thus suggesting a relationship between maternal nutrition and offspring neurogenesis. In this study, we evaluated the impact of maternal monosaccharide consumption based on a glucose (GLU) or fructose (FRU) diet during pregnancy and lactation in adolescent and young adult offspring rats of both sexes on cognitive, locomotor, and emotional disturbances. Locomotor activity, short-term memory, anxiety-like and depressive-like behavior were evaluated in the offspring. We report for the first time that the maternal GLU or FRU diet is sufficient to evoke anxiety-like behavior among adolescent and young adult offspring. Moreover, we found that maternal monosaccharide diets lead to hyperactivity and depressive-like behavior in male adolescent rats. We also noticed that a maternal FRU diet significantly enhanced novelty-seeking behavior only in young adult male rats. Our novel findings indicated that the maternal monosaccharide diet, especially a diet enriched in FRU, resulted in strong behavioral alterations in offspring rats at early life stages. This study also revealed that male rats were more susceptible to hyperactivity and anxiety- and depressive-like phenotypes than female rats. These results suggest that maternal monosaccharide consumption during pregnancy and lactation is an important factor affecting the emotional status of offspring.

5-HT2C Receptor Stimulation in Obesity Treatment: Orthosteric Agonists vs. Allosteric Modulators.

Obesity is a substantial health and economic issue, and serotonin (5-hydroxytryptamine, 5-HT) is an important neurotransmitter system involved in the regulation of body weight. The 5-HT2C receptors (5-HT2CRs), one of 16 of the 5-HT receptor (5-HTRs) subtypes, play a significant role in food intake and body weight control. In this review, we focused on the 5-HTR agonists, such as fenfluramines, sibutramine, and lorcaserin, which act directly or indirectly at 5-HT2CRs and have been introduced into the clinic as antiobesity medications. Due to their unwanted effects, they were withdrawn from the market. The 5-HT2CR positive allosteric modulators (PAMs) can be potentially safer active drugs than 5-HT2CR agonists. However, more in vivo validation of PAMs is required to fully determine if these drugs will be effective in obesity prevention and antiobesity pharmacology treatment. Methodology strategy: This review focuses on the role of 5-HT2CR agonism in obesity treatment, such as food intake regulation and weight gain. The literature was reviewed according to the review topic. We searched the PubMed and Scopus databases and Multidisciplinary Digital Publishing Institute open-access scientific journals using the following keyword search strategy depending on the chapter phrases: (1) "5-HT2C receptor" AND "food intake", and (2) "5-HT2C receptor" AND "obesity" AND "respective agonists", and (3) "5-HT2C receptor" AND "PAM". We included preclinical studies (only present the weight loss effects) and double-blind, placebo-controlled, randomized clinical trials published since the 1975s (mostly related to antiobesity treatment), and excluded the pay-walled articles. After the search process, the authors selected, carefully screened, and reviewed appropriate papers. In total, 136 articles were included in this review.

A High-Sugar Diet Consumption, Metabolism and Health Impacts with a Focus on the Development of Substance Use Disorder: A Narrative Review.

Carbohydrates are important macronutrients in human and rodent diet patterns that play a key role in crucial metabolic pathways and provide the necessary energy for proper body functioning. Sugar homeostasis and intake require complex hormonal and nervous control to proper body energy balance. Added sugar in processed food results in metabolic, cardiovascular, and nervous disorders. Epidemiological reports have shown enhanced consumption of sweet products in children and adults, especially in reproductive age and in pregnant women, which can lead to the susceptibility of offspring's health to diseases in early life or in adulthood and proneness to mental disorders. In this review, we discuss the impacts of high-sugar diet (HSD) or sugar intake during the perinatal and/or postnatal periods on neural and behavioural disturbances as well as on the development of substance use disorder (SUD). Since several emotional behavioural disturbances are recognized as predictors of SUD, we also present how HSD enhances impulsive behaviour, stress, anxiety and depression. Apart from the influence of HSD on these mood disturbances, added sugar can render food addiction. Both food and addictive substances change the sensitivity of the brain rewarding neurotransmission signalling. The results of the collected studies could be important in assessing sugar intake, especially via maternal dietary patterns, from the clinical perspective of SUD prevention or pre-existing emotional disorders. Methodology: This narrative review focuses on the roles of a high-sugar diet (HSD) and added sugar in foods and on the impacts of glucose and fructose on the development of substance use disorder (SUD) and on the behavioural predictors of drugs abuse. The literature was reviewed by two authors independently according to the topic of the review. We searched the PubMed and Scopus databases and Multidisciplinary Digital Publishing Institute open access scientific journals using the following keyword search strategy depending on the theme of the chapter: "high-sugar diet" OR "high-carbohydrate diet" OR "sugar" OR "glucose" OR "fructose" OR "added sugar" AND keywords. We excluded inaccessible or pay-walled articles, abstracts, conference papers, editorials, letters, commentary, and short notes. Reviews, experimental studies, and epidemiological data, published since 1990s, were searched and collected depending on the chapter structure. After the search, all duplicates are thrown out and full texts were read, and findings were rescreened. After the selection process, appropriate papers were included to present in this review.

Intravenous administration of Tat-NR2B9c peptide, a PSD95 inhibitor, attenuates reinstatement of cocaine-seeking behavior in rats.

Cocaine use disorder is a serious, chronic and relapsing disease of the nervous system, for which effective treatments do not yet exist. Recently, the role of the N-methyl-d-aspartate (NMDA) receptor subunit GluN2B has been highlighted in cocaine abstinence followed by extinction training. Since the GluN2B subunit is stabilized at synaptic level by the interaction with its scaffolding protein PSD95, in this study we aimed at investigating efficacy of Tat-NR2B9c peptide, a PSD95 inhibitor, which disrupts the interaction of PSD95 with GluN2B, in the attenuation of cocaine seeking-behavior or cue-induced reinstatement. We found that Tat-NR2B9c, administered intravenously, attenuated the reinstatement of active lever presses induced by a priming dose of cocaine or by drug-associated conditioned stimuli. At the same time, the GluN2B/PSD95 complex levels were decreased in the ventral hippocampus of rats that previously self-administered cocaine injected with Tat-NR2B9c during cocaine- or cue-induced reinstatement. In conclusion, we here provide the first evidence showing that the disruption of the GluN2B/PSD95 complexes during cocaine abstinence followed by extinction training may represent a useful strategy to reduce reinstatement of cocaine-seeking behavior.

Mesencephalic Astrocyte-Derived Neurotrophic Factor Regulates Morphology of Pigment-Dispersing Factor-Positive Clock Neurons and Circadian Neuronal Plasticity in Drosophila melanogaster.

Mesencephalic Astrocyte-derived Neurotrophic Factor (MANF) is one of a few neurotrophic factors described in Drosophila melanogaster (DmMANF) but its function is still poorly characterized. In the present study we found that DmMANF is expressed in different clusters of clock neurons. In particular, the PDF-positive large (l-LNv) and small (s-LNv) ventral lateral neurons, the CRYPTOCHROME-positive dorsal lateral neurons (LNd), the group 1 dorsal neurons posterior (DN1p) and different tim-positive cells in the fly's visual system. Importantly, DmMANF expression in the ventral lateral neurons is not controlled by the clock nor it affects its molecular mechanism. However, silencing DmMANF expression in clock neurons affects the rhythm of locomotor activity in light:dark and constant darkness conditions. Such phenotypes correlate with abnormal morphology of the dorsal projections of the s-LNv and with reduced arborizations of the l-LNv in the medulla of the optic lobe. Additionally, we show that DmMANF is important for normal morphology of the L2 interneurons in the visual system and for the circadian rhythm in the topology of their dendritic tree. Our results indicate that DmMANF is important not only for the development of neurites but also for maintaining circadian plasticity of neurons.

On Variations in the Level of PER in Glial Clocks of Drosophila Optic Lobe and Its Negative Regulation by PDF Signaling.

We show that the level of the core protein of the circadian clock Period (PER) expressed by glial peripheral oscillators depends on their location in the Drosophila optic lobe. It appears to be controlled by the ventral lateral neurons (LNvs) that release the circadian neurotransmitter Pigment Dispersing Factor (PDF). We demonstrate that glial cells of the distal medulla neuropil (dMnGl) that lie in the vicinity of the PDF-releasing terminals of the LNvs possess receptors for PDF (PDFRs) and express PER at significantly higher level than other types of glia. Surprisingly, the amplitude of PER molecular oscillations in dMnGl is increased twofold in PDF-free environment, that is in Pdf0 mutants. The Pdf0 mutants also reveal an increased level of glia-specific protein REPO in dMnGl. The photoreceptors of the compound eye (R-cells) of the PDF-null flies, on the other hand, exhibit de-synchrony of PER molecular oscillations, which manifests itself as increased variability of PER-specific immunofluorescence among the R-cells. Moreover, the daily pattern of expression of the presynaptic protein Bruchpilot (BRP) in the lamina terminals of the R-cells is changed in Pdf0 mutant. Considering that PDFRs are also expressed by the marginal glia of the lamina that surround the R-cell terminals, the LNv pacemakers appear to be the likely modulators of molecular cycling in the peripheral clocks of both the glial cells and the photoreceptors of the compound eye. Consequently, some form of PDF-based coupling of the glial clocks and the photoreceptors of the eye with the central LNv pacemakers must be operational.