Intravenous haloperidol and cocaine alter the distribution of T CD3+ CD4+ , non-T/NK and NKT cells in rats.

The modulation of dopamine transmission evokes strong behavioural effects that can be achieved by commonly used psychoactive drugs such as haloperidol or cocaine. Cocaine non-specifically increases dopamine transmission by blocking dopamine active transporter (DAT) and evokes behavioural arousal, whereas haloperidol is a non-specific D2-like dopamine receptor antagonist with sedative effects. Interestingly, dopamine has been found to affect immune cells in addition to its action in the central nervous system. Here, we address the possible interactions between haloperidol and cocaine and their effects on both immune cells and behaviour in freely moving rats. We use an intravenous model of haloperidol and binge cocaine administration to evaluate the drugs' impact on the distribution of lymphocyte subsets in both the peripheral blood and the spleen. We assess the drugs' behavioural effects by measuring locomotor activity. Cocaine evoked a pronounced locomotor response and stereotypic behaviours, both of which were completely blocked after pretreatment with haloperidol. The results suggest that blood lymphopenia, which was induced by haloperidol and cocaine (except for natural killer T cells), is independent of D2-like dopaminergic activity and most likely results from the massive secretion of corticosterone. Haloperidol pretreatment prevented the cocaine-induced decrease in NKT cell numbers. Moreover, the increased systemic D2-like dopaminergic activity after cocaine administration is a significant factor in retaining T CD3+ CD4+ lymphocytes and non-T/NK CD45RA+ cells in the spleen.

Preconceptional Resveratrol Supplementation Partially Counteracts Age-Related Reproductive Complications in C57BL/6J Female Mice.

Aging is associated with a drastic decline in fertility/fecundity and with an increased risk of pregnancy complications. Resveratrol (RES), a natural polyphenolic compound, has shown anti-oxidant and anti-inflammatory activities in both human and animal models, thus representing a potential therapeutic and prophylactic anti-aging supplement. Here, we investigated whether preconceptional resveratrol supplementation improved reproductive outcomes in mid-aged (8-month-old) and old (12-month-old) C57BL/6J female mice. Female siblings were cohoused and assigned to either RES or vehicle supplementation to drinking water for 10 consecutive weeks. Subsequently, females were mated with non-supplemented males and their pregnancy outcomes were monitored. RES improved mating success in old, but not in mid-aged females, and prevented the occurrence of delivery complications in the latter. These results indicate that preconceptional RES supplementation could partially improve age-related reproductive complications, but it was not sufficient to restore fecundity in female mice at a very advanced age.

Antimicrobial Properties of Mandelic Acid, Gallic Acid and their Derivatives.

PURPOSE: Alpha-hydroxy acids (AHAs) are one of the classes of hydroxy acids being beneficial for human health. The manuscript summarizes the biological properties of two popular members of AHAs, i.e., Mandelic Acid (MA) and Gallic Acid (GA), with particular emphasis on antimicrobial properties. Moreover, attempts to design new derivatives improving the natural properties of AHAs by using the chemical and physical approach are discussed. METHODS: Antimicrobial properties of MA, an arylalkyl AHA containing phenyl group attached to α- carbon, and GA, an aromatic trihydroxybenzoic acid containing the phenolic ring and carboxylic acid functional group, and their derivatives against common human and plant pathogenic fungi have been reviewed. RESULTS: The antimicrobial activity of MA and GA is a complex phenomenon strictly correlated with other properties exhibited by these acids, e.g., pro-oxidative activity and hydrophobicity. In most cases, the acids derivatives exhibited higher antimicrobial activity than the acids themselves. This is probably because of the higher lipophilicity of moiety that allows better penetration through the cell membrane. CONCLUSION: MA and GA present an excellent health-promoting tool and are valuable starting materials for the design of new compounds such as metal complexes with alkali, or alkali earth metals. The lipophilic, antimicrobial, and pro-oxidative properties act synergistically, supporting the pharmacological and therapeutic effect of acids and their derivatives.

Health Benefits of Plant-Derived Sulfur Compounds, Glucosinolates, and Organosulfur Compounds.

The broad spectrum of the mechanism of action of immune-boosting natural compounds as well as the complex nature of the food matrices make researching the health benefits of various food products a complicated task. Moreover, many routes are involved in the action of most natural compounds that lead to the inhibition of chronic inflammation, which results in a decrease in the ability to remove a pathogen asymptomatically and is connected to various pathological events, such as cancer. A number of cancers have been associated with inflammatory processes. The current review strives to answer the question of whether plant-derived sulfur compounds could be beneficial in cancer prevention and therapy. This review focuses on the two main sources of natural sulfur compounds: alliaceous and cruciferous vegetables. Through the presentation of scientific data which deal with the study of the chosen compounds in cancer (cell lines, animal models, and human studies), the discussion of food processing's influence on immune-boosting food content is presented. Additionally, it is demonstrated that there is still a need to precisely demonstrate the bioavailability of sulfur-containing compounds from various types of functional food, since the inappropriate preparation of vegetables can significantly reduce the content of beneficial sulfur compounds. Additionally, there is an urgent need to carry out more epidemiological studies to reveal the benefits of several natural compounds in cancer prevention and therapy.

The Effect of Acute and Chronic Social Stress on the Hippocampal Transcriptome in Mice.

Psychogenic stress contributes to the formation of brain pathology. Using gene expression microarrays, we analyzed the hippocampal transcriptome of mice subjected to acute and chronic social stress of different duration. The longest period of social stress altered the expression of the highest number of genes and most of the stress-induced changes in transcription were reversible after 5 days of rest. Chronic stress affected genes involved in the functioning of the vascular system (Alas2, Hbb-b1, Hba-a2, Hba-a1), injury response (Vwf, Mgp, Cfh, Fbln5, Col3a1, Ctgf) and inflammation (S100a8, S100a9, Ctla2a, Ctla2b, Lcn2, Lrg1, Rsad2, Isg20). The results suggest that stress may affect brain functions through the stress-induced dysfunction of the vascular system. An important issue raised in our work is also the risk of the contamination of brain tissue samples with choroid plexus. Such contamination would result in a consistent up- or down-regulation of genes, such as Ttr, Igf2, Igfbp2, Prlr, Enpp2, Sostdc1, 1500015O10RIK (Ecrg4), Kl, Clic6, Kcne2, F5, Slc4a5, and Aqp1. Our study suggests that some of the previously reported, supposedly specific changes in hippocampal gene expression, may be a result of the inclusion of choroid plexus in the hippocampal samples.

Genetic and Epigenetic Mechanisms Linking Pain and Psychiatric Disorders.

The neurophysiological link between neuropathic pain and depression remains unknown despite evident high comorbidity of these two disorders. However, there is convincing evidence that genotype plays a role in both pain and depression. Using various types of genetic analysis - population genetics, cytogenetics and molecular technologies - specific genes have been implicated in mediating almost all aspects of nociception and mood disorders. The current review attempts to identify specific genes and epigenetic mechanisms common to both disorders. It is concluded that external and internal factors (inflammation, stress, gender, etc.) that contribute to the pathologies may do so through epigenetic mechanisms that may affect expression of these particular genes. The possible involvement of epigenetic regulation in pain and psychiatric disorders suggests that treatments targeting epigenetic mechanisms that mediate adverse life events should be considered.

Novel candidate genes for alcoholism--transcriptomic analysis of prefrontal medial cortex, hippocampus and nucleus accumbens of Warsaw alcohol-preferring and non-preferring rats.

OBJECTIVE: Animal models provide opportunity to study neurobiological aspects of human alcoholism. Changes in gene expression have been implicated in mediating brain functions, including reward system and addiction. The current study aimed to identify genes that may underlie differential ethanol preference in Warsaw High Preferring (WHP) and Warsaw Low Preferring (WLP) rats. METHODS: Microarray analysis comparing gene expression in nucleus accumbens (NAc), hippocampus (HP) and medial prefrontal cortex (mPFC) was performed in male WHP and WLP rats bred for differences in ethanol preference. RESULTS: Differential and stable between biological repeats expression of 345, 254 and 129 transcripts in NAc, HP and mPFC was detected. Identified genes and processes included known mediators of ethanol response (Mx2, Fam111a, Itpr1, Gabra4, Agtr1a, LTP/LTD, renin-angiotensin signaling pathway), toxicity (Sult1c2a, Ces1, inflammatory response), as well as genes involved in regulation of important addiction-related brain systems such as dopamine, tachykinin or acetylcholine (Gng7, Tac4, Slc5a7). CONCLUSIONS: The identified candidate genes may underlie differential ethanol preference in an animal model of alcoholism. COMMENT: Names of genes are written in italics, while names of proteins are written in standard font. Names of human genes/proteins are written in all capital letters. Names of rodent genes/proteins are written in capital letter followed by small letters.

Social stress increases expression of hemoglobin genes in mouse prefrontal cortex.

BACKGROUND: In order to better understand the effects of social stress on the prefrontal cortex, we investigated gene expression in mice subjected to acute and repeated social encounters of different duration using microarrays. RESULTS: The most important finding was identification of hemoglobin genes (Hbb-b1, Hbb-b2, Hba-a1, Hba-a2, Beta-S) as potential markers of chronic social stress in mice. Expression of these genes was progressively increased in animals subjected to 8 and 13 days of repeated stress and was correlated with altered expression of Mgp (Mglap), Fbln1, 1500015O10Rik (Ecrg4), SLC16A10, and Mndal. Chronic stress increased also expression of Timp1 and Ppbp that are involved in reaction to vascular injury. Acute stress did not affect expression of hemoglobin genes but it altered expression of Fam107a (Drr1) and Agxt2l1 (Etnppl) that have been implicated in psychiatric diseases. CONCLUSIONS: The observed up-regulation of genes associated with vascular system and brain injury suggests that stressful social encounters may affect brain function through the stress-induced dysfunction of the vascular system.

Stress susceptibility-specific phenotype associated with different hippocampal transcriptomic responses to chronic tricyclic antidepressant treatment in mice.

BACKGROUND: The effects of chronic treatment with tricyclic antidepressant (desipramine, DMI) on the hippocampal transcriptome in mice displaying high and low swim stress-induced analgesia (HA and LA lines) were studied. These mice displayed different depression-like behavioral responses to DMI: stress-sensitive HA animals responded to DMI, while LA animals did not. RESULTS: To investigate the effects of DMI treatment on gene expression profiling, whole-genome Illumina Expression BeadChip arrays and qPCR were used. Total RNA isolated from hippocampi was used. Expression profiling was then performed and data were analyzed bioinformatically to assess the influence of stress susceptibility-specific phenotypes on hippocampal transcriptomic responses to chronic DMI. DMI treatment affected the expression of 71 genes in HA mice and 41 genes in LA mice. We observed the upregulation of Igf2 and the genes involved in neurogenesis (HA: Sema3f, Ntng1, Gbx2, Efna5, and Rora; LA: Otx2, Rarb, and Drd1a) in both mouse lines. In HA mice, we observed the upregulation of genes involved in neurotransmitter transport, the termination of GABA and glycine activity (Slc6a11, Slc6a9), glutamate uptake (Slc17a6), and the downregulation of neuropeptide Y (Npy) and corticotropin releasing hormone-binding protein (Crhbp). In LA mice, we also observed the upregulation of other genes involved in neuroprotection (Ttr, Igfbp2, Prlr) and the downregulation of genes involved in calcium signaling and ion binding (Adcy1, Cckbr, Myl4, Slu7, Scrp1, Zfp330). CONCLUSIONS: Several antidepressant treatment responses are similar in individuals with different sensitivities to stress, including the upregulation of Igf2 and the genes involved in neurogenesis. However, the findings also reveal that many responses to antidepressant treatments, involving the action of individual genes engaged in neurogenesis, neurotransmitter transport and neuroprotection, depend on constitutive hippocampal transcriptomic profiles and might be genotype dependent. The results suggest that, when and if this becomes feasible, antidepressant treatment should take into consideration individual sensitivity to stress.

Epigenetics of stress adaptations in the brain.

Recent findings in epigenetics shed new light on the regulation of gene expression in the central nervous system (CNS) during stress. The most frequently studied epigenetic mechanisms are DNA methylation, histone modifications and microRNA activity. These mechanisms stably determine cell phenotype but can also be responsible for dynamic molecular adaptations of the CNS to stressors. The limbic-hypothalamic-pituitary-adrenal axis (LHPA) is the primary circuit that initiates, regulates and terminates a stress response. The same brain areas that control stress also react to stress dynamically and with long-term consequences. One of the biological processes evoking potent adaptive changes in the CNS such as changes in behavior, gene activity or synaptic plasticity in the hippocampus is psychogenic stress. This review summarizes the current data regarding the epigenetic basis of molecular adaptations in the brain including genome-wide epigenetic changes of DNA methylation and particular genes involved in epigenetic responses that participate in the brain response to chronic psychogenic stressors. It is concluded that specific epigenetic mechanisms in the CNS are involved in the stress response.

Recreational use of D-lysergamide from the seeds of Argyreia nervosa, Ipomoea tricolor, Ipomoea violacea, and Ipomoea purpurea in Poland.

Recently, there are important changes in recreational drug use. The aim of the present study was to analyse reports published on a recreational web site by drug users who ingested seeds of plants belonging to the Convolvulaceae family and to compare them with available medical case reports. We have also included reports describing the effects induced by "druids fantasy," which is a new drug allegedly containing the same alkaloid as the seeds of A. nervosa. Our search reveals the reoccurrence of recreational use of I. tricolor and violacea (morning glory), which had not been reported in medical literature since 1968. We have also found that drug users are experimenting with other species, such as I. purpurea, whose psychoactive properties are unknown. Symptoms and doses reported by drug users were comparable with the few available medical case reports. The most worrying symptom was suicidal ideation reported by two subjects who ingested A. nervosa and Ipomoea seeds. Effects induced by druids fantasy were comparable with the effects induced by A. nervosa and various Ipomoea species. The ingestion of seeds was frequently associated with taking drugs such as cannabis and hashish, although other combinations, for example with dextromethorphan, were also reported.

Effects of chronic stress on prefrontal cortex transcriptome in mice displaying different genetic backgrounds.

There is increasing evidence that depression derives from the impact of environmental pressure on genetically susceptible individuals. We analyzed the effects of chronic mild stress (CMS) on prefrontal cortex transcriptome of two strains of mice bred for high (HA)and low (LA) swim stress-induced analgesia that differ in basal transcriptomic profiles and depression-like behaviors. We found that CMS affected 96 and 92 genes in HA and LA mice, respectively. Among genes with the same expression pattern in both strains after CMS, we observed robust upregulation of Ttr gene coding transthyretin involved in amyloidosis, seizures, stroke-like episodes, or dementia. Strain-specific HA transcriptome affected by CMS was associated with deregulation of genes involved in insulin secretion (Acvr1c, Nnat, and Pfkm), neuropeptide hormone activity (Nts and Trh), and dopamine receptor mediated signaling pathway (Clic6, Drd1a, and Ppp1r1b). LA transcriptome affected by CMS was associated with genes involved in behavioral response to stimulus (Fcer1g, Rasd2, S100a8, S100a9, Crhr1, Grm5, and Prkcc), immune effector processes (Fcer1g, Mpo, and Igh-VJ558), diacylglycerol binding (Rasgrp1, Dgke, Dgkg, and Prkcc), and long-term depression (Crhr1, Grm5, and Prkcc) and/or coding elements of dendrites (Crmp1, Cntnap4, and Prkcc) and myelin proteins (Gpm6a, Mal, and Mog). The results indicate significant contribution of genetic background to differences in stress response gene expression in the mouse prefrontal cortex.

Selection for stress-induced analgesia affects the mouse hippocampal transcriptome.

Stress responsiveness, including pain sensitivity and stress-induced analgesia (SIA), depends on genotype and, partially, is mediated by hippocampus. The present study examined differences in constitutive gene expression in hippocampus in lines of mice bred for high (HA) and low (LA) swim SIA. Between the lines, we found 1.5-fold or greater differences in expression of 205 genes in the hippocampus in nonstressed animals. The identity of these genes indicates that selective breeding for swim SIA affected many aspects of hippocampal neurons physiology, including metabolism, structural changes, and cellular signaling. Genes involved in calcium signaling pathway, including Slc8a1, Slc8a2, Prkcc, and Ptk2b, were upregulated in LA mice. In HA mice, robust upregulation of genes coding some transcription factors (Klf5) or receptors for neurotensin (Ntsr2) and GABA (Gabard) suggests the genetic basis for a novel mechanism of the non-opioid type of SIA in HA animals. Additional groups of differentially expressed genes represented functional networks involved in carbohydrate metabolism, gene expression regulation, and molecular transport. Our data indicate that selection for a single and very specific stress response trait, swim SIA, alters hippocampal gene expression. The results suggest that individual stress responsiveness may be associated with characteristics of the constitutive hippocampal transcriptome.

Effect of chronic mild stress on hippocampal transcriptome in mice selected for high and low stress-induced analgesia and displaying different emotional behaviors.

There is increasing evidence that mood disorders may derive from the impact of environmental pressure on genetically susceptible individuals. Stress-induced hippocampal plasticity has been implicated in depression. We studied hippocampal transcriptomes in strains of mice that display high (HA) and low (LA) swim stress-induced analgesia and that differ in emotional behaviors and responses to different classes of antidepressants. Chronic mild stress (CMS) affected expression of a number of genes common for both strains. CMS also produced strain specific changes in expression suggesting that hippocampal responses to stress depend on genotype. Considerably larger number of genes, biological processes, molecular functions, biochemical pathways, and gene networks were affected by CMS in LA than in HA mice. The results suggest that potential drug targets against detrimental effects of stress include glutamate transporters, and cholinergic, cholecystokinin (CCK), glucocorticoids, and thyroid hormones receptors. Furthermore, some biological processes evoked by stress and different between the strains, such as apoptosis, neurogenesis and chromatin modifications, may be responsible for the long-term, irreversible effects of stress and suggest a role for epigenetic regulation of mood related stress responses.

Cannabidiol decreases body weight gain in rats: involvement of CB2 receptors.

Cannabidiol (CBD) is a major non-psychotropic constituent of Cannabis sativa, with well recognized therapeutic potential. Considering the importance of the endogenous cannabinoid system to the regulation of food intake and energy balance we studied the effects of repeated CBD administration on body weight gains in rats. Male Wistar rats (260 ± 20 g at start of study) received intraperitoneal injections of CBD at doses of 2.5 and 5mg/kg/day for 14 consecutive days and body weight gains were monitored. Both doses of CBD produced significant decrease in body weight gain, with the effect produced by 5mg/kg being more pronounced. The CB2 receptor selective antagonist, AM630, blocked the decrease in body weight gain. AM630 alone did not affect body weight gain. The results suggest that CBD has the ability to alter body weight gain, possibly via the CB2 receptor. CB2 receptors may play a role in the regulation of body weight and the effects of CB2 specific ligands should be further investigated in studies of body weight regulation.

Cocaine administration increases CD4/CD8 lymphocyte ratio in peripheral blood despite lymphopenia and elevated corticosterone.

The CD4/CD8 lymphocyte ratio in peripheral blood is used in the diagnosis of HIV infection, autoimmune disorders or susceptibility to infections. The present experiment aimed to evaluate the lymphocyte subsets, their distribution and CD4/CD8 ratio in blood after repeated, intravenous administration of cocaine. Adult male Wistar rats received three daily, in 30 min intervals, intravenous infusions of cocaine hydrochloride (5 mg/kg) or saline for 14 consecutive days. After each infusion the locomotor-activating effects of cocaine were assessed. Blood samples were collected 30 min after the last daily infusion on the 1st, 7th and 14th day of treatment. Total leukocyte numbers, percentages of leukocyte subpopulations, and T, B, NK, T CD4+, and T CD8+ lymphocyte subsets, IFN-γ, and plasma corticosterone were determined. Repeated cocaine treatment resulted in an increase in neutrophil numbers and a significant decrease in total leukocyte and lymphocyte numbers involving a significant reduction in numbers of T, B, and NK lymphocyte subsets. T CD4+ and T CD8+ lymphocyte numbers were reduced but with a considerably smaller decrease in T CD4+ number. Cocaine treatment altered proportions between the lymphocyte subsets by decreasing the percentages of T CD8+, B, and NK cells but increasing a percentage of T CD4+ cells. Destabilization in proportions between T CD4+ and T CD8+ was manifested as an elevated CD4/CD8 ratio that occurred despite increased plasma corticosterone and the lymphocytopenia. Cocaine did not affect the concentration of IFN-γ. The results suggest that although cocaine induced lymphopenia, it did not suppress the overall immune activity in terms of the CD4/CD8 ratio.

Opposite effects of alcohol in regulating stress-induced changes in body weight between the two mouse lines with enhanced or low opioid system activity.

Considering the involvement of the opioid system in alcoholism, depression and metabolism - known risk factors in human obesity, we studied the effects of chronic mild stress (CMS) and alcohol intake on body weight in two mouse lines selected for high (HA-high analgesia) or low (LA-low analgesia) swim stress-induced analgesia. In comparison to LA mice, HA mice exhibit an upregulation of opioid receptor system function, different depression-like behavior and reduced energy expenditure in stress. LA animals showed enhanced basal and CMS-induced alcohol drinking versus HA. Now we report different effects of alcohol under no stress (control) and CMS conditions on food intake and body weight between the lines. CMS in animals with no access to alcohol increased body weight in both HA and LA mice, with no effect of CMS on food intake in either line and without differences between the lines. In LA mice alcohol reduced body weight under both conditions although significantly more under the control than CMS conditions. In contrast, in HA mice alcohol increased body weight more under the CMS than under control conditions. The results suggest that opioid system may modulate effects of alcohol on stress -induced changes in body weight.

Properties of gap junction blockers and their behavioural, cognitive and electrophysiological effects: animal and human studies.

Gap junctions play an important role in brain physiology. They synchronize neuronal activity and connect glial cells participating in the regulation of brain metabolism and homeostasis. Gap junction blockers (GJBs) include various chemicals that impair gap junction communication, disrupt oscillatory neuronal activity over a wide range of frequencies, and decrease epileptic discharges. The behavioural and clinical effects of GJBs suggest that gap junctions can be involved in the regulation of locomotor activity, arousal, memory, and breathing. Severe neuropsychiatric side effects suggest the involvement of gap junctions in mechanisms of consciousness. Unfortunately, the available GJBs are not selective and can bind to targets other than gap junctions. Other problems in behavioural studies include the possible adverse effects of GJBs, for example, retinal toxicity and hearing disturbances, changes in blood-brain transport, and the metabolism of other drugs. Therefore, it is necessary to design experiments properly to avoid false, misleading or uninterpretable results. We review the pharmacological properties and electrophysiological, behavioural and cognitive effects of the available gap junction blockers, such as carbenoxolone, glycyrrhetinic acid, quinine, quinidine, mefloquine, heptanol, octanol, anandamide, fenamates, 2-APB, several anaesthetics, retinoic acid, oleamide, spermine, aminosulfonates, and sodium propionate. It is concluded that despite a number of different problems, the currently used gap junction blockers could be useful tools in pharmacology and neuroscience.

Alcohol reverses depressive and pronociceptive effects of chronic stress in mice with enhanced activity of the opioid system.

The role of the opioid system in mediating effects of alcoholism and stress in depression is far from clear. We studied, therefore, the effects of chronic mild stress (CMS) and alcohol drinking on depression-like behavior and nociception in lines of mice selected for high (HA) or low (LA) swim stress-induced analgesia. Compared to the LA mice, the HA animals display up-regulation of opioid receptor system function and depression-like behavior in tail suspension test (TST). We report now that alcohol reverses depressive and pronociceptive effect of CMS in HA mice. In contrast, in LA mice CMS does not affect nociception or behavior in TST and the animals are not susceptible to alcohol under CMS. The results suggest that opioid system activity may determine the effects of alcohol on behavior under stress and, therefore, link predispositions to depression and to alcoholism.

Differences in ethanol drinking between mice selected for high and low swim stress-induced analgesia.

Alcoholism is a complex disorder, still not fully understood, in which environmental and inherited risk factors play essential roles. Of particular importance may be chronic exposure to stress thought to increase preference for ethanol in genetically susceptible individuals. Animal and human data suggest that the opioid system may be involved in the development of alcohol dependence. We studied the effects of chronic mild stress (CMS) on the voluntary intake of 8% ethanol in the mouse lines displaying high (HA) or low (LA) swim stress-induced analgesia. These lines differ in the activity of the endogenous opioid system. Normally, 8% ethanol is aversive to rodents. We found that LA mice with the low opioid system activity exposed to CMS manifested greater ethanol intake than under no stress conditions. No such effect of CMS on ethanol consumption was observed in HA mice that display the enhanced opioid system activity. We conclude that CMS imposed on individuals with a genetically determined low opioid activity may favor the development of ethanol abuse.