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Evidence suggests that there is a link between the endocannabinoid system (ECS) and neuropsychiatric illnesses, including schizophrenia. Whilst the ECS has been shown to be involved in immune system regulation in various ways, it is known that infections during pregnancy can modulate the immune system of the mother and increase the risk for schizophrenia in offspring. In animal studies, maternal immune activation following administration of viral or bacterial mimics has been shown to reproduce many key structural, behavioural, and pharmacological abnormalities in offspring that resemble schizophrenia. In the present study, we used Positron Emission Tomography (PET) and [(18)F]MK-9470, a selective high-affinity inverse agonist radioligand for cannabinoid type 1 receptors (CB1R), to longitudinally assess CB1R expression in the progeny of female rats exposed to the viral mimic polyriboinosinic-polyribocytidilic acid (poly I:C) (4mg/kg i.v.) or vehicle at gestational day 15 (GD 15). PET scans were performed in offspring at postnatal days (PND) 32-42 (adolescence) and in the same animals again at PNDs 75-79 (adulthood). Sixteen regions of interest were assessed, encompassing the whole rat brain. At adolescence, offspring exposed prenatally to poly I:C had significantly lower CB1R relative Standard Uptake Values (rSUV) compared to controls in the globus pallidus (p=0.046). In adulthood, however, poly I:C exposed offspring had higher levels of CB1R rSUV in sensory cortex (p=0.034) and hypothalamus (p=0.032) compared to controls. Our results suggest that prenatal poly I:C leads to long term alterations in the integrity of the ECS that are age and region-specific. The increased CB1R expression in adulthood following poly I:C mirrors the increased CB1R observed in patients with schizophrenia in post-mortem and in vivo PET studies., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: MicroRNAs are small non-coding RNA molecules that regulate gene expression, including genes involved in neuronal function and plasticity that have relevance for brain function and mental health. We therefore performed a systematic review of miRNAs in general adult psychiatric disorders., Method: Systematic searches in PubMed/MEDLINE and Web of Science were conducted to identify published clinical articles on microRNAs in general adult psychiatric disorders. We also reviewed references from included articles., Results: There is mounting evidence of microRNAs' regulatory roles in a number of central nervous system processes, including neurogenesis and synaptic plasticity. The majority of clinical studies of microRNAs in psychiatric disorders are in schizophrenia, where a number of specific microRNAs have been identified in separate studies. There is some evidence of marked downregulation of some microRNAs in affective disorders. Treatment with antidepressants appears to upregulate microRNA levels. There is currently little evidence from human studies in anxiety, addiction or other psychiatric disorders., Conclusion: MicroRNA research in psychiatry is currently in a nascent period, but represents an emerging and exciting area, with the potential to clarify molecular mechanisms of disease and identify novel biomarkers and therapeutic agents., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: Epigenetics has recently emerged as a potential mechanism by which adverse environmental stimuli can result in persistent changes in gene expression. Epigenetic mechanisms function alongside the DNA sequence to modulate gene expression and ultimately influence protein production. The current review provides an introduction and overview of epigenetics with a particular focus on preclinical and clinical studies relevant to major depressive disorder (MDD)., Methods: PubMed and Web of Science databases were interrogated from January 1995 up to December 2012 using combinations of search terms, including "epigenetic", "microRNA" and "DNA methylation" cross referenced with "depression", "early life stress" and "antidepressant"., Results: There is an association between adverse environmental stimuli, such as early life stress, and epigenetic modification of gene expression. Epigenetic changes have been reported in humans with MDD and may serve as biomarkers to improve diagnosis. Antidepressant treatments appear to reverse or initiate compensatory epigenetic alterations that may be relevant to their mechanism of action., Limitations: As a narrative review, the current report was interpretive and qualitative in nature., Conclusion: Epigenetic modification of gene expression provides a mechanism for understanding the link between long-term effects of adverse life events and the changes in gene expression that are associated with depression. Although still a developing field, in the future, epigenetic modifications of gene expression may provide novel biomarkers to predict future susceptibility and/or onset of MDD, improve diagnosis, and aid in the development of epigenetics-based therapies for depression., (© 2013 Published by Elsevier B.V.)

Brain inflammation in early life has been proposed to play important roles in the development of anxiety and psychosis-related behaviors in adulthood, behaviors that rely on the integrity of dopamine and/or serotonin systems. Moreover recent behavioral and anatomical evidence suggests involvement of CB1 receptors in the control of emotion and mood. In this study, we determined the effects of neonatal LPS treatment on dopamine, serotonin, and cannabinoid receptor binding in adulthood. Rats were treated with the bacterial endotoxin lipopolysaccharide (LPS) on postnatal day (PND) 3 and 5. Dopamine D1, D2, serotonin 5HT1A, 5HT2A, and serotonin transporter and cannabinoid CB1 receptor binding across several brain regions were measured autoradiographically in adulthood (PND 85). Neonatal LPS treatment caused a significant increase in dopamine D2 in the nucleus accumbens and olfactory tubercle, a decrease in 5HT1A receptor binding in the hippocampus CA1 and ventromedial hypothalamus. A decrease in CB1 receptor binding after neonatal LPS was observed in the amygdala. Neonatal LPS had no significant impact on dopamine D1, serotonin 5HT2A or serotonin transporter binding in any of the brain regions examined. Our results suggest long lasting, region specific effects and differential impact on dopamine, serotonin and cannabinoid receptor systems following neonatal inflammation, that may form the basis for compromised anxiety and psychosis related behaviors., (Copyright © 2013 Wiley Periodicals, Inc.)

Infections during pregnancy and adolescent cannabis use have both been identified as environmental risk factors for schizophrenia. We combined these factors in an animal model and looked at their effects, alone and in combination, on serotonin 5HT1A receptor binding (5HT1AR) binding longitudinally from late adolescence to adulthood. Pregnant rats were exposed to the viral mimic poly I:C on embryonic day 15. Adolescent offspring received daily injections of the cannabinoid HU210 for 14 days starting on postnatal day (PND) 35. Hippocampal and cortical 5HT1AR binding was quantified autoradiographically using [(3)H]8-OH-DPAT, in late adolescent (PND 55), young adult (PND 65) and adult (PND 90) rats. Descendants of poly I:C treated rats showed significant increases of 15-18% in 5HT1AR in the hippocampus (CA1) compared to controls at all developmental ages. Offspring of poly I:C treated rats exposed to HU210 during adolescence exhibited even greater elevations in 5HT1AR (with increases of 44, 29, and 39% at PNDs 55, 65, and 90). No effect of HU210 alone was observed. Our results suggest a synergistic effect of prenatal infection and adolescent cannabinoid exposure on the integrity of the serotoninergic system in the hippocampus that may provide the neurochemical substrate for abnormal hippocampal-related functions relevant to schizophrenia.

Objective: In humans, a single exposure to phencyclidine (PCP) can induce a schizophrenia-like psychosis which can persist for up to two weeks. In rats, an acute dose of PCP increases dopaminergic activity and causes changes in dopamine related behaviours some of which are sexually dimorphic. To better understand the effects of PCP on dopamine receptor adaptations in the short term we examined dopamine D1-like receptors (D1R) and D2-like receptors (D2R) in the mesolimbic and nigrostriatal dopamine pathways, 4 hours after exposure to PCP in female rats., Methods: Animals received a single dose of 40 mg/kg PCP and were sacrificed 4 hours later. In vitro autoradiography was carried out using [(3)H] SCH 23390 and [(3)H] raclopride that target D1R and D2R respectively, in cryostat brain sections., Results: Two way analysis of variance (ANOVA), revealed an overall effect of PCP treatment (F [1,63]=9.065; p=0.004) on D1R binding with an 18% decrease (p<0.01) in binding in the medial caudate putamen. PCP treatment also had an overall effect on D2R binding (F [1,47]=5.450; p=0.024) and a trend for an increase in D2R binding across all the brain regions examined., Conclusion: These results suggest opposing D1R and D2R adaptations in striatal subregions of female rats following acute exposure to PCP that may occur through indirect mechanisms.

A number of studies suggest a dysregulation of the endogenous cannabinoid system in schizophrenia (SCZ). In the present study, we examined cannabinoid CB(1) receptor (CB(1)R) binding and mRNA expression in the dorsolateral prefrontal cortex (DLPFC) (Brodmann's area 46) of SCZ patients and controls, post-mortem. Receptor density was investigated using autoradiography with the CB(1)R ligand [(3)H] CP 55,940 and CB(1)R mRNA expression was measured using quantitative RT-PCR in a cohort of 16 patients with paranoid SCZ, 21 patients with non-paranoid SCZ and 37 controls matched for age, post-mortem interval and pH. All cases were obtained from the University of Sydney Tissue Resource Centre. Results were analyzed using one-way analysis of variance (ANOVA) and post hoc Bonferroni tests and with analysis of covariance (ANCOVA) to control for demographic factors that would potentially influence CB(1)R expression. There was a main effect of diagnosis on [(3)H] CP 55,940 binding quantified across all layers of the DLPFC (F(2,71) = 3.740, p = 0.029). Post hoc tests indicated that this main effect was due to patients with paranoid SCZ having 22% higher levels of CB(1)R binding compared with the control group. When ANCOVA was employed, this effect was strengthened (F(2,67) = 6.048, p = 0.004) with paranoid SCZ patients differing significantly from the control (p = 0.004) and from the non-paranoid group (p = 0.016). In contrast, no significant differences were observed in mRNA expression between the different disease subtypes and the control group. Our findings confirm the existence of a CB(1)R dysregulation in SCZ and underline the need for further investigation of the role of this receptor particularly in those diagnosed with paranoid SCZ.

Animal studies suggest differential effects of cannabinoids on dopamine-related behaviours in adolescence and adulthood however few studies have investigated the underlying neurochemical effects of cannabinoids during adolescence. The aim of the present study was to compare the effects of treatment with the synthetic cannabinoid, HU210, on dopamine receptor density in adolescent and adult rats. Adolescent (postnatal day (PND) 35) and adult (PND 70) rats received a single dose of 100μg/kg HU210 or 25, 50 or 100μg/kg HU210 for 4 or 14 days. Dopamine D1 receptor (D1R) or D2 receptor (D2R) density was measured in the medial and lateral (CPUL) caudate putamen, nucleus accumbens, olfactory tubercle (TU) and substantia nigra (D1R only) using in vitro autoradiography. D1R and D2R densities were 1.6-1.7- and 1.1-1.4-fold higher respectively in adolescent control rats compared to adults. In adult rats, D1R density was increased by 1.2- and 1.3-fold (p<0.05) in CPUL and TU respectively compared to controls, after 14 days of HU210 treatment. A significant overall effect of treatment (p<0.05) on D2R density was also observed in adults after the single dose and 4 and 14 days administration of HU210. In adolescents, an overall effect of treatment on D1R density after a single exposure to HU210 was seen (p=0.0026) but no changes in D1R or D2R densities were observed in other treatment groups. These results suggest that the adolescent rat brain does not display the same compensatory mechanisms activated in the adult brain following cannabinoid treatment., (Copyright © 2010 Elsevier B.V. All rights reserved.)

The short- and long-term behavioral effects of cannabinoids differ in adolescent and adult rodents. Few studies though have examined the underlying neurochemical changes that occur in the brain following adolescent cannabinoid exposure. In this study, we examined the effect of treatment with the synthetic cannabinoid, HU210, on CB1 receptor density in the brain and on body weight in adolescent male rats. Rats were treated daily with 25, 50, or 100 μg/kg HU210 for 4 or 14 days, or received a single dose of 100 μg/kg HU210 and sacrificed 24 h later. Receptor density was investigated using in vitro autoradiography with the CB1 receptor ligand [(3)H] CP55,940. In contrast to adult animals treated under the same paradigm in a previous study, adolescents continued on average, to gain weight over the course of the study. Weight gain was slowest in the 100 μg/kg group and improved dose dependently with controls gaining the most weight. Following the acute dose of HU210, a trend for a reduction in [(3)H] CP55,940 binding and a significant effect of treatment was observed. Statistically significant, dose-dependent, region-specific decreases in binding were observed in all brain regions examined following 4 and 14 days treatment. The pattern of CB1 receptor downregulation was similar to that observed in adults treated with cannabinoids in previous studies; however, its magnitude was smaller in adolescents. This reduced compensatory response may contribute to some acute behavioral effects, the pharmacological cross-tolerance and the long-lasting, adverse psychological consequences of cannabinoid exposure during adolescence.

Cannabinoids are known to induce transient psychotic symptoms and cognitive dysfunction in healthy individuals and contribute to trigger schizophrenia in vulnerable individuals, particularly during adolescence. Converging preclinical evidence suggests important interactions between cannabinoid and GABAergic systems. In the present study, we compared the effects of cannabinoid treatment on GABA(A) receptor binding in the brain of adolescent and adult rats. Adolescent (5 weeks old) and adult (10 weeks old) rats were treated with the synthetic cannabinoid HU210 (25, 50 or 100 microg/kg/day) or vehicle for 1, 4 or 14 days. Rats were sacrificed 24 h after the last injection and GABA(A) receptor density was measured in several brain regions using [(35)S]TBPS and in vitro autoradiography. Adolescent rats had higher numbers of GABA(A) receptors compared to adults. A 24% increase of binding in adult rats treated with 100 microg/kg HU210 for 14 days compared to controls was observed in the CA1 region of the hippocampus (16.1 versus 12.9 fmol/mg tissue equivalent, t=2.720, p<0.05). HU210 did not affect GABA(A) receptors in adolescent rats in any treatment regimen and in adult rats treated with HU210 for 1 or 4 days. These data suggest that long-term, high-dose treatment with HU210 increases GABA(A) receptors in the hippocampus of adult rats, changes that may interfere with associated hippocampal cognitive functions such as learning and memory. In addition, our results suggest that the adolescent brain does not display the same compensatory mechanisms that are activated in the adult brain following cannabinoid treatment., (2010 Elsevier B.V. All rights reserved.)

The endocannabinoid and serotonin systems share a high level of overlap in terms of the physiological processes that they regulate, however, little is known about their functional interactions particularly during adolescence, a vulnerable period for both the development of psychosis and for initiation to substance use. In the present study, the effects of cannabinoid treatment on serotonin 5HT1A receptor density and mRNA expression were investigated in two age groups: Adolescent (postnatal day 35) and adult (postnatal day 70) rats were injected with the synthetic cannabinoid HU210 (25, 50 or 100 microg/kg) or vehicle for 1, 4 or 14 days and sacrificed 24 h after the last injection. 5HT1A receptor density was measured in different brain regions using [(3)H]8-OH-DPAT quantitative autoradiography whereas mRNA expression was measured in adjacent brain sections. Higher levels of both serotonin 5HT1A receptor binding and mRNA expression were observed in limbic regions in adolescent control animals compared to adults. 5HT1A receptor density was increased by 23% in the CA1 region of the hippocampus of adult rats treated with 100 microg/kg HU210 for 4 days compared to vehicle treated controls. The same treatment increased mRNA expression by 27% and by 14% in the CA1 region and dentate gyrus of the hippocampus respectively. 5HT1A receptor density was increased by 22% in the CA1 of adult animals treated with 50 microg HU210, by 26% in the dentate gurus of adult rats treated with 100 microg for 14 days. By contrast, 5HT1A receptor density or mRNA expression was not affected in the brain of adolescent animals in any of the brain regions examined. These results suggest that cannabinoid treatment has differential effects on serotonin-related neurochemistry in adolescent compared to adult rats. The effects in the adult brain may compromise hippocampal function and could account for the cognitive deficits seen in habitual heavy cannabis users., (Copyright (c) 2010 IBRO. Published by Elsevier Ltd. All rights reserved.)

Capsaicin, the hot chemical in chillies, administered to neonatal rats, causes destruction of polymodal nociceptive primary afferent neurons by acting on TRPV1 receptors causing intrinsic somatosensory deprivation. Although the effects of neonatal capsaicin treatment in the periphery have been extensively investigated, less is known about the brain networks to which the capsaicin sensory neurons are relayed. In the present study the effect of neonatal capsaicin treatment on brain receptors that have been shown to interact with TRPV1 was examined. Wistar rats were treated on neonatal day 2 with capsaicin and at 15-16 weeks of age, brains were processed to measure levels of muscarinic M(1)/M(2) and M(2)/M(4), serotonin 5HT(2A), cannabinoid CB(1), dopamine D(1), D(2) receptors and dopamine transporter. Overall increases in levels of muscarinic M(1)/M(4) (F=8.219, df=1, p=0.005), muscarinic M(2)/M(4) (F=99.759, df=1, p<0.0001), serotonin 5HT(2A) (F=28.892, df=1, p<0.0001), dopamine D(1) (F=8.726, df=1, p=0.008) and cannabinoid CB(1) (F=25.084, df=1, p<0.0001) receptors were found in the brains of capsaicin-treated rats, although significant regional changes occurred only in muscarinic M(2)/M(4) and serotonin 5HT(2A) receptors. The results of the present study suggest that neonatal intrinsic somatosensory deprivation may have a significant impact on substrates at the central nervous system that manifest as changes in central cholinergic, monaminergic and cannabinoid systems in the adult animal.

Evidence from mammalian studies suggests that brain derived neurotrophic factor (BDNF) and its receptor, trk B, are upregulated in neuronal cell bodies after injury. Although fish possess neurotrophins and display rapid functional and morphological recovery after central nervous system (CNS) injury, to date few studies have examined neurotrophin expression during CNS regeneration. In this study, RT-PCR was used to investigate the effect of complete spinal cord transection on the mRNA expression of BDNF and its receptor, trk B, in the eel brain at a range of timepoints after injury. The spatial expression pattern of BDNF mRNA in the brain was also assessed before and after injury using in situ hybridization. Marked changes in BDNF and trk B mRNA levels in the eel brain were not detected during the recovery period after cord transection. In addition, the spatial expression pattern of BDNF mRNA in the eel brain appeared unchanged after injury. Our results are in contrast with the increase reported in mammals but are in line with studies examining neurotrophin expression during CNS regeneration in other anamniotic vertebrates.

In vitro autoradiography was used to examine changes in cannabinoid CB1 receptors (targeted with [(3)H] CP55,940) in rats treated with the potent cannabinoid agonist HU210. Animals were administered with HU210 (25, 50, 100 microg/kg) for 4 or 14 days or received a single 100 microg/kg injection of HU210 and sacrificed 24 h later. The acute dose resulted in a decrease in binding in the caudate putamen and hippocampus. A dose dependent, region-specific reduction (P < 0.0001) in [(3)H] CP55,940 binding was seen in all brain regions examined after 4 and 14 days treatment. A decrease in body weight was recorded during the first 4 days of treatment but after this animals began to gain weight. Correlations (0.865 < r < 0.659, P < 0.0001) between body weight on day four and CB1 receptor binding were found in all brain regions examined suggesting that downregulation of CB1 receptors may contribute to the induction of tolerance to body weight loss induced by HU210.

The spatial expression pattern of Brain-Derived Neurotrophic Factor (BDNF) mRNA in the brain of the European eel (Anguilla anguilla) was determined using non-radioactive in situ hybridization, and mapped and compared to that of other vertebrates. Riboprobes were prepared based on a partial cDNA coding sequence for A. anguilla BDNF that was amplified using degenerate primers, cloned and sequenced. As in other animal groups, in the eel, BDNF mRNA expression was seen in the telencephalon, hypothalamus, tectum, many primary and secondary sensory centers, and cranial motor nuclei. However, in contrast to mammals, BDNF mRNA expression was observed in some brain stem nuclei, such as the reticular formation, that contain cell bodies of neurons that project down the spinal cord. We suggest that these differences might relate to the continual growth of teleost fish., (Copyright 2009 S. Karger AG, Basel.)