Rat Frontal Cortex Research Articles

Effects of cadmium on Bcl-2/ Bax expression ratio in rat cortex brain and hippocampus.

To investigate the underlying mechanism of neurotoxicity of cadmium, we examined the effects of intraperitoneal injection of cadmium on messenger RNA (mRNA) expression of Bcl-2 (B-cell lymphoma 2) and Bax (Bcl2-associated x) genes and caspase-3/7 activation in rat hippocampus and frontal cortex. Twenty-eight male Wistar rats weighing 200-250 g were randomly divided into four groups. Control group received saline and three other groups received cadmium at doses of 1, 2 and 4 mg/kg (body weight) for 15 successive days. One day after the last injection, the hippocampus and frontal cortex were dissected and removed and then the expression of Bcl-2 and Bax genes was evaluated using real-time polymerase chain reaction and apoptotic studies was done using caspase-3/7 activation assay. Cadmium reduced the mRNA level of Bcl-2 in the control group at doses of 1 ( p < 0.01), 2 and 4 mg/kg ( p < 0.001) in rat hippocampus and cortex cells. The mRNA level of Bax increased significantly compared to the control group at the doses of 1 ( p < 0.05), 2 and 4 mg/kg ( p < 0.001) in rat hippocampus. The mRNA level of Bax was increased significantly compared to the control group at the doses of 2 and 4 mg/kg ( p < 0.001) in rat cortex cells. Cadmium increased caspase-3/7 activity at doses of 1, 2 and 4 mg/kg in rat hippocampus. Caspase-3/7 activity was increased significantly at dose of 4 mg/kg in rat cortex. This decreased Bcl-2/Bax mRNA ratio induces cell apoptosis. Apoptotic effect of cadmium may be through the mitochondrial pathway by the activation of caspase-3/7.

Overpressure blast injury-induced oxidative stress and neuroinflammation response in rat frontal cortex and cerebellum

Background & aimOverpressure blast-wave induced brain injury (OBI) and its long-term neurological outcome pose significant concerns for military personnel. Our aim is to investigate the mechanism of injury due to OBI. MethodsRats were divided into 3 groups: (1) Control, (2) OBI (exposed 30psi peak pressure, 2–2.5ms), (3) Repeated OBI (r-OBI) (three exposures over one-week period). Lung and brain (cortex and cerebellum) tissues were collected at 24h post injury. ResultsThe neurological examination score was worse in OBI and r-OBI (4.2±0.6 and 3.7±0.5, respectively) versus controls (0.7±0.2). A significant positive correlation between lung and brain edema was found. Malondialdehyde (index for lipid peroxidation), significantly increased in OBI and r-OBI groups in cortex (p<0.05) and cerebellum (p<0.01–0.001). The glutathione (endogenous antioxidant) level decreased in cortex (p<0.01) and cerebellum (p<0.05) of r-OBI group when compared with the controls. Myeloperoxidase activity indicating neutrophil infiltration, was significantly (p<0.01–0.05) elevated in r-OBI. Additionally, tissue thromboplastin activity, a coagulation marker, was elevated, indicating a tendency to bleed. NGF and NF-κB proteins along with Iba-1 and GFAP immunoreactivity significantly augmented in the frontal cortex demonstrating microglial activation. Serum biomarkers of injury, NSE, TNF-alpha and leptin, were also elevated. ConclusionOBI triggers both inflammation and oxidative injury in the brain. This data in conjunction with our previous observations suggests that OBI triggers a cascade of events beginning with impaired cerebral vascular function leading to ischemia and chronic neurological consequences.

The involvement of BDNF-CREB signaling pathways in the pharmacological mechanism of combined SSRI- antipsychotic treatment in schizophrenia

Previous studies into the mechanism of SSRI-antipsychotic synergism in our laboratory identified unique changes in the brain, particularly in the γ-aminobutyric acid (GABA)-A receptor and its modulators. This study examined the role of brain derived neurotrophic factor (BDNF)-cAMP response element binding (CREB) protein signaling pathways, including protein kinase B (AKT), glycogen synthase kinase (GSK)-3β and related molecules in the molecular response to haloperidol, fluvoxamine, combined haloperidol+fluvoxamine and clozapine treatments in rat frontal cortex, hippocampus and primary cortical neuronal cultures. The effect of fluvoxamine augmentation on BDNF-CREB pathways in peripheral mononuclear cells (PMC׳s) of medicated schizophrenia patients was also studied. Chronic haloperidol (1mg/kg) +fluvoxamine (10mg/kg) treatment increased TrkB receptor and BDNF expression levels, and the phosphorylation of AKT/CREB/GSK-3β, compared to the individual drugs in rat brain. In addition, haloperidol+fluvoxamine treatment improved cognitive functions in rats, indicating that the molecular changes may have a role in behavioral improvement. In primary neuronal cell cultures, pretreatment with a selective PI3K inhibitor abolished the haloperidol+fluvoxamine-induced phosphorylation of AKT and GSK-3β, but did not affect the upregulation of CREB phosphorylation. In the clinic, PMC׳s of treated patients showed upregulation of mRNA expression and protein levels of BDNF, CREB and AKT after addition of fluvoxamine. Analyses of PMC genes and proteins showed significant inter-correlations and some gene changes correlated with improvement in negative and cognitive symptoms. Our study provides new knowledge of the molecular mechanisms of symptom amelioration in schizophrenia and may advance development of new drugs for this disease and other neuropsychiatric disorders.

Methamphetamine‐Induced Changes to Serotonergic Markers in the Frontal Cortex

Methamphetamine use is associated with a variety of negative health outcomes including psychosis. Alternations in the frontal cortex including changes in serotonin (5HT) 2A receptors are thought to contribute to psychosis‐like behaviors. Previously we have reported that methamphetamine self‐administration changes serotonin in the frontal cortex of rats. The purpose of this study was to investigate changes in serotonergic markers in the frontal cortex following methamphetamine self‐administration and how these changes relate to hallucination‐like behavior. Male and female rats were allowed to self‐administer either methamphetamine or saline and were sacrificed either one hour after the last self‐administration session or following extinction training. Serotonin transporters (SERT) and 5HT2A receptors were assessed in the frontal cortex via autoradiography. No changes in SERT autoradiography was observed in the orbitofrontal, prelimbic, or infralimbic cortices one hour after self‐administration or after extinction training. However, preliminary findings suggest time dependent changes in 5HT2A receptors in the frontal cortex. One hour after the last self‐administration session 5HT2A receptors were increased in the orbitofrontal cortex. Further, there was a trend towards an increase in prelimbic 5HT2A receptors in rats that self‐administered methamphetamine. However, no changes were found in male rats following extinction training. To assess the functioning of the 5HT2A receptors, the 5HT2A/2C agonist, DOI, was administered in a separate group of animals following extinction training. Preliminary results suggest that rats with a history of METH self‐administration have reduced hyperthermia following the administration of DOI. Efforts are underway to quantify DOI‐induced head twitches which are thought to reflect 5HT2A receptor function in the brain and hallucination‐like behavior. Overall, results of the current study suggest that methamphetamine self‐administration causes time dependent changes in 5HT2A receptors but not SERT in the frontal cortex. Ongoing studies will examine how methamphetamine‐induced changes in the frontal cortex may result in changes in behaviors associated with psychosis such as hallucinations.Support or Funding InformationFunding for this study was provided the NIH grant DA036012.

The mRNA expression of insulin-like growth factor-1 (Igf1) is decreased in the rat frontal cortex following gamma-hydroxybutyrate (GHB) administration

In recent years, growth hormone (GH), together with its secondary mediators insulin-like growth factor-1 (IGF-1) and insulin-like growth factor-2 (IGF-2), have been highlighted for their beneficial effects in the central nervous system (CNS), in particular as cognitive enhancers. Cognitive processes, such as learning and memory, are known to be impaired in individuals suffering from substance abuse. In the present study, we investigated the effect of gamma-hydroxybuturate (GHB), an illicit drug used for its sedating and euphoric properties, on genes associated with the somatotrophic axis in regions of the brain important for cognitive function. Sprague Dawley rats (n=36) were divided into three groups and administered either saline, GHB 50mg/kg or GHB 300mg/kg orally for seven days. The levels of Ghr, Igf1 and Igf2 gene transcripts were analyzed using qPCR in brain regions involved in cognition and dependence. The levels of IGF-1 in blood plasma were also determined using ELISA. The results demonstrated a significant down-regulation of Igf1 mRNA expression in the frontal cortex in high-dose treated rats. Moreover, a significant correlation between Igf1 and Ghr mRNA expression was found in the hippocampus, the frontal cortex, and the caudate putamen, indicating local regulation of the GH/IGF-1 axis. To summarize, the current study concludes that chronic GHB treatment influences gene expression of Ghr and Igf1 in brain regions involved in cognitive function.

Perinatal nicotine treatment induces transient increases in NACHO protein levels in the rat frontal cortex

The nicotinic acetylcholine receptor (nAChR) regulator chaperone (NACHO) was recently identified as an important regulator of nAChR maturation and surface expression. Here we show that NACHO levels decrease during early postnatal development in rats. This decrease occurs earlier and to a greater degree in the frontal cortex (FC) compared with the hippocampus (HIP). We further show that rats exposed to nicotine during pre- and postnatal development exhibit significantly higher NACHO levels in the FC at postnatal day (PND) 21, but not at PND60. Repeated exposure to nicotine selectively during early (PND8–14) or late (PND54–60) postnatal stages did not affect NACHO protein levels in the FC or HIP, neither did exposure to high doses of the selective α7 nAChR agonists SSR180711, A-582941, or PNU-282987. However, we found significantly increased NACHO protein levels in the FC of PND36 rats after a single exposure to a combination of nicotine and the type II α7 nAChR positive allosteric modulator (PAM) PNU-120596, but not the type I PAM AVL-3288. These findings suggest that exposure to nAChR agonism affects NACHO protein levels, and that this effect is more pronounced during pre- or early postnatal development. The effect of PNU-120596 further suggests that the increase in NACHO expression is caused by activation rather than desensitization of nAChRs.

Effects of filgrastim on gene expression of cholinergic system in the rat hippocampus

Background: Filgrastim is a granulocyte colony-stimulating factor (G-CSF), which also showed effects on memory and cognation. Although recent studies have begun to explore G-CSF-related mechanisms of action in memory, little is known about its effects on cholinergic system. Since the cholinergic system has a key role in memory and some studies reported effects of G-CSF on cholinergic activity. Choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) gene expression was examined in the rat frontal cortex and hippocampus. Aims and Objectives: This study was designed to investigate the effect of G-CSF treatment on gene expression of AChE and ChAT in the frontal cortex and hippocampus during learning. Materials and Methods: In this study, male Wistar rats were treated for 2 week with filgrastim intraperitoneally at doses of 10, 50, 70 μg/kg/day. All rats received Morris water maze training (4 trials/day for 5 days). Moreover, ChAT and AChE gene expression was assessed by real-time polymerase chain reaction in the rat frontal cortex and hippocampus. Results: Over 5 days of training, filgrastim at doses 10, 50 and 70 μg/kg/day did not change the gene expression of ChAT and AChE in frontal cortex and hippocampus although at dose of 50 ug/kg a little changes but not significant observed. Conclusions: The findings observed in this study propose that G-CSF memory enhancer effects doesn’t only cholinergic and other mechanism may be involve.

Antidepressant Mechanism Research of Acupuncture: Insights from a Genome-Wide Transcriptome Analysis of Frontal Cortex in Rats with Chronic Restraint Stress.

Major depressive disorder (MDD) is a chronic disease that adversely affects mood and cognition. In this study, we randomly divided the rats into control group (C), model group (M), fluoxetine group (F), and acupuncture group (A), used open-field test to ascertain whether acupuncture affects chronic restraint stress (CRS) induced depression-like behaviors of rats, and explored the antidepressant mechanism of acupuncture at the molecular level of transcriptome in the frontal cortex of CRS rats by RNA-sequencing (RNA-seq). According to differentially expressed genes (DEG) analysis, we identified 134, 46, and 89 response genes differentially expressed in C versus M, F versus M, and A versus M, respectively. Through Gene Ontology (GO) term enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, we identified the gene sets involved in extracellular space, inflammatory response, Toll-like receptor signaling pathway, chemokine signaling pathway, and TNF signaling pathway. In this study, RNA-seq technology was used to investigate the frontal cortex genome-wide transcriptomes in depression rats under CRS, which suggested that the antidepressant effect of acupuncture is effective and has a multitarget characteristic, which may be related to amino acid metabolism and inflammatory pathways, especially the Toll-like receptor signaling pathway, TNF signaling pathway, and NF-kappa B signaling pathway.

Propofol, Sevoflurane, and Ketamine Induce a Reversible Increase in Delta-Gamma and Theta-Gamma Phase-Amplitude Coupling in Frontal Cortex of Rat.

Studies from human and non-human species have demonstrated a breakdown of functional corticocortical connectivity during general anesthesia induced by anesthetics with diverse molecular, neurophysiological, and pharmacological profiles. Recent studies have demonstrated that changes in long-range neural communication, and by corollary, functional connectivity, might be influenced by cross-frequency coupling (CFC) between the phase of slow oscillations and the amplitude of local fast oscillations. Phase-amplitude coupling (PAC) between slow oscillations and alpha rhythm during general anesthesia reveal distinct patterns depending on the anesthetic. In this study, we analyzed the effect of three clinically used anesthetics (propofol: n = 6, sevoflurane: n = 10, and ketamine: n = 8) with distinct molecular mechanisms on changes in PAC in the frontal cortex of rat. The loss of righting reflex was used as a surrogate for unconsciousness. PAC was calculated using the modulation index (MI) algorithm between delta (1–4 Hz), theta (4–10 Hz), low gamma (25–55 Hz), and high gamma (65–125 Hz) bands. A linear mixed model with fixed effects was used for statistical comparisons between waking, anesthetized, and post-anesthesia recovery epochs. All three anesthetics increased the coupling between delta and low gamma (p < 0.0001) as well as between theta and low gamma (p < 0.0001) oscillations, which returned to baseline waking levels during the post-anesthetic recovery period. In addition, a reversible reduction in high gamma power (p < 0.0001) was a consistent change during anesthesia induced by all three agents. The changes in delta-high gamma and theta-high gamma PAC as well as power spectral changes in delta, theta, and low gamma bandwidths did not show a uniform response across the three anesthetics. These results encourage the study of alternative PAC patterns as drug-invariant markers of general anesthesia in humans.

Voluntary Physical Exercise Induces Expression and Epigenetic Remodeling of VegfA in the Rat Hippocampus.

A healthy lifestyle, including regular physical exercise, is generally believed to improve cognitive function and enhance neurogenesis. Such physical exercise-induced effects are associated with increased brain expression of neurotrophic and growth factors. In the present study, we investigated Bdnf, Igf-1, Fgf-2, Egf, and VegfA messenger RNA (mRNA) expression levels in the male rat hippocampus and frontal cortex after 2weeks of voluntary physical exercise. Whereas the expression of Fgf-2 was upregulated in the hippocampus and prefrontal cortex by physical exercise, the expression levels of Bdnf transcript 1, Bdnf transcript 4, Igf-1, and VegfA were upregulated only in the hippocampus. We focused our subsequent analyses on the VegfA gene, which encodes vascular endothelial growth factor, a signaling molecule important for angiogenesis, vasculogenesis, and neurogenesis. To study the epigenetic mechanisms involved in the physical exercise-mediated induction of VegfA expression, we used oxidative and non-oxidative bisulfite pyrosequencing to analyze VegfA promoter DNA methylation and DNA hydroxymethylation. We observed discrete DNA hypomethylation at specific CpG sites in rats that engaged in physical exercise relative to sedentary rats. This is exemplified by a CpG site located within a VegfA promoter Sp1/Sp3 transcription factor recognition element. DNA hydroxymethylation was present at the VegfA promoter, but no differences in DNA hydroxymethylation were observed in rats that engaged in physical exercise relative to sedentary rats. Moreover, we observed increased Tet1 and decreased Dnmt3b mRNA expression in the hippocampi of rats that engaged in physical exercise. The presented results substantiate the involvement of epigenetics as a mediator of the beneficial effects of physical exercise and point to the importance of analyzing factors beyond Bdnf to delineate the mechanisms behind the functional impacts of physical exercise in mediating benefits to the brain.

Discovery of 4-chloro-2-(2,4-dichloro-6-methylphenoxy)-1-methyl-7-(pentan-3-yl)-1H-benzimidazole, a novel CRF1 receptor antagonist

Compound 1 exhibits potent binding inhibition activity against a corticotropin-releasing factor 1 (CRF1) receptor (IC50=9.5nM) and in vitro antagonistic activity (IC50=88nM) but is rapidly metabolized by human hepatic microsomes (182μL/min/mg). Here we identified metabolically stable compounds with potent CRF binding inhibitory activity. Structure–activity relationship (SAR) studies considering in vitro metabolic stability revealed that 4-chloro-2-(2,4-dichloro-6-methylphenoxy)-1-methyl-7-(pentan-3-yl)-1H-benzimidazole 24d was more stable in human microsomes (87μL/min/mg) than compound 1. Compound 24d demonstrated potent CRF binding inhibitory activity (IC50=4.1nM), in vitro antagonistic activity (IC50=44nM), and slow dissociation from the CRF1 receptor. Orally administered compound 24d (6–24μmol/kg) showed ex vivo CRF1 receptor binding in the rat pituitary, olfactory bulb, and frontal cortex and suppressed stress-induced adrenocorticotropic hormone (ACTH) secretion. In this report, we discuss SAR studies on the metabolic stability as well as CRF binding inhibitory activity of the benzimidazole series as CRF1 receptor antagonists and the pharmacological profiles of compound 24d.

MicroRNA may regulate the content of the brain-derived neurotrophic factor in the frontal cortex of rats after spontaneous morphine withdrawal

Brain-derived neurotrophic factor (BDNF) is involved in the formation of dependence on opiates. BDNF mRNA expression is altered during opiate dependence; however, the biological basis of this phenomenon has been insufficiently studied. At the posttranscriptional level, microRNAs may potentially regulate BDNF expression. Short non-coding microRNAs bind in a complementary manner, mostly to the 3'-noncoding area (3'-UTR) of mRNA and thus initiate degradation of a target by the RNA-induced silencing complex (RISC). In the present study, the potential contribution of microRNAs to the regulation of the BDNF mRNA expression was evaluated in the brain of rats with morphine dependence after spontaneous withdrawal. In order to form dependence in rats, morphine was injected twice a day in increasing doses of 10᾿00 mg/kg for 6 days. Expression of BDNF mRNA and microRNA, which may potentially regulate BDNF, was studied in brain regions 40 h after spontaneous morphine withdrawal using the real-time PCR method. Interaction of the Argonaute 2 protein (Ago-2), a component of RISC, with 3'-UTR BDNF mRNA was evaluated using RNA immunoprecipitation. We found that morphine withdrawal was followed by an increase in the BDNF exon I-containing mRNA in the frontal cortex and midbrain. In the frontal cortex, the increased BDNF mRNA level observed in abstinence was associated with a decrease in the miR-206 microRNA and Ago-2 bound to 3'-UTR BDNF mRNA contents. In the midbrain the abstinence condition was accompanied by a decrease in the miR-382 level, whereas Ago-2 binding to 3'-UTR BDNF mRNA remained unchanged. We believe that the weakening of miR-206-mediated degradation of BDNF mRNA may be responsible for the elevated BDNF expression in the frontal cortex in the conditions of morphine dependence.

P.4.a.013 - Chronic mild stress-induced alterations in ΔFosB protein and histone H3 acetylation in the frontal cortex of rats

P.4.a.013 - Chronic mild stress-induced alterations in ΔFosB protein and histone H3 acetylation in the frontal cortex of rats

P.1.g.014 - The effects of electroconvulsive seizure on the transcription of PAR family of bZIP genes via changes in Egr1 expression in the rat frontal cortex

P.1.g.014 - The effects of electroconvulsive seizure on the transcription of PAR family of bZIP genes via changes in Egr1 expression in the rat frontal cortex

Cplx2 gene expression following semax or PGP administration under conditions of two experimental models of rat-brain ischemia

Complexin 2 is a cytosolic protein participating in synaptic-vesicle exocytosis. The RT-PCR technique was used in a real-time study of the dynamics of variation of expression of the Cplx2 gene that encodes this protein. The study was performed in the rat brain. Measurements under the conditions of incomplete global ischemia were performed during 1 day; measurements under the conditions of focal ischemia were carried out 3, 24, and 72 h after irreversible occlusion of the medial cerebral artery. The most significant decrease in Cplx2 transcripts under the conditions of incomplete global ischemia was observed in the hippocampus and the frontal cortex of rats 12 and 24 h after irreversible occlusion of the common carotid arteries, respectively. Under conditions of focal ischemia, a decrease in the content of Cplx2 transcripts was observed only in focal lesions of the frontoparietal cortex 24 h after occlusion. The effect of Semax neuroprotector peptide and its C-terminal fragment Pro-Gly-Pro on Cplx2 expression was examined under the model ischemia conditions. In the case of incomplete global ischemia, application of Semax compensated for the maximum decrease in Cplx2 expression in the frontal cortex and hippocampus in rats caused by lesions. However, the peptide had no effect when used in rats with focal ischemia. The effect of PGP on Cplx2 expression under conditions of experimental ischemia was more complicated and did not always coincide with the effect of Semax. The obtained results provide insight into the specific features of Cplx2 expression under the conditions of experimental brain ischemia and help to better understand the mechanisms of activity of peptide preparations.

Risperidone and escitalopram co-administration: A potential treatment of schizophrenia symptoms with less side effects.

Schizophrenia is a psychiatric disorder characterized by positive and negative symptoms often accompanied by depression and cognitive deficits. Positive symptoms, like delusions and hallucinations are caused by an excess of dopamine (DA) signaling and are treated with the second generation antipsychotic drugs. Negative symptoms of schizophrenia are represented by social withdrawal, apathy and blunted emotional response. It was demonstrated that co-administration of risperidone and selective serotonin reuptake inhibitors alleviated depressive symptoms and cognitive dysfunction in animal models of schizophrenia. Moreover, combination of fluoxetine or mirtazapine with risperidone increased DA and 5-hydroxytryptamine (5-HT) release in the rat frontal cortex more potently than either drug given separately. The present study aimed to investigate whether combination of risperidone and escitalopram is effective in increasing DA and 5-HT release. The extracellular level of neurotransmitters in the rat frontal cortex and nucleus accumbens was examined using microdialysis in freely moving animals. The dialysate concentration of DA and 5-HT was assayed by HPLC. It was found that risperidone (0.2 and 1mg/kg) and escitalopram (5 and 10mg/kg) given together significantly increased cortical DA and 5-HT levels and were more efficient in enhancing neurotransmitter concentrations than any single-drug treatment. A similar effect on DA and 5-HT release was observed in the nucleus accumbens after administration of risperidone (1mg/kg) and escitalopram (5mg/kg). The present study demonstrates that co-administration of risperidone and escitalopram may be used to treat positive and negative symptoms of schizophrenia and will allow to minimize the drugs' side effects.

Morphine dependence is attenuated by red ginseng extract and ginsenosides Rh2, Rg3, and compound K

BackgroundRed ginseng and ginsenosides have shown plethoric effects against various ailments. However, little is known regarding the effect of red ginseng on morphine-induced dependence and tolerance. We therefore investigated the effect of red ginseng extract (RGE) and biotransformed ginsenosides Rh2, Rg3, and compound K on morphine-induced dependence in mice and rats. MethodsWhile mice were pretreated with RGE and then morphine was injected intraperitoneally, rats were infused with ginsenosides and morphine intracranially for 7 days. Naloxone-induced morphine withdrawal syndrome was estimated and conditioned place preference test was performed for physical and psychological dependence, respectively. Western blotting was used to measure protein expressions. ResultsWhereas RGE inhibited the number of naloxone-precipitated jumps and reduced conditioned place preference score, it restored the level of glutathione in mice. Likewise, ginsenosides Rh2, Rg3, and compound K attenuated morphine-dependent behavioral patterns such as teeth chattering, grooming, wet-dog shake, and escape behavior in rats. Moreover, activated N-methyl-D-aspartate acid receptor subunit 1 and extracellular signal-regulated kinase in the frontal cortex of rats, and cultured cortical neurons from mice were downregulated by ginsenosides Rh2, Rg3, and compound K despite their differential effects. ConclusionRGE and biotransformed ginsenosides could be considered as potential therapeutic agents against morphine-induced dependence.

Neurotoxic Effects of 5-MeO-DIPT: A Psychoactive Tryptamine Derivative in Rats.

5-Methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT, ‘foxy’) is one of the most popular tryptamine hallucinogens in the illicit drug market. It produces serious adverse effects, but its pharmacological profile is not well recognized. In vitro data have shown that 5-MeO-DIPT acts as a potent serotonin transporter (SERT) inhibitor and displays high affinity at serotonin 5-HT1A, 5-HT2A, and 5-HT2C receptors. In this study, using microdialysis in freely moving rats, we examined the effect of 5-MeO-DIPT on dopamine (DA), serotonin (5-HT), and glutamate release in the rat striatum, nucleus accumbens, and frontal cortex. In search of a possible neurotoxic effect of 5-MeO-DIPT, we measured DA and 5-HT tissue content in the above rat brain regions and also determined the oxidative DNA damage with the comet assay. Moreover, we tested drug-elicited head-twitch response and a forepaw treading induced by 8-OH-DPAT. 5-MeO-DIPT at doses of 5, 10, and 20 mg/kg increased extracellular DA, 5-HT, and glutamate level but the differences in the potency were found between brain regions. 5-MeO-DIPT increased 5-HT and decreased 5-HIAA tissue content which seems to result from SERT inhibition. On the other hand, a decrease in DA, DOPAC, and HVA tissue contents suggests possible adaptive changes in DA turnover or damage of DA terminals by 5-MeO-DIPT. DNA single and double-strand breaks persisted up to 60 days after the treatment, indicating marked neurotoxicity of 5-MeO-DIPT. The induction of head-twitch response and potentiation of forepaw treading induced by 8-OH-DPAT indicate that hallucinogenic activity seems to be mediated through the stimulation of 5-HT2A and 5-HT1A receptors by 5-MeO-DIPT.

PM483. Gene expression changes in the rat frontal cortex caused by sex steroid hormones

PM483. Gene expression changes in the rat frontal cortex caused by sex steroid hormones

A single dose of vortioxetine, but not ketamine or fluoxetine, increases plasticity-related gene expression in the rat frontal cortex

Ketamine is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist that has been shown to induce a rapid antidepressant effect in treatment-resistant patients. Vortioxetine is a multimodal-acting antidepressant that exert its therapeutic activity through serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibition and modulation of several 5-HT receptors. In clinical trials, vortioxetine improves depression symptoms and cognitive dysfunction. Neuroplasticity as well as serotonergic and glutamatergic signaling attain significant roles in depression pathophysiology and antidepressant responses.Here, we investigate the effects of ketamine and vortioxetine on gene expression related to serotonergic and glutamatergic neurotransmission as well as neuroplasticity and compare them to those of the selective serotonin reuptake inhibitor fluoxetine. Rats were injected with fluoxetine (10mg/kg), ketamine (15mg/kg), or vortioxetine (10mg/kg) at 2, 8, 12, or 27h prior to harvesting of the frontal cortex and hippocampus. mRNA levels were measured by real-time quantitative polymerase chain reaction (qPCR).The main finding was that vortioxetine enhanced plasticity-related gene expression (Mtor, Mglur1, Pkcα, Homer3, Spinophilin, and Synapsin3) in the frontal cortex at 8h after a single dose. Ingenuity pathway analysis of this subset of data identified a biological network that was engaged by vortioxetine and is plausibly associated with neuroplasticity. Transcript levels had returned to baseline levels 12h after injection. Only minor effects on gene expression were found for ketamine or fluoxetine.In conclusion, acute vortioxetine, but not fluoxetine or ketamine, transiently increased plasticity-related gene expression in the frontal cortex. These effects may be ascribed to the direct 5-HT receptor activities of vortioxetine.