TC-G 1008 facilitates epileptogenesis by acting selectively at the GPR39 receptor but non-selectively activates CREB in the hippocampus of pentylenetetrazole-kindled mice.

The pharmacological activation of the GPR39 receptor has been proposed as a novel strategy for treating seizures; however, this hypothesis has not been verified experimentally. TC-G 1008 is a small molecule agonist increasingly used to study GPR39 receptor function but has not been validated using gene knockout. Our aim was to assess whether TC-G 1008 produces anti-seizure/anti-epileptogenic effects in vivo and whether the effects are mediated by GPR39. To obtain this goal we utilized various animal models of seizures/epileptogenesis and GPR39 knockout mice model. Generally, TC-G 1008 exacerbated behavioral seizures. Furthermore, it increased the mean duration of local field potential recordings in response to pentylenetetrazole (PTZ) in zebrafish larvae. It facilitated the development of epileptogenesis in the PTZ-induced kindling model of epilepsy in mice. We demonstrated that TC-G 1008 aggravated PTZ-epileptogenesis by selectively acting at GPR39. However, a concomitant analysis of the downstream effects on the cyclic-AMP-response element binding protein in the hippocampus of GPR39 knockout mice suggested that the molecule also acts via other targets. Our data argue against GPR39 activation being a viable therapeutic strategy for treating epilepsy and suggest investigating whether TC-G 1008 is a selective agonist of the GPR39 receptor.

Acute stress modulates noradrenergic signaling in the ventral tegmental area-amygdalar circuit.

Noradrenergic neurotransmission is a critical mediator of stress responses. In turn, exposure to stress induces noradrenergic system adaptations, some of which are implicated in the etiology of stress-related disorders. Adrenergic receptors (ARs) in the ventral tegmental area (VTA) have been demonstrated to regulate phasic dopamine (DA) release in the forebrain, necessary for behavioral responses to conditional cues. However, the impact of stress on noradrenergic modulation of the VTA has not been previously explored. We demonstrate that ARs in the VTA regulate dopaminergic activity in the VTA-BLA (basolateral amygdala) circuit, a key system for processing stress-related stimuli; and that such control is altered by acute stress. We utilized fast-scan cyclic voltammetry to assess the effects of intra-VTA microinfusion of α1 -AR and α2 -AR antagonists (terazosin and RX-821002, respectively), on electrically evoked phasic DA release in the BLA in stress-naïve and stressed (unavoidable electric shocks - UES) anesthetized male Sprague-Dawley rats. In addition, we used western blotting to explore UES-induced alterations in AR protein level in the VTA. Intra-VTA terazosin or RX-821002 dose-dependently attenuated DA release in the BLA. Interestingly, UES decreased the effects of intra-VTA α2 -AR blockade on DA release (24 h but not 7 days after stress), while the effects of terazosin were unchanged. Despite changes in α2 -AR physiological function in the VTA, UES did not alter α2 -AR protein levels in either intracellular or membrane fractions. These findings demonstrate that NA-ergic modulation of the VTA-BLA circuit undergoes significant alterations in response to acute stress, with α2 -AR signaling indicated as a key target.

Limbic System Response to Psilocybin and Ketamine Administration in Rats: A Neurochemical and Behavioral Study.

The pathophysiology of depression is related to the reduced volume of the hippocampus and amygdala and hypertrophy of the nucleus accumbens. The mechanism of these changes is not well understood; however, clinical studies have shown that the administration of the fast-acting antidepressant ketamine reversed the decrease in hippocampus and amygdala volume in depressed patients, and the magnitude of this effect correlated with the reduction in depressive symptoms. In the present study, we attempted to find out whether the psychedelic substance psilocybin affects neurotransmission in the limbic system in comparison to ketamine. Psilocybin and ketamine increased the release of dopamine (DA) and serotonin (5-HT) in the nucleus accumbens of naive rats as demonstrated using microdialysis. Both drugs influenced glutamate and GABA release in the nucleus accumbens, hippocampus and amygdala and increased ACh levels in the hippocampus. The changes in D2, 5-HT1A and 5-HT2A receptor density in the nucleus accumbens and hippocampus were observed as a long-lasting effect. A marked anxiolytic effect of psilocybin in the acute phase and 24 h post-treatment was shown in the open field test. These data provide the neurobiological background for psilocybin's effect on stress, anxiety and structural changes in the limbic system and translate into the antidepressant effect of psilocybin in depressed patients.

Effect of Psilocybin and Ketamine on Brain Neurotransmitters, Glutamate Receptors, DNA and Rat Behavior.

Clinical studies provide evidence that ketamine and psilocybin could be used as fast-acting antidepressants, though their mechanisms and toxicity are still not fully understood. To address this issue, we have examined the effect of a single administration of ketamine and psilocybin on the extracellular levels of neurotransmitters in the rat frontal cortex and reticular nucleus of the thalamus using microdialysis. The genotoxic effect and density of glutamate receptor proteins was measured with comet assay and Western blot, respectively. An open field test, light-dark box test and forced swim test were conducted to examine rat behavior 24 h after drug administration. Ketamine (10 mg/kg) and psilocybin (2 and 10 mg/kg) increased dopamine, serotonin, glutamate and GABA extracellular levels in the frontal cortex, while psilocybin also increased GABA in the reticular nucleus of the thalamus. Oxidative DNA damage due to psilocybin was observed in the frontal cortex and from both drugs in the hippocampus. NR2A subunit levels were increased after psilocybin (10 mg/kg). Behavioral tests showed no antidepressant or anxiolytic effects, and only ketamine suppressed rat locomotor activity. The observed changes in neurotransmission might lead to genotoxicity and increased NR2A levels, while not markedly affecting animal behavior.

Inhibition of BET Proteins during Adolescence Affects Prefrontal Cortical Development: Relevance to Schizophrenia.

BACKGROUND: The present study investigated the role of proteins from the bromodomain and extra-terminal (BET) family in schizophrenia-like abnormalities in a neurodevelopmental model of schizophrenia induced by prenatal methylazoxymethanol (MAM) administration (MAM-E17). METHODS: An inhibitor of BET proteins, JQ1, was administered during adolescence on postnatal days (P) 23-P29, and behavioural responses (sensorimotor gating, recognition memory) and prefrontal cortical (mPFC) function (long-term potentiation (LTP), molecular and proteomic analyses) studies were performed in adult males and females. RESULTS: Deficits in sensorimotor gating and recognition memory were observed only in MAM-treated males. However, adolescent JQ1 treatment affected animals of both sexes in the control but not MAM-treated groups and reduced behavioural responses in both sexes. An electrophysiological study showed LTP impairments only in male MAM-treated animals, and JQ1 did not affect LTP in the mPFC. In contrast, MAM did not affect activity-dependent gene expression, but JQ1 altered gene expression in both sexes. A proteomic study revealed alterations in MAM-treated groups mainly in males, while JQ1 affected both sexes. CONCLUSIONS: MAM-induced schizophrenia-like abnormalities were observed only in males, while adolescent JQ1 treatment affected memory recognition and altered the molecular and proteomic landscape in the mPFC of both sexes. Thus, transient adolescent inhibition of the BET family might prompt permanent alterations in the mPFC.

Chronic Lorcaserin Treatment Reverses the Nicotine Withdrawal-Induced Disruptions to Behavior and Maturation in Developing Neurons in the Hippocampus of Rats.

Preclinical data have shown that treatment with serotonin (5-HT)2C receptor agonists inhibits the behavioral effects of nicotine, including self-administration, reinstatement, and locomotor responses to nicotine. Since the data on the effects of 5-HT2C receptor agonism on nicotine withdrawal signs are limited, we aimed to investigate whether 5-HT2C receptor agonism alleviated the behavioral and neurobiochemical (hippocampal neurogenesis) consequences of nicotine withdrawal in Sprague-Dawley rats. Our data indicate that withdrawal from nicotine self-administration induced locomotor hyperactivity, lengthened immobility time (the forced swim test), induced 'drug-seeking' behavior and deficits in cognition-like behavior (the novel object recognition task). A two-week exposure to the 5-HT2C receptor agonist lorcaserin attenuated locomotor hyperactivity and induced recovery from depression-like behavior. Analyses of brain slices from nicotine-withdrawn animals revealed that lorcaserin treatment recovered the reduced number of doublecortin (DCX)-positive cells, but it did not affect the number of Ki-67- or 5-bromo-2'-deoxyuridine (BrdU)-positive cells or the maturation of proliferating neurons in drug-weaned rats. To summarize, we show that lorcaserin alleviated locomotor responses and depression-like state during nicotine withdrawal. We propose that the modulatory effect of lorcaserin on the 'affective' aspects of nicotine cessation may be linked to the positive changes caused by the compound in hippocampal neurogenesis during nicotine withdrawal.

Prenatal Exposure to Triclocarban Impairs ESR1 Signaling and Disrupts Epigenetic Status in Sex-Specific Ways as Well as Dysregulates the Expression of Neurogenesis- and Neurotransmitter-Related Genes in the Postnatal Mouse Brain.

Triclocarban is a highly effective and broadly used antimicrobial agent. Humans are continually exposed to triclocarban, but the safety of prenatal exposure to triclocarban in the context of neurodevelopment remains unknown. In this study, we demonstrated for the first time that mice that had been prenatally exposed to environmentally relevant doses of triclocarban had impaired estrogen receptor 1 (ESR1) signaling in the brain. These mice displayed decreased mRNA and protein expression levels of ESR1 as well as hypermethylation of the Esr1 gene in the cerebral cortex. Prenatal exposure to triclocarban also diminished the mRNA expression of Esr2, Gper1, Ahr, Arnt, Cyp19a1, Cyp1a1, and Atg7, and the protein levels of CAR, ARNT, and MAP1LC3AB in female brains and decreased the protein levels of BCL2, ARNT, and MAP1LC3AB in male brains. In addition, exposure to triclocarban caused sex-specific alterations in the methylation levels of global DNA and estrogen receptor genes. Microarray and enrichment analyses showed that, in males, triclocarban dysregulated mainly neurogenesis-related genes, whereas, in females, the compound dysregulated mainly neurotransmitter-related genes. In conclusion, our data identified triclocarban as a neurodevelopmental risk factor that particularly targets ESR1, affects apoptosis and autophagy, and in sex-specific ways disrupts the epigenetic status of brain tissue and dysregulates the postnatal expression of neurogenesis- and neurotransmitter-related genes.

Adolescent social isolation affects parvalbumin expression in the medial prefrontal cortex in the MAM-E17 model of schizophrenia.

Altered parvalbumin (PV) expression is observed in the prefrontal cortex of subjects with schizophrenia. Environmental context, particularly during adolescence, might regulate PV expression. In the present study, we investigated the effect of adolescent social isolation (SI) on PV expression in the medial prefrontal cortex in a neurodevelopmental model (MAM-E17) of schizophrenia. SI exposure occurred from postnatal day 30 to 40, followed by resocialization until late adolescence or early adulthood. PV mRNA and protein levels, as well as the number of PV cells, were analysed at these ages. Moreover, epigenetic regulation of PV expression by histone methylation was examined by measuring the total and PV gene-bound H3K4me3 levels. MAM only decreased levels of the PV mRNA and protein in adulthood. Decreases in total H3K4me3 levels and its level at the PV gene were also observed at this age. In contrast, in late adolescence, SI induced a decrease in the expression of the PV mRNA in the MAM group that was related to the reduction in total and PV gene-bound H3K4me3 levels. However, at this age, SI increased the levels of the PV protein in both the control and MAM groups. In adulthood, SI did not affect PV mRNA or H3K4me3 levels but decreased levels of the PV protein in both groups. Both MAM and SI failed to change the number of PV cells at any age. The results indicate that adolescent SI accelerated epigenetic impairments of PV expression in MAM-E17 rats; however, subsequent resocialization abolished this dysfunction, but failed to prevent alterations in PV protein.

Psychedelics action and schizophrenia.

Psychedelics are compounds acting by serotonin 5-hydroxytryptamine (5-HT)2A receptor activation and induce several behavioral responses. They are of special interest because of their positive effects on neuropsychiatric disorders (depression and posttraumatic stress disorder). However, several findings revealed that some psychedelic actions are similar to symptoms observed in schizophrenia (psychosis, sensorimotor gating impairments, attention, and working memory deficits) which might limit their clinical applications. Psychedelics activate some neurotransmitters, i.e., serotonergic, and glutamatergic, that are also impaired in schizophrenia. Therefore, the neurobiological background of psychedelics and schizophrenia is partially similar. Another important aspect to discuss is the perspective of using psychedelics in schizophrenia therapy. Postmortem studies showed a loss of synapses in schizophrenia, and the positive effects of psychedelics on neuroplasticity (synaptogenesis, neurogenesis, and neuritogenesis) might be essential in the context of schizophrenia therapy. However, because of psychedelics' psychotic action, the recommended doses of psychedelics in schizophrenia treatment are not established, and subpsychedelic dosing or microdosing are considered. Exploratory studies are needed to determine the tolerability of treatment and appropriate dosing regimen. Another therapeutic option is using non-hallucinogenic psychedelic analogs that also induce neuroplastic outcomes but do not have psychotogenic effects. Further preclinical and clinical studies are needed to recognize the potential effectiveness of 5-HT2A agonists in schizophrenia therapy.

Gene Expression and Epigenetic Regulation in the Prefrontal Cortex of Schizophrenia.

Schizophrenia pathogenesis remains challenging to define; however, there is strong evidence that the interaction of genetic and environmental factors causes the disorder. This paper focuses on transcriptional abnormalities in the prefrontal cortex (PFC), a key anatomical structure that determines functional outcomes in schizophrenia. This review summarises genetic and epigenetic data from human studies to understand the etiological and clinical heterogeneity of schizophrenia. Gene expression studies using microarray and sequencing technologies reported the aberrant transcription of numerous genes in the PFC in patients with schizophrenia. Altered gene expression in schizophrenia is related to several biological pathways and networks (synaptic function, neurotransmission, signalling, myelination, immune/inflammatory mechanisms, energy production and response to oxidative stress). Studies investigating mechanisms driving these transcriptional abnormalities focused on alternations in transcription factors, gene promoter elements, DNA methylation, posttranslational histone modifications or posttranscriptional regulation of gene expression mediated by non-coding RNAs.

Epigenetic Targets in Schizophrenia Development and Therapy.

Schizophrenia is regarded as a neurodevelopmental disorder with its course progressing throughout life. However, the aetiology and development of schizophrenia are still under investigation. Several data suggest that the dysfunction of epigenetic mechanisms is known to be involved in the pathomechanism of this mental disorder. The present article revised the epigenetic background of schizophrenia based on the data available in online databases (PubMed, Scopus). This paper focused on the role of epigenetic regulation, such as DNA methylation, histone modifications, and interference of non-coding RNAs, in schizophrenia development. The article also reviewed the available data related to epigenetic regulation that may modify the severity of the disease as a possible target for schizophrenia pharmacotherapy. Moreover, the effects of antipsychotics on epigenetic malfunction in schizophrenia are discussed based on preclinical and clinical results. The obtainable data suggest alterations of epigenetic regulation in schizophrenia. Moreover, they also showed the important role of epigenetic modifications in antipsychotic action. There is a need for more data to establish the role of epigenetic mechanisms in schizophrenia therapy. It would be of special interest to find and develop new targets for schizophrenia therapy because patients with schizophrenia could show little or no response to current pharmacotherapy and have treatment-resistant schizophrenia.

Hallucinogenic activity, neurotransmitters release, anxiolytic and neurotoxic effects in Rat's brain following repeated administration of novel psychoactive compound 25B-NBOMe.

2-(4-Bromo-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)etanoamine (25B-NBOMe) is a highly selective 5-HT2A receptor agonist, exhibiting a potent hallucinogenic activity. In the present study, we investigated the effect of a 7-day treatment with 25B-NBOMe in a dose of 0.3 mg/kg on the following: the neurotransmitter release in vivo using microdialysis in freely moving animals, hallucinogenic activity measured in the Wet Dog Shake (WDS) test, anxiety level as measured in the light/dark box (LDB) and locomotor activity in the open field (OF) test, DNA damage with the comet assay, and on a number of neuronal and glial cells with immunohistochemistry. Repeated administration of 25B-NBOMe decreased the response to a challenge dose (0.3 mg/kg) on DA, 5-HT and glutamatergic neurons in the rats' frontal cortex, striatum, and nucleus accumbens. The WDS response dropped drastically after the second day of treatment, suggesting a rapid development of tolerance. LDB and OF tests showed that the effect of 25B-NBOMe on anxiety depends on the treatment and environmental settings. Results obtained with the comet assay indicate a genotoxic properties in the frontal cortex and hippocampus. An increase in immunopositive glial but not neuronal cells was observed in the cortical regions but not in the hippocampus. In conclusion, our study showed that a chronic administration of 25B-NBOMe produces the development of tolerance observed in the neurotransmitters release and hallucinogenic activity. The oxidative damage of cortical and hippocampal DNA implies the generation of free radicals by the drug, resulting in genotoxicity but rather not in neurotoxic tissue damage. Behavioral tests show that 25B-NBOMe exerts anxiogenic effect after single and repeated treatment.

Neurotoxicological profile of the hallucinogenic compound 25I-NBOMe.

4-Iodo-2,5-dimethoxy-N-(2-methoxybenzyl)phenethylamine (25I-NBOMe) is a new psychoactive substance with strong hallucinogenic properties. Our previous data reported increased release of dopamine, serotonin, and glutamate after acute injections and a tolerance development in the neurotransmitters release and rats' behavior after chronic treatment with 25I-NBOMe. The recreational use of 25I-NBOMe is associated with severe intoxication and deaths in humans. There is no data about 25I-NBOMe in vivo toxicity towards the brain tissue. In this article 25I-NBOMe-crossing through the blood-brain barrier (BBB), the impact on DNA damage, apoptosis induction, and changes in the number of cortical and hippocampal cells were studied. The presence of 25I-NBOMe in several brain regions shortly after the drug administration and its accumulation after multiple injections was found. The DNA damage was detected 72 h after the chronic treatment. On the contrary, at the same time point apoptotic signal was not identified. A decrease in the number of glial but not in neural cells in the frontal (FC) and medial prefrontal cortex (mPFC) was observed. The obtained data indicate that 25I-NBOMe passes easily across the BBB and accumulates in the brain tissue. Observed oxidative DNA damage may lead to the glial cells' death.

Hetero-dimerization of serotonin 5-HT(2A) and dopamine D(2) receptors.

In the present study, detailed information is presented on the hetero-dimerization of the serotonin 5-HT(2A) receptor and the dopamine D(2) receptor. Biophysical approaches (fluorescence spectroscopy as well as fluorescence lifetime microscopy) were used to determine the degree of fluorescence resonance energy transfer (FRET) between cyan and yellow fluorescent protein labeled receptor variants co-expressed in human embryonic kidney 293 cells (HEK293). Recorded data demonstrate the existence of energy transfer between the wild-type forms of 5-HT(2A)R and D(2)R, pointing toward the formation of hetero-5-HT(2A)R/D(2)R dimers and homo-5-HT(2A)R/5-HT(2A)R dimers. Moreover, the present study investigates the role of specific motifs (one containing adjacent arginine residues (217RRRRKR222) in the third intracellular loop (ic3) of D(2)R, and the other consisting of acidic glutamate residues (454EE455) in the C-tail of (5-HT(2A)R) in the formation of noncovalent complexes between these receptors. Our results suggest that these regions of 5-HT(2A)R and D(2)R may be involved in the interaction between these two proteins. On the other hand, the above-mentioned motifs do not play an important role in the homo-dimerization of these receptors. Furthermore, we estimated the influence of specific receptor ligands on the dimerization processes. Agonists (DOI and quinpirole) and antagonists (ketanserin and butaclamol) cause different effects on FRET efficiency depending on whether homo- or hetero-complexes are present. These data may have therapeutic implications, since (using the immunofluorescence double labeling protocols) the co-localization of these two receptors was demonstrated in the medial prefrontal cortex and pars reticulate of the substantia nigra of the rat brain.

Prenatal MAM treatment altered fear conditioning following social isolation: Relevance to schizophrenia.

Adolescent social isolation (SI) might change the trajectory of brain development. In the present study, we investigated the effect of short-term adolescent SI on fear memory, anxiety and protein levels in the adult medial prefrontal cortex of rats prenatally treated with methylazoxymethanol, MAM-E17 model of schizophrenia. The animals were maintained in standard housing (SH) or social isolation (P30-P40, SI) conditions. Behavioural tests (trace or delay fear conditioning, light/dark box) were performed in late adolescence and early adulthood. The results showed that MAM treatment did not alter fear memory, which was investigated with the use of either trace or delay fear conditioning, at any age, and SI decreased the fear response in adult control animals only under trace conditioning. Neither MAM nor SI influenced anxiety-related behaviour measured in the light/dark box. A proteomics study showed that both MAM and SI changed the protein levels related to synapse maturation and cytoskeletal organization, energy transfer and metabolic processes. Prenatal or adolescent environmental factors are able to change the expression of proteins that are correlated with behavioural impairments. Moreover, SI reversed some alterations in proteins induced by MAM. Thus, normally developing brains showed different responses to adolescent SI than those with altering courses of MAM administration.

Knockdown of the astrocytic glucocorticoid receptor in the central nucleus of the amygdala diminishes conditioned fear expression and anxiety.

The amygdala is a key structure involved in both physiological and behavioural effects of fearful and stressful stimuli. The central stress response is controlled by the activity of the hypothalamic-pituitary-adrenal (HPA) axis via glucocorticoid hormones, acting mainly through glucocorticoid receptors (GR), widely expressed among different brain regions, including the central nucleus of the amygdala (CeA). Although to date, neuronal GR was postulated to be involved in the mediating stress effects, increasing evidence points to the vital role of glial GR. Here, we aimed to evaluate the role of astrocytic GR in CeA in various aspects of the stress response. We used a lentiviral vector to disrupt an astrocytic GR in the CeA of Aldh1l1-Cre transgenic mice. Astrocytic GR knockdown mice (GR KD) exhibited an attenuated expression of fear-related memory in the fear conditioning paradigm. Interestingly, the consolidation of non-stressful memory in the novel object recognition test remained unchanged. Moreover, GR KD group presented reduced anxiety, measured in the open field test. However, knockdown of astrocytic GR in the CeA did not affect an acute response to stress in the tail suspension test. Taken together, obtained results suggest that astrocytic GR in the CeA promotes aversive memory consolidation and some aspects of anxiety behaviour.

5-HT7 receptors enhance inhibitory synaptic input to principal neurons in the mouse basal amygdala.

The basal amygdala (BA) has been implicated in encoding fear and its extinction. The level of serotonin (5-HT) in the BA increases due to arousal and stress related to aversive stimuli. The effects of 5-HT7 receptor (5-HT7R) activation and blockade on the activity of BA neurons have not yet been investigated. In the present study, a transgenic mouse line carrying green fluorescent protein (GFP) reporter gene was used to identify neurons that express the 5-HT7R. GFP immunoreactivity was present mainly in cells that also expressed GAD67 or parvalbumin (PV), the phenotypic markers for GABAergic interneurons. Most cells showing GFP fluorescence demonstrated firing patterns characteristic of BA inhibitory interneurons. Activation of 5-HT7Rs resulted in a depolarization and/or occurrence of spontaneous spiking activity of BA interneurons that was accompanied by an increase in the mean frequency and mean amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs) recorded from BA principal neurons. These effects were blocked by a specific 5-HT7R antagonist, SB269970 and were absent in slices from 5-HT7R knockout mice. Activation of 5-HT7Rs also decreased the mean frequency of spontaneous excitatory postsynaptic currents (sEPSCs) recorded from BA principal neurons, which was blocked by the GABAA receptor antagonist picrotoxin. Neither inhibitory nor excitatory miniature postsynaptic currents (mIPSCs/mEPSCs) were affected by 5-HT7R activation. These results show that in the BA 5-HT7Rs stimulate an activity-dependent enhancement of inhibitory input from local interneurons to BA principal neurons and provide insights about the possible involvement of BA serotonergic receptors in neuronal mechanisms underlying fear memory.

Early-life blockade of NMDA receptors induces epigenetic abnormalities in the adult medial prefrontal cortex: possible involvement in memory impairment in trace fear conditioning.

RATIONALE: Several findings indicate that early-life dysfunction of N-methyl-D-aspartate (NMDA) receptors might cause schizophrenia-like abnormalities in adulthood that might be induced by impairments in epigenetic regulation. OBJECTIVES: In the present study, we investigated whether postnatal blockade of NMDA receptors (within the first 3 weeks of life) by the competitive antagonist CGP 37849 (CGP) might affect some epigenetic markers in the adult medial prefrontal cortex (mPFC). METHODS: Histone H3 phosphorylation at serine 10 (H3S10ph), histone H3 acetylation at lysine 9 or 14 (H3K9ac or H3K14ac, respectively), or expression of histone deacetylase (HDAC) 2, HDAC5, myocyte enhancer factor (MEF) 2D and activity-regulated cytoskeleton-associated protein (Arc) were analysed. Moreover, we also evaluated whether the deacetylase inhibitor sodium butyrate (SB; 1.2 mg/kg, ip) could prevent behavioural and neurochemical changes in the mPFC induced by CGP during memory retrieval in the trace fear conditioning paradigm. RESULTS: The results showed that CGP administration increased the number of H3S10ph nuclei but did not affect H3K9ac and H3K14ac or HDAC2 protein levels. However, CGP administration altered the HDAC5 mRNA and protein levels and increased the mRNA and protein levels of MEF2D. CGP also increased Arc mRNA, which was correlated with an increase in the amount of Arc DNA bound to MEF2D. SB given 2 h after training prevented impairment of the freezing response and disruption of epigenetic markers (H3S10ph, HDAC5, MEF2D) and Arc expression during memory retrieval induced by CGP administration. CONCLUSIONS: The early-life blockade of NMDA receptors impairs some epigenetic regulatory processes in the mPFC that are involved in fear memory formation.

Cocaine decreases the expression of PSA-NCAM protein and attenuates long-term potentiation via glucocorticoid receptors in the rat dentate gyrus.

The present study investigated a potential role for glucocorticoid (GR) and mineralocorticoid (MR) receptors in the detrimental effects of single cocaine (COC) administration on both the number of polysialylated neural cell adhesion molecule (PSA-NCAM)-positive neurons and the induction of long-term potentiation (LTP) in the rat dentate gyrus (DG). The effects of COC (15 mg/kg i.p.) on the number of PSA-NCAM-positive neurons and the induction of LTP observed 2 days after COC administration were abolished either by depleting circulating corticosterone after administration of metyrapone (100 mg/kg s.c. given 3 h before COC) or by pharmacologically blocking GRs using mifepristone (RU 38486, 10 mg/kg s.c. given 1 h before COC). Administration of the MR blocker spironolactone (50 mg/kg s.c. given 1 h before COC) did not alter the effects of COC on the number of PSA-NCAM-positive neurons or LTP induction. Results have also shown that COC does not change the rate of cell proliferation, as measured by the presence of Ki-67 and the incorporation of bromodeoxyuridine (100 mg/kg i.p. given 2 h after COC) into the newly born cells in the DG 2 days after COC administration. Finally, we observed that GRs colocalized with some, but not all, PSA-NCAM-positive neurons, whereas MRs showed no colocalization with neurons positive for PSA-NCAM in the DG. These data indicate that a single dose of COC may arrest hippocampal susceptibility to plastic changes and lead to functional impairments through the alteration of hippocampal structure and the formation of memory traces.

Detrimental effect of postnatal blockade of N-methyl-D-aspartate receptors on sensorimotor gating is reversed by neuroleptic drugs.

Postnatal hypofunction of N-methyl-D-aspartate (NMDA) receptors leads to several behavioral deficits in adult rats resembling deficits typical of schizophrenia-like deficits of sensorimotor gating. Thus far, it is not known whether the above disruptions are sensitive to neuroleptic drugs. In order to verify the above model in pharmacological terms, we investigated whether deficits in the sensorimotor gating evoked by administration of NMDA receptor antagonists in the postnatal period is sensitive to neuroleptic drugs. We also investigated whether such treatment evoked alterations in the expression of dopamine D(1), D(2) and D(3) receptors in the nucleus accumbens, a key structure for dopamine-dependent alterations in sensorimotor gating. CGP 40116, a competitive antagonist of NMDA receptors was given in doses of 1.25 mg/kg on days 1, 3, 6 and 9; 2.5 mg/kg on days 12, 15 and 18; and 5 mg/kg on day 21 (all injections were sc). The efficacy of sensorimotor gating was tested on rats at the age of 60 days using a prepulse-induced inhibition of the startle reflex. In order to measure the expression of dopamine D(1), D(2) and D(3) receptors, we used quantitative autoradiography and tritiated ligands i.e. [(3)H]-SCH 23390, [(3)H]-Spiperone and [(3)H]-7-OH-DPAT, respectively. Haloperidol (0.1 mg/kg, sc), risperidone (1.0 mg/kg, sc) and clozapine (2.5 mg/kg, sc) reversed deficits of sensorimotor gating observed in adult rats evoked by the postnatal administration of CGP 40116. We also observed enhanced density of dopamine D(3), but not D(1) and D(2) receptors in the nucleus accumbens of CGP40116 treated rats. It is concluded that models of cognitive dysfunction, typical for schizophrenia based on postnatal administration of NMDA receptor antagonists, are sensitive to neuroleptic drugs and possibly not dependent on alteration in the density of dopaminergic receptors.