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Cocaine exposure alters brain-derived neurotrophic factor (BDNF) expression in the brain. BDNF signaling through TrkB receptors differentially modulates cocaine self-administration, depending on the brain regions involved. In the present study, we determined how brain-wide inhibition of TrkB signaling affects cocaine intake, the motivation for the drug, and reinstatement of drug taking after extinction. To overcome the inability of TrkB ligands to cross the blood-brain barrier, the TrkB antagonist cyclotraxin-B was fused to the nontoxic transduction domain of the tat protein fromhumanimmunodeficiency virus type 1 (tat-cyclotraxin-B). Intravenous injection of tat-cyclotraxin-B dose-dependently reduced cocaine intake, motivation for cocaine (as measured under a progressive ratio schedule of reinforcement), and reinstatement of cocaine taking in rats allowed either short or long access to cocaine self-administration. In contrast, the treatment did not affect operant responding for a highly palatable sweet solution, demonstrating that the effects of tat-cyclotraxin-B are specific for cocaine reinforcement. Cocaine self-administration increased TrkB signaling and activated the downstream Akt pathway in the nucleus accumbens, and had opposite effects in the prefrontal cortex. Pretreatment with tat-cyclotraxin-B normalized protein levels in these two dopamine-innervated brain regions. Cocaine self-administration also increased TrkB signaling in the ventral tegmental area, where the dopaminergic projections originate, but pretreatment with tat-cyclotraxin-B did not alter this effect. Altogether, our data show that systemic administration of a brain-penetrant TrkB antagonist leads to brain region-specific effects and may be a potential pharmacological strategy for the treatment of cocaine addiction. [ABSTRACT FROM AUTHOR]

ABSTRACT We previously demonstrated that nELAV/GAP-43 pathway is pivotal for learning and its hippocampal expression is up-regulated by acute stress following repeated cocaine administration. We therefore hypothesized that abstinence-induced stress may sustain nELAV/GAP-43 pathway during early abstinence following 2 weeks of cocaine self-administration. We found that contingent, but not non-contingent, cocaine exposure selectively increases hippocampal nELAV, but not GAP-43, expression immediately after the last self-administration session, an effect that wanes after 24 h and that comes back 7 days later when nELAV activation becomes associated with increased expression of GAP-43, an effect again observed only in animals self-administering the psychostimulant. Such effect is specific for nELAV since the ubiquitous ELAV/HuR is unchanged. This nELAV profile suggests that its initial transient alteration is perhaps related to the daily administration of cocaine, while the increase in the nELAV/GAP-43 pathway following a week of abstinence may reflect the activation of this cascade as a target of stressful conditions associated with drug-related memories. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Although evidence exists that chronic cocaine exposure during adulthood is associated with changes in BDNF expression, whether and how cocaine exposure during adolescence modulates BDNF is still unknown. To address this issue, we exposed rats to repeated cocaine injections from post-natal day (PD) 28 to PD 42, a period that roughly approximates adolescence in humans, and we carried out a detailed analysis of the BDNF system in the medial prefrontal cortex (mPFC) of rats sacrificed 3 d (PD 45) and 48 d (PD 90) after the last cocaine treat-ment. We found that developmental exposure to cocaine altered transcriptional and translational mechanisms governing neurotrophin expression. Total BDNF mRNA levels, in fact, were enhanced in the mPFC of PD 90 rats exposed to cocaine in adolescence, an effect sustained by changes in BDNF exon IV through the transcription factors CaRF and NF-kB. While a profound reduction of specific BDNF-related miRNAs (let7d, miR124 and miR132) may contribute to explaining the increased proBDNF levels, the up-regulation of the extracellular pro-teases tPA is indicative of increased processing leading to higher levels of released mBDNF. These changes were associated with increased activation of the trkB-Akt pathway resulting in enhanced pmTOR and pS6 kinase, which ultimately produced an up-regulation of Arc and a consequent reduction of GluAl expression in the mPFC of PD 90 cocaine-treated rats. These findings demonstrate that developmental exposure to cocaine dy-namically dysregulates BDNF and its signaling network in the mPFC of adult rats, providing novel mechanisms that may contribute to cocaine-induced changes in synaptic plasticity. [ABSTRACT FROM AUTHOR]

Increases in alpha calcium/calmodulin-dependent protein kinase type II (αCaMKII) activity in the nucleus accumbens shell has been proposed as a core component in the motivation to self-administer cocaine and in priming-induced drug-seeking. Since cocaine withdrawal promotes drug-seeking, we hypothesized that abstinence from cocaine self-administration should enhance αCaMKII as well.We found that short-term abstinence from contingent, but not non-contingent, cocaine i.v. self-administration (2 h/d for 14 d; 0.25 mg/0.1 ml, 6s infusion) elevates αCaMKII autophosphorylation, but not the kinase expression, in a dynamic, time- and brain region-dependent manner. Increased αCaMKII autophosphorylation in the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC), but not dorsolateral striatum (dlS), was found 24 h, but not immediately, after the last cocaine self-administration session. Notably, in the mPFC, but not NAc and dlS, αCaMKII autophosphorylation was still enhanced 7 d later. The persistent enhancement in the mPFC of abstinent rats may represent a previously unappreciated contribution to initial incubation of cocaine-seeking. [ABSTRACT FROM AUTHOR]

We have previously observed changes in the RNA editing of AMPA receptors after acute spinal cord injury (SCI); this implies that post-transcriptional modifications are capable of affecting the physiological properties of glutamate receptor channels and related signal transduction in this neurodegenerative condition. Here, we report that the editing of the ionotropic KAR is markedly decreased at both GluK1 and GluK2 Q/R sites in the epicenter of the lesion and with distinct magnitude and kinetics also in the caudal and rostral portions of the injured cord. These effects are persistent, being observed as late as 30 days after lesioning. In addition, also the I/V and Y/C sites of GluK2 were severely affected after SCI. These findings add novel information to the relevance of editing of glutamate receptors following acute SCI, thus expanding the recently emerged role of post-transcriptional mechanisms under these experimental conditions. [ABSTRACT FROM AUTHOR]

Rationale: Our study stems from four related lines of evidence: (1) FGF-2 is expressed in the developing brain; (2) psychostimulants modulate FGF-2 expression; (3) stress alters FGF-2 expression; and (4) exogenous administration of FGF-2 long-lastingly alters cocaine acquisition of self-administration. Objectives: This research aims to study the effects of adolescent cocaine exposure on FGF-2 mRNA levels and its influence on the response to stress. Materials and methods: Rats were treated subcutaneously with saline or cocaine from postnatal day (PND) 28 to PND 42, a period that roughly approximates adolescence in humans. At PND 45 and PND 90, rats were exposed to an acute stress. Real-time PCRs were performed on total RNA extracted from the prefrontal cortex, hippocampus, nucleus accumbens and striatum. Results: In the prefrontal cortex, repeated cocaine treatment during adolescence increased FGF-2 mRNA levels in PND 90 rats and altered its response to an acute stress in both PND 45 and PND 90 rats. In the hippocampus of PND 45 rats, we found an increase of FGF-2 mRNA levels following repeated cocaine administration. No changes in the trophic factor gene expression were found in the striatum and nucleus accumbens. Conclusions: Our data show that cocaine exposure during adolescence alters FGF-2 mRNA levels throughout life in rat prefrontal cortex and modulates its response to an adverse event. These results point to FGF-2 as a potential molecular target through which exposure to cocaine early in life may dynamically and persistently alter brain homeostasis. [ABSTRACT FROM AUTHOR]

It is known that long-term treatment with antipsychotic drugs (APDs) produces neuroadaptive changes through the modulation of different proteins that, by enhancing neuronal plasticity and cellular resiliency, may improve core disease symptoms. The aim of this study was to investigate the ability of chronic treatment with the novel antipsychotic lurasidone to modulate BDNF expression in hippocampus and prefrontal cortex, under basal conditions or in response to an acute stress, a major precipitating element in psychiatric disorders. By means of real-time PCR, we found that (1) chronic lurasidone treatment increases total BDNF mRNA levels in rat prefrontal cortex and, to less extent, in hippocampus; (2) the modulation of BDNF mRNA levels in response to acute swim stress in lurasidone-treated rats was markedly potentiated in hippocampus, and to less extent in prefrontal cortex, through the selective regulation of different neurotrophin isoforms. The increase of BDNF mRNA levels in prefrontal cortex was paralleled by an enhancement of mature BDNF protein levels. In conclusion, repeated exposure to lurasidone regulates BDNF expression, through a finely tuned modulation of its transcripts. This effect may contribute to the amelioration of functions, such as cognition, closely associated with neuronal plasticity, which are deteriorated in schizophrenia patients. [ABSTRACT FROM PUBLISHER]

Because stress represents a major precipitating event for psychiatric disorders, it is important to identify molecular mechanisms that may be altered in vulnerable individuals when exposed to stress. Here, we studied GluR-A−/− mice, animals with compromised AMPA receptor signaling, and characterized by a schizophrenic as well as depressive phenotype to investigate changes occurring in response to an acute stress. Wild-type and GluR-A−/− mice were exposed to a single immobilization stress and sacrificed immediately after the end of the stress for the analysis of activity regulated genes and of glutamatergic synapse responsiveness. The acute stress produced a marked increase in the hippocampal expression of Arc (activity-regulated cytoskeletal-associated protein) in GluR-A−/−, but not in wild-type mice, which was associated with a similar increase of phospho-CaMKII, a partner in the action of Arc. When looking at the glutamatergic response to stress in wild-type animals, we found that stress increased GluR-A phosphorylation on serine831, an effect that was paralleled by a significant increase of the phosphorylation of the main NMDA receptor subunits, that is, NR-1 and NR-2B. Conversely, the stress-induced modulation of NMDA receptor subunits was not observed in GluR-A−/− mice. We suggest that enhanced stress responsiveness in GluR-A−/− mice may be due, at least in part, to their inability to activate NMDA-mediated glutamatergic neurotransmission, suggesting that the integrity of AMPA/NMDA receptor function may be important for successful coping under stressful conditions. © 2010 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Abstract: In this report we provide evidence that repeated stress prevents cocaine-induced activation of BDNF expression and signaling in rat prefrontal cortex. A single injection of cocaine up-regulates BDNF expression in sham (i.e. unstressed) rats but not in repeatedly stressed rats. Similarly, the expression as well as trafficking of the high affinity BDNF receptor trkB promoted by the psychostimulant is impaired in chronically-stressed rats challenged with cocaine. Moreover, among the different intracellular signaling pathways that can be activated by the neurotrophin, i.e. ERK1/2-, Akt- and PLCγ-pathway, we found that cocaine is able to selectively activate the ERK1/2 pathway in sham animals, but not in rats exposed to repeated stress. Notably, such changes take place in chronically-stressed animals although they still retain the ability to increase neuronal activity as measured by the enhancement of Arc gene expression. In summary, we have demonstrated that stress globally interferes with BDNF-mediated signaling responses to cocaine challenge, providing key insights into the molecular basis of stress-cocaine interaction and indicating the critical role of the prefrontal cortex in mediating such interaction. [Copyright &y& Elsevier]

Abstract: We found that, in the striatum, acute injections of the first generation antipsychotic (FGA) haloperidol or the second generation antipsychotic (SGA) olanzapine enhanced Arc mRNA levels, however such induction persisted for at least 2 h in haloperidol-treated rats whereas it waned as early as 1 h after olanzapine injection. Conversely, repeated injections led to a persistent decrease of striatal Arc gene expression, regardless of the agent examined. In the frontal cortex, acute injection of both antipsychotics caused a reduction of Arc mRNA levels which persisted for at least 2 h. Following repeated treatment, olanzapine reduced Arc mRNA levels 2 h, but not 24 h, post-treatment whereas haloperidol was ineffective. Of note, the SGA quetiapine regulated the Arc gene expression similarly to olanzapine. Given the particular nature of Arc, our findings show its fine tuning following antipsychotic administration to be highly dependent on the length of the treatment and on the brain region investigated and suggest that antipsychotic drugs affect this marker of neuronal activity differently. [Copyright &y& Elsevier]

Synthetic cathinones have gained popularity among young drug users and are widely used in the clandestine market. While the cathinone-induced behavioral profile has been extensively investigated, information on their neuroplastic effects is still rather fragmentary. Accordingly, we have exposed male mice to a single injection of MDPV and α-PVP and sacrificed the animals at different time points (i.e., 30 min, 2 h, and 24 h) to have a rapid readout of the effect of these psychostimulants on neuroplasticity in the frontal lobe and hippocampus, two reward-related brain regions. We found that a single, low dose of MDPV or α-PVP is sufficient to alter the expression of neuroplastic markers in the adult mouse brain. In particular, we found increased expression of the transcription factor Npas4, increased ratio between the vesicular GABA transporter and the vesicular glutamate transporter together with changes in the expression of the neurotrophin Bdnf, confirming the widespread impact of these cathinones on brain plasticity. To sum up, exposure to low dose of cathinones can impair cortical and hippocampal homeostasis, suggesting that abuse of these cathinones at much higher doses, as it occurs in humans, could have an even more profound impact on neuroplasticity. [ABSTRACT FROM AUTHOR]

Bipolar disorder (BD) is a highly burdensome psychiatric disorder characterized by alternating states of mania and depression. A major challenge in the clinic is the switch from depression to mania, which is often observed in female BD patients during antidepressant treatment such as imipramine. However, the underlying neural basis is unclear. To investigate the potential neuronal pathways, serotonin transporter knockout (SERT KO) rats, an experimental model of female BD patients, were subjected to a battery of behavioral tests under chronic treatment of the antidepressant imipramine. In addition, the expression of brain-derived neurotrophic factor (BDNF) and its downstream signaling was examined in the prefrontal cortex. Chronic exposure to imipramine reduced anxiety and sociability and problem-solving capacity, and increased thigmotaxis and day/night activity in all animals, but specifically in female SERT KO rats, compared to female wild-type (WT) rats. Further, we found an activation of BDNF-TrkB-Akt pathway signaling in the infralimbic, but not prelimbic, cortex after chronic imipramine treatment in SERT KO, but not WT, rats. Repeated testing behaviors could potentially affect the results. Additionally, the imipramine induced changes in behavior and in the BDNF system were measured in separate animals. Our study indicates that female SERT KO rats, which mirror the female BD patients with the 5-HTTLPR s-allele, are at higher risk of a switch to mania-like behaviors under imipramine treatment. Activation of the BDNF-TrkB-Akt pathway in the infralimbic cortex might contribute to this phenotype, but causal evidence remains to be provided. • Serotonin transporter knockout rats can model patients with bipolar disorder. • Imipramine treatment increases signs of mania-like behavior in female model rats. • Imipramine activates the brain BDNF-TrkB-Akt pathway in female model rats. [ABSTRACT FROM AUTHOR]

• Memory is based on the acquisition, integration, and processing of new information. • Deletion of a consolidated memory is a memory-related process as well. • Environmental rewarding and aversive stimuli influence memory and active forgetting. • Dopamine regulates both appetitive and aversive memory formation. • Learning and memory active forgetting are regulated by dopamine. Dopaminergic neurons projecting from the Substantia Nigra to the Striatum play a critical role in motor functions while dopaminergic neurons originating in the Ventral Tegmental Area (VTA) and projecting to the Nucleus Accumbens, Hippocampus and other cortical structures regulate rewarding learning. While VTA mainly consists of dopaminergic neurons, excitatory (glutamate) and inhibitory (GABA) VTA-neurons have also been described: these neurons may also modulate and contribute to shape the final dopaminergic response, which is critical for memory formation. However, given the large amount of information that is handled daily by our brain, it is essential that irrelevant information be deleted. Recently, apart from the well-established role of dopamine (DA) in learning, it has been shown that DA plays a critical role in the intrinsic active forgetting mechanisms that control storage information, contributing to the deletion of a consolidated memory. These new insights may be instrumental to identify therapies for those disorders that involve memory alterations. [ABSTRACT FROM AUTHOR]

Environmental enrichment (EE) has been shown to produce beneficial effects in addiction disorders; however, due to its configurational complexity, the underlying mechanisms are not yet fully elucidated. Recent evidence suggests that EE, acting as a metaplastic agent, may affect glutamatergic mechanisms underlying appetitive memory and, in turn, modulate reward‐seeking behaviours: here, we have investigated such a possibility following a brief EE exposure. Adult male Sprague–Dawley rats were exposed to EE for 22 h and the expression of critical elements of the glutamate synapse was measured 2 h after the end of EE in the medial prefrontal cortex (mPFC), nucleus accumbens (NAc) and hippocampus (Hipp) brain areas, which are critical for reward and memory. We focused our investigation on the expression of NMDA and AMPA receptor subunits, their scaffolding proteins SAP102 and SAP97, vesicular and membrane glutamate transporters vGluT1 and GLT‐1, and critical structural components such as proteins involved in morphology and function of glutamatergic synapses, PSD95 and Arc/Arg3.1. Our findings demonstrate that a brief EE exposure induces metaplastic changes in glutamatergic mPFC, NAc and Hipp. Such changes are area‐specific and involve postsynaptic NMDA/AMPA receptor subunit composition, as well as changes in the expression of their main scaffolding proteins, thus influencing the retention of such receptors at synaptic sites. Our data indicate that brief EE exposure is sufficient to dynamically modulate the glutamatergic synapses in mPFC‐NAc‐Hipp circuits, which may modulate rewarding and memory processes. [ABSTRACT FROM AUTHOR]

Structural neuroplasticity of the hippocampus in the form of neurogenesis and dendritic remodelling underlying morphine tolerance is still less known. Therefore, in this study, we aimed to assess whether unconditioned‐ and conditioned‐morphine tolerance can trigger structural neuroplasticity in the dorsal and ventral parts of the adult male rat hippocampus. Evaluation of the levels of neurogenesis markers (Ki67 and DCX) by immunohistochemistry shows that conditioned morphine tolerance is sufficient to increase the baseline topographic level of hippocampal neurogenesis in adult rats. Dendritic spine visualization by Golgi staining shows that the behavioural testing paradigms themselves are sufficient to trigger the hippocampus subregion‐specific changes in the dendritic remodelling along the apical dendrites of hippocampal CA1 pyramidal neurons and dentate granule cells in adult rats. Quantitative reverse transcription polymerase chain reaction of Bdnf, Trkb, Rac‐1 and RhoA mRNA levels as pro‐plasticity molecules, shows that the conditioned morphine tolerance is effective in changing Bdnf and RhoA mRNA levels in the ventral hippocampus of adult rats. In summary, we demonstrate that the acquisition of morphine tolerance promotes adult neurogenesis, dendritic remodelling and pro‐plasticity molecules such as Bdnf/Trkb in the rat hippocampus. Indeed, the structural neuroplasticity of the hippocampus may underlie the newly formed aberrant memory and could provide the initial basis for understanding the neurobiological mechanisms of morphine‐tolerance plasticity in the hippocampus. [ABSTRACT FROM AUTHOR]

Alzheimer's disease is a chronic neurodegenerative devastating disorder affecting a high percentage of the population over 65 years of age and causing a relevant emotional, social, and economic burden. Clinically, it is characterized by a prominent cognitive deficit associated with language and behavioral impairments. The molecular pathogenesis of Alzheimer's disease is multifaceted and involves changes in neurotransmitter levels together with alterations of inflammatory, oxidative, hormonal, and synaptic pathways, which may represent a drug target for both prevention and treatment; however, an effective treatment for Alzheimer's disease still represents an unmet goal. As neurotrophic factors participate in the modulation of the above-mentioned pathways, they have been highlighted as critical contributors of Alzheimer's disease etiology, whose modulation might be beneficial for Alzheimer's disease. We focused on the neurotrophin brain-derived neurotrophic factor, providing several lines of evidence pointing to brain-derived neurotrophic factor as a plausible endophenotype of cognitive deficits in Alzheimer's disease, illustrating some of the most recent possibilities to modulate the expression of this neurotrophin in the brain in an attempt to ameliorate cognition and delay the progression of Alzheimer's disease. This review shows that otherwise disparate pharmacologic or non-pharmacologic approaches converge on brain-derived neurotrophic factor, providing a means whereby apparently unrelated medical approaches may nevertheless produce similar synaptic and cognitive outcomes in Alzheimer's disease pathogenesis, suggesting that brain-derived neurotrophic factor-based synaptic repair may represent a modifying strategy to ameliorate cognition in Alzheimer's disease. [ABSTRACT FROM AUTHOR]