The noradrenergic component in tapentadol action counteracts \u3bc-opioid receptor-mediated adverse effects on adult neurogenesis

Opiates were the first drugs shown to negatively impact neurogenesis in the adult mammalian hippocampus. Literature data also suggest that norepinephrine is a positive modulator of hippocampal neurogenesis in vitro and in vivo. On the basis of these observations, we investigated whether tapentadol, a novel central analgesic combining \u3bc-opioid receptor (MOR) agonism with norepinephrine reuptake inhibition (NRI), may produce less inhibition of hippocampal neurogenesis compared with morphine. When tested in vitro, morphine inhibited neuronal differentiation, neurite outgrowth, and survival of adult mouse hippocampal neural progenitors and their progeny, via MOR interaction. By contrast, tapentadol was devoid of these adverse effects on cell survival and reduced neurite outgrowth and the number of newly generated neurons only at nanomolar concentrations where the MOR component is predominant. On the contrary, at higher (micromolar) concentrations, tapentadol elicited proneurogenic and antiapoptotic effects via activation of \u3b22 and \u3b12 adrenergic receptors, respectively. Altogether, these data suggest that the noradrenergic component in tapentadol has the potential to counteract the adverse MOR-mediated effects on hippocampal neurogenesis. As a proof of concept, we showed that reboxetine, an NRI antidepressant, counteracted both antineurogenic and apoptotic effects of morphine in vitro. In line with these observations, chronic tapentadol treatment did not negatively affect hippocampal neurogenesis in vivo. In light of the increasing long-term use of opiates in chronic pain, in principle, the tapentadol combined mechanism of action may result in less or no reduction in adult neurogenesis compared with classic opiates

\u3b12\u3b4 Ligands Act as Positive Modulators of Adult Hippocampal Neurogenesis and Prevent Depression-Like Behavior Induced by Chronic Restraint Stress

Although the role of adult hippocampal neurogenesis remains to be fully elucidated, several studies suggested that the process is involved in cognitive and emotional functions and is deregulated in various neuropsychiatric disorders, including major depression. Several psychoactive drugs, including antidepressants, can modulate adult neurogenesis. Here we show for the first time that the \u3b12\u3b4 ligands gabapentin [1-(aminomethyl)cyclohexaneacetic acid] and pregabalin (PGB) [(S)-(+)-3-isobutyl-GABA or (S)-3-(aminomethyl)-5-methylhexanoic acid] can produce concentration-dependent increases in the numbers of newborn mature and immature neurons generated in vitro from adult hippocampal neural progenitor cells and, in parallel, a decrease in the number of undifferentiated precursor cells. These effects were confirmed in vivo, because significantly increased numbers of adult cell-generated neurons were observed in the hippocampal region of mice receiving prolonged treatment with PGB (10 mg/kg i.p. for 21 days), compared with vehicle-treated mice. We demonstrated that PGB administration prevented the appearance of depression-like behaviors induced by chronic restraint stress and, in parallel, promoted hippocampal neurogenesis in adult stressed mice. Finally, we provided data suggesting involvement of the \u3b12\u3b41 subunit and the nuclear factor-\u3baB signaling pathway in drug-mediated proneurogenic effects. The new pharmacological activities of \u3b12\u3b4 ligands may help explain their therapeutic activity as supplemental therapy for major depression and depressive symptoms in post-traumatic stress disorder and generalized anxiety disorders. These data contribute to the identification of novel molecular pathways that may represent potential targets for pharmacological modulation in depression

Direct current stimulation modulates LTP and protein expression in rat hippocampus.

Introduction: Transcranial direct current stimulation (tDCS) can produce a lasting polarity-specific modulation of cortical excitability in the brain and it is increasingly used in experimental and clinical settings. A large amount of evidence supports the view that the after-effects of tDCS are mediated by the interaction with molecular mechanisms of activity-dependent synaptic plasticity. The level of this interaction is unknown. Some immediate early genes, such as c-fos and zif268, are rapidly induced following neuronal activation and may act as regulators of downstream target genes in coupling short-term events with long-term functional modifications of synaptic function. Objectives: (1) To assess the effect of DCS on the induction of one of the most studied NMDA receptor-dependent forms of long-term potentiation (LTP) of synaptic activity; (2) to shed light on the molecular basis of DCS after-effects. Methods: We investigated the effect of anodal and cathodal DCS, applied to rat brain slices, on LTP induction at CA3-CA1 hippocampal synapses (Shaffer collateral pathway). In the same experimental model, we also explored by immunohistochemistry the effect of DCS on the expression of c-fos and zif268 proteins in CA and DG regions of the hippocampus. Results: DCS determined a bidirectional modulation of LTP, that was increased by anodal and reduced by cathodal DCS. Moreover, we found that both polarities of DCS produce a marked and consistent increase in the expression of zif268 in the CA region of the hippocampus, while the same protocols of stimulation produce a less pronounced increase in c-fos expression, that was observed in both the CA and DG regions. Conclusions: The present data confirm the interaction of DCS with the molecular pathways underlying activity-dependent synaptic plasticity. The modulation of this processes might become of use in neurological diseases to help enhancing the adaptive and suppress the maladaptive forms of brain plasticity

Contribution of early-life unpredictability to neuropsychiatric symptom patterns in adulthood.

BackgroundRecent studies in both human and experimental animals have identified fragmented and unpredictable parental and environmental signals as a novel source of early-life adversity. Early-life unpredictability may be a fundamental developmental factor that impacts brain development, including reward and emotional memory circuits, affecting the risk for psychopathology later in life. Here, we tested the hypothesis that self-reported early-life unpredictability is associated with psychiatric symptoms in adult clinical populations.MethodsUsing the newly validated Questionnaire of Unpredictability in Childhood, we assessed early-life unpredictability in 156 trauma-exposed adults, of which 65% sought treatment for mood, anxiety, and/or posttraumatic stress disorder (PTSD) symptoms. All participants completed symptom measures of PTSD, depression and anhedonia, anxiety, alcohol use, and chronic pain. Relative contributions of early-life unpredictability versus childhood trauma and associations with longitudinal outcomes over a 6-month period were determined.ResultsEarly-life unpredictability, independent of childhood trauma, was significantly associated with higher depression, anxiety symptoms, and anhedonia, and was related to higher overall symptom ratings across time. Early-life unpredictability was also associated with suicidal ideation, but not alcohol use or pain symptoms.ConclusionsEarly-life unpredictability is an independent and consistent predictor of specific adult psychiatric symptoms, providing impetus for studying mechanisms of its effects on the developing brain that promote risk for psychopathology

Exposure to extremely low-frequency (50 Hz) electromagnetic fields enhances adult hippocampal neurogenesis in C57BL/6 mice

Throughout life, new neurons are continuously generated in the hippocampus, which is therefore a major site of structural plasticity in the adult brain. We recently demonstrated that extremely low-frequency electromagnetic fields (ELFEFs) promote the neuronal differentiation of neural stem cells in vitro by upregulating Cav1-channel activity. The aim of the present study was to determine whether 50-Hz/1 mT ELFEF stimulation also affects adult hippocampal neurogenesis in vivo, and if so, to identify the molecular mechanisms underlying this action and its functional impact on synaptic plasticity. ELFEF exposure (1 to 7 h/day for 7 days) significantly enhanced neurogenesis in the dentate gyrus (DG) of adult mice, as documented by increased numbers of cells double-labeled for 5-bromo-deoxyuridine (BrdU) and doublecortin. Quantitative RT-PCR analysis of hippocampal extracts revealed significant ELFEF exposure-induced increases in the transcription of pro-neuronal genes (Mash1, NeuroD2, Hes1) and genes encoding Cav1.2 channel α1C subunits. Increased expression of NeuroD1, NeuroD2 and Cav1 channels was also documented by Western blot analysis. Immunofluorescence experiments showed that, 30 days after ELFEF stimulation, roughly half of the newly generated immature neurons had survived and become mature dentate granule cells (as shown by their immunoreactivity for both BrdU and NeuN) and were integrated into the granule cell layer of the DG. Electrophysiological experiments demonstrated that the new mature neurons influenced hippocampal synaptic plasticity, as reflected by increased long-term potentiation. Our findings show that ELFEF exposure can be an effective tool for increasing in vivo neurogenesis, and they could lead to the development of novel therapeutic approaches in regenerative medicine

Exposure to extremely low-frequency (50 Hz) electromagnetic fields enhances adult hippocampal neurogenesis in C57BL/6 mice

Throughout life, new neurons are continuously generated in the hippocampus, which is therefore a major site of structural plasticity in the adult brain. We recently demonstrated that extremely low-frequency electromagnetic fields (ELFEFs) promote the neuronal differentiation of neural stem cells in vitro by upregulating Cav1-channel activity. The aim of the present study was to determine whether 50-Hz/1 mT ELFEF stimulation also affects adult hippocampal neurogenesis in vivo, and if so, to identify the molecular mechanisms underlying this action and its functional impact on synaptic plasticity. ELFEF exposure (1 to 7 h/day for 7 days) significantly enhanced neurogenesis in the dentate gyrus (DG) of adult mice, as documented by increased numbers of cells double-labeled for 5-bromo-deoxyuridine (BrdU) and doublecortin. Quantitative RT-PCR analysis of hippocampal extracts revealed significant ELFEF exposure-induced increases in the transcription of pro-neuronal genes (Mash1, NeuroD2, Hes1) and genes encoding Cav1.2 channel α1C subunits. Increased expression of NeuroD1, NeuroD2 and Cav1 channels was also documented by Western blot analysis. Immunofluorescence experiments showed that, 30 days after ELFEF stimulation, roughly half of the newly generated immature neurons had survived and become mature dentate granule cells (as shown by their immunoreactivity for both BrdU and NeuN) and were integrated into the granule cell layer of the DG. Electrophysiological experiments demonstrated that the new mature neurons influenced hippocampal synaptic plasticity, as reflected by increased long-term potentiation. Our findings show that ELFEF exposure can be an effective tool for increasing in vivo neurogenesis, and they could lead to the development of novel therapeutic approaches in regenerative medicine

The dual role of Cav1 channels in neurogenesis and neurodegeneration.

Calcium signals generated through Cav1 channels activate intracellular pathways affecting the expression of genes controlling cell death and differentiation. Aim of our study was to determine the role of Cav1 channel signals in the pathophysiology of neurodegenerative diseases, and their impact on neurogenesis. We demonstrated that the different neurotoxicity of amyloid-\u3b2 protein (A\u3b2) variants found in the brains of Alzheimer's disease patients depends on their ability to upregulate Cav1 channel expression and activate Ca2+-dependent pro-apoptotic pathways (1,2). Cav1 channels also gave a prominent contribution to intracellular Ca2+ signals triggered by the binding of herpes simplex virus type 1 (HSV-1) to the plasma membrane of neurons. These HSV-1-induced Ca2+ signals promoted amyloid precursor protein (APP) phosphorylation and processing, with consequent intracellular and extracellular accumulation of A\u3b2 and other neurotoxic APP fragments (3,4). In neural stem cells (NSC) up-regulation of Cav1 channel signals caused opposite effects, i.e., increased in vitro NSC differentiation toward the neuronal phenotype and enhanced adult hippocampal neurogenesis in vivo (5,6). These effects are mediated by Cav1 channel-depended phosphorylation of CREB and increased expression of the pro-neuronal genes Mash1, NeuroD and Hes1. Collectively, our findings suggest that modulation of Cav1 channel signals have the potential to counteract neurodegeneration and promote brain repair