scholarly journals Ibogaine Modifies GDNF, BDNF and NGF Expression in Brain Regions Involved in Mesocorticolimbic and Nigral Dopaminergic Circuits

2018 ◽  
Author(s):  
Soledad Marton ◽  
Bruno González ◽  
Sebastián Rodríguez ◽  
Ernesto Miquel ◽  
Laura Martínez Palma ◽  
...  
Keyword(s):  
Neurotrophic Factor ◽  
Dopaminergic Neurons ◽  
Brain Regions ◽  
Dopamine Neurons ◽  
Acute Administration ◽  
Dependent Manner ◽  
Self Administration ◽  
Seeking Behavior ◽  
A Site ◽  
Dose Dependent

<p>Ibogaine is a psychedelic alkaloid which has been subject of intense scientific research due to its reported ability to attenuate drug-seeking behavior. Recent work suggested that ibogaine effects on alcohol self-administration in rats was related to the release of Glial Cell Derived Neurotrophic Factor (GDNF) in the Ventral Tegmental Area (VTA), a mesencephalic region which hosts soma of dopamine neurons. It is well known that neurotrophic factors (NFs) mediate the neuroadaptations induced in the mesocorticolimbic dopaminergic system by repeated exposure to drugs. Although previous reports have shown ibogaine´s ability to induce GDNF expression in rat midbrain, there are no studies addressing its effect on the expression of GDNF, Brain Derived Neurotrophic Factor (BDNF) or Nerve Growth Factor (NGF) in distinct regions containing dopaminergic neurons. In this work, we examined the effect of ibogaine acute administration on the expression of these NFs in the VTA, Prefrontal Cortex (PFC), Nucleus Accumbens (NAcc) and the Substantia Nigra (SN). Thus, rats were i.p. treated with ibogaine 20 mg/kg (I<sub>20</sub>), 40 mg/kg (I<sub>40</sub>) or vehicle, and NFs expression was analyzed after 3 and 24 hours. Only at 24 h an increase of the expression for the three NFs were observed in a site and dose dependent manner. Results for GDNF showed that only I<sub>40</sub> selectively upregulated its expression in the VTA and SN. Both doses of ibogaine elicited a large increase in the expression of BDNF in the NAcc, SN and PFC, while a significant effect was found in the VTA only for I<sub>40</sub>. Finally, NGF was found to be upregulated in all regions after I<sub>40</sub>, while a selective upregulation was found in PFC and VTA for the I<sub>20</sub> treatment. An increase in the content of mature GDNF was observed in the VTA but no significant increase in the mature BDNF protein content was found in all the studied areas. Interestingly, an increase in the content of proBDNF was detected in the NAcc for both treatments. Further research is needed to understand the neurochemical bases of these changes, and to confirm their contribution to the anti-addictive properties of ibogaine. </p>

scholarly journals Ibogaine Modifies GDNF, BDNF and NGF Expression in Brain Regions Involved in Mesocorticolimbic and Nigral Dopaminergic Circuits

2018 ◽  
Author(s):  
Soledad Marton ◽  
Bruno González ◽  
Sebastián Rodríguez ◽  
Ernesto Miquel ◽  
Laura Martínez Palma ◽  
...  
Keyword(s):  
Neurotrophic Factor ◽  
Dopaminergic Neurons ◽  
Brain Regions ◽  
Dopamine Neurons ◽  
Acute Administration ◽  
Dependent Manner ◽  
Self Administration ◽  
Seeking Behavior ◽  
A Site ◽  
Dose Dependent

<p>Ibogaine is a psychedelic alkaloid which has been subject of intense scientific research due to its reported ability to attenuate drug-seeking behavior. Recent work suggested that ibogaine effects on alcohol self-administration in rats was related to the release of Glial Cell Derived Neurotrophic Factor (GDNF) in the Ventral Tegmental Area (VTA), a mesencephalic region which hosts soma of dopamine neurons. It is well known that neurotrophic factors (NFs) mediate the neuroadaptations induced in the mesocorticolimbic dopaminergic system by repeated exposure to drugs. Although previous reports have shown ibogaine´s ability to induce GDNF expression in rat midbrain, there are no studies addressing its effect on the expression of GDNF, Brain Derived Neurotrophic Factor (BDNF) or Nerve Growth Factor (NGF) in distinct regions containing dopaminergic neurons. In this work, we examined the effect of ibogaine acute administration on the expression of these NFs in the VTA, Prefrontal Cortex (PFC), Nucleus Accumbens (NAcc) and the Substantia Nigra (SN). Thus, rats were i.p. treated with ibogaine 20 mg/kg (I<sub>20</sub>), 40 mg/kg (I<sub>40</sub>) or vehicle, and NFs expression was analyzed after 3 and 24 hours. Only at 24 h an increase of the expression for the three NFs were observed in a site and dose dependent manner. Results for GDNF showed that only I<sub>40</sub> selectively upregulated its expression in the VTA and SN. Both doses of ibogaine elicited a large increase in the expression of BDNF in the NAcc, SN and PFC, while a significant effect was found in the VTA only for I<sub>40</sub>. Finally, NGF was found to be upregulated in all regions after I<sub>40</sub>, while a selective upregulation was found in PFC and VTA for the I<sub>20</sub> treatment. An increase in the content of mature GDNF was observed in the VTA but no significant increase in the mature BDNF protein content was found in all the studied areas. Interestingly, an increase in the content of proBDNF was detected in the NAcc for both treatments. Further research is needed to understand the neurochemical bases of these changes, and to confirm their contribution to the anti-addictive properties of ibogaine. </p>

scholarly journals Modeling Uncertainty-Seeking Behavior Mediated by Cholinergic Influence on Dopamine

2019 ◽  
Author(s):  
Marwen Belkaid ◽  
Jeffrey L. Krichmar
Keyword(s):  
Decision Making ◽  
Dopaminergic Neurons ◽  
Cholinergic System ◽  
Dopamine Neurons ◽  
Comprehensive Understanding ◽  
Dopaminergic Activity ◽  
Integrate And Fire ◽  
Major Implication ◽  
Seeking Behavior

AbstractRecent findings suggest that acetylcholine mediates uncertainty-seeking behaviors through its projection to dopamine neurons – another neuromodulatory system known for its major implication in reinforcement learning and decision-making. In this paper, we propose a leaky-integrate-and-fire model of this mechanism. It implements a softmax-like selection with an uncertainty bonus by a cholinergic drive to dopaminergic neurons, which in turn influence synaptic currents of downstream neurons. The model is able to reproduce experimental data in two decision-making tasks. It also predicts that i) in the absence of cholinergic input, dopaminergic activity would not correlate with uncertainty, and that ii) the adaptive advantage brought by the implemented uncertainty-seeking mechanism is most useful when sources of reward are not highly uncertain. Moreover, this modeling work allows us to propose novel experiments which might shed new light on the role of acetylcholine in both random and directed exploration. Overall, this study thus contributes to a more comprehensive understanding of the roles of the cholinergic system and its involvement in decision-making in particular.

High-affinity choline uptake in regions of rat brain and the effect of antidepressants

1979 ◽  
Vol 57 (6) ◽  
pp. 595-599 ◽  
Author(s):  
P. D. Hrdina ◽  
K. Elson
Keyword(s):  
Rat Brain ◽  
Tricyclic Antidepressants ◽  
Brain Regions ◽  
Choline Uptake ◽  
Dependent Manner ◽  
Choline Transport ◽  
High Affinity ◽  
Michaelis Constants ◽  
Dose Dependent ◽  
The Brain

The effect of tricyclic antidepressants, chlorpromazine, and some monoamine oxidase inhibitors on the accumulation of [14C]choline by crude synaptosomal (P2) fraction from different regions of rat brain (cortex, striatum, and hippocampus) was investigated. Analysis of choline uptake kinetics resulted in high- and low-affinity components with different Michaelis constants. All tricyclic antidepressants tested inhibited in a dose-dependent manner the high-affinity choline uptake in the three regions, amitriptyline being the most potent. The IC50 values correlated significantly with the relative potencies of imipramine congeners in binding to muscarinic receptors in the brain. Neither tranylcypromine nor pargyline in concentrations up to 0.1 mM had any effect on choline transport. Concentrations of tricyclic antidepressants effective in inhibiting the uptake of choline failed to influence significantly the activity of choline acetyltransferase in brain regions examined. The results suggest that the effect of imipramine congeners on high-affinity choline uptake may be reflected in the anticholinergic properties of these compounds.

Catecholaminergic neurons supplying the hindgut of the crayfish Procambarus clarkii

1991 ◽  
Vol 69 (11) ◽  
pp. 2778-2785 ◽  
Author(s):  
A. Joffre Mercier ◽  
Ian Orchard ◽  
Arthur Schmoeckel
Keyword(s):  
Dopaminergic Neurons ◽  
High Performance ◽  
Procambarus Clarkii ◽  
Dependent Manner ◽  
Catecholamine Biosynthesis ◽  
Catecholaminergic Neurons ◽  
Rate Limiting Step ◽  
Single Axon ◽  
Rate Limiting ◽  
Dose Dependent

The crayfish hindgut is surrounded by a dense plexus of nerve terminals which are known to contain catecholamines. This plexus is positively stained using a monoclonal antibody to tyrosine hydroxylase, the enzyme that catalyzes the rate-limiting step in catecholamine biosynthesis. Two immunoreactive neurons, whose cell bodies are located in the third and fourth abdominal ganglia, contribute to the nerve plexus. Each of these neurons sends a single axon posteriorly through the ventral nerve cord and into the intestinal nerve, where the axon bifurcates to supply the anterior and posterior hindgut regions. High-performance liquid chromatography, coupled to electrochemical detection, demonstrates the presence of dopamine in the intestinal nerve of Procambarus clarkii. Dopamine increases the motility of the isolated hindgut in a dose-dependent manner. The results suggest that two dopaminergic neurons are involved in the neurogenic coordination of hindgut movements.

2Hz-Electroacupuncture Attenuates Conditioned Cue-Evoked Heroin-Seeking Behavior and Increase CB2-Rs Expression in Relapse-Relevant Brain Regions in Heroin-Addicted Rats

2014 ◽  
Vol 998-999 ◽  
pp. 164-168 ◽  
Author(s):  
Lin Chen ◽  
Bao Miao Ma ◽  
Kai Yue ◽  
Qin Ru ◽  
Xiang Tian ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Nucleus Accumbens ◽  
Rat Model ◽  
Fixed Ratio ◽  
Brain Regions ◽  
Inhibitory Effect ◽  
Control Group ◽  
Self Administration ◽  
Seeking Behavior

In order to investigate the influence of electroacupuncture on heroin seeking behavior and the expression of CB2-Rs in the relapse-relevant brain regions, heroin self-administration rat model which represents the heroin relapse behaviors was developed with progressive fixed ratio program. The model rats were randomly divided into 3 groups: control group, heroin-addicted group and 2Hz electroacupuncture group (stimulating on acupoints zusanli and sanyinjiao). The expression of CB2-Rs in the relapse-relevant brain regions were assessed with immunohistochemistry technologies. The reinstatement of heroin seeking behavior induced by conditioned cue priming showed that compared with the heroin-addicted group, active pokes in the 2Hz electroacupuncture group decreased significantly (p<0.05). Compared with the control group, the expression of CB2-Rs in prefrontal cortex (PFC) and nucleus accumbens (NAc) was significantly decreased (p<0.05) in heroin-addicted group and increaseed significantly recover (p<0.05) in the 2Hz electroacupuncture group. Our present results showed that 2Hz-electroacupuncture could attenuate the conditioned cue-evoked heroin-seeking behavior and the inhibitory effect was mediated partially by the increase CB2-Rs expression in relapse-relevant brain regions in heroin-addicted rats.

scholarly journals Dopamine transporter is a master regulator of dopaminergic neural network connectivity

2021 ◽  
Author(s):  
Douglas Miller ◽  
Dylan T. Guenther ◽  
Andrew P. Maurer ◽  
Carissa A. Hansen ◽  
Andrew Zalesky ◽  
...  
Keyword(s):  
Dopamine Transporter ◽  
Dopaminergic Neurons ◽  
D2 Receptor ◽  
Neuronal Loss ◽  
Network Connectivity ◽  
Brain Regions ◽  
Dopamine Neurons ◽  
Differential Sensitivity ◽  
Network Clustering ◽  
Whole Cell Patch Clamp

AbstractDopaminergic neurons of the substantia nigra (SNC) and ventral tegmental area (VTA) exhibit spontaneous firing activity. The dopaminergic neurons in these regions have been shown to exhibit differential sensitivity to neuronal loss and psychostimulants targeting dopamine transporter. However, it remains unclear whether these regional differences scale beyond individual neuronal activity to regional neuronal networks. Here we utilized live-cell calcium imaging to show that network connectivity greatly differs between SNC and VTA regions with higher incidence of hub-like neurons in the VTA. Specifically, the frequency of hub-like neurons was significantly lower in SNC dopamine neurons than in the adjacent VTA, consistent with the interpretation of a lower network resilience to SNC neuronal loss. We tested this hypothesis when activity of an individual dopaminergic neuron is suppressed, through whole-cell patch clamp electrophysiology, in either SNC, or VTA networks. Neuronal loss in the SNC decreased network clustering, whereas the larger number of hub-neurons in the VTA overcompensated by increasing network clustering in the VTA. We further show that network properties are regulatable via a dopamine transporter but not a D2 receptor dependent mechanism. Our results demonstrate novel regulatory mechanisms of functional network topology in dopaminergic brain regions.

scholarly journals Repression of Ets-2-Induced Transactivation of the Tau Interferon Promoter by Oct-4

2001 ◽  
Vol 21 (23) ◽  
pp. 7883-7891 ◽  
Author(s):  
Toshihiko Ezashi ◽  
Debjani Ghosh ◽  
R. Michael Roberts
Keyword(s):  
Luciferase Reporter ◽  
Dependent Manner ◽  
Dna Binding Domains ◽  
Binding Domains ◽  
Pou Domain ◽  
Choriocarcinoma Cells ◽  
A Site ◽  
Dose Dependent ◽  
Developmental Switch

ABSTRACT Oct-4 is a POU family transcription factor associated with potentially totipotent cells. Genes expressed in the trophectoderm but not in embryos prior to blastocyst formation may be targets for silencing by Oct-4. Here, we have tested this hypothesis with the tau interferon genes (IFNT genes), which are expressed exclusively in the trophectoderm of bovine embryos. IFNTpromoters contain an Ets-2 enhancer, located at −79 to −70, and are up-regulated about 20-fold by the overexpression of Ets-2 in human JAr choriocarcinoma cells, which are permissive for IFNTexpression. This enhancement was reversed in a dose-dependent manner by coexpression of Oct-4 but not either Oct-1 or Oct-2. When cells were transfected with truncated bovine IFNT promoters designed to eliminate potential octamer sites sequentially, luciferase reporter expression from each construct was still silenced by Oct-4. Full repression required both the N-terminal and POU domains of Oct-4, but neither domain used alone was an effective silencer. Oct-4 and Ets-2 formed a complex in vitro in the absence of DNA through binding of the POU domain of Oct-4 to a site located between the “pointed” and DNA binding domains of Ets-2. The two transcription factors were also coimmunoprecipitated after being expressed together in JAr cells. Oct-4, therefore, silences IFNT promoters by quenching Ets-2 transactivation. The POU domain most probably binds to Ets-2 directly, while the N-terminal domain inhibits transcription. These findings provide further evidence that the developmental switch to the trophectoderm is accompanied by the loss of Oct-4 silencing of key genes.

scholarly journals Intranasal administration of α-synuclein preformed fibrils triggers microglial iron deposition in the substantia nigra of Macaca fascicularis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jian-Jun Guo ◽  
Feng Yue ◽  
Dong-Yan Song ◽  
Luc Bousset ◽  
Xin Liang ◽  
...  
Keyword(s):  
Substantia Nigra ◽  
Dopaminergic Neurons ◽  
Cellular Response ◽  
Macaca Fascicularis ◽  
Brain Regions ◽  
Cellular Level ◽  
Pathological Process ◽  
Iron Deposition ◽  
Dependent Manner ◽  
Axonal Swelling

AbstractIron deposition is present in main lesion areas in the brains of patients with Parkinson’s disease (PD) and an abnormal iron content may be associated with dopaminergic neuronal cytotoxicity and degeneration in the substantia nigra of the midbrain. However, the cause of iron deposition and its role in the pathological process of PD are unclear. In the present study, we investigated the effects of the nasal mucosal delivery of synthetic human α-synuclein (α-syn) preformed fibrils (PFFs) on the pathogenesis of PD in Macaca fascicularis. We detected that iron deposition was clearly increased in a time-dependent manner from 1 to 17 months in the substantia nigra and globus pallidus, highly contrasting to other brain regions after treatments with α-syn PFFs. At the cellular level, the iron deposits were specifically localized in microglia but not in dopaminergic neurons, nor in other types of glial cells in the substantia nigra, whereas the expression of transferrin (TF), TF receptor 1 (TFR1), TF receptor 2 (TFR2), and ferroportin (FPn) was increased in dopaminergic neurons. Furthermore, no clear dopaminergic neuron loss was observed in the substantia nigra, but with decreased immunoreactivity of tyrosine hydroxylase (TH) and appearance of axonal swelling in the putamen. The brain region-enriched and cell-type-dependent iron localizations indicate that the intranasal α-syn PFFs treatment-induced iron depositions in microglia in the substantia nigra may appear as an early cellular response that may initiate neuroinflammation in the dopaminergic system before cell death occurs. Our data suggest that the inhibition of iron deposition may be a potential approach for the early prevention and treatment of PD.

scholarly journals Intracranial self-stimulation and concomitant behaviors following systemic methamphetamine administration in Hnrnph1 mutant mice

2020 ◽  
Author(s):  
Kristyn N. Borrelli ◽  
Carly R. Langan ◽  
Kyra R. Dubinsky ◽  
Karen K. Szumlinski ◽  
William A. Carlezon ◽  
...  
Keyword(s):  
Locomotor Activity ◽  
The United States ◽  
Reward Sensitivity ◽  
Public Health Issue ◽  
Dependent Manner ◽  
Self Administration ◽  
Additional Measure ◽  
Frameshift Deletion ◽  
Self Stimulation ◽  
Dose Dependent

ABSTRACTRationaleAddiction to methamphetamine (MA) is a major public health issue in the United States. While psychostimulant use disorders are heritable, their genetic basis remains poorly understood. We previously identified heterogeneous nuclear ribonucleoprotein H1 (Hnrnph1; H1) as a quantitative trait gene underlying sensitivity to MA-induced locomotor activity. Mice heterozygous for a frameshift deletion in the first coding exon of H1 (H1+/-) showed reduced MA phenotypes including oral self-administration, locomotor activity, dopamine release, and dose-dependent differences in MA conditioned place preference. However, the effects of H1+/- on innate and MA-modulated reward sensitivity are not known.ObjectivesWe examined innate reward sensitivity and modulation by MA in H1+/- mice via intracranial self-stimulation (ICSS).MethodsWe used intracranial self-stimulation (ICSS) of the medial forebrain bundle to assess shifts in reward sensitivity following acute, ascending doses of MA (0.5-4.0 mg/kg, i.p.) using a within-subjects design. We also assessed video-recorded behaviors during ICSS testing sessions.ResultsH1+/- mice displayed reduced normalized maximum response rates, H1+/- females showed lower normalized M50 values compared to wild-type females following MA, and H1+/- influenced ICSS responding relative to maximum baseline rates. There was a dose-dependent reduction in distance to the response wheel following MA administration, providing an additional measure of reward-related behavior.ConclusionsH1+/- mice displayed reduced reward facilitation following MA in a sex- and dose-dependent manner. This result expands upon the set of MA-induced phenotypes observed in H1+/- mice.

scholarly journals Exposure to Sub-Lethal Doses of Permethrin Is Associated with Neurotoxicity: Changes in Bioenergetics, Redox Markers, Neuroinflammation and Morphology

Toxics ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 337
Author(s):  
Teresita Guadalupe López-Aceves ◽  
Elvia Coballase-Urrutia ◽  
Francisco Estrada-Rojo ◽  
América Vanoye-Carlo ◽  
Liliana Carmona-Aparicio ◽  
...  
Keyword(s):  
Cell Damage ◽  
Brain Regions ◽  
Protein Carbonyl ◽  
Histopathological Analysis ◽  
Synthetic Pyrethroids ◽  
Dependent Manner ◽  
Mitochondrial Uncoupling ◽  
Respiratory Parameters ◽  
Species Production ◽  
Dose Dependent

Permethrin (PERM) is a member of the class I family of synthetic pyrethroids. Human use has shown that it affects different systems, with wide health dysfunctions. Our aim was to determine bioenergetics, neuroinflammation and morphology changes, as redox markers after subacute exposure to PERM in rats. We used MDA determination, protein carbonyl assay, mitochondrial O2 consumption, expression of pro-inflammatory cytokines and a deep histopathological analysis of the hippocampus. PERM (150 mg/kg and 300 mg/kg body weight/day, o.v.) increased lipoperoxidation and carbonylated proteins in a dose-dependent manner in the brain regions. The activities of antioxidant enzymes glutathione peroxidase, reductase, S-transferase, catalase, and superoxide dismutase showed an increase in all the different brain areas, with dose-dependent effects in the cerebellum. Cytokine profiles (IL-1β, IL-6 and TNF-α) increased in a dose-dependent manner in different brain tissues. Exposure to 150 mg/kg of permethrin induced degenerated and/or dead neurons in the rat hippocampus and induced mitochondrial uncoupling and reduction of oxidative phosphorylation and significantly decreased the respiratory parameters state 3-associated respiration in complex I and II. PERM exposure at low doses induces reactive oxygen species production and imbalance in the enzymatic antioxidant system, increases gene expression of pro-inflammatory interleukins, and could lead to cell damage mediated by mitochondrial functional impairment.

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