Publications by authors named "Maria A de Souza Silva"

60 Publications

The medial prefrontal cortex - hippocampus circuit that integrates information of object, place and time to construct episodic memory in rodents: Behavioral, anatomical and neurochemical properties.

Neurosci Biobehav Rev 2020 06 13;113:373-407. Epub 2020 Apr 13.

Center for Behavioral Neuroscience, Institute of Experimental Psychology, Heinrich-Heine University, Düsseldorf, Germany. Electronic address:

Rats and mice have been demonstrated to show episodic-like memory, a prototype of episodic memory, as defined by an integrated memory of the experience of an object or event, in a particular place and time. Such memory can be assessed via the use of spontaneous object exploration paradigms, variably designed to measure memory for object, place, temporal order and object-location inter-relationships. We review the methodological properties of these tests, the neurobiology about time and discuss the evidence for the involvement of the medial prefrontal cortex (mPFC), entorhinal cortex (EC) and hippocampus, with respect to their anatomy, neurotransmitter systems and functional circuits. The systematic analysis suggests that a specific circuit between the mPFC, lateral EC and hippocampus encodes the information for event, place and time of occurrence into the complex episodic-like memory, as a top-down regulation from the mPFC onto the hippocampus. This circuit can be distinguished from the neuronal component memory systems for processing the individual information of object, time and place.
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http://dx.doi.org/10.1016/j.neubiorev.2020.04.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7302494PMC
June 2020

Intranasal pregnenolone increases acetylcholine in frontal cortex, hippocampus, and amygdala-Preferentially in the hemisphere ipsilateral to the injected nostril.

J Neurochem 2020 04 12;153(2):189-202. Epub 2019 Dec 12.

M et P Pharma AG, Emetten, Switzerland.

This study determined the effects of intranasal pregnenolone (IN-PREG) on acetylcholine (ACh) levels in selected areas of the rat brain, using in vivo microdialysis. Previous studies showed that PREG rapidly reaches the rodent brain after intranasal administration and that direct infusion of PREG and PREG-S into the basal forebrain modulates ACh release in frontal cortex, amygdala, and hippocampus. In the present study, we investigated the effects of IN-PREG on the cholinergic system in the rat brain. In the first experiment, IN-PREG (5.6 and 11.2 mg/ml) or vehicle was applied bilaterally, and we hypothesized that IN-PREG would increase ACh levels in amygdala, hippocampus, and frontal cortex, relative to baseline and vehicle. Dialysate was collected for 100 min, based on pilot data of duration of effect. Bilateral IN-PREG (5.6 and 11.2 mg/ml) increased frontal cortex and hippocampal ACh relative to both baseline and vehicle. Moreover, 11.2 mg/ml PREG increased ACh in the amygdala relative to baseline, the lower dose, and vehicle. Therefore, in the second experiment, IN-PREG (11.2 mg/ml) was applied only into one nostril, with vehicle applied into the other nostril, in order to determine whether ACh is predominantly increased in the ipsilateral relative to the contralateral amygdala. Unilateral application of IN-PREG increased ACh in the ipsilateral amygdala, whereas no effect was observed on the contralateral side, suggesting that PREG was transported from the nostrils to the brain via the olfactory epithelial pathway, but not by circulation. The present data provide additional information on IN-PREG action in the cholinergic system of frontal cortex, amygdala, and hippocampus. This may be relevant for therapeutic IN application of PREG in neurogenerative and neuropsychiatric disorders.
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http://dx.doi.org/10.1111/jnc.14923DOI Listing
April 2020

Disrupted-in-Schizophrenia 1 (DISC1) Overexpression and Juvenile Immune Activation Cause Sex-Specific Schizophrenia-Related Psychopathology in Rats.

Front Psychiatry 2019 9;10:222. Epub 2019 Apr 9.

Department of Psychiatry and Psychotherapy, University Hospital, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.

Synaptic pruning is a critical refinement step during neurodevelopment, and schizophrenia has been associated with overpruning of cortical dendritic spines. Both human studies and animal models implicate disrupted-in-schizophrenia 1 (DISC1) gene as a strong susceptibility factor for schizophrenia. Accumulating evidence supports the involvement of DISC1 protein in the modulation of synaptic elimination during critical periods of neurodevelopment and of dopamine D2-receptor-mediated signaling during adulthood. In many species, synaptic pruning occurs during juvenile and adolescent periods and is mediated by microglia, which can be over-activated by an immune challenge, giving rise to overpruning. Therefore, we sought to investigate possible interactions between a transgenic DISC1 model (tgDISC1) and juvenile immune activation (JIA) by the bacterial cell wall endotoxin lipopolysaccharide on the induction of schizophrenia-related behavioral and neurochemical disruptions in adult female and male rats. We examined possible behavioral aberrations along three major symptom dimensions of schizophrenia including psychosis, social and emotional disruptions, and cognitive impairments. We detected significant gene-environment interactions in the amphetamine-induced locomotion in female animals and in the amphetamine-induced anxiety in male animals. Surprisingly, gene-environment interactions improved social memory in both male and female animals. JIA alone disrupted spatial memory and recognition memory, but only in male animals. DISC1 overexpression alone induced an improvement in sensorimotor gating, but only in female animals. Our neurochemical analyses detected sex- and manipulation-dependent changes in the postmortem monoamine content of animals. Taken together, we here report sex-specific effects of environment and genotype as well as their interaction on behavioral phenotypes and neurochemical profiles relevant for schizophrenia.
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http://dx.doi.org/10.3389/fpsyt.2019.00222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6465888PMC
April 2019

Aβ dimers induce behavioral and neurochemical deficits of relevance to early Alzheimer's disease.

Neurobiol Aging 2018 09 17;69:1-9. Epub 2018 Apr 17.

Center for Behavioral Neuroscience, Institute of Experimental Psychology, University of Düsseldorf, Düsseldorf, Germany.

We examined behaviors and neurotransmitter levels in the tgDimer mouse, a model for early Alzheimer's disease, that expresses exclusively soluble amyloid beta (Aβ) dimers and is devoid of Aβ plaques, astrogliosis, and neuroinflammation. Seven-month-old mice were subjected to tests of motor activity, attention, anxiety, habituation learning, working memory, and depression-related behaviors. They were impaired in nonselective attention and motor learning and showed anxiety- and despair-related behaviors. In 7- and 12-month-old mice, levels of acetylcholine, dopamine, and serotonin were measured in neostriatum, ventral striatum, prefrontal cortex, hippocampus, amygdala, and entorhinal cortex by high-performance liquid chromatography. The tgDimer mice had lower serotonin turnover rates in hippocampus, ventral striatum, and amygdala relative to wild type controls. The aged tgDimer mice had less hippocampal acetylcholine than adult tgDimers. Stress-test results, based on corticosterone levels, indicated an intact hypothalamus-pituitary-adrenal axis in 12-month-old mice. Since neither Aβ plaques nor astrogliosis or neuroinflammation was responsible for these phenotypes, we conclude that Aβ dimers contribute to neurotransmitter dysfunction and behavioral impairments, characteristic for the early stages of Alzheimer's disease.
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http://dx.doi.org/10.1016/j.neurobiolaging.2018.04.005DOI Listing
September 2018

GABAergic Control of Nigrostriatal and Mesolimbic Dopamine in the Rat Brain.

Front Behav Neurosci 2018 14;12:38. Epub 2018 Mar 14.

Clinic of Nuclear Medicine, University Hospital Düsseldorf, Düsseldorf, Germany.

The present study assessed the effects of the GABA receptor (R) agonist muscimol (MUS), and the GABAR antagonist bicuculline (BIC) on neocortical and subcortical radioligand binding to dopamine DRs in relation to motor and exploratory behaviors in the rat. DR binding was measured with small animal SPECT in baseline and after challenge with either 1 mg/kg MUS or 1 mg/kg BIC, using [I]IBZM as radioligand. Motor/exploratory behaviors were assessed for 30 min in an open field prior to radioligand administration. Anatomical information was gained with a dedicated small animal MRI tomograph. Based on the Paxinos rat brain atlas, regions of interest were defined on SPECT-MRI overlays. Estimations of the binding potentials in baseline and after challenges were obtained by computing ratios of the specifically bound compartments to the cerebellar reference region. After MUS, DR binding was significantly reduced in caudateputamen, nucleus accumbens, thalamus, substania nigra/ventral tegmental area, and posterior hippocampus relative to baseline (0.005 ≤ ≤ 0.012). In all these areas, except for the thalamus, DR binding was negatively correlated with grooming in the first half and positively correlated with various motor/exploratory behaviors in the second half of the testing session. After BIC, DR binding was significantly elevated in caudateputamen ( = 0.022) and thalamus ( = 0.047) relative to baseline. DR binding in caudateputamen and thalamus was correlated negatively with sitting duration and sitting frequency and positively with motor/exploratory behaviors in the first half of the testing time. Findings indicate direct GABAergic control over nigrostriatal and mesolimbic dopamine levels in relation to behavioral action. This may be of relevance for neuropsychiatric conditions such as anxiety disorder and schizophrenia, which are characterized by both dopaminergic and GABAergic dysfunction.
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http://dx.doi.org/10.3389/fnbeh.2018.00038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5862131PMC
March 2018

Quantitative Proteomics of Synaptosomal Fractions in a Rat Overexpressing Human DISC1 Gene Indicates Profound Synaptic Dysregulation in the Dorsal Striatum.

Front Mol Neurosci 2018 6;11:26. Epub 2018 Feb 6.

Department of Neuroproteomics, Paracelsus Private Medical University, Salzburg, Austria.

Disrupted-in-schizophrenia 1 (DISC1) is a key protein involved in behavioral processes and various mental disorders, including schizophrenia and major depression. A transgenic rat overexpressing non-mutant human DISC1, modeling aberrant proteostasis of the DISC1 protein, displays behavioral, biochemical and anatomical deficits consistent with aspects of mental disorders, including changes in the dorsal striatum, an anatomical region critical in the development of behavioral disorders. Herein, dorsal striatum of 10 transgenic DISC1 (tgDISC1) and 10 wild type (WT) littermate control rats was used for synaptosomal preparations and for performing liquid chromatography-tandem mass spectrometry (LC-MS)-based quantitative proteomics, using isobaric labeling (TMT10plex). Functional enrichment analysis was generated from proteins with level changes. The increase in DISC1 expression leads to changes in proteins and synaptic-associated processes including membrane trafficking, ion transport, synaptic organization and neurodevelopment. Canonical pathway analysis assigned proteins with level changes to actin cytoskeleton, Gαq, Rho family GTPase and Rho GDI, axonal guidance, ephrin receptor and dopamine-DARPP32 feedback in cAMP signaling. DISC1-regulated proteins proposed in the current study are also highly associated with neurodevelopmental and mental disorders. Bioinformatics analyses from the current study predicted that the following biological processes may be activated by overexpression of DISC1, i.e., regulation of cell quantities, neuronal and axonal extension and long term potentiation. Our findings demonstrate that the effects of overexpression of non-mutant DISC1 or its misassembly has profound consequences on protein networks essential for behavioral control. These results are also relevant for the interpretation of previous as well as for the design of future studies on DISC1.
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http://dx.doi.org/10.3389/fnmol.2018.00026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5808171PMC
February 2018

Deficits in episodic memory and mental time travel in patients with post-traumatic stress disorder.

Prog Neuropsychopharmacol Biol Psychiatry 2018 04 26;83:42-54. Epub 2017 Dec 26.

Mental Health Research and Treatment Center, Ruhr-University Bochum, Bochum, Germany.

Post-traumatic stress disorder (PTSD) is characterized by impairments in mnestic functions, especially in the domain of episodic memory. These alterations might affect different aspects of episodic memory functioning. Here we tested PTSD patients and healthy controls (matched for age, sex and education) in a newly developed virtual reality episodic memory test (VR-EMT), a test for mental time travel, episodic future thinking, and prospective memory (M3xT). In a cross-validation experiment, their performance was further evaluated in the Rivermead Behavioral Memory Test (RBMT). PTSD patients demonstrated impairments in episodic memory formation and mental time travel and showed difficulties in utilizing information from episodic memory to solve problems. Diminished attention and concentration in PTSD did not account for performance deficits in these tasks but higher levels of negative arousal were found in PTSD patients. Furthermore, performance in the VR-EMT and RBMT in PTSD patients correlated negatively with self-reported measures of stress and depression. Our results suggest that deficits in episodic memory formation and mental time travel in PTSD lead to difficulties in utilizing the content of episodic memories for solving problems in the present or to plan future behavior. Clinical implications of these findings and suggestions for cognitive-behavioral treatment of PTSD are discussed.
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http://dx.doi.org/10.1016/j.pnpbp.2017.12.014DOI Listing
April 2018

Interaction between the medial prefrontal cortex and hippocampal CA1 area is essential for episodic-like memory in rats.

Neurobiol Learn Mem 2017 May 3;141:72-77. Epub 2017 Apr 3.

Center for Behavioral Neuroscience, University of Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany. Electronic address:

The interplay between medial prefrontal cortex (mPFC) and hippocampus, particularly the hippocampal CA3 area, is critical for episodic memory. To what extent the mPFC also interacts with the hippocampus CA1 subregion still requires elucidation. To investigate this issue, male rats received unilateral N-methyl--aspartate lesions of the mPFC together with unilateral lesions of the hippocampal CA1 area, either in the same (control) or in the opposite hemispheres (disconnection). They underwent an episodic-like memory test, combining what-where-when information, and separate tests for novel object preference (what), object place preference (where) and temporal order memory (when). Compared to controls, the disconnected mPFC-CA1 rats exhibited disrupted episodic-like memory with an impaired integration of the what-where-when elements. Both groups showed intact memories for what and when, while only the control group showed intact memory for where. These findings suggest that the functional interaction of the mPFC-CA1 circuit is crucial for the processing of episodic memory and, in particular, for the integration of the spatial memory component.
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http://dx.doi.org/10.1016/j.nlm.2017.03.019DOI Listing
May 2017

Chronic corticosterone treatment enhances extinction-induced depression in aged rats.

Horm Behav 2016 11 12;86:21-26. Epub 2016 Sep 12.

Center for Behavioral Neuroscience, Institute of Experimental Psychology, Heinrich-Heine-University of Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany.

Withdrawal and avoidance behavior are common symptoms of depression and can appear as a consequence of absence of reward, i.e. extinction-induced depression (EID). This is particularly relevant for the aged organism subjected to pronounced loss of former rewards. Avoidance of the former site of reward and increased withdrawal into a distant compartment accompany extinction of food-rewarded behavior in rodent models. During extinction, behavioral markers for re-learning dissociate from indicators of extinction-induced depression. Here we examined the effect of a chronic treatment with corticosterone (CORT), a well-known inducer of depression-related behavior, on EID in adult and aged rats. Adult (3-4months) and aged (18months) male rats were treated with CORT via drinking water for 3weeks prior to extinction of a cued food-reward task. CORT treatment increased the distance from the site of reward and decreased goal tracking behavior during extinction, especially in the aged rats. Plasma hormone levels measured before and after restraint stress showed a decline in basal ACTH- and CORT-levels after chronic CORT treatment in aged animals. The treatment significantly impaired the HPA-axis activation after acute stress in both, adult and aged animals, alike. Altogether, these findings show an enhancement of EID after chronic CORT treatment in the aged organism, which may be mediated by an impaired HPA-axis sensitivity. These findings may have special relevance for the investigation of human geriatric depression.
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http://dx.doi.org/10.1016/j.yhbeh.2016.09.003DOI Listing
November 2016

Promnestic effects of intranasally applied pregnenolone in rats.

Neurobiol Learn Mem 2016 09 14;133:185-195. Epub 2016 Jul 14.

Oceanographic Center, Nova Southeastern University, Fort Lauderdale, FL 33314, USA; M et P Pharma AG, 6376 Emmetten, Switzerland. Electronic address:

The neurosteroid pregnenolone (PREG) has been shown to have memory-enhancing and anti-depressant action. The present study addresses the question of whether intranasally applied pregnenolone (IN-PREG) also has promnestic properties in the rat. We examined the effects of IN-PREG at doses of 0.187 and 0.373mg/kg on memory for objects and their location on learning and retention of escape in a water maze, and on behavior on the elevated plus maze. The main findings were: (a) Pre-trial, but not post-trial, administration of IN-PREG facilitated long-term memory in a novel object-preference test and a novel object-location preference test when tested 48h after dosing. (b) Over the duration of 5days of extinction trials, after learning to escape onto a hidden platform in a water maze, the animals treated with IN-PREG spent more time in searching for the absent platform, indicating either, or both, superior memory for the former position of the escape platform, or a higher resistance to extinction. (c) Administration of the anticholinergic, scopolamine, disrupted learning to escape from the water maze in the vehicle-treated group. The IN-PREG treated groups exhibited superior escape learning in comparison with vehicle controls, indicating that the treatment countered the scopolamine effect. IN-PREG treatment had no influence on behaviors on the elevated plus maze. Our results demonstrate that IN-PREG is behaviorally active with cognitive enhancing properties comparable to those known from studies employing systemic PREG administration.
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http://dx.doi.org/10.1016/j.nlm.2016.07.012DOI Listing
September 2016

Intranasal Dopamine Reduces In Vivo [(123)I]FP-CIT Binding to Striatal Dopamine Transporter: Correlation with Behavioral Changes and Evidence for Pavlovian Conditioned Dopamine Response.

Front Behav Neurosci 2016 22;10:80. Epub 2016 Apr 22.

Clinic of Nuclear Medicine, University Hospital Düsseldorf Düsseldorf, Germany.

Purpose: Dopamine (DA), which does not cross the blood-brain barrier, has central and behavioral effects when administered via the nasal route. Neither the mechanisms of central action of intranasal dopamine (IN-DA), nor its mechanisms of diffusion and transport into the brain are well understood. We here examined whether IN-DA application influences dopamine transporter (DAT) binding in the dorsal striatum and assessed the extent of binding in relation to motor and exploratory behaviors. We hypothesized that, based on the finding of increased extracellular DA in the striatum induced by application of IN-DA, binding of [(123)I]FP-CIT to the DAT should be decreased due to competition at the receptor.

Methods: Rats were administered 3 mg/kg IN-DA and vehicle (VEH), with IN-DA injection either preceding or following VEH. Then motor and exploratory behaviors (traveled distance, velocity, center time, sitting, rearing, head-shoulder motility, grooming) were assessed for 30 min in an open field prior to administration of [(123)I]FP-CIT. DAT binding after IN-DA and VEH was measured with small animal SPECT 2 h following administration of the radioligand.

Results: (1) After IN-DA application, striatal DAT binding was significantly lower as compared to VEH, indicating that the nasally delivered DA had central action and increased DA levels comparable to that found previously with L-DOPA administration; and (2) DAT binding in response to intranasal VEH was lower when IN-DA application preceded VEH treatment. This finding is suggestive of Pavlovian conditioning of DA at the level of the DAT, since the DA treatment modified (decreased) the binding in response to the subsequent VEH treatment. VEH treatment also reduced motor and exploratory behaviors more when applied before, as compared to when it followed IN-DA application, also indicative of behavioral Pavlovian conditioning akin to that found upon application of various psychostimulant drugs.

Conclusions:

The Results: (a) demonstrate a direct central action of intranasally applied DA on the DAT in the dorsal striatum, indicating enhanced DA availability; and (b) provide first evidence of a Pavlovian conditioned DA response at the DAT. The latter results have relevance to understanding neurochemical mechanisms that underlie placebo action in the treatment of Parkinsonian patients.
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http://dx.doi.org/10.3389/fnbeh.2016.00080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4840254PMC
May 2016

Corrigendum: Relationship Between L-DOPA-Induced Reduction in Motor and Exploratory Activity and Striatal Dopamine D2 Receptor Binding in the Rat.

Front Behav Neurosci 2016 15;10:36. Epub 2016 Mar 15.

Clinic of Nuclear Medicine, University Hospital Düsseldorf Düsseldorf, Germany.

[This corrects the article on p. 352 in vol. 9, PMID: 26778989.].
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http://dx.doi.org/10.3389/fnbeh.2016.00036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4791392PMC
March 2016

Concurrent assessment of memory for object and place: Evidence for different preferential importance of perirhinal cortex and hippocampus and for promnestic effect of a neurokinin-3 R agonist.

Neurobiol Learn Mem 2016 Apr 17;130:149-58. Epub 2016 Feb 17.

Center for Behavioral Neuroscience, University of Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany. Electronic address:

We here explore the utility of a paradigm that allows the simultaneous assessment of memory for object (what) and object location (where) and their comparative predominance. Two identical objects are presented during a familiarity trial; during the test trial one of these is displaced, and a new object is presented in a familiar location. When tested 5 or 80min later, rats explored both the novel and the displaced objects more than two familiar stationary objects, indicating intact memory for both, object and place. When tested 24h later rats explored the novel object more than the displaced familiar one, suggesting that forgetting differently influenced object and place memory, with memory for object being more robust than memory for place. Animals that received post-trial administration of the neurokinin-3 receptor agonist senktide and were tested 24h later, now explored the novel and displaced objects equally, suggesting that the treatment prevented the selective decay of memory for location. Next, animals received NMDA lesions in either the perirhinal cortex or the hippocampus, which are hypothesized to be preferentially involved in memory for objects and memory for place, respectively. When tested 5 or 80min later, the perirhinal cortex lesion group explored the displaced object more, indicating relatively deficient object memory, while the hippocampal lesion led to the opposite pattern, demonstrating comparatively deficient place memory. These results suggest different preferential engagement of the perirhinal cortex and hippocampus in their processing of memory for object and place. This preference test lends itself to application in the comparison of selective lesions of neural sites and projection systems as well as to the assessment of possible preferential action of pharmacological agents on neurochemical processes that subserve object vs place learning.
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http://dx.doi.org/10.1016/j.nlm.2016.02.007DOI Listing
April 2016

A sphingolipid mechanism for behavioral extinction.

J Neurochem 2016 05 15;137(4):589-603. Epub 2016 Mar 15.

Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.

Reward-dependent instrumental behavior must continuously be re-adjusted according to environmental conditions. Failure to adapt to changes in reward contingencies may incur psychiatric disorders like anxiety and depression. When an expected reward is omitted, behavior undergoes extinction. While extinction involves active re-learning, it is also accompanied by emotional behaviors indicative of frustration, anxiety, and despair (extinction-induced depression). Here, we report evidence for a sphingolipid mechanism in the extinction of behavior. Rapid extinction, indicating efficient re-learning, coincided with a decrease in the activity of the enzyme acid sphingomyelinase (ASM), which catalyzes turnover of sphingomyelin to ceramide, in the dorsal hippocampus of rats. The stronger the decline in ASM activity, the more rapid was the extinction. Sphingolipid-focused lipidomic analysis showed that this results in a decline of local ceramide species in the dorsal hippocampus. Ceramides shape the fluidity of lipid rafts in synaptic membranes and by that way can control neural plasticity. We also found that aging modifies activity of enzymes and ceramide levels in selective brain regions. Aging also changed how the chronic treatment with corticosterone (stress) or intranasal dopamine modified regional enzyme activity and ceramide levels, coinciding with rate of extinction. These data provide first evidence for a functional ASM-ceramide pathway in the brain involved in the extinction of learned behavior. This finding extends the known cellular mechanisms underlying behavioral plasticity to a new class of membrane-located molecules, the sphingolipids, and their regulatory enzymes, and may offer new treatment targets for extinction- and learning-related psychopathological conditions. Sphingolipids are common lipids in the brain which form lipid domains at pre- and postsynaptic membrane compartments. Here we show a decline in dorsal hippocampus ceramide species together with a reduction of acid sphingomyelinase activity during extinction of conditioned behavior in rats. This reduction was associated with expression of re-learning-related behavior, but not with emotional behaviors. Read the Editorial Highlight for this article on page 485.
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http://dx.doi.org/10.1111/jnc.13537DOI Listing
May 2016

Relationship Between L-DOPA-Induced Reduction in Motor and Exploratory Activity and Striatal Dopamine D2 Receptor Binding in the Rat.

Front Behav Neurosci 2015 6;9:352. Epub 2016 Jan 6.

Clinic of Nuclear Medicine, University Hospital Düsseldorf Düsseldorf, Germany.

Purpose: The present study assessed the influence of L-DOPA administration on neostriatal dopamine (DA) D2 receptor binding in relation to motor and exploratory behaviors in the rat.

Methods: D2 receptor binding was measured in baseline, after challenge with the aromatic L-amino acid decarboxylase inhibitor benserazide, and after challenge with either 5 or 10 mg/kg L-DOPA plus benserazide. Additional rats received injections of saline. For baseline and challenges, striatal equilibrium ratios (V[Formula: see text]) were computed as estimation of the binding potential. Motor and exploratory behaviors were assessed for 30 min in an open field prior to administration of [(123)I]IBZM. D2 receptor binding was measured with small animal SPECT 2 h after radioligand administration for 60 min.

Results: Both L-DOPA doses significantly reduced D2 receptor binding relative to baseline and led to significantly less ambulation, less head-shoulder motility, and more sitting relative to saline. Moreover, 10 mg/kg L-DOPA induced less head-shoulder motility, more sitting, and more grooming than 5 mg/kg L-DOPA. Analysis of time-behavior curves showed that L-DOPA-treated animals relative to saline exhibited a faster rate of decrease of ambulation frequency and a slower rate of decrease of both duration and frequency of head-shoulder motility from a lower maximum level.

Conclusions: The reductions of striatal D2 receptor binding after L-DOPA may be conceived to reflect elevated concentrations of synaptic DA. L-DOPA-treated animals showed less ambulation and less head-shoulder motility than saline-treated animals, indicating an association between less behavioral activity and increased availability of striatal DA. The faster rate of decrease of ambulation frequency and the lower maximum levels of both head-shoulder motility duration and frequency may be interpreted in terms of influence of increased DA availability on behavioral habituation to a novel environment.
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http://dx.doi.org/10.3389/fnbeh.2015.00352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4701934PMC
January 2016

Amyloid-β dimers in the absence of plaque pathology impair learning and synaptic plasticity.

Brain 2016 Feb 10;139(Pt 2):509-25. Epub 2015 Dec 10.

1 Department Neuropathology, Heinrich Heine University, Düsseldorf, Germany.

Despite amyloid plaques, consisting of insoluble, aggregated amyloid-β peptides, being a defining feature of Alzheimer's disease, their significance has been challenged due to controversial findings regarding the correlation of cognitive impairment in Alzheimer's disease with plaque load. The amyloid cascade hypothesis defines soluble amyloid-β oligomers, consisting of multiple amyloid-β monomers, as precursors of insoluble amyloid-β plaques. Dissecting the biological effects of single amyloid-β oligomers, for example of amyloid-β dimers, an abundant amyloid-β oligomer associated with clinical progression of Alzheimer's disease, has been difficult due to the inability to control the kinetics of amyloid-β multimerization. For investigating the biological effects of amyloid-β dimers, we stabilized amyloid-β dimers by an intermolecular disulphide bridge via a cysteine mutation in the amyloid-β peptide (Aβ-S8C) of the amyloid precursor protein. This construct was expressed as a recombinant protein in cells and in a novel transgenic mouse, termed tgDimer mouse. This mouse formed constant levels of highly synaptotoxic soluble amyloid-β dimers, but not monomers, amyloid-β plaques or insoluble amyloid-β during its lifespan. Accordingly, neither signs of neuroinflammation, tau hyperphosphorylation or cell death were observed. Nevertheless, these tgDimer mice did exhibit deficits in hippocampal long-term potentiation and age-related impairments in learning and memory, similar to what was observed in classical Alzheimer's disease mouse models. Although the amyloid-β dimers were unable to initiate the formation of insoluble amyloid-β aggregates in tgDimer mice, after crossbreeding tgDimer mice with the CRND8 mouse, an amyloid-β plaque generating mouse model, Aβ-S8C dimers were sequestered into amyloid-β plaques, suggesting that amyloid-β plaques incorporate neurotoxic amyloid-β dimers that by themselves are unable to self-assemble. Our results suggest that within the fine interplay between different amyloid-β species, amyloid-β dimer neurotoxic signalling, in the absence of amyloid-β plaque pathology, may be involved in causing early deficits in synaptic plasticity, learning and memory that accompany Alzheimer's disease.
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http://dx.doi.org/10.1093/brain/awv355DOI Listing
February 2016

The medial prefrontal cortex-lateral entorhinal cortex circuit is essential for episodic-like memory and associative object-recognition.

Hippocampus 2016 May 5;26(5):633-45. Epub 2015 Nov 5.

Center for Behavioral Neuroscience, University of Düsseldorf, Universitätsstr. 1, Düsseldorf, 40225, Germany.

The prefrontal cortex directly projects to the lateral entorhinal cortex (LEC), an important substrate for engaging item-associated information and relaying the information to the hippocampus. Here we ask to what extent the communication between the prefrontal cortex and LEC is critically involved in the processing of episodic-like memory. We applied a disconnection procedure to test whether the interaction between the medial prefrontal cortex (mPFC) and LEC is essential for the expression of recognition memory. It was found that male rats that received unilateral NMDA lesions of the mPFC and LEC in the same hemisphere, exhibited intact episodic-like (what-where-when) and object-recognition memories. When these lesions were placed in the opposite hemispheres (disconnection), episodic-like and associative memories for object identity, location and context were impaired. However, the disconnection did not impair the components of episodic memory, namely memory for novel object (what), object place (where) and temporal order (when), per se. Thus, the present findings suggest that the mPFC and LEC are a critical part of a neural circuit that underlies episodic-like and associative object-recognition memory.
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http://dx.doi.org/10.1002/hipo.22547DOI Listing
May 2016

Evidence for a Specific Integrative Mechanism for Episodic Memory Mediated by AMPA/kainate Receptors in a Circuit Involving Medial Prefrontal Cortex and Hippocampal CA3 Region.

Cereb Cortex 2016 07 5;26(7):3000-9. Epub 2015 Jun 5.

Center for Behavioral Neuroscience, University of Düsseldorf, Düsseldorf 40225, Germany.

We asked whether episodic-like memory requires neural mechanisms independent of those that mediate its component memories for "what," "when," and "where," and if neuronal connectivity between the medial prefrontal cortex (mPFC) and the hippocampus (HPC) CA3 subregion is essential for episodic-like memory. Unilateral lesion of the mPFC was combined with unilateral lesion of the CA3 in the ipsi- or contralateral hemispheres in rats. Episodic-like memory was tested using a task, which assesses the integration of memories for "what, where, and when" concomitantly. Tests for novel object recognition (what), object place (where), and temporal order memory (when) were also applied. Bilateral disconnection of the mPFC-CA3 circuit by N-methyl-d-aspartate (NMDA) lesions disrupted episodic-like memory, but left the component memories for object, place, and temporal order, per se, intact. Furthermore, unilateral NMDA lesion of the CA3 plus injection of (6-cyano-7-nitroquinoxaline-2,3-dione) (CNQX) (AMPA/kainate receptor antagonist), but not AP-5 (NMDA receptor antagonist), into the contralateral mPFC also disrupted episodic-like memory, indicating the mPFC AMPA/kainate receptors as critical for this circuit. These results argue for a selective neural system that specifically subserves episodic memory, as it is not critically involved in the control of its component memories for object, place, and time.
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http://dx.doi.org/10.1093/cercor/bhv112DOI Listing
July 2016

Neuropharmacology of light-induced locomotor activation.

Neuropharmacology 2015 Aug 2;95:243-51. Epub 2015 Apr 2.

Department of Psychiatry and Psychotherapy, Friedrich-Alexander-University Erlangen-Nuremberg, Schwabachanlage 6, 91054 Erlangen, Germany. Electronic address:

Presentation of non-aversive light stimuli for several seconds was found to reliably induce locomotor activation and exploratory-like activity. Light-induced locomotor activity (LIA) can be considered a convenient simple model to study sensory-motor activation. LIA was previously shown to coincide with serotonergic and dopaminergic activation in specific cortical areas in freely moving and anesthetized animals. In the present study we explore the neuropharmacology of LIA using a receptor antagonist/agonist approach in rats. The non-selective 5-HT2-receptor antagonist ritanserin (1.5-6 mg/kg, i.p.) dose-dependently reduced LIA. Selective antagonism of either the 5-HT2A-receptor by MDL 11,939 (0.1-0.4 mg/kg, i.p.), or the 5-HT2C-receptor by SDZ SER 082 (0.125-0.5 mg/kg, i.p.), alone or in combination, had no significant influence on LIA. Also the selective 5-HT1A-receptor antagonist, WAY 100635 (0.4 mg/kg, i.p.) did not affect LIA. Neither did the preferential dopamine D2-receptor antagonist, haloperidol (0.025-0.1 mg/kg, i.p.) nor the D2/D3-receptor agonist, quinpirole (0.025-0.5 mg/kg, i.p.) affect the expression of LIA. However, blocking the glutamatergic NMDA-receptor with phencyclidine (PCP, 1.5-6 mg/kg, i.p.) dose-dependently reduced LIA. This effect was also observed with ketamine (10 mg/kg, i.p.). These findings suggest that serotonin and dopamine receptors abundantly expressed in the cortex do not mediate light-stimulus triggered locomotor activity. PCP and ketamine effects, however, suggest an important role of NMDA receptors in LIA.
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http://dx.doi.org/10.1016/j.neuropharm.2015.03.023DOI Listing
August 2015

The neurokinin-3 receptor agonist senktide facilitates the integration of memories for object, place and temporal order into episodic memory.

Neurobiol Learn Mem 2014 Oct 24;114:178-85. Epub 2014 Jun 24.

Center for Behavioral Neuroscience, Institute of Experimental Psychology, University of Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany.

Senktide, a potent neurokinin-3 receptor (NK3-R) agonist, has been shown to have promnestic effects in adult and aged rodents and to facilitate episodic-like memory (ELM) in mice when administrated before the learning trial. In the present study we assessed the effects of senktide on memory consolidation by administering it post-trial (after the learning trial) in adult rats. We applied an ELM test, based on the integrated memory for object, place and temporal order, which we developed (Kart-Teke, de Souza Silva, Huston, & Dere, 2006). This test involves two learning trials and one test trial. We examined intervals of 1h and 23 h between the learning and test trials (experiment 1) in untreated animals and found that they exhibited intact ELM after a delay of 1 h, but not 23 h. In another test for ELM performed 7 days later, vehicle or senktide (0.2 mg/kg, s.c.) was applied immediately after the second learning trial and the test was conducted 23 h later (experiment 2). Senktide treatment recovered components of ELM (memory for place and object) compared with vehicle-treated animals. After one more week, vehicle or senktide (0.2 mg/kg, s.c.) was applied post-trial and the test conducted 6h later (experiment 3). The senktide-treated group exhibited intact ELM, unlike the vehicle-treated group. Finally, animals received post-trial treatment with either vehicle or SR142801, a selective NK3-R antagonist (6 mg/kg, i.p.), 1 min before senktide injection (0.2 mg/kg, s.c.) in the ELM paradigm and were tested 6h later (experiment 4). The vehicle+senktide group showed intact ELM, while the SR142801+senktide group did not. The results indicate that senktide facilitated the consolidation or the expression of ELM and that the senktide effect was NK3-R dependent.
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http://dx.doi.org/10.1016/j.nlm.2014.06.009DOI Listing
October 2014

NK₃ receptor agonism reinstates temporal order memory in the hemiparkinsonian rat.

Behav Brain Res 2015 May 11;285:208-12. Epub 2014 Jun 11.

Center for Behavioral Neuroscience, University of Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany.

Animals treated with unilateral 6-hydroxydopamine (6-ODHA) injections, an animal model of Parkinson's disease, exhibit deficits in memory for temporal order, but show intact novel object recognition. Since senktide, a potent neurokinin-3 receptor (NK3-R) agonist, has been shown to have promnestic effects in the aged rat and to alleviate scopolamine-induced impairment, the present study aimed to assess possible promnestic effects of senktide in the hemiparkinsonian rat model. Animals received unilateral 6-ODHA microinjections into the medial forebrain bundle. Two weeks later, they were randomly assigned to treatment with vehicle, 0.2, or 0.4 mg/kg senktide. Temporal order memory and place recognition tests were conducted, locomotor activity and turning behavior were assessed in the open field and anxiety-related behavior was measured in the light-dark box. Treatments were administered 30 min prior to behavioral testing with an interval of seven days between tests. The animals treated with 0.2 mg/kg senktide exhibited temporal order memory, unlike the vehicle-treated group. No significant treatment effects were found in the open field and light-dark box. Administration of 0.2 mg/kg senktide may influence the prefrontal cortex and hippocampus, leading to compensations for deficits in memory for temporal order.
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http://dx.doi.org/10.1016/j.bbr.2014.06.006DOI Listing
May 2015

Generation of topically transgenic rats by in utero electroporation and in vivo bioluminescence screening.

J Vis Exp 2013 Sep 24(79):e50146. Epub 2013 Sep 24.

Department of Neuropathology, Medical School Düsseldorf.

In utero electroporation (IUE) is a technique which allows genetic modification of cells in the brain for investigating neuronal development. So far, the use of IUE for investigating behavior or neuropathology in the adult brain has been limited by insufficient methods for monitoring of IUE transfection success by non-invasive techniques in postnatal animals. For the present study, E16 rats were used for IUE. After intraventricular injection of the nucleic acids into the embryos, positioning of the tweezer electrodes was critical for targeting either the developing cortex or the hippocampus. Ventricular co-injection and electroporation of a luciferase gene allowed monitoring of the transfected cells postnatally after intraperitoneal luciferin injection in the anesthetized live P7 pup by in vivo bioluminescence, using an IVIS Spectrum device with 3D quantification software. Area definition by bioluminescence could clearly differentiate between cortical and hippocampal electroporations and detect a signal longitudinally over time up to 5 weeks after birth. This imaging technique allowed us to select pups with a sufficient number of transfected cells assumed necessary for triggering biological effects and, subsequently, to perform behavioral investigations at 3 month of age. As an example, this study demonstrates that IUE with the human full length DISC1 gene into the rat cortex led to amphetamine hypersensitivity. Co-transfected GFP could be detected in neurons by post mortem fluorescence microscopy in cryosections indicating gene expression present at ≥6 months after birth. We conclude that postnatal bioluminescence imaging allows evaluating the success of transient transfections with IUE in rats. Investigations on the influence of topical gene manipulations during neurodevelopment on the adult brain and its connectivity are greatly facilitated. For many scientific questions, this technique can supplement or even replace the use of transgenic rats and provide a novel technology for behavioral neuroscience.
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http://dx.doi.org/10.3791/50146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3935637PMC
September 2013

Neurokinin3 receptor as a target to predict and improve learning and memory in the aged organism.

Proc Natl Acad Sci U S A 2013 Sep 27;110(37):15097-102. Epub 2013 Aug 27.

Center for Behavioral Neuroscience, Institute of Experimental Psychology, University of Düsseldorf, 40225 Düsseldorf, Germany.

Impaired learning and memory performance is often found in aging as an early sign of dementia. It is associated with neuronal loss and reduced functioning of cholinergic networks. Here we present evidence that the neurokinin3 receptors (NK3-R) and their influence on acetylcholine (ACh) release may represent a crucial mechanism that underlies age-related deficits in learning and memory. Repeated pharmacological stimulation of NK3-R in aged rats was found to improve learning in the water maze and in object-place recognition. This treatment also enhanced in vivo acetylcholinergic activity in the frontal cortex, hippocampus, and amygdala but reduced NK3-R mRNA expression in the hippocampus. Furthermore, NK3-R agonism incurred a significantly higher increase in ACh levels in aged animals that showed superior learning than in those that were most deficient in learning. Our findings suggest that the induced activation of ACh, rather than basal ACh activity, is associated with superior learning in the aged. To test whether natural variation in NK3-R function also determines learning and memory performance in aged humans, we investigated 209 elderly patients with cognitive impairments. We found that of the 15 analyzed single single-nucleotide ploymorphism (SNPs) of the NK3-R-coding gene, TACR3, the rs2765 SNP predicted the degree of impairment of learning and memory in these patients. This relationship could be partially explained by a reduced right hippocampus volume in a subsample of 111 tested dementia patients. These data indicate the NK3-R as an important target to predict and improve learning and memory performance in the aged organism.
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http://dx.doi.org/10.1073/pnas.1306884110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3773732PMC
September 2013

Active avoidance learning in zebrafish (Danio rerio)--the role of sensory modality and inter-stimulus interval.

Behav Brain Res 2013 Jul 17;248:141-3. Epub 2013 Apr 17.

Oceanographic Center, Nova Southeastern University, Dania, FL, USA.

The zebrafish (Danio rerio) promises to meet the growing need of a high throughput model in the fields of gerontological and neurobehavioral research by possessing highly conserved anatomy and physiology with vertebrates, while having low maintenance costs. Here we further explore the conditions of active avoidance learning in zebrafish. Two pairs of distinct aversive conditioning experiments using shuttle boxes were designed to compare the effects of sensory modality and conditioned-unconditioned stimulus interval (CS-US interval) upon memory formation and retention. We found that olfactory conditioning with phenylethyl alcohol as a CS was significantly more likely to produce a successful outcome than with a visual CS. Likewise a 10 s CS-US interval yielded significantly more successful memory formation than a 15 s interval. These conditions may further facilitate the use of zebrafish to explore the genetic and neuronal base of active avoidance learning and its neuropharmacological improvement.
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http://dx.doi.org/10.1016/j.bbr.2013.04.009DOI Listing
July 2013

Animal models of extinction-induced depression: loss of reward and its consequences.

Neurosci Biobehav Rev 2013 Nov 4;37(9 Pt A):2059-70. Epub 2013 Mar 4.

Center for Behavioral Neuroscience, Institute of Experimental Psychology, University of Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany. Electronic address:

The absence or loss of rewards or reinforcers holds a major role in the development of depression in humans. In spite of the prevalence of extinction-induced depression (EID) in humans, few attempts have been made to establish animal models thereof. Here we present the concept of extinction-related depression and summarize the results of two sets of studies in our attempt to create animal models of EID, one set based on extinction after positive reinforcement in the Skinner-box, the other on extinction after negative reinforcement - escape from water. We found various behaviors emitted during the extinction trials that responded to treatment with antidepressant drugs: Accordingly, the important behavioral marker for EID during extinction of escape from the water was immobility. During extinction after positive reinforcement the important indices for extinction-induced depression are the withdrawal from the former site of reward, biting behavior and rearing up on the hind legs. Avoidance behavior and biting may model aspects of human depressive behavior, which may include withdrawal or avoidance as well as aggressive-like behaviors.
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http://dx.doi.org/10.1016/j.neubiorev.2013.02.016DOI Listing
November 2013

What's conditioned in conditioned place preference?

Trends Pharmacol Sci 2013 Mar 4;34(3):162-6. Epub 2013 Feb 4.

Center for Behavioral Neuroscience, Institute of Experimental Psychology, University of Düsseldorf, 40204 Düsseldorf, Germany.

Conditioned place preference (CPP) is a learned behavior shown in many vertebrates, including humans. CPP occurs when a subject comes to prefer one place more than others because the preferred location has been paired previously with rewarding events. The CPP paradigm is widely used to explore the reinforcing effects of natural and pharmacological stimuli, including drugs of addiction. There is a general assumption that an acquired place preference is based on classical conditioning derived 'incentive motivation'. However, this may be an oversimplification of the multiple learning processes involved. We argue that although CPP may appear as an incentive-driven behavior related to secondary reinforcers, it may also be a result of operant conditioning of behavior prevailing at the conditioning site, as well as a result of conditioned treatment effects. Here, we outline alternative explanations for an observed CPP, which may fundamentally affect the interpretation of results with this paradigm in its use as a screening tool for rewarding properties of treatments.
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http://dx.doi.org/10.1016/j.tips.2013.01.004DOI Listing
March 2013

Sensitization of hypervigilance effects of cocaine can be induced by NK3 receptor activation in marmoset monkeys.

Drug Alcohol Depend 2013 Feb 11;128(1-2):155-60. Epub 2012 Oct 11.

Department of Pharmaceutical Sciences, School of Health Sciences, University of Brasilia, 70910-900 Brasilia, DF, Brazil.

Background: Cocaine is a widely abused drug which can result in the establishment of addiction. The neurokinin3-receptor (NK3-R) has been linked to cocaine addiction by genetic, epigenetic, and pharmacological studies suggesting that a cocaine-induced increase in NK3-R signaling may contribute to the establishment of cocaine addiction-related behaviors.

Methods: Here we measured cocaine-induced sensitization of vigilance- and locomotor behaviors in marmoset monkeys (Callithrix penicillata) in an open field.

Results: We found a sensitization of vigilance-related, but not locomotor behaviors after repeated cocaine (7mg/kg, i.p.) treatment. There was a cross-sensitization for scan frequency, but not of glance frequency, both vigilance-related behaviors, after repeated treatment with the NK3-R agonist senktide (0.2mg/kg, i.p.) given for 7 days, after a cocaine challenge (5mg/kg, i.p.).

Conclusions: These data suggest that in marmoset monkeys, repeated cocaine treatment leads to a sensitization of vigilance-related behaviors, which have a prominent role in spontaneously expressed activities in this species, but not of locomotor activity. Repeated activation of NK3-Rs can mimic some of the behavioral sensitization effect and may thus contribute to the establishment of cocaine related behaviors.
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http://dx.doi.org/10.1016/j.drugalcdep.2012.08.020DOI Listing
February 2013

Repeated cocaine administration in marmoset monkeys induces hypervigilance-related behaviors, but no changes in locomotion and cortisol levels.

Pharmacol Biochem Behav 2012 Dec 11;103(2):279-83. Epub 2012 Aug 11.

Department of Pharmaceutical Sciences, School of Health Sciences, University of Brasilia, 70910-900 Brasilia, DF, Brazil.

Although cocaine induces several behavioral and hormonal effects, little is known about non-contingent repeated administrations in non-human primates. Therefore, we analyzed behavioral (locomotion, vigilance) and hormonal (cortisol) responses of adult black tufted-ear marmosets during repeated administrations and withdrawal trials. The subjects were divided into two groups (saline or cocaine 5mg/kg, ip) and submitted to nine treatment trials and four withdrawal trials in the absence of any treatment in an open-field arena. Blood samples were obtained on five different time points of the procedure to evaluate the effects of repeated cocaine treatment on basal cortisol levels. Cocaine repeatedly administered to drug-naïve marmosets induced a slow-onset hypervigilance effect (i.e., scan - long-lasting sweeping movements of the head directed at the environment; and glance - single rapid movement of the head directed at the environment), with no concomitant change in locomotion. Treatment cessation during withdrawal immediately reversed the cocaine-induced hypervigilance effect. Cortisol levels remained constant throughout the procedure. Therefore, marmosets seem to have a similar behavioral - but not hormonal - response as humans and other nonhuman primates repeatedly injected with cocaine, but differ from rats in their absence of hyperlocomotor activity. The development of hypervigilance with repeated application may constitute a unique measure to assess cocaine-induced changes in behavior in the marmoset and other nonhuman primates.
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http://dx.doi.org/10.1016/j.pbb.2012.08.003DOI Listing
December 2012

Lentiviral-mediated gene delivery reveals distinct roles of nucleus accumbens dopamine D2 and D3 receptors in novelty- and light-induced locomotor activity.

Eur J Neurosci 2012 Apr 7;35(8):1344-53. Epub 2012 Mar 7.

MRC-SGDP-Centre, Institute of Psychiatry, King's College London, De Crespigny Park, PO80, London SE5 8AF, UK.

The importance of the dopaminergic system for proper brain activity is demonstrated by findings that alterations in this system lead to severe disabilities, including motor impairment observed in various neurological and psychiatric disorders. Although the roles of specific dopamine receptors in behaviour have been extensively investigated using pharmacological agents and knockout mice, non-specificity of ligands and compensatory molecular adaptations in mutated animals restrict the interpretation of the results. To overcome these limitations and further explore the role of the dopamine D2 and D3 receptors (D2R and D3R) in rats, we used lentivirus-mediated gene knockdown and overexpression to specifically manipulate expression levels of these genes in the rat nucleus accumbens (NAcc), a brain area important for spontaneous and induced locomotor responses. Lentiviruses, inducing expression of rat D2R or D3R, or efficient knockdown of either receptor by small hairpin (sh)RNAs, were stereotaxically injected into the NAcc. While knockdown of either receptor significantly reduced spontaneous locomotor activity in a novel but not in a habituated environment, D2R and D3R appeared to contribute in opposite ways to light-induced locomotor activity. D2R knockdown increased while D3R knockdown decreased locomotor activity in this test. Altogether, our findings suggest that D2R and D3R, expressed in the NAcc, have both shared and non-overlapping roles in transduction of alerting signals elicited by potentially important sensory and environmental cues.
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http://dx.doi.org/10.1111/j.1460-9568.2012.08028.xDOI Listing
April 2012

The NK3 receptor agonist senktide ameliorates scopolamine-induced deficits in memory for object, place and temporal order.

Neurobiol Learn Mem 2012 Feb 22;97(2):235-40. Epub 2011 Dec 22.

Center for Behavioral Neuroscience, University of Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany.

Senktide, a potent neurokinin-3 receptor (NK3-R) agonist, increases acetylcholine (ACh) release in the striatum, the prefrontal cortex (Schäble et al., 2011), the amygdala and hippocampus, presumably via postsynaptic mechanisms. A promnestic action of NK3-R agonists has been described in a variety of learning/memory tasks. The memory-enhancing effects of NK3-R agonists and their activating influence on ACh suggest a possible role of the NK3-R in learning and memory via cholinergic modulation. Deterioration of the cholinergic system in the basal forebrain has been associated with learning and memory deficits and cholinergic agents have promnestic effects in a variety of learning paradigms. The anticholinergic drug, scopolamine, a muscarinic ACh receptor antagonist, incurs deficits in a variety of learning tasks and provides a useful tool to investigate the role of the cholinergic systems in mechanisms underlying learning and memory. The aim of this study was to ascertain the effect of the NK3-R agonist, senktide, in the scopolamine-induced deficit model. We hypothesized that senktide treatment would attenuate scopolamine-induced (subcutaneous--s.c. 0.75 mg/kg) memory impairment in three novelty preference paradigms based on spontaneous object exploration: namely object recognition, object-place recognition and object recognition for temporal order. Administration of senktide reversed the scopolamine-induced memory deficits by re-establishing object recognition (s.c. 0.2 mg/kg), object-place recognition (0.2 and 0.4 mg/kg), as well as object recognition for temporal order (0.4 mg/kg) in adult Wistar rats. These results indicate memory enhancing effects of senktide in animals subjected to scopolamine-induced memory impairments and indicate that the promnestic action of NK3-R agonists is mediated by muscarinic cholinergic mechanisms.
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http://dx.doi.org/10.1016/j.nlm.2011.12.007DOI Listing
February 2012