Publications by authors named "Guy Drolet"

40 Publications

Delta Opioid Receptor Signaling Promotes Resilience to Stress Under the Repeated Social Defeat Paradigm in Mice.

Front Mol Neurosci 2018 6;11:100. Epub 2018 Apr 6.

Axe Neurosciences, Centre de Recherche du CHU de Québec-Université Laval, Québec, QC, Canada.

The adaptation to chronic stress is highly variable across individuals. Resilience to stress is a complex process recruiting various brain regions and neurotransmitter systems. The aim of this study was to investigate the involvement of endogenous opioid enkephalin (ENK) signaling in the development of stress resilience in mice. The translational model of repeated social defeat (RSD) stress was selected to mimic the unpredictable disruptions of daily life and induce resilience or vulnerability to stress. As in humans, adult C57BL/6J mice demonstrated a great variability in their response to stress under this paradigm. A social interaction (SI) test was used to discriminate between the phenotypes of resilience or vulnerability to stress. After social defeat, the expression levels of ENK mRNA and their delta opioid receptors (DOPr) were quantified in the basolateral amygdala (BLA) and BLA-target areas by hybridization. In this manner, ENK mRNA levels were found to decrease in the BLA and those of DOPr in the ventral hippocampus (HPC) CA1 of vulnerable mice only. Stimulating the DOPr pathway during social defeat by pharmacological treatment with the nonpeptide, selective DOPr agonist SNC80 further induced a resilient phenotype in a majority of stressed animals, with the proportion of resilient ones increasing from 33% to 58% of the total population. Ultrastructural analyses additionally revealed a reduction of oxidative stress markers in the pyramidal cells and interneurons of the ventral HPC CA1 upon SNC80 treatment, thus proposing a mechanism by which ENK-DOPr signaling may prevent the deleterious effects of chronic social stress.
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http://dx.doi.org/10.3389/fnmol.2018.00100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5897549PMC
April 2018

Enkephalins: Endogenous Analgesics with an Emerging Role in Stress Resilience.

Neural Plast 2017 11;2017:1546125. Epub 2017 Jul 11.

Axe Neurosciences, Centre de Recherche du CHU de Québec - Université Laval, Québec, QC, Canada.

Psychological stress is a state of mental or emotional strain or tension that results from adverse or demanding circumstances. Chronic stress is well known to induce anxiety disorders and major depression; it is also considered a risk factor for Alzheimer's disease. Stress resilience is a positive outcome that is associated with preserved cognition and healthy aging. Resilience presents psychological and biological characteristics intrinsic to an individual conferring protection against the development of psychopathologies in the face of adversity. How can we promote or improve resilience to chronic stress? Numerous studies have proposed mechanisms that could trigger this desirable process. The roles of enkephalin transmission in the control of pain, physiological functions, like respiration, and affective disorders have been studied for more than 30 years. However, their role in the resilience to chronic stress has received much less attention. This review presents the evidence for an emerging involvement of enkephalin signaling through its two associated opioid receptors, opioid peptide receptor and opioid peptide receptor, in the natural adaptation to stressful lifestyles.
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http://dx.doi.org/10.1155/2017/1546125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5525068PMC
May 2018

Regional expression and ultrastructural localization of EphA7 in the hippocampus and cerebellum of adult rat.

J Comp Neurol 2016 08 26;524(12):2462-78. Epub 2016 Feb 26.

Département de neurosciences and Groupe de recherche sur le système nerveux central (GRSNC), Université de Montréal, Montréal, QC, Canada.

EphA7 is expressed in the adult central nervous system (CNS), where its roles are yet poorly defined. We mapped its distribution using in situ hybridization (ISH) and immunohistochemistry (IHC) combined with light (LM) and electron microscopy (EM) in adult rat and mouse brain. The strongest ISH signal was in the hippocampal pyramidal and granule cell layers. Moderate levels were detected in habenula, striatum, amygdala, the cingulate, piriform and entorhinal cortex, and in cerebellum, notably the Purkinje cell layer. The IHC signal distribution was consistent with ISH results, with transport of the protein to processes, as exemplified in the hippocampal neuropil layers and weakly stained pyramidal cell layers. In contrast, in the cerebellum, the Purkinje cell bodies were the most strongly immunolabeled elements. EM localized the cell surface-expression of EphA7 essentially in postsynaptic densities (PSDs) of dendritic spines and shafts, and on some astrocytic leaflets, in both hippocampus and cerebellum. Perikaryal and dendritic labeling was mostly intracellular, associated with the synthetic and trafficking machineries. Immunopositive vesicles were also observed in axons and axon terminals. Quantitative analysis in EM showed significant differences in the frequency of labeled elements between regions. Notably, labeled dendrites were ∼3-5 times less frequent in cerebellum than in hippocampus, but they were individually endowed with ∼10-40 times higher frequencies of PSDs, on their shafts and spines. The cell surface localization of EphA7, being preferentially in PSDs, and in perisynaptic astrocytic leaflets, provides morphologic evidence that EphA7 plays key roles in adult CNS synaptic maintenance, plasticity, or function. J. Comp. Neurol. 524:2462-2478, 2016. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/cne.23962DOI Listing
August 2016

EphA4 is Involved in Sleep Regulation but Not in the Electrophysiological Response to Sleep Deprivation.

Sleep 2016 Mar 1;39(3):613-24. Epub 2016 Mar 1.

Center for Advanced Research in Sleep Medicine and Research Center, Hôpital du Sacré-Coeur de Montréal, Montreal, QC, Canada.

Study Objectives: Optimal sleep is ensured by the interaction of circadian and homeostatic processes. Although synaptic plasticity seems to contribute to both processes, the specific players involved are not well understood. The EphA4 tyrosine kinase receptor is a cell adhesion protein regulating synaptic plasticity. We investigated the role of EphA4 in sleep regulation using electrocorticography in mice lacking EphA4 and gene expression measurements.

Methods: EphA4 knockout (KO) mice, Clock(Δ19/Δ19) mutant mice and littermates, C57BL/6J and CD-1 mice, and Sprague-Dawley rats were studied under a 12 h light: 12 h dark cycle, under undisturbed conditions or 6 h sleep deprivation (SLD), and submitted to a 48 h electrophysiological recording and/or brain sampling at different time of day.

Results: EphA4 KO mice showed less rapid eye movement sleep (REMS), enhanced duration of individual bouts of wakefulness and nonrapid eye movement sleep (NREMS) during the light period, and a blunted daily rhythm of NREMS sigma activity. The NREMS delta activity response to SLD was unchanged in EphA4 KO mice. However, SLD increased EphA4 expression in the thalamic/hypothalamic region in C57BL/6J mice. We further show the presence of E-boxes in the promoter region of EphA4, a lower expression of EphA4 in Clock mutant mice, a rhythmic expression of EphA4 ligands in several brain areas, expression of EphA4 in the suprachiasmatic nuclei of the hypothalamus (SCN), and finally an unchanged number of cells expressing Vip, Grp and Avp in the SCN of EphA4 KO mice.

Conclusions: Our results suggest that EphA4 is involved in circadian sleep regulation.
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http://dx.doi.org/10.5665/sleep.5538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4763357PMC
March 2016

Extracellular Na(+) levels regulate formation and activity of the NaX/alpha1-Na(+)/K(+)-ATPase complex in neuronal cells.

Front Cell Neurosci 2014 4;8:413. Epub 2014 Dec 4.

Centre de Recherche du CHU de Québec, Axe Neurosciences QC, Canada ; Faculté de Médecine, Département de Psychiatrie et Neurosciences, Université Laval QC, Canada.

MnPO neurons play a critical role in hydromineral homeostasis regulation by acting as sensors of extracellular sodium concentration ([Na(+)]out). The mechanism underlying Na(+)-sensing involves Na(+)-flow through the NaX channel, directly regulated by the Na(+)/K(+)-ATPase α1-isoform which controls Na(+)-influx by modulating channel permeability. Together, these two partners form a complex involved in the regulation of intracellular sodium ([Na(+)]in). Here we aim to determine whether environmental changes in Na(+) could actively modulate the NaX/Na(+)/K(+)-ATPase complex activity. We investigated the complex activity using patch-clamp recordings from rat MnPO neurons and Neuro2a cells. When the rats were fed with a high-salt-diet, or the [Na(+)] in the culture medium was increased, the activity of the complex was up-regulated. In contrast, drop in environmental [Na(+)] decreased the activity of the complex. Interestingly under hypernatremic condition, the colocalization rate and protein level of both partners were up-regulated. Under hyponatremic condition, only NaX protein expression was increased and the level of NaX/Na(+)/K(+)-ATPase remained unaltered. This unbalance between NaX and Na(+)/K(+)-ATPase pump proportion would induce a bigger portion of Na(+)/K(+)-ATPase-control-free NaX channel. Thus, we suggest that hypernatremic environment increases NaX/Na(+)/K(+)-ATPase α1-isoform activity by increasing the number of both partners and their colocalization rate, whereas hyponatremic environment down-regulates complex activity via a decrease in the relative number of NaX channels controlled by the pump.
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http://dx.doi.org/10.3389/fncel.2014.00413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4255601PMC
December 2014

Respiratory manifestations of panic disorder in animals and humans: a unique opportunity to understand how supramedullary structures regulate breathing.

Respir Physiol Neurobiol 2014 Dec 16;204:3-13. Epub 2014 Jul 16.

Université Laval, Québec, QC, Canada.

The control of breathing is commonly viewed as being a "brainstem affair". As the topic of this special issue of Respiratory Physiology and Neurobiology indicates, we should consider broadening this notion since the act of breathing is also tightly linked to many functions other than close regulation of arterial blood gases. Accordingly, "non-brainstem" structures can exert a powerful influence on the core elements of the respiratory control network and as it is often the case, the importance of these structures is revealed when their dysfunction leads to disease. There is a clear link between respiration and anxiety and key theories of the psychopathology of anxiety (including panic disorders; PD) focus on respiratory control and related CO2 monitoring system. With that in mind, we briefly present the respiratory manifestations of panic disorder and discuss the role of the dorso-medial/perifornical hypothalamus, the amygdalar complex, and the periaqueductal gray in respiratory control. We then present recent advances in basic research indicating how adult rodent previously subjected to neonatal stress may provide a very good model to investigate the pathophysiology of PD.
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http://dx.doi.org/10.1016/j.resp.2014.06.013DOI Listing
December 2014

Enkephalin knockdown in the basolateral amygdala reproduces vulnerable anxiety-like responses to chronic unpredictable stress.

Neuropsychopharmacology 2014 Apr 11;39(5):1159-68. Epub 2013 Nov 11.

Centre de recherche du CHU de Québec, Axe Neurosciences, Université Laval, Quebec, QC, Canada.

The endogenous enkephalins (ENKs) are potential candidates participating in the naturally occurring variations in coping styles and determining the individual capacities for adaptation during chronic stress exposure. Here we demonstrate that there is a large variance in individual behavioral, as well as in physiological outcomes, in a population of Sprague-Dawley rats subjected to 3 weeks of chronic unpredictable stress (CUS). Separation of resilient and vulnerable subpopulations reveals specific long-term neuroadaptation in the ENKergic brain circuits. ENK mRNA expression was greatly reduced in the posterior basolateral nucleus of amygdala (BLAp) in vulnerable individuals. In contrast, ENK mRNA levels were similar in resilient and control (unstressed) individuals. Another group of rats were used for lentiviral-mediated knockdown of ENK to assess whether a decrease of ENK expression in the BLAp reproduces the behavioral disturbances found in vulnerable individuals. ENK knockdown specifically located in the BLAp was sufficient to increase anxiety in the behavioral tests, such as social interaction and elevated plus maze when compared with control individuals. These results show that specific neuroadaptation mediated by the ENKergic neurotransmission in the BLAp is a key regulator of resilience, whereas a decrease of the ENK in the BLAp is a maladaptation mechanism, which mediates the behavioral dichotomy observed between vulnerable and resilient following 3 weeks of CUS.
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http://dx.doi.org/10.1038/npp.2013.316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3957109PMC
April 2014

Enkephalin downregulation in the nucleus accumbens underlies chronic stress-induced anhedonia.

Stress 2014 Jan 31;17(1):88-96. Epub 2013 Oct 31.

Centre de recherche du CHU, Axe Neurosciences and Université Laval , Québec, QC , Canada.

Restraint and immobilization have been extensively used to study habituation of the neuroendocrine response to a repeated stressor, but behavioral consequences of this stress regimen remain largely uncharacterized. In this study, we used sucrose preference and the elevated-plus maze to probe behavioral alterations resulting from 14 days of restraint in rats. We observed a decrease in sucrose preference in stressed animals, particularly in a subgroup of individuals, but no alteration in anxiety behaviors (as measured in the elevated-plus maze) four days following the last restraint. In these low-sucrose preference animals, we observed a downregulation of the expression of preproenkephalin mRNA in the nucleus accumbens. Furthermore, we observed a strong correlation between enkephalin expression and sucrose preference in the shell part of the nucleus accumbens, with a lower level of enkephalin expression being associated with lower sucrose preference. Interestingly, quantification of the corticosterone response revealed a delayed habituation to restraint in the low-sucrose preference population, which suggests that vulnerability to stress-induced deficits might be associated with prolonged exposure to glucocorticoids. The induction of ΔFosB is also reduced in the nucleus accumbens shell of the low-sucrose preference population and this transcription factor is expressed in enkephalin neurons. Taken together, these results suggest that a ΔFosB-mediated downregulation of enkephalin in the nucleus accumbens might underlie the susceptibility to chronic stress. Further experiments will be needed to determine causality between these two phenomena.
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http://dx.doi.org/10.3109/10253890.2013.850669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4457518PMC
January 2014

Striatal pre-enkephalin overexpression improves Huntington's disease symptoms in the R6/2 mouse model of Huntington's disease.

PLoS One 2013 11;8(9):e75099. Epub 2013 Sep 11.

Axe Neurosciences, Centre de recherche du CHU de Québec, CHUL, Québec, Canada.

The reduction of pre-enkephalin (pENK) mRNA expression might be an early sign of striatal neuronal dysfunction in Huntington's disease (HD), due to mutated huntingtin protein. Indeed, striatopallidal (pENK-containing) neurodegeneration occurs at earlier stage of the disease, compare to the loss of striatonigral neurons. However, no data are available about the functional role of striatal pENK in HD. According to the neuroprotective properties of opioids that have been recognized recently, the objective of this study was to investigate whether striatal overexpression of pENK at early stage of HD can improve motor dysfunction, and/or reduce striatal neuronal loss in the R6/2 transgenic mouse model of HD. To achieve this goal recombinant adeno-associated-virus (rAAV2)-containing green fluorescence protein (GFP)-pENK was injected bilaterally in the striatum of R6/2 mice at 5 weeks old to overexpress opioid peptide pENK. Striatal injection of rAAV2-GFP was used as a control. Different behavioral tests were carried out before and/or after striatal injections of rAAV2. The animals were euthanized at 10 weeks old. Our results demonstrate that striatal overexpression of pENK had beneficial effects on behavioral symptoms of HD in R6/2 by: delaying the onset of decline in muscular force; reduction of clasping; improvement of fast motor activity, short-term memory and recognition; as well as normalization of anxiety-like behavior. The improvement of behavioral dysfunction in R6/2 mice having received rAAV2-GFP-pENK associated with upregulation of striatal pENK mRNA; the increased level of enkephalin peptide in the striatum, globus pallidus and substantia nigra; as well as the slight increase in the number of striatal neurons compared with other groups of R6/2. Accordingly, we suggest that at early stage of HD upregulation of striatal enkephalin might play a key role at attenuating illness symptoms.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0075099PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3770591PMC
July 2014

Multiple episodes of sodium depletion in the rat: a remodeling of the electrical properties of median preoptic nucleus neurons.

Eur J Neurosci 2013 Sep 5;38(5):2730-41. Epub 2013 Jun 5.

Université Laval, Laurier, Québec, Canada.

In rat brain, the detection and integration of chemosensory and neural signals are achieved, inter alia, by the median preoptic nucleus (MnPO) during a disturbance of the hydromineral balance. This is allowed through the presence of the sodium (Na(+) ) sensor neurons. Interestingly, enkephalins and mu-opioid receptors (μ-ORs) are known for their role in ingestive behaviors and have previously been shown to regulate the excitability of MnPO neurons following a single Na(+) depletion. However, little is known about the role of these μ-ORs in the response enhancement following repeated Na(+) challenge. Therefore, we used whole-cell recordings in acute brain slices to determine neuronal plasticity in the electrical properties of the MnPO Na(+) sensor-specific neuronal population following multiple Na(+) depletions. Our results show that the population of Na(+) sensor neurons was represented by 80% of MnPO neurons after a single Na(+) depletion and was reduced after three Na(+) depletions. Interestingly, the subpopulation of Na(+) sensors responding to D-Ala(2) ,N-MePhe(4) ,Gly-ol-enkephalin (DAMGO), a specific μ-OR agonist, represented 11% of MnPO neurons after a single Na(+) depletion and the population doubled after three Na(+) depletions. Moreover, Na(+) sensor neurons displayed modifications in the discharge pattern distribution and shape of calcium action potentials after three Na(+) depletions but these changes did not occur in Na(+) sensors responding to DAMGO. Thus, the reinforced μ-OR functionality in Na(+) sensors might take place to control the neuronal hyperexcitability and this plasticity in opioid-sensitive and Na(+) detection MnPO networks might sustain the enhanced salt ingestion induced by repeated exposure to Na(+) depletion.
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http://dx.doi.org/10.1111/ejn.12273DOI Listing
September 2013

Enkephalin and dynorphin mRNA expression are associated with resilience or vulnerability to chronic social defeat stress.

Physiol Behav 2013 Oct 9;122:237-45. Epub 2013 May 9.

Centre de recherche du CHU de Québec (CHUL), Axe Neurosciences, Université Laval, Québec, QC, Canada. Electronic address:

There are important and enduring differences between individuals in the magnitude of all aspects of the stress response. Among the neuropeptide systems, the endogenous opioids enkephalin (ENK) and dynorphin (DYN), are very interesting candidates to participate in the naturally occurring variations in coping styles and to determine the individual capacity for adaptation during chronic stress exposure. Under chronic social stress exposure, we hypothesize that changes in the ENKergic vs DYNergic neuronal systems within specific nuclei of the basal forebrain contribute to naturally occurring variations in coping styles and will determine individual capacities for stress adaptation. Sprague-Dawley rats were exposed to a resident-intruder model of defeat for 7 days. The average latency to be defeated over seven consecutive days was calculated for each intruder rat. Based on this distribution, we chose an average defeat latency of 350s as a cutoff criterion to define resilient and vulnerable rats. A subpopulation assumed a subordinate posture in a relatively short latency (<350s, SL) and the other subpopulation resisted defeat resulting in longer latencies (>350s, LL) to assume this posture and were identified as being vulnerable and resilient respectively. Rats were euthanized 24h after the last stress session. ENK mRNA expression was lower in the basolateral nucleus of the amygdala in vulnerable compared to control and resilient individuals. In contrast, there was no difference between resilient and control individuals. DYN mRNA is increased only within the dorsal and medial shell of the NAc of vulnerable rats compared to control individuals. There was no difference between resilient and control individuals. DYN mRNA is increased in resilient individuals in the central area of the striatum, caudal part, compared to control individuals. DYN is also increased in medial area of the striatum, caudal part in resilient and vulnerable compared to control individuals. These results have broad implications for understanding the functional roles of opioid neurotransmission following repeated social stress and suggest that ENK could facilitate the adaptation of behavioral responses by opposition to the DYN neurotransmission that appears to promote maladaptive behavioral response to chronic social stress.
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http://dx.doi.org/10.1016/j.physbeh.2013.04.009DOI Listing
October 2013

Neonatal stress augments the hypoxic chemoreflex of adult male rats by increasing AMPA receptor-mediated modulation.

Exp Physiol 2013 Aug 19;98(8):1312-24. Epub 2013 Apr 19.

Department of Pediatrics, Université Laval, Centre de recherche du CHU de Québec, Hôpital St-François d’Assise, Québec, QC, Canada.

Neonatal stress disrupts the developmental trajectory of homeostatic systems. Adult (8- to 10-week-old) male rats exposed to maternal separation (a form of neonatal stress) display several traits reported in patients suffering from sleep-disordered breathing, including an augmented hypoxic chemoreflex. To understand the mechanisms behind this effect, we tested the hypothesis that neonatal stress augments glutamatergic neurotransmission in three regions involved in respiratory regulation, namely the nucleus of the solitary tract, the paraventricular nucleus of the hypothalamus and the phrenic motor nucleus. Maternal separation was performed for 3 h day(-1) from postnatal day 3 to 12. Control pups were undisturbed. Adult rats were instrumented for intracerebroventricular injection of the AMPA/kainate receptor antagonist CNQX (0-4.3 μm). Using plethysmography, ventilatory activity was measured at rest in awake animals during normoxia (fractional inspired O2 = 0.21) and during acute hypoxia (fractional inspired O2 = 0.12; 20 min). Following vehicle injection, the hypoxic ventilatory response of stressed rats was 35% greater than that of controls. Microinjection of CNQX attenuated the hypoxic ventilatory response, but the effect observed in stressed rats was greater than that in control animals. Autoradiography experiments showed that neonatal stress augments expression of AMPA receptors within the paraventricular nucleus of the hypothalamus and the phrenic motor nucleus. Quantification of brain-derived neurotrophic factor showed that neonatal stress augments brain-derived neurotrophic factor expression only within the paraventricular nucleus. We conclude that neonatal stress augments the hypoxic chemoreflex by increasing the efficacy of glutamatergic synaptic inputs projecting onto key respiratory structures, especially the paraventricular nucleus of the hypothalamus. These data provide new insight into the aetiology of sleep-disordered breathing.
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http://dx.doi.org/10.1113/expphysiol.2013.072090DOI Listing
August 2013

Regulation of central Na+ detection requires the cooperative action of the NaX channel and α1 Isoform of Na+/K+-ATPase in the Na+-sensor neuronal population.

J Neurosci 2013 Feb;33(7):3067-78

Axe Neurosciences du Centre de Recherche du Centre Hospitalier Université de Québec (CHUQ), Université Laval, Québec, QC, Canada G1V 4G2.

The median preoptic nucleus (MnPO) holds a strategic position in the hypothalamus. It is adjacent to the third ventricle; hence, it can directly access the ionic composition of the CSF. MnPO neurons play a critical role in hydromineral homeostasis regulation by acting as central sensors of extracellular Na(+) concentration ([Na(+)](ext)). The mechanism underlying Na(+) sensing involves the atypical Na(+) channel, Na(X). Here we sought to determine whether Na(+) influx in Na(+) sensors is actively regulated via interaction with other membrane proteins involved in cellular Na(+) homeostasis, such as Na(+)/K(+)-ATPase. The Na(+)/K(+)-ATPase role was investigated using patch-clamp recordings in rat MnPO dissociated neurons. Na(+) current evoked with hypernatriuric solution was diminished in the absence of ATP/GTP, indicating that Na(+)/K(+)-ATPase play a central role in [Na(+)](ext) detection. Specific blockers of α1 and α3 isoforms of Na(+)/K(+)-ATPase, ouabain or strophanthidin, inhibited this Na(+) current. However, strophanthidin, which selectively blocks the α1 isoform, was more effective in blocking Na(+) current, suggesting that the Na(+)/K(+)-ATPase-α1 isoform is specifically involved in [Na(+)](ext) detection. Although strophanthidin did not alter either the membrane resistance or the Na(+) reversal potential, the conductance and the permeability of the Na(X) channel decreased significantly. Our results suggest that Na(+)/K(+)-ATPase interacts with the Na(X) channel and regulates the high [Na(+)](ext)-evoked Na(+) current via influencing the Na(+) influx rate. This study describes a novel intracellular regulatory pathway of [Na(+)](ext) detection in MnPO neurons. The α1 isoform of Na(+)/K(+)-ATPase acts as a direct regulatory partner of the Na(X) channel and influences Na(+) influx via controlling the Na(+) permeability of the channel.
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http://dx.doi.org/10.1523/JNEUROSCI.4801-12.2013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6619214PMC
February 2013

Enkephalin knockdown in the central amygdala nucleus reduces unconditioned fear and anxiety.

Eur J Neurosci 2013 Apr 1;37(8):1357-67. Epub 2013 Feb 1.

Centre de recherche du CHU de Québec, Axe Neurosciences, Université Laval, Québec, QC, Canada.

The endogenous opioid enkephalins (ENK) are highly expressed in the central nucleus of the amygdaloid complex (CeA) where several lines of evidence point to a potential role in the modulation of fear and anxiety. In this study, we aimed to assess the role of CeA ENK using local injections of a lentiviral vector expressing a short hairpin RNA (shRNA) targeting ENK in Sprague-Dawley rats. We injected this vector in the CeA and a 56% downregulation of ENK mRNA was observed in animals when compared with scrambled shRNA animals. Anxiety-like behaviors were also assessed using the elevated plus maze and social interaction test. There was an increase in exploration of open arms of the elevated plus maze in ENK knockdown animals compared with controls, but no change in social interaction. In addition, we used the contextual fear conditioning procedure to assess fear expression and learning in these animals. There was a reduction in freezing induced by acute shocks during the training procedure. Interestingly, associative learning was not affected, and ENK knockdown animals displayed an equivalent freezing when re-exposed to the conditioning chamber 48 h later. These results contrast with knockout mice studies, which ascribed anxiolytic properties to ENK, and they demonstrate the need for a thorough understanding and characterization of neuroanatomically distinct ENK pathways.
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http://dx.doi.org/10.1111/ejn.12134DOI Listing
April 2013

Intrinsic properties of the sodium sensor neurons in the rat median preoptic nucleus.

Am J Physiol Regul Integr Comp Physiol 2012 Oct 8;303(8):R834-42. Epub 2012 Aug 8.

Axe Neurosciences du Centre de recherche du CHUQ, Université Laval, Québec, QC, Canada.

The essential role of the median preoptic nucleus (MnPO) in the integration of chemosensory information associated with the hydromineral state of the rat relies on the presence of a unique population of sodium (Na+) sensor neurons. Little is known about the intrinsic properties of these neurons; therefore, we used whole cell recordings in acute brain slices to determine the electrical fingerprints of this specific neural population of rat MnPO. The data collected from a large sample of neurons (115) indicated that the Na+ sensor neurons represent a majority of the MnPO neurons in situ (83%). These neurons displayed great diversity in both firing patterns induced by transient depolarizing current steps and rectifying properties activated by hyperpolarizing current steps. This diversity of electrical properties was also present in non-Na+ sensor neurons. Subpopulations of Na+ sensor neurons could be distinguished, however, from the non-Na+ sensor neurons. The firing frequency was higher in Na+ sensor neurons, showing irregular spike discharges, and the amplitude of the time-dependent rectification was weaker in the Na+ sensor neurons than in non-Na+ sensor neurons. The diversity among the electrical properties of the MnPO neurons contrasts with the relative function homogeneity (Na+ sensing). However, this diversity might be correlated with a variety of direct synaptic connections linking the MnPO to different brain areas involved in various aspects of the restoration and conservation of the body fluid homeostasis.
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http://dx.doi.org/10.1152/ajpregu.00260.2012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3469662PMC
October 2012

The Expression Pattern of the Na(+) Sensor, Na(X) in the Hydromineral Homeostatic Network: A Comparative Study between the Rat and Mouse.

Front Neuroanat 2012 19;6:26. Epub 2012 Jul 19.

Axe Neurosciences du CRCHUQ (CHUL), Faculté de Médecine, Université Laval Québec, QC, Canada.

The Scn7a gene encodes for the specific sodium channel Na(X), which is considered a primary determinant of sodium sensing in the brain. Only partial data exist describing the Na(X) distribution pattern and the cell types that express Na(X) in both the rat and mouse brain. To generate a global view of the sodium detection mechanisms in the two rodent brains, we combined Na(X) immunofluorescence with fluorescent cell markers to map and identify the Na(X)-expressing cell populations throughout the network involved in hydromineral homeostasis. Here, we designed an anti-Na(X) antibody targeting the interdomain 2-3 region of the Na(X) channel's α-subunit. In both the rat and mouse, Na(X) immunostaining was colocalized with vimentin positive cells in the median eminence and with magnocellular neurons immunopositive for neurophysin associated with oxytocin or vasopressin in both the supraoptic and paraventricular nuclei. Na(X) immunostaining was also detected in neurons of the area postrema. In addition to this common Na(X) expression pattern, several differences in Na(X) immunostaining for certain structures and cell types were found between the rat and mouse. Na(X) was present in both NeuN and vimentin positive cells in the subfornical organ and the vascular organ of the lamina terminalis of the rat whereas Na(X) was only colocalized with vimentin positive cells in the mouse circumventricular organs. In addition, Na(X) immunostaining was specifically observed in NeuN immunopositive cells in the median preoptic nucleus of the rat. Overall, this study characterized the Na(X)-expressing cell types in the network controlling hydromineral homeostasis of the rat and mouse. Na(X) expression pattern was clearly different in the nuclei of the lamina terminalis of the rat and mouse, indicating that the mechanisms involved in systemic and central Na(+) sensing are specific to each rodent species.
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http://dx.doi.org/10.3389/fnana.2012.00026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3400090PMC
October 2012

Increased anxiety-like behaviors in rats experiencing chronic inflammatory pain.

Behav Brain Res 2012 Apr 8;229(1):160-7. Epub 2012 Jan 8.

Department of Physiology and Biophysics, Faculty of Medicine and Health Sciences, Institut de pharmacologie de Sherbrooke, Université de Sherbrooke, Sherbrooke, QC, Canada.

For many patients, chronic pain is often accompanied, and sometimes amplified, by co-morbidities such as anxiety and depression. Although it represents important challenges, the establishment of appropriate preclinical behavioral models contributes to drug development for treating chronic inflammatory pain and associated psychopathologies. In this study, we investigated whether rats experiencing persistent inflammatory pain induced by intraplantar injection of complete Freund's adjuvant (CFA) developed anxiety-like behaviors, and whether clinically used analgesic and anxiolytic drugs were able to reverse CFA-induced anxiety-related phenotypes. These behaviors were evaluated over 28 days in both CFA- and saline-treated groups with a variety of behavioral tests. CFA-induced mechanical allodynia resulted in increased anxiety-like behaviors as evidenced by: (1) a significant decrease in percentage of time spent and number of entries in open arms of the elevated-plus maze (EPM), (2) a decrease in number of central squares visited in the open field (OF), and (3) a reduction in active social interactions in the social interaction test (SI). The number of entries in closed arms in the EPM and the distance traveled in the OF used as indicators of locomotor performance did not differ between treatments. Our results also reveal that in CFA-treated rats, acute administration of morphine (3mg/kg, s.c.) abolished tactile allodynia and anxiety-like behaviors, whereas acute administration of diazepam (1mg/kg, s.c) solely reversed anxiety-like behaviors. Therefore, pharmacological treatment of anxiety-like behaviors induced by chronic inflammatory pain can be objectively evaluated using multiple behavioral tests. Such a model could help identify/validate alternative potential targets that influence pain and cognitive dimensions of anxiety.
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http://dx.doi.org/10.1016/j.bbr.2012.01.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3848972PMC
April 2012

Neuroanatomical characterization of endogenous opioids in the bed nucleus of the stria terminalis.

Prog Neuropsychopharmacol Biol Psychiatry 2009 Nov 4;33(8):1356-65. Epub 2009 Jul 4.

Centre de recherche du CHUQ (CHUL), Neurosciences, Université Laval, Québec, QC, Canada.

Numerous neuroanatomical data indicate that the bed nucleus of the stria terminalis (BST) provides an interface between cortical and amygdaloid neurons, and effector neurons modulating motor, autonomic and neuroendocrine responses. Distinct divisions of the BST may be involved in stress response, homeostatic regulation, nociception, and motivated behaviors. Endogenous opioid peptides and receptors are expressed in the BST, but their exact distribution is poorly characterized. The present study used in situ hybridization in order to characterize the endogenous opioid system of the BST, focusing on both enkephalin and dynorphin neuropeptides, as well as their respective receptors (mu, delta, and kappa opioid receptors). We report that preprodynorphin mRNA is observed in distinct nuclei of the BST, namely the fusiform, oval and anterior lateral nuclei. In contrast, there is a widespread expression of preproenkephalin mRNA in both anterior and posterior divisions of the BST. Similarly, mu and kappa opioid receptors are broadly expressed in the BST, whereas delta opioid receptor mRNA was observed only in the principal nucleus. For further characterization of enkephalin-expressing neurons of the BST, we performed a double fluorescent in situ hybridization in order to reveal the coexpression of enkephalin peptides and markers of GABAergic and glutamatergic neurons. Although most neurons of the BST are GABAergic, there is also a modest population of glutamatergic cells expressing vesicular glutamate transporter 2 (VGLUT2) in specific nuclei of the BST. Finally, we identified a previously unreported population of enkephalinergic neurons expressing VGLUT2, which is principally located in the posterior BST.
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http://dx.doi.org/10.1016/j.pnpbp.2009.06.021DOI Listing
November 2009

Postsynaptic mu-opioid receptor response in the median preoptic nucleus is altered by a systemic sodium challenge in rats.

Eur J Neurosci 2008 Mar;27(5):1197-209

Centre de recherche du CHUL (CHUQ), Unité de Neurosciences et Université Laval, Québec, QC, Canada G1V 4G2.

The median preoptic nucleus (MnPO) is an integrator site for the chemosensory and neural signals induced by a perturbation in the hydromineral balance, and it is highly involved in controlling fluid and electrolyte ingestion. Here, we hypothesize that opioid peptides, previously recognized to control ingestive behaviors, may regulate the excitability of MnPO neurons and that this regulatory action may depend on the natriuric (Na(+)) status of body fluid compartments. Our results show that activation of mu-, but not delta-, opioid receptors (OR) triggered a membrane hyperpolarization by recruiting a G-protein-regulated inward-rectifier K(+) (GIRK) conductance in 41% of the neurons tested. Interestingly, 24 h Na(+) depletion strengthened this opioid-mediated control of neuronal excitability. In Na(+)-depleted animals, the neuronal population displaying the mu-OR-induced hyperpolarization expanded to 60% (Z-test, P = 0.012), whereas Na(+) repletion restored this population to the control level (39%; Z-test, P = 0.037). Among the neurons displaying mu-OR-induced hyperpolarization, Na(+) depletion specifically increased the neuronal population responsive to variation in ambient Na(+) (from 27% to 43%; Z-test, P = 0.029). In contrast, Na(+) repletion dramatically reduced the population that was unresponsive to Na(+) (from 17% to 3%; Z-test, P = 0.031). Neither the basic properties of the neurons nor the characteristics of the mu-OR-induced response were altered by the body Na(+) challenge. Our results indicate that an episode of Na(+) depletion/Na(+) repletion modifies the organization of the opioid-sensitive network of the MnPO. Such network plasticity might be related to the avid salt ingestion triggered by repeated Na(+) depletion.
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http://dx.doi.org/10.1111/j.1460-9568.2008.06087.xDOI Listing
March 2008

Neonatal maternal separation and enhancement of the inspiratory (phrenic) response to hypoxia in adult rats: disruption of GABAergic neurotransmission in the nucleus tractus solitarius.

Eur J Neurosci 2008 Mar;27(5):1174-88

Pediatrics Research Unit, Centre Hospitalier Universitaire de Québec, Université Laval, Québec, Canada.

Neonatal maternal separation (NMS) alters respiratory control development. Adult male rats previously subjected to NMS show a hypoxic ventilatory response 25% greater than controls. During hypoxia, gamma-aminobutyric acid (GABA) release within the nucleus tractus solitarius (NTS) modulates the magnitude of the ventilatory response. Because development of GABAergic receptors is sensitive to NMS, we tested the hypothesis that in adults, a change in responsiveness to GABA within the NTS contributes to NMS-related enhancement of the inspiratory (phrenic) response to hypoxia. Pups subjected to NMS were placed in an incubator for 3 h/day for 10 consecutive days [postnatal days 3 to 12]. Controls were undisturbed. Adult (8-10 weeks old) rats were anaesthetized (urethane; 1.6 g/kg), paralysed and artificially ventilated to record phrenic activity. Rats either received a 50-nL microinjection of GABA (5 microm) or phosphate-buffered saline (sham) within the caudal NTS, or no injection prior to being exposed to hypoxia (FiO(2) = 0.12; 5 min). NMS enhanced both the frequency and amplitude components of the phrenic response to hypoxia vs controls. GABA microinjection attenuated the phrenic responses in NMS rats only. This result is supported by ligand binding autoradiography results showing that the number of GABA(A) receptors within the NTS was 69% greater in NMS vs controls. Despite this increase, the phrenic response to hypoxia of NMS rats is larger than controls, suggesting that the higher responsiveness to GABA microinjection within the NTS is part of a mechanism that aims to compensate for: (i) a deficient GABAergic modulation; (ii) enhancement of excitatory inputs converging onto this structure; or (iii) both.
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http://dx.doi.org/10.1111/j.1460-9568.2008.06082.xDOI Listing
March 2008

Enkephalin co-expression with classic neurotransmitters in the amygdaloid complex of the rat.

J Comp Neurol 2008 Feb;506(6):943-59

Centre de Recherche du CHUL (CHUQ), Neurosciences, Université Laval, Québec, QC, G1V 4G2, Canada.

This study aimed at characterizing the neurotransmitter phenotype of enkephalin neurons in the rat amygdaloid complex. We first established the detailed distribution of vesicular glutamate transporters 1 and 2 (VGLUT1 and -2) and glutamate decarboxylase 65 (GAD65) in the amygdala by using in situ hybridization. In the amygdaloid complex, GAD65 is strongly expressed in striatal-like divisions, namely, the anterior amygdaloid area, the central nucleus (CEA), the intercalated nuclei, and the dorsal part of the medial nucleus (MEA). VGLUT1 and -2 expression is mostly segregated to specific divisions of the amygdale, with VGLUT2 being expressed only in the MEA, the anterior cortical nucleus (COAa), and the anterior basomedial nucleus (BMAa), whereas VGLUT1 is expressed in all other divisions of the amygdala. Second, we assessed the co-expression of preproenkephalin (ppENK) with GAD65, VGLUT1, or VGLUT2 by using double fluorescent in situ hybridization. We found that ppENK mRNA co-localized exclusively with GAD65 in all striatal-like structures of the amygdaloid complex with the exception of the MEA, where ENK also co-localized with VGLUT2 mRNA. This co-localization is most apparent in the posteroventral part of the MEA, where 70% of ENKergic cells expressed VGLUT2. In addition, ppENK also co-localized with VGLUT1 because more than 95% of ENK cells in the basolateral amygdala expressed VGLUT1. In contrast, less than 25% of ENKergic cells expressed VGLUT1 in the lateral nucleus of the amygdale, with the majority of ENK cells expressing GAD65 mRNA in this nucleus. These results have broad implications for understanding the functional roles of enkephalinergic neurotransmission in the amygdaloid complex.
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http://dx.doi.org/10.1002/cne.21587DOI Listing
February 2008

Neonatal maternal separation and enhancement of the hypoxic ventilatory response in rat: the role of GABAergic modulation within the paraventricular nucleus of the hypothalamus.

J Physiol 2007 Aug 14;583(Pt 1):299-314. Epub 2007 Jun 14.

Pediatrics Unit, Centre de Recherche du Centre Hospitalier Universitaire de Québec, QC, Canada G1L 3L5.

Neonatal maternal separation (NMS) affects respiratory control development as adult male (but not female) rats previously subjected to NMS show a hypoxic ventilatory response 25% greater than controls. The paraventricular nucleus of the hypothalamus (PVN) is an important modulator of respiratory activity. In the present study, we hypothesized that in awake rats, altered GABAergic inhibition within the PVN contributes to the enhancement of hypoxic ventilatory response observed in rats previously subjected to NMS. During normoxia, the increase in minute ventilation following microinjection of bicuculline (1 mm) within the PVN is greater in NMS versus control rats. These data show that regulation of ventilatory activity related to tonic inhibition of the PVN is more important in NMS than control rats. Microinjection of GABA or muscimol (1 mM) attenuated the ventilatory response to hypoxia (12% O2) in NMS rats only. The higher efficiency of microinjections in NMS rats is supported by results from GABAA receptor autoradiography which revealed a 22% increase in GABAA receptor binding sites within the PVN of NMS rats versus controls. Despite this increase, however, NMS rats still show a larger hypoxic ventilatory response than controls, suggesting that within the PVN the larger number of GABAA receptors either compensate for (1) a deficient GABAergic modulation, (2) an increase in the efficacy of excitatory inputs converging onto this structure, or (3) both. Together, these results show that the life-long consequences of NMS are far reaching as they can compromise the development of vital homeostatic function in a way that may predispose to respiratory disorders.
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http://dx.doi.org/10.1113/jphysiol.2007.135160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2277229PMC
August 2007

Challenged sodium balance and expression of angiotensin type 1A receptor mRNA in the hypothalamus of Wistar and Dahl rat strains.

Regul Pept 2007 Jul 3;142(1-2):44-51. Epub 2007 Feb 3.

Centre de recherche du CHUL (CHUQ), Unité de Neurosciences et Faculté de médecine, Université Laval, Québec, Canada.

The present study investigates the influence of a chronic high Na+ diet (8% Na+) on the expression of the angiotensin type 1A (AT1A) receptor gene in the lamina terminalis and paraventricular nucleus of the hypothalamus (PVH) in normotensive Wistar (W) rats, as well as in Dahl salt-resistant (DR) and Dahl salt-sensitive (DS) rats. Three weeks of 8% Na+ diet led to a higher blood pressure in DS rats compared to DR and W rats. Moreover, the high Na+ diet was correlated with a decreased expression of AT1A receptor mRNA in the median preoptic nucleus (MnPO) and in the PVH of DS rats, compared to DR and W rats. Contrastingly, the AT1A receptor mRNA expression was not altered by the high Na+ diet in the forebrain circumventricular organs of all the rat strains. Interestingly, a furosemide-induced Na+ depletion was correlated with an increased expression of AT1A receptor mRNA in the PVH, MnPO and SFO of both the DS and DR rats. It is concluded that chronic high Na+ diet did differently regulate the expression of AT1A receptor mRNA in two hypothalamic integrative centers for hydromineral and cardiovascular balance (the PVH and MnPO) in DS rats, compared to DR and W rats. However, the AT1A receptor mRNA expression was similarly regulated in DS and DR rats in response to an acute Na+ depletion, suggesting a distinct high Na+ -induced regulation of the AT1A receptor gene in the PVH and MnPO of DS rats.
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http://dx.doi.org/10.1016/j.regpep.2007.01.005DOI Listing
July 2007

Neonatal maternal separation induces sex-specific augmentation of the hypercapnic ventilatory response in awake rat.

J Appl Physiol (1985) 2007 Apr 21;102(4):1416-21. Epub 2006 Dec 21.

Pediatrics, Centre de Recherche du Centre Hospitalier Universitaire de Québec, Université Laval, Québec, Canada .

Neonatal maternal separation (NMS) is a form of stress that exerts persistent, sex-specific effects on the hypoxic ventilatory response. Adult male rats previously subjected to NMS show a 25% increase in the response, whereas NMS females show a response 30% lower than controls (8). To assess the extent to which NMS affects ventilatory control development, we tested the hypothesis that NMS alters the ventilatory response to hypercapnia in awake, unrestrained rats. Pups subjected to NMS were placed in a temperature- and humidity-controlled incubator 3 h/day for 10 consecutive days (P3 to P12). Control pups were undisturbed. At adulthood (8 to 10 wk old), rats were placed in a plethysmography chamber for measurement of ventilatory parameters under baseline and hypercapnic conditions (inspired CO(2) fraction = 0.05). After 20 min of hypercapnia, the minute ventilation response measured in NMS males was 47% less than controls, owing to a lower tidal volume response (22%). Conversely, females previously subjected to NMS showed minute ventilation and tidal volume responses 63 and 18% larger than controls respectively. Although a lower baseline minute ventilation contributes to this effect, the higher minute ventilation/CO(2) production response observed in NMS females suggests a greater responsiveness to CO(2)/H(+) in this group. We conclude that NMS exerts sex-specific effects on the hypercapnic ventilatory response and that the neural mechanisms affected by NMS likely differ from those involved in the hypoxic chemoreflex.
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http://dx.doi.org/10.1152/japplphysiol.00454.2006DOI Listing
April 2007

Enkephalinergic afferents of the centromedial amygdala in the rat.

J Comp Neurol 2006 Jun;496(6):859-76

Centre de Recherche du CHUQ (CHUL), Neurosciences, Université Laval, Québec, Canada.

The connectivity of the amygdaloid complex has been extensively explored with both anterograde and retrograde tracers. Even though the afferents of the centromedial amygdala [comprising the central (CEA) and medial (MEA) amygdaloid nuclei] are well established, relatively little is known about the neuropeptide phenotype of these connections. In this study, we first examined the distribution of mu-opioid receptor (MOR) and delta-opioid receptor (DOR) in the amygdala via in situ hybridization and immunohistochemistry. We then investigated the distribution of Met-enkephalin (ENK) and Leu-ENK fibers with immunohistochemistry and examined the distribution of preproenkephalin mRNA in the amygdala by using in situ hybridization. Finally, we examined the ENK projections to the CEA and MEA by using stereotaxic injections of the retrograde tracer cholera toxin subunit B or fluorogold revealed by immunohistochemistry combined with in situ hybridization to identify ENKergic neurons. Our results indicate that the centromedial amygdala receives ENK afferents, as indicated by the presence of MOR, DOR, and ENK fibers in the CEA and MEA, originating primarily from the bed nucleus of the stria terminalis (BST) and from other amygdaloid nuclei. The posterior BST, the basomedial nucleus (BMA), and the cortical nucleus of the amygdala (COA) were found to be the major ENK afferents of the MEA, whereas the anterolateral BST, the COA, the MEA, and the BMA provided the main ENKergic innervation of the CEA. In addition, we found that the ventromedial nucleus of the hypothalamus and the pontine parabrachial nucleus provide a moderate ENK input to the CEA and MEA. The functional implications of these connections in stress, anxiety, and nociception are discussed.
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http://dx.doi.org/10.1002/cne.20956DOI Listing
June 2006

Intracerebroventricular D-Pen2, D-Pen5-enkephalin administration soon after stressor imposition influences behavioral responsivity to a subsequent stressor encounter in CD-1 mice.

Pharmacol Biochem Behav 2005 Nov 10;82(3):453-69. Epub 2005 Nov 10.

Laboratory of Molecular Neurobiology, Dalhousie University, Halifax, NS, Canada.

Endogenous opioid peptide systems diminish stress-induced autonomic nervous system, neuroendocrine (hypothalamic-pituitary-adrenal axis) and behavioral responses, attenuating a collection of physiological symptoms basic to emotional and affective states. Neurogenic stressors may incite specific central changes in opioid peptide availability as well as changes in mu and delta-opioid receptor function. The present investigation evaluated the proactive influence of an intracerebroventricular injection of the opioid receptor agonist D-Pen2, D-Pen5-enkephalin (DPDPE) (0 microg, 0.005 microg, 1.0 microg or 2.5 microg) on locomotor behavior of mice following uncontrollable footshock (Shock) or novel shock chamber exposure (No Shock). It was expected that DPDPE administration following Shock on Day 1 would restore locomotor activity up to 1 week and prevent shock-associated behavior of mice encountering a brief session of footshock 18 days later. Exposure to Shock reduced horizontal locomotor and vertical locomotor (rearing) activity of mice while 2.5 microg DPDPE restored behavior. Eighteen days following Shock and DPDPE challenge, mice were exposed to either an abbreviated session of footshock (Mild Stress) or the shock chamber (Cues). Mice in the No Shock and Shock groups administered 2.5 microg DPDPE on Day 1 did not exhibit any locomotor deficits in response to Mild Stress on Day 18. Mice in the Shock group administered 0.005 microg DPDPE on Day 1, did not exhibit exaggerated rearing deficits following ensuing Mild Stressor encounter relative to mice reexposed to Cues on Day 18. Taken together, these data show that (a) footshock differentially affects rearing and locomotor activity, (b) DPDPE administration increases locomotor activity for up to 1 week following footshock and DPDPE administration, (c) reexposure to Mild Stress affects rearing and locomotor performance differently depending on previous stressor history and DPDPE dose, (d) DPDPE affords long-lasting protection to previously non-stressed mice against the deleterious effects of subsequent mild stress on locomotor activity, while a low dose of DPDE is sufficient to prevent shock-induced sensitization of rearing deficits, 18 days following original stressor and drug presentation. Finally, our investigation demonstrates that DPDPE administration alters the behavioral impact of future stressful encounters and emphasizes the importance of investigating opioid mechanisms in chronic stress disorders.
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http://dx.doi.org/10.1016/j.pbb.2005.10.001DOI Listing
November 2005

Cholecystokinin and endogenous opioid peptides: interactive influence on pain, cognition, and emotion.

Prog Neuropsychopharmacol Biol Psychiatry 2005 Dec 20;29(8):1225-38. Epub 2005 Oct 20.

Department of Pharmacology, Faculty of Medicine, Dalhousie University, Sir Charles Tupper Medical Building, 5850 College Street, Halifax, NS, Canada B3H 1X5.

It is well documented that stressful life experiences contribute to the etiology of human mood disorders. Cholecystokinin (CCK) is a neuropeptide found in high concentrations throughout the central nervous system, where it is involved in numerous physiological functions. A role for CCK in the induction and persistence of anxiety and major depression appears to be conspicuous. While increased CCK has been associated with motivational loss, anxiety and panic attacks, an increase in mesocorticolimbic opioid availability has been associated with coping and mood elevation. The close neuroanatomical distribution of CCK with opioid peptides in the limbic system suggests that there may be an opioid-CCK link in the modulation and expression of anxiety or stressor-related behaviors. In effect, while CCK induces relatively protracted behavioral disturbances in both animal and human subjects following stressor applications, opioid receptor activation may change the course of psychopathology. The antagonistic interaction of CCK and opioid peptides is evident in psychological disturbances as well as stress-induced analgesia. There appears to be an intricate balance between the memory-enhancing and anxiety-provoking effects of CCK on one hand, and the amnesic and anxiolytic effects of opioid peptides on the other hand. Potential anxiogenic and mnemonic influences of site-specific mesocorticolimbic CCK and opioid peptide availability, the relative contributions of specific CCK and opioid receptors, as well as the time course underlying neuronal substrates of long-term behavioral disturbances as a result of stressor manipulations, are discussed.
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http://dx.doi.org/10.1016/j.pnpbp.2005.08.008DOI Listing
December 2005

Galanin-mediated anxiolytic effect in rat central amygdala is not a result of corelease from noradrenergic terminals.

Synapse 2006 Jan;59(1):27-40

Department of Pharmacology and Center for Biomedical Neuroscience, University of Texas Health Science Center, San Antonio, 78229, USA.

Galanin is colocalized extensively with norepinephrine in brain. Although this suggests possible activity-dependent neurotransmitter interactions, the functional significance of such colocalization remains elusive. Previously, we showed that enhancing stress-activation of the noradrenergic system by yohimbine pretreatment released galanin in central amygdala, attenuating the anxiety-like behavioral response to stress on the elevated plus-maze. The present study was conducted to determine, in this context, whether galanin was indeed coreleased from noradrenergic terminals, or instead from another galanin afferent or local stress-responsive galanin neurons in the amygdala. In experiment 1, galanin-mediated anxiolytic effects on the plus-maze following yohimbine + stress were unaltered by lesioning the noradrenergic innervation of central amygdala. In experiment 2, combining immunohistochemistry and in situ hybridization, galanin neurons specifically activated by yohimbine + stress treatment were found only in the locus coeruleus and intraamygdalar bed nucleus of the stria terminalis, adjacent to central amygdala. In experiment 3, retrograde tracing combined with in situ hybridization revealed few if any galanin cells projecting to central amygdala in locus coeruleus or nucleus tractus solitarius, sources of noradrenergic innervation. Indeed, few retrogradely-labeled galanin neurons were observed anywhere in the brain, including a small number in the intraamygdalar bed nucleus. Together, these results suggest that stress following yohimbine may have induced galanin release from an afferent to central amygdala originating in the bed nucleus, or from local neurons in the intraamygdalar bed nucleus, but that anxiolytic effects exerted by galanin in this context of elevated noradrenergic activity were not the result of corelease from noradrenergic terminals innervating central amygdala.
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http://dx.doi.org/10.1002/syn.20208DOI Listing
January 2006

One for all or one for one: does co-transmission unify the concept of a brain galanin "system" or clarify any consistent role in anxiety?

Neuropeptides 2005 Jun 28;39(3):289-92. Epub 2005 Jan 28.

Department of Pharmacology and Center for Biomedical Neuroscience, University of Texas Health Science Center, MC 7764, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA.

Galanin (GAL) is a potential target for novel antidepressant or anti-anxiety drug development. However, no integrated role for a "brain galanin system" in anxiety has yet emerged. It is possible that such a function may be revealed by examining the interaction of GAL with norepinephrine (NE), with which it is prominently co-localized. We showed previously that enhancing stress-activation of the NE system by yohimbine (YOH) pretreatment induced the release of GAL in central amygdala (CeA) to exert an anxiolytic effect on the elevated plus-maze. However, it remained to be demonstrated conclusively that GAL was co-released from NE terminals in CeA in this context, or if a multi-synaptic circuit activated GAL release from another afferent to CeA, or from local GAL neurons in the vicinity of CeA. In studies presented at the Third International Symposium on Galanin and Its Receptors, we utilized a combination of behavioral pharmacological approaches, testing the effects of YOH on the behavioral response to stress on the plus-maze after lesioning NE afferents to CeA with 6-OHDA, and anatomical approaches to identify GAL afferents to CeA that are activated in the context of stress with yohimbine pretreatment, to address these alternatives. Our results suggest that GAL was not co-released from noradrenergic terminals innervating CeA to exert an anxiolytic influence when noradrenergic activation was amplified by yohimbine pretreatment. Rather, it most likely originated from GAL neurons immediately adjacent to CeA that were activated by a non-noradrenergic afferent arising from elsewhere in the brain, itself activated by increasing NE activity. Thus, any role for brain GAL in anxiety remains region-specific, pathway specific, response specific and context-specific, which is likely to continue to present challenges to the development of novel agents targeting brain GAL for treatment of depression or anxiety.
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http://dx.doi.org/10.1016/j.npep.2004.12.008DOI Listing
June 2005

Neonatal maternal separation and early life programming of the hypoxic ventilatory response in rats.

Respir Physiol Neurobiol 2005 Nov;149(1-3):313-24

Pediatrics, Centre de Recherche Hospitalier Universitaire de Québec, Université Laval, Québec, Qué., Canada.

The neonatal period is critical for central nervous system (CNS) development. Recent studies have shown that this basic neurobiological principle also applies to the neural circuits regulating respiratory activity as exposure to excessive or insufficient chemosensory stimuli during early life can have long-lasting consequences on the performance of this vital system. Although the tactile, olfactory, and auditory stimuli that the mother provides to her offspring during the neonatal period are not directly relevant to respiratory homeostasis, they likely contribute to respiratory control development. This review outlines the rationale for the link between maternal stimuli and programming of the hypoxic ventilatory response during early life, and presents recent results obtained in rats indicating that experimental disruption of mother-pup interaction during this critical period elicits significant phenotypic plasticity of the hypoxic ventilatory response.
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http://dx.doi.org/10.1016/j.resp.2005.04.014DOI Listing
November 2005
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