ArticleLiterature Review

Neuropeptides in learning and memory processes with focus on galanin

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Abstract

Neuropeptides represent by far the most common signalling molecules in the central nervous system. They are involved in a wide range of physiological functions and can act as neurotransmitters, neuromodulators or hormones in the central nervous system and in the periphery. Accumulating evidence during the past 40 years has implicated a number of neuropeptides in various cognitive functions including learning and memory. A major focus has been on the possibility that neuropeptides, by coexisting with classical neurotransmitters, can modulate classical transmitter function of importance for cognition. It has become increasingly clear that most transmitter systems in the brain can release a cocktail of signalling molecules including classical transmitters and several neuropeptides. However, the neuropeptides seem to come into action mainly under conditions of severe stress or aversive events, which have linked their action also to regulation of affective components of behaviour. This paper summarises some of the results of three neuropeptides, which can impact on hippocampal cognition by intrinsic (dynorphins, nociceptin) or extrinsic (galanin) modulation. The results obtained with these neuropeptides in rodent studies indicate that they are important for various aspects of hippocampal learning and memory as well as hippocampal plasticity. Recent studies in humans have also shown that dysregulation of these neuropeptides may be of importance for both neurodegenerative and neuropsychiatric disorders associated with cognitive impairments. It is concluded that compounds acting on neuropeptide receptor subtypes will represent novel targets for a number of disorders, which involve cognitive deficiencies.

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... There is a wealth of pharmacological and genetic pre-clinical data to link the neuropeptide and its three G-protein coupled receptors (Gal 1 , Gal 2 , and Gal 3 ) to a range of physiological and pathological functions. These include metabolism, feeding and endocrinology, cognition, epilepsy, chronic anxiety and depression, addiction, neuroprotection, neuronal regeneration, and pain (see recent reviews (Lang et al., 2007;Ogren et al., 2010;Picciotto et al., 2010)). Some, but by no means all, of these rodent findings are paralleled by human studies demonstrating associations between single nucleotide polymorphisms (SNPs) in the GAL gene and/or one of its three receptors, and depression or anxiety disorders (Unschuld et al., 2008;Wray et al., 2010;Juhasz et al., 2014) and addictive behaviours that include smoking (Gold et al., 2012), alcohol (Belfer et al., 2006), and heroin (Levran et al., 2008). ...
... We initially identified four broad areas that galanin has been linked to in previous epidemiological studies; metabolism, cognition, depression, and addiction (see recent reviews (Lang et al., 2007;Ogren et al., 2010;Picciotto et al., 2010)). We then selected traits from the phenotypically-rich ALSPAC cohort which best represented these epidemiological areas of interest (see below and supporting information). ...
... We have undertaken extensive analyses to investigate the effects of a galanin enhancer genotype (rs2513280) on a range of phenotypes that are related to known functions of the galaninergic system (see recent reviews (Lang et al., 2007;Ogren et al., 2010;Picciotto et al., 2010)). Despite finding evidence of association with cannabis use in the ALSPAC cohort, we were unable to replicate this effect in the YNTR and Yale-UPenn cohorts. ...
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There is a large body of pre-clinical and some clinical data to link the neuropeptide galanin to a range of physiological and pathological functions that include metabolism, depression, and addiction. An enhancer region upstream of the human GAL transcriptional start site has previously been characterised. In-vitro transfection studies in rat hypothalamic neurons demonstrated that the CA allele was 40% less active than the GG allele in driving galanin expression. Our hypothesis was to investigate the effect of this galanin enhancer genotype on a range of variables that relate to the known functions of the galaninergic system in the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort of young adults (N = 169–6,078). Initial findings showed a positive relationship of cannabis usage (OR = 2.070, P = 0.007, N = 406 (individuals who had used cannabis at least once within the last 12 months, total sample size 2731) with the GG haplotype, consistent with the previous published data linking galanin with an increased release of dopamine. As our sample size was relatively small we replicated the analysis in a larger cohort of 2,224 African Americans and 1,840 European Americans, but no discernible trend across genotypes was observed for the relationship with cannabis usage. Further, we found no association of the galanin enhancer genotype with any of the other pathophysiological parameters measured. These findings emphasise that preclinical data does not always predict clinical outcomes in cohort studies, noting that association studies are subject to multiple confounders. © 2014 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics published by Wiley Periodicals, Inc.
... Other mediators might modulate neural communication, such as neuropeptides (Sudhof and Starke, 2004). The involvement of several neuropeptides, such as nociceptin, neuropeptide Y, galanin, and also endogenous opioids, in memory processes has been previously reported (Ogren et al., 2010;Pleil et al., 2015). Unlike the classical neurotransmitters, neuropeptides seem to be recruited mainly under conditions of intense stress or aversive events, suggesting that these neuromodulators could be vitally involved in the processing of exaggerated or potentiated negative emotional memories (Ogren et al., 2010). ...
... The involvement of several neuropeptides, such as nociceptin, neuropeptide Y, galanin, and also endogenous opioids, in memory processes has been previously reported (Ogren et al., 2010;Pleil et al., 2015). Unlike the classical neurotransmitters, neuropeptides seem to be recruited mainly under conditions of intense stress or aversive events, suggesting that these neuromodulators could be vitally involved in the processing of exaggerated or potentiated negative emotional memories (Ogren et al., 2010). Contextual aversive memory is processed in several brain regions, including the dorsal hippocampus (DH). ...
... The working hypothesis was the DH kORs would be specifically up-regulated following associative aversive experience. Given the fact that neuropeptides are mainly expressed under intense stress conditions or aversive events (Ogren et al., 2010), and that dynorphin requires much higher electrical stimulation frequencies to be released (Wagner et al., 1991), we raised one more hypothesis: the DH kORs would be required and sufficient to modulate a strong, but not a weak CAC experience. Thus, our third objective was to investigate the effects of the DH kORs antagonism on memory consolidation following different CAC protocol intensities. ...
Article
The main κ opioid receptors (κORs) subtypes already described (κ1ORs and κ2ORs) are expressed in brain regions involved in aversive memory consolidation, including the dorsal hippocampus (DH). However, the role of DH κORs in consolidation of aversive memories with varied intensity and specificity is still uncertain. The present study aimed to investigate this question using pharmacological agents in rats subjected to a weak, moderate or strong contextual aversive conditioning (CAC) protocol. Antagonizing DH κORs with nor-binaltorphimine (nor-BNI), immediately after, but not 6 h later, a moderate CAC leads to intensified freezing behavior in the re-exposure to the paired context. Thus, indicating that DH κORs have an inhibitory role in the consolidation of an aversive memory. Increased DH κORs expression 1 h and 3 h after the moderate CAC was also observed. This up-regulation was absent in animals only exposed to the context or to the shock, indicating that this phenomenon requires a shock-context pairing to occur. Intra-DH nor-BNI infusion induced no changes following a weak CAC, but it was able to potentiate the expression of freezing behavior in novel and unpaired context after a strong CAC, indicating that DH κORs also modulate the consolidation of a generalized memory. Moreover, infusing the κ2ORs agonist GR 89696, but not the κ1ORs agonist U-69593, into the DH reduced the conditioned freezing expression. Nor-BNI pretreatment in a sub-effective dose prevented the κ2ORs agonist effects. Altogether, the present findings provide convergent evidence that κORs activation negatively modulates contextual aversive memory consolidation in rat dorsal hippocampus.
... GALR can form dimer and heterodimers (e.g., %-HT1A or NPY Y2), changing the postreceptor signaling. Animal studies suggested that galanin may act as both excitatory and inhibitory neuropeptide on cognition and its effects may be mediated by other mechanisms, e.g., release of endogenous excitatory amino acids or acetylcholine [170][171][172][173][174]. ...
... In the hippocampus galanin receptors GALR1 and GALR2 are differently and species dependently expressed. Thus, the effects of the administrated galanin on cognition are both site and dose dependent [153,[174][175][176]. In rats, galanin is modulator of cholinergic transmission [177] while in monkeys and humans galanin is not co-localized in acetylcholine neurons of the nucleus basalis of Meynert [178]. ...
... In rodents, ICV administration of galanin led to an impairment of memory related tasks [174,176], and acquisition, but not retrieval of partial memory in rats [179]. Memory consolidation was also negatively affected by ICV administration of galanin [180]. ...
Article
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Regular physical activity (PA) improves cognitive functions, prevents brain atrophy, and delays the onset of cognitive decline, dementia, and Alzheimer’s disease. Presently, there are no specific recommendations for PA producing positive effects on brain health and little is known on its mediators. PA affects production and release of several peptides secreted from peripheral and central tissues, targeting receptors located in the central nervous system (CNS). This review will provide a summary of the current knowledge on the association between PA and cognition with a focus on the role of (neuro)peptides. For the review we define peptides as molecules with less than 100 amino acids and exclude myokines. Tachykinins, somatostatin, and opioid peptides were excluded from this review since they were not affected by PA. There is evidence suggesting that PA increases peripheral insulin growth factor 1 (IGF-1) levels and elevated serum IGF-1 levels are associated with improved cognitive performance. It is therefore likely that IGF-1 plays a role in PA induced improvement of cognition. Other neuropeptides such as neuropeptide Y (NPY), ghrelin, galanin, and vasoactive intestinal peptide (VIP) could mediate the beneficial effects of PA on cognition, but the current literature regarding these (neuro)peptides is limited.
... Specific disruption of neuropeptides has been reported in the hippocampus in early-stage AD patients (Kapogiannis and Mattson, 2011;Saxena and Caroni, 2011). For instance, hippocampal dynorphin level is elevated in AD patients, contributing to the loss of afferents in the dentate gyrus (DG) (Ogren et al., 2010). Meanwhile, reduced somatostatin levels in the cerebral cortex and cerebrospinal fluid (CSF) have been reported in AD patients (Ogren et al., 2010). ...
... For instance, hippocampal dynorphin level is elevated in AD patients, contributing to the loss of afferents in the dentate gyrus (DG) (Ogren et al., 2010). Meanwhile, reduced somatostatin levels in the cerebral cortex and cerebrospinal fluid (CSF) have been reported in AD patients (Ogren et al., 2010). These lines of evidence suggest that neuropeptide-based modulation of neural circuitry is a possible approach for protecting the vulnerable hippocampal network and maintaining cognitive function. ...
Article
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Hippocampal synaptic plasticity is modulated by neuropeptides, the disruption of which might contribute to cognitive deficits observed in Alzheimer’s disease (AD). Although pro-opiomelanocortin (POMC)-derived neuropeptides and melanocortin 4 receptor (MC4R) are implicated in hippocampus-dependent synaptic plasticity, how the POMC/MC4R system functions in the hippocampus and its role in synaptic dysfunction in AD are largely unknown. Here, we mapped a functional POMC circuit in the mouse hippocampus, wherein POMC neurons in the cornu ammonis 3 (CA3) activate MC4R in the CA1. Suppression of hippocampal MC4R activity in the APP/PS1 transgenic mouse model of AD exacerbates long-term potentiation impairment, which is alleviated by the replenishment of hippocampal POMC/MC4R activity or activation of hippocampal MC4R-coupled Gs signaling. Importantly, MC4R activation rescues amyloid-β-induced synaptic dysfunction via a Gs/cyclic AMP (cAMP)/PKA/cAMP-response element binding protein (CREB)-dependent mechanism. Hence, disruption of this hippocampal POMC/MC4R circuit might contribute to synaptic dysfunction observed in AD, revealing a potential therapeutic target for the disease.
... However, many classes of interneurons are known to co-express with GABA a variety of neuropeptides that often define separate interneuron classes [8]. Although pharmacological studies using injections of neuropeptides or their antagonists indicate that these agents can exert powerful effects to modulate neural excitability, synaptic transmission, and various behaviors [9][10][11][12], relatively little is known about whether neuropeptide release from defined classes of hippocampal interneurons under physiological conditions is recruited to mediate the encoding of memory. ...
... As a result, recent studies implicating VIP neurons in regulating circuit function and learning behavior, including amygdaladependent fear memory [5], hippocampal-dependent goal learning [4] and avoidance behavior [6], and sensory perceptual learning [7], have focused on this rapid disinhibitory action, either explicitly or implicitly. However, VIPexpressing neurons, like many other classes of inhibitory neurons, express a number of neuropeptides [8] known to exert powerful modulatory actions on the intrinsic excitability and pre-and postsynaptic properties of various neurons [9][10][11][12]. Our study is one of the first to elucidate how release of neuropeptides contributes to the physiological and behavioral effects of a given class of interneurons. ...
Article
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The hippocampus contains a diverse array of inhibitory interneurons that gate information flow through local cortico-hippocampal circuits to regulate memory storage. Although most studies of interneurons have focused on their role in fast synaptic inhibition mediated by GABA release, different classes of interneurons express unique sets of neuropeptides, many of which have been shown to exert powerful effects on neuronal function and memory when applied pharmacologically. However, relatively little is known about whether and how release of endogenous neuropeptides from inhibitory cells contributes to their behavioral role in regulating memory formation. Here we report that vasoactive intestinal peptide (VIP)-expressing interneurons participate in social memory storage by enhancing information transfer from hippocampal CA3 pyramidal neurons to CA2 pyramidal neurons. Notably, this action depends on release of the neuropeptide enkephalin from VIP neurons, causing long-term depression of feedforward inhibition onto CA2 pyramidal cells. Moreover, VIP neuron activity in the CA2 region is increased selectively during exploration of a novel conspecific. Our findings, thus, enhance our appreciation of how GABAergic neurons can regulate synaptic plasticity and mnemonic behavior by demonstrating that such actions can be mediated by release of a specific neuropeptide, rather than through classic fast inhibitory transmission.
... All rights reserved. with a wide-range of biological effects in both the CNS and PNS (Ogren et al. 2010, Bartfai et al. 1993, Gundlach et al. 2001, Lang et al. 2007). Galanin is involved in metabolism and reproduction (Barson et al. 2010) (Merchenthaler 2010), survival, regeneration (Hobson et al. 2010) and cognition (Crawley 1999, Ogren et al. 2010). ...
... with a wide-range of biological effects in both the CNS and PNS (Ogren et al. 2010, Bartfai et al. 1993, Gundlach et al. 2001, Lang et al. 2007). Galanin is involved in metabolism and reproduction (Barson et al. 2010) (Merchenthaler 2010), survival, regeneration (Hobson et al. 2010) and cognition (Crawley 1999, Ogren et al. 2010). In addition, several studies have shown that galanin plays a role in pathological conditions such as pain (Liu & Hokfelt 2002), AD (Counts et al. 2010), addiction (Picciotto 2010) and epilepsy (Lerner et al. 2010). ...
Article
Type 2 diabetes (T2D) impairs adult neurogenesis which could play a role in the CNS complications of this serious disease. The goal of this study was to determine the potential role of galanin in protecting adult neural stem cells (NSCs) from glucolipotoxicity and to analyze whether apoptosis and the unfolded protein response (UPR) were involved in the galanin-mediated effect. We also studied the regulation of galanin and its receptor subtypes under diabetes in NSCs in vitro and in the subventricular zone (SVZ) in vivo. The viability of mouse SVZ-derived NSCs and the involvement of apoptosis (Bcl-2, cleaved caspase-3) and UPR (CHOP, BIP, XBP1, JNK phosphorylation) were assessed in the presence of glucolipotoxic conditions after 24 hours. The effect of diabetes on the regulation of galanin and its receptor subtypes was assessed on NSCs in vitro and in SVZ tissues isolated from normal and T2D ob/ob mice.We show increased NSC viability following GalR3 activation. This protective effect correlated with decreased apoptosis and CHOP levels. We also report how galanin and its receptors are regulated by diabetes in vitro and in vivo. This study shows GalR3-mediated neuroprotection, supporting a potential future therapeutic development, based on GalR3 activation, for the treatment of brain disorders. This article is protected by copyright. All rights reserved.
... Dynorphins and nociceptin are documented to be of prime role in hippocampal learning, memory and neuroplasticity. 39 It was reviewed that endorphins mediate learning process especially in association with stress. 40 The importance of opioids in learning is recently emphasized by studies, which again showed its role in aversive learning. ...
... Galanin is a neuropeptide attributed for hippocampal learning and memory. 39 Several other peptides such as somatostatin, cortistatin, tachykinin, vasoactive intestinal polypeptide, calcitonin gene related peptide, neuropeptide Y and pituitary adenylate cyclase activating polypeptide have also been shown to play an important role in learning and memory. 49 Similarly, neurotrophic factors such as nerve growth factor, and neurotrophins have been shown to affect memory via modulation of cholinergic and glutaminergic systems. ...
Article
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Learning and memory being highly specialized process of human brain involves complex interaction between neurotransmitters and cellular events. Over the years, the understandings of these processes have been evolving from psychological, neurophysiological, and pharmacological perspectives. The most widely appraised model of learning and memory involves attention, acquisition, storage and retrieval. Each of these events involve interplay of neurotransmitters such as dopamine, acetylcholine, norepinephrine, N-methyl-d-aspartic acid, gamma-aminobutyric acid, though preponderance of specific neurotransmitter have been documented. The formation of long-term memory involves cellular events with neuroplasticity. Further, dopamine is documented to play crucial role in the process of forgetting. Understanding of the processes of learning and memory not only facilitates drug discovery, but also helps to understand actions of several existing drugs. In addition, it would also help to enhance psychological interventions in children with learning disabilities. Thus, the review intends to summarize role of neurotransmitters and neuromodulators during different phases of learning and memory.
... receptor in the cell body and axon terminal of choliner- gic cells (18). Spexin and galanin genes originate from a common ancestor gene, therefore, these 2 peptides have enough similarity to bind with the same receptor (15). ...
... Galanin is a 29-amino acid (aa) long (30 aa long in humans) neuropeptide encoded for by the GAL gene (Tatemoto et al. 1983). It is widely distributed in the brains of rodents (Skofitsch and Jacobowitz 1985;Melander et al. 1986), nonhuman primates (Kordower et al. 1992), and humans (Le Maître et al. 2013;Gentleman et al. 1989), where it helps regulate several physiological processes, including aspects of cognition, food intake, nociception, and sexual behavior (Vrontakis 2002;Ogren et al. 2010). Expression levels of galanin and galanin receptors were shown to be altered in the brains of patients diagnosed with neurological disorders, including Alzheimer's disease (AD) (Beal et al. 1990) and multiple sclerosis (Wraith et al. 2009). ...
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Parkinson’s disease (PD) is conventionally seen as resulting from single-system neurodegeneration affecting nigrostriatal dopaminergic neurons. However, accumulating evidence indicates multi-system degeneration and neurotransmitter deficiencies, including cholinergic neurons which degenerate in a brainstem nucleus, the pedunculopontine nucleus (PPN), resulting in motor and cognitive impairments. The neuropeptide galanin can inhibit cholinergic transmission, while being upregulated in degenerating brain regions associated with cognitive decline. Here we determined the temporal-spatial profile of progressive expression of endogenous galanin within degenerating cholinergic neurons, across the rostro-caudal axis of the PPN, by utilizing the lactacystin-induced rat model of PD. First, we show progressive neuronal death affecting nigral dopaminergic and PPN cholinergic neurons, reflecting that seen in PD patients, to facilitate use of this model for assessing the therapeutic potential of bioactive peptides. Next, stereological analyses of the lesioned brain hemisphere found that the number of PPN cholinergic neurons expressing galanin increased by 11%, compared to sham-lesioned controls, and increasing by a further 5% as the neurodegenerative process evolved. Galanin upregulation within cholinergic PPN neurons was most prevalent closest to the intra-nigral lesion site, suggesting that galanin upregulation in such neurons adapt intrinsically to neurodegeneration, to possibly neuroprotect. This is the first report on the extent and pattern of galanin expression in cholinergic neurons across distinct PPN subregions in both the intact rat CNS and lactacystin-lesioned rats. The findings pave the way for future work to target galanin signaling in the PPN, to determine the extent to which upregulated galanin expression could offer a viable treatment strategy for ameliorating PD symptoms associated with cholinergic degeneration.
... In the central nervous system, galanin receptor (GalR) 3 expression is less abundant and more restricted than GalR1 and GalR2 (Mennicken et al., 2002;Mitsukawa et al., 2008). Galanin is localized to the same brain regions as norepinephrine (LC), serotonin (dorsal raphe nucleus (DRN)), and dopamine (ventral-tegmental area (VTA)) (Holmes and Picciotto, 2006;Ö gren et al., 2010). As such, galanin has been implicated in regulating anxiety, depression, and addiction-like behaviors (Charney, 2004;Lu et al., 2007;Kuteeva et al., 2008;Picciotto, 2008). ...
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There is high comorbidity between stress-related psychiatric disorders and addiction, suggesting they may share one or more common neurobiological mechanisms. Because of its roles in both depressive and addictive behaviors, the galanin system is a strong candidate for such a mechanism. In this study, we tested if galanin and its receptors are involved in stress-associated behaviors and drug addiction. Mice were exposed to 21 days of chronic restraint stress (CRS); subsequently, mRNA levels of galanin, galanin receptors, and the rate-limiting enzymes for synthesis of monoamine autoreceptors were measured in the nucleus accumbens by qRT-PCR. Moreover, we tested the effects of this stress on morphine-induced addictive behaviors. We found that CRS induced anxiety and depression-like behaviors, impaired the formation and facilitated the extinction process in morphine-induced conditioned place preference (CPP), and also blocked morphine-induced behavioral sensitization. These behavioral results were accompanied by a CRS-dependent increase in the mRNA expression of galanin, galanin receptor 1 (GalR1), tyrosine hydroxylase (TH), tryptophan hydroxylase 2, and 5-HT1B receptor. Interestingly, treatment with a commonly used antidepressant, fluoxetine, normalized the CRS-induced behavioral changes based on reversing the higher expression of galanin and TH while increasing the expression of GalR2 and α2A-adrenceptor. These results indicate that activating the galanin system, with corresponding changes to noradrenergic systems, following chronic stress may modulate stress-associated behaviors and opiate addiction. Our findings suggest that galanin and galanin receptors are worthy of further exploration as potential therapeutic targets to treat stress-related disorders and drug addiction.
... GAL is a small protein consisting of 29 amino acids (30 amino acids in humans) encoded by the galanin gene, and cleaved into its active form from the 123-amino-acid precursor molecule pre-pro galanin (Kofler et al., 1996). As for other neuroactive peptides, GAL has been Neuropeptides xxx (2016) xxx-xxx detected not only in the central nervous system, where it is involved in a plethora of processes, such as stress physiology (Kormos and Gaszner, 2013), feeding behavior (Adams et al., 2008;Hagen et al., 2013) and memory function (Ogren et al., 2010), but also in the periphery. Here, GAL is involved in glucose metabolism, skin functions, and also various inflammatory processes (Lang et al., 2015;Lang and Kofler, 2011) and again, this far from complete listing illustrates the functional diversity of neuro-regulatory peptides. ...
Article
Galanin (GAL) is a neuro-regulatory peptide involved in many physiological and pathophysiological processes. While data of GAL origin/distribution in the human eye are rather fragmentary and since recently the presence of GAL-receptors in the normal human eye has been reported, we here systematically search for sources of ocular GAL in the human eye.
... The neuropeptide galanin is widely distributed in the brain (Melander et al., 1988, Takatsu et al., 2001 and is involved in drug dependence (Picciotto, 2010(Picciotto, , 2010 and feeding behavior (Crawley, 1999). Galanin regulates mesolimbic dopaminergic neurotransmission (Tsuda et al., 1998, Robinson andBrewer, 2008), and thus may affect the rewarding effect of drugs of abuse, for review see (Hokfelt and Tatemoto, 2008, Ogren et al., 2010, Picciotto, 2010. Multiple single-nucleotide polymorphisms (SNP) in the galanin receptor 1 (Galr1) gene were found to be associated with self-reported heavy smoking (Jackson et al., 2011). ...
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Prescription opioid abuse, for example of oxycodone, is a pressing public health issue. This study focuses on how chronic oxycodone self-administration (SA) affects the reward pathways in the mouse brain. In this study, we tested the hypothesis that the expression of reward-related genes in the ventral and dorsal striatum, areas involved in different aspects of opioid addiction models, was altered within 1 hour after chronic oxycodone SA, using transcriptome-wide sequencing (RNA-seq). Based on results from earlier human genetic and rodent studies, we focused on a set of genes that may be associated with the development of addictive diseases and the rewarding effect of drugs of abuse, primarily in the opioid, stress response and classical neurotransmitter systems. We found that 32 transcripts in the ventral striatum, and 7 in the dorsal striatum, were altered significantly in adult mice that had self-administered oxycodone (n=5) for 14 consecutive days (4 hours/day) compared with yoked saline controls (n=5). The following 5 genes in the ventral striatum showed experiment-wise significant changes: proopiomelanocortin (Pomc) and serotonin 5-HT-2A receptor (Htr2a) were upregulated; serotonin receptor 7 (Htr7), galanin receptor1 (Galr1) and glycine receptor 1 (Glra1) were downregulated. Some genes detected by RNA-seq were confirmed by quantitative polymerase chain reaction (qPCR). Conclusion: A RNA-seq study shows that chronic oxycodone SA alters the expression of several reward-related genes in the dorsal and ventral striatum. These results suggest potential mechanisms underlying neuronal adaptation to chronic oxycodone self-exposure, of relevance to our mechanistic understanding of prescription opioid abuse.
... Gal combines with GalR2 which is on the membrane of NSC of SGZ, to activate PKC-ERK/MAPK signal pathway, induce NSC to mitosis, proliferation, and directional differentiation, then promote new neurons of SGZ brain region to survival, regeneration, and maturity and transfer to dentate gyrus, and then finish this neural circuitry integration [49][50][51]. Furthermore, activation of dorsal hippocampal GalR2 receptors facilitates cognition whereas activation of GalR1 in the ventral hippocampus impairs cognitive performance [52,53], suggesting that a change in the overall action of Gal would occur when the balance between GalR1 and GalR2 is altered [46]. Therefore, we speculated that the reason which EA treatment could increase the expression of Gal might be that EA could activate GalR2 in the dorsal area of hippocampus to protect and promote the formation of cognitive function then to antidepression [38,54]. ...
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To explore new noninvasive treatment options for depression, this study investigated the effects of electric acupuncture (EA) for depression rat models. Depression in rats was induced by unpredictable chronic mild stress (UCMS) combined with isolation for 21 days. Eighteen male Sprague-Dawley rats were randomly assigned into three groups: control, model, and EA groups. Rats were treated by EA once daily for 21 days. The results showed that body weight and sucrose consumption were significantly increased in EA group than in the model group. The crossing numbers and rearing numbers in the open field test significantly decreased in the model group but not in the EA group. And EA treatments upregulated levels of hippocampus galanin (Gal) in UCMS rats back to relative normal levels. The present study suggested that EA had antidepressant effects on UCMS model rats. The potential antidepressant effect may be related to upregulating Gal expression in hippocampus.
... It is widely distributed in the peripheral and central nervous system [1]. Studies have shown that galanin is involved in the regulation of many physiological processes and possibly associated pathologies, such as feeding behavior, nociception, learning and memory processes, central cardiovascular control, depressionlike behaviors, epilepsy, and Alzheimer's disease [2][3][4][5][6][7][8][9][10][11][12][13]. ...
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Galanin receptor 2 (GAL2R) is a G protein-coupled receptor for the neuropeptide galanin that regulates many important physiological functions and pathological processes. To investigate the molecular mechanism governing GAL2R gene transcription, the rat GAL2R promoter was isolated and analyzed. We found that the region from −320 to −300 of the GAL2R promoter contains two putative ETS-1 elements and plays an important role in regulating GAL2R promoter activity. We also showed that transcription factor ETS-1 bound to this region in vitro and in vivo. Overexpression of ETS-1 significantly increased GAL2R promoter activity and transcription of the GAL2R gene, whereas knockdown of ETS-1 produced the opposite effects. In addition, we showed that ETS-1 recruited co-activator p300 to the GAL2R promoter. These data indicate a role for ETS-1 in the control of the GAL2R gene expression and provide a basis for understanding the transcriptional regulation of the GAL2R gene.
... Dynorphin is known to be distributed abundantly in the central nervous system, especially in the hippocampus and amygdala, which are important brain regions for learning and memory, and presumably cognitive function (Borbely et al., 2013). Considerable evidence has shown that opioid peptides have a complex role in mediating stress-coping actions and synaptic plasticity in the hippocampus ( Ogren et al., 2010). In agreement with these findings, it has been demonstrated that the metabolic disturbance of the endogenous opioid system is involved in the pathological process of several cognitive dysfunction diseases, such as AD (Cai and Ratka, 2012). ...
... In contrast, depending on the dose or site of administration, improvement of learning or lack of effect have also been observed. Several data are avaible about its essential function in this field, and two comprehensive reviews demonstrated the main characteristics of galanin and its relevance to cognitive functions (Beck and Pourié, 2013;Ögren et al., 2010). Thus, here only the latest results are summarized regarding the functions and the possible involvement of galanin and its receptors in the therapeutic palette. ...
... Natural peptides or peptide-based molecules preventing amyloid formation or its progression have been recognized [3,14] as molecules with possible interference in amyloidogenic mechanisms including stabilizing non-toxic amyloid species, redirecting aggregation pathways, trapping toxic amyloid species or retaining native protein conformation [15]. In turn, dysregulation of neuropeptides may play a role in aging-induced impairments and accelerate the formation of amyloid deposits [16]. PACAP is a highly effective neuro-and general-cytoprotective peptide that provides endogenous control in tissue damage by exerting a unique combination of simultaneous promotion of anti-inflammatory, anti-apoptotic, and antioxidant pathways mainly via PAC1 receptor and VPAC1/2 receptors [1,2,[17][18][19][20][21]. ...
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Dysregulation of neuropeptides may play an important role in aging‐induced impairments. Among them, pituitary adenylate cyclase activating polypeptide (PACAP) is a potent cytoprotective peptide that provides an endogenous control against a variety of tissue‐damaging stimuli. We hypothesized that the progressive decline of PACAP throughout life, and the well‐known general cytoprotective effects of PACAP lead to age‐related pathophysiological changes in PACAP deficiency, supported by the increased vulnerability to various stressors of animals partially or totally lacking PACAP. Using young and aging CD1 PACAP knockout (KO) and wild type (WT) mice, we demonstrated pre‐senile amyloidosis in young PACAP KO animals and showed that senile amyloidosis appeared accelerated, more generalized, more severe, and affected more individuals. Histopathology showed age‐related systemic amyloidosis with mainly kidney, spleen, liver, skin, thyroid, intestinal, tracheal and esophageal involvement. Mass spectrometry‐based proteomic analysis, re‐confirmed with immunohistochemistry, revealed that apolipoprotein‐AIV was the main amyloid protein in the deposits together with several accompanying proteins. Although the local amyloidogenic protein expression was disturbed in KO animals, no difference was found in laboratory lipid parameters, suggesting a complex pathway leading to increased age‐related degeneration with amyloid deposit in the absence of PACAP. In spite of no marked inflammatory histological changes or blood test parameters, we detected a disturbed cytokine profile that possibly creates a pro‐inflammatory milieu favoring amyloid deposition. In summary, here we describe accelerated systemic senile amyloidosis in PACAP gene deficient mice, which might indicate an early aging phenomenon in this mouse strain. Thus, PACAP KO mice could serve as a model of accelerated aging with human relevance. This article is protected by copyright. All rights reserved
... Generally, neuropeptides behave as neuromodulators exerting multiple actions on physiological brain functions and, consequently, on behavior. Their effects involve changes in membrane excitability, trophic actions, gene transcription, changes in affinity of receptors and modulation of neurotransmitter release [27]. Modulatory effect of RFamide peptides on neurotransmitter releases has been established. ...
Article
Little is known about the action of neuropeptide AF (NPAF) on anxiety and depression. Only our previous study provides evidence that NPAF induces anxiety-like behavior in rats. Therefore, the aim of the present study was to investigate the action of NPAF on depression-like behavior and the underlying neurotransmissions in mice. In order to determine whether there are species differences between rats and mice, we have investigated the action of NPAF on anxiety-like behavior in mice as well. A modified forced swimming test (mFST) and an elevated plus maze test (EPMT) were used to investigate the depression and anxiety-related behaviors, respectively. Mice were treated with NPAF 30min prior to the tests. In the mFST, the animals were pretreated with a non-selective muscarinic acetylcholine receptor antagonist, atropine, a non-selective 5-HT2 serotonergic receptor antagonist, cyproheptadine, a mixed 5-HT1/5-HT2 serotonergic receptor antagonist, methysergide, a D2/D3/D4 dopamine receptor antagonist, haloperidol, a alpha1/alpha2beta-adrenergic receptor antagonist, prazosin or a non-selective beta-adrenergic receptor antagonist, propranolol 30min before the NPAF administration. In the mFST, NPAF decreased the immobility time and increased the climbing and swimming times. This action was reversed completely by methysergide and partially by atropine, whereas cyproheptadine, haloperidol, prazosin and propranolol were ineffective. In the EPMT, NPAF decreased the time spent in the arms (open/open+closed). Our results demonstrate that NPAF induces anti-depressant-like behavior in mice, which is mediated, at least in part, through 5HT2-serotoninergic and muscarinic cholinergic neurotransmissions. In addition, the NPAF-induced anxiety is species-independent, since it develops also in mice.
... Functional consequences of neuropeptides are most evident in pathophysiological processes, tissue injury, or stress situations when they promote cellular plasticity and protection against harmful stimuli. Recent human studies have revealed that dysregulation of neuropeptides may play an important role in aging-induced impairments (Ma et al. 2015;Ogren et al. 2010). In the long list of neuropeptides, pituitary adenylate cyclaseactivating polypeptide (PACAP) represents a highly effective cytoprotective peptide that provides an endogenous control against a variety of tissue-damaging stimuli. ...
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Dysregulation of neuropeptides may play an important role in aging-induced impairments. In the long list of neuropeptides, pituitary adenylate cyclase–activating polypeptide (PACAP) represents a highly effective cytoprotective peptide that provides an endogenous control against a variety of tissue-damaging stimuli. PACAP has neuro- and general cytoprotective effects due to anti-apoptotic, anti-inflammatory, and antioxidant actions. As PACAP is also a part of the endogenous protective machinery, it can be hypothesized that the decreased protective effects in lack of endogenous PACAP would accelerate age-related degeneration and PACAP knockout mice would display age-related degenerative signs earlier. Recent results support this hypothesis showing that PACAP deficiency mimics aspects of age-related pathophysiological changes including increased neuronal vulnerability and systemic degeneration accompanied by increased apoptosis, oxidative stress, and inflammation. Decrease in PACAP expression has been shown in different species from invertebrates to humans. PACAP-deficient mice display numerous pathological alterations mimicking early aging, such as retinal changes, corneal keratinization and blurring, and systemic amyloidosis. In the present review, we summarize these findings and propose that PACAP deficiency could be a good model of premature aging.
... Importantly we show that transcript levels of galanin are upregulated in the dorsal hippocampus after just 72 h on a HFD. One of the many roles galanin is known to play in the central nervous system is that of a neurotrophic and neuroprotective factor [27,[36][37][38][39]. Specifically in the hippocampus, galanin has been implicated as having both beneficial [26,40,41] and detrimental [25,41,42] effects regarding learning and memory, due mainly to its ability to regulate neural activity in the hippocampus through modulation of cholinergic transmission [43]. Galanin is also rapidly upregulated in septohippocampal neurons following either lesion of the area or blockade of neuronal activity [44]. ...
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Background: Recent evidence identifies the hippocampus, a brain structure commonly associated with learning and memory, as key to the regulation of food intake and the development and consequences of obesity. Intake of a high fat diet (HFD) results in altered consumptive behavior, hippocampal damage, and cognitive deficits. While many studies report the effects of HFD after chronic consumption and in the instance of obesity, few examine the events that occur following acute HFD consumption. In this study, male rats were fed either a control diet (10% fat by kcal) or HFD (45% fat by kcal) for 72 h. At the end of the 72-h period, serum and tissues were collected and weighed. Brains were rapidly frozen or formalin-fixed in preparation for qRT-PCR or immunohistochemistry, respectively. Results: Acute intake of HFD resulted in higher serum levels of leptin and cholesterol, with no significant changes in final body weight or adipose tissue mass. In the dorsal hippocampus, transcription of the neuroprotective peptide galanin was significantly upregulated along with a trend for an increase in brain-derived neurotrophic factor and histone deacetylase 2 in the rats fed HFD. In the ventral hippocampus, there was a significant increase in histone deacetylase 4 and a decrease in galanin receptor 1 in this group. Results from immunohistochemistry validate strong presence of the galanin peptide in the CA1/CA2 region of the dorsal hippocampus. Conclusions: These results provide evidence for a distinct response in specific functional regions of the hippocampus following acute HFD intake.
... Neuromodulators travel through neurons in dense core vesicles (DCVs) and, upon secretion, regulate neuronal excitability, synaptic plasticity, and neurite outgrowth (2)(3)(4). Dysregulation of DCV secretion is linked to many brain disorders (5)(6)(7). However, the molecular mechanisms that regulate neuromodulator secretion remain largely elusive. ...
Article
Neuropeptides and neurotrophic factors secreted from dense core vesicles (DCVs) control many brain functions, but the calcium sensors that trigger their secretion remain unknown. Here, we show that in mouse hippocampal neurons, DCV fusion is strongly and equally reduced in synaptotagmin-1 (Syt1)- or Syt7-deficient neurons, but combined Syt1/Syt7 deficiency did not reduce fusion further. Cross-rescue, expression of Syt1 in Syt7-deficient neurons, or vice versa, completely restored fusion. Hence, both sensors are rate limiting, operating in a single pathway. Overexpression of either sensor in wild-type neurons confirmed this and increased fusion. Syt1 traveled with DCVs and was present on fusing DCVs, but Syt7 supported fusion largely from other locations. Finally, the duration of single DCV fusion events was reduced in Syt1-deficient but not Syt7-deficient neurons. In conclusion, two functionally redundant calcium sensors drive neuromodulator secretion in an expression-dependent manner. In addition, Syt1 has a unique role in regulating fusion pore duration.
... 216 At all doses, galanin does not alter motor functions, such as swimming speed in the water maze. 216 Injection of galanin antagonists (M40 and M35) significantly blocks the effects of galanin and facilitates acquisition of spatial memory, [216][217][218] as reviewed in Ogren et al. 219 Therefore, the effects of galanin appear to be dependent on both site and dose. Some results may also differ slightly, depending on the rat strain used in the water maze. ...
Article
The hippocampus is a brain region of primary importance for neurogenesis, which occurs during early developmental states as well as during adulthood. Increases in neuronal proliferation and in neuronal death with age have been associated with drastic changes in memory and learning. Numerous neurotransmitters are involved in these processes, and some neuropeptides that mediate neurogenesis also modulate feeding behavior. Concomitantly, feeding peptides, which act primarily in the hypothalamus, are also present in the hippocampus. This review aims to ascertain the role of several important feeding peptides in cognitive functions, either through their local synthesis in the hippocampus or through their actions via specific receptors in the hippocampus. A link between neurogenesis and the orexigenic or anorexigenic properties of feeding peptides is discussed.
... Galanin participates in biological processes such as feeding [415], nociception [416], nerve regeneration [417], arousal/sleep regulation [418], sexual behavior [419], learning [420], memory [421], neuroendocrine release [422] and gut secretion and contractility [423]. ...
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Epilepsy is a chronic brain disease that affects approximately 65 million people worldwide. However, despite the continuous development of antiepileptic drugs, over 30% patients with epilepsy progress to drug-resistant epilepsy. For this reason, it is a high priority objective in preclinical research to find novel therapeutic targets and to develop effective drugs that prevent or reverse the molecular mechanisms underlying epilepsy progression. Among these potential therapeutic targets, we highlight currently available information involving signaling pathways (Wnt/β-catenin, Mammalian Target of Rapamycin (mTOR) signaling and zinc signaling), enzymes (carbonic anhydrase), proteins (erythropoietin, copine 6 and complement system), channels (Transient Receptor Potential Vanilloid Type 1 (TRPV1) channel) and receptors (galanin and melatonin receptors). All of them have demonstrated a certain degree of efficacy not only in controlling seizures but also in displaying neuroprotective activity and in modifying the progression of epilepsy. Although some research with these specific targets has been done in relation with epilepsy, they have not been fully explored as potential therapeutic targets that could help address the unsolved issue of drug-resistant epilepsy and develop new antiseizure therapies for the treatment of epilepsy.
... [6][7][8][9] Pharmacological and genetic preclinical data have also linked the neuroprotective and neuronal regenerative capacity of this neuropeptide and to a range of physiological and pathological functions including epilepsy, chronic anxiety, depression, and pain. [9][10][11] These multitude regulatory effects are mediated through interaction with three G-protein coupled receptors, namely Galanin receptor 1 (GalR1), Galanin receptor 2 (GalR2) and Galanin receptor 3 (GalR3); their roles have been the focus of intense investigation. [12][13][14] The pertussis toxin (PTX) sensitive guanine nucleotide binding proteins, inhibitory G-proteins (Gi/Go) are chiefly involved in the signal transduction mechanism of these receptors. ...
Article
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Galanin (GAL) is a 29-amino-acid neuropeptide that serves multiple physiological functions throughout the central and peripheral nervous system. Its role involves in a range of physiological and pathological functions including control of food intake, neuro-protection, neuronal regeneration, energy expenditure, reproduction, water balance, mood, nociception and various neuroendocrine functions. The use of currently available antidepres-sant drugs raises concerns regarding efficacy and onset of action; therefore, the need for antidepressants with novel mechanisms is increasing. Presently, various studies revealed the link between GAL and depression. Attenuation of depressive symptoms is achieved through inhibition of GalR1 and GalR3 and activation of GalR2. However, lack of receptor selectiv-ity of ligands has limited the complete elucidation of effects of different receptors in depression-like behavior. Studies have suggested that GAL enhances the action of selective serotonin reuptake inhibitors (SSRIs) and promotes availability of transcription proteins. This review addresses the role of GAL, GAL receptors (GALRs) ligands including selective peptides, and the mechanism of ligand receptor interaction in attenuating depressive symptoms.
... [6][7][8][9] Pharmacological and genetic preclinical data have also linked the neuroprotective and neuronal regenerative capacity of this neuropeptide and to a range of physiological and pathological functions including epilepsy, chronic anxiety, depression, and pain. [9][10][11] These multitude regulatory effects are mediated through interaction with three G-protein coupled receptors, namely Galanin receptor 1 (GalR1), Galanin receptor 2 (GalR2) and Galanin receptor 3 (GalR3); their roles have been the focus of intense investigation. [12][13][14] The pertussis toxin (PTX) sensitive guanine nucleotide binding proteins, inhibitory G-proteins (Gi/Go) are chiefly involved in the signal transduction mechanism of these receptors. ...
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Desalegn Getnet Demsie,1 Birhanetensay Masresha Altaye,2 Etsay Weldekidan,1 Hagazi Gebremedhin,1 Niguse Meles Alema,3 Mulugeta Mihrete Tefera,3 Abere Tilahun Bantie4 1College of Medicine and Health Sciences, Department of Pharmacy, Adigrat University, Adigrat, Ethiopia; 2College of Health Sciences, Debre Berhan University, Debre Berhan, Ethiopia; 3Bahir Dar Health Science College, Bahir Dar, Ethiopia; 4College of Medicine and Health Sciences, Department of Anesthesia, Adigrat University, Adigrat, EthiopiaCorrespondence: Desalegn Getnet Demsie Tel +251 937404956Email desget361@gmail.comAbstract: Galanin (GAL) is a 29-amino-acid neuropeptide that serves multiple physiological functions throughout the central and peripheral nervous system. Its role involves in a range of physiological and pathological functions including control of food intake, neuro-protection, neuronal regeneration, energy expenditure, reproduction, water balance, mood, nociception and various neuroendocrine functions. The use of currently available antidepressant drugs raises concerns regarding efficacy and onset of action; therefore, the need for antidepressants with novel mechanisms is increasing. Presently, various studies revealed the link between GAL and depression. Attenuation of depressive symptoms is achieved through inhibition of GalR1 and GalR3 and activation of GalR2. However, lack of receptor selectivity of ligands has limited the complete elucidation of effects of different receptors in depression-like behavior. Studies have suggested that GAL enhances the action of selective serotonin reuptake inhibitors (SSRIs) and promotes availability of transcription proteins. This review addresses the role of GAL, GAL receptors (GALRs) ligands including selective peptides, and the mechanism of ligand receptor interaction in attenuating depressive symptoms.Keywords: Galanin (GAL), depression, Galanin (GAL) receptors
... Studies on experimental animals, mainly rats, have also shown that stressful situations can cause to exhibit negative effects on the hippocampal GABAergic system, whose dysfunction is present in mood disorders (Brambilla et al., 2003). Important groups of GABAergic neurons of the hippocampus are the neuropeptide Y-, somatostatin-, dynorphin-and parvalbumin-positive (PV+) interneurons, which represent an especially vulnerable neuronal population in chronic stress (Ogren et al., 2010;Filipović et al., 2013;Czéh et al., 2015). Furthermore, changes in the amino acid neurotransmitter systems in learned helplessness model of depression have shown that increased ratio of glutamate/GABA in the hippocampus may lead to a defective neuroprotection against excitotoxicity, contributing to depressive disorders (Sartorius et al., 2007). ...
Article
The hippocampus is a brain structure involved in the regulation of hypothalamic-pituitary-adrenal (HPA) axis and stress response. It plays an important role in the formation of declarative, spatial and contextual memory, as well as in the processing of emotional information. As a part of the limbic system, it is a very susceptible structure towards the effects of various stressors. The molecular mechanisms of structural and functional alternations that occur in the hippocampus under chronic stress imply an increased level of circulating glucocorticoids (GCs), which is an HPA axis response to stress. Certain data show that changes induced by chronic stress may be independent from the GCs levels, opening the possibility of existence of other poorly explored mechanisms and pathways through which stressors act. The hippocampal GABAergic parvalbumin-positive (PV+) interneurons represent an especially vulnerable population of neurons in chronic stress, which may be of key importance in the development of mood disorders. However, cellular and molecular hippocampal changes that arise as a consequence of chronic stress still represent a large and unexplored area. This review discusses the current knowledge about the PV+ interneurons of the hippocampus and the influence of chronic stress on this intriguing population of neurons.
... Neuropeptides are particularly interesting candidates because their release often correlates physiological stimuli, and brain state to changing circuit dynamics. Notably, work in the hippocampus links local neuropeptide release to environmental and social learning stressors or enrichment (Ögren et al., 2010;Grégoire et al., 2014;Li et al., 2017). Furthermore, neuropeptides have a long-lasting nature and broad effective areas, which make neuropeptides ideal brain state sensors and circuit regulators (Neumann, 2008;van den Pol, 2012). ...
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An essential characteristic of nervous systems is their capacity to reshape functional connectivity in response to physiological and environmental cues. Endogenous signals, including neuropeptides, governs nervous system plasticity. Particularly, oxytocin has been recognized for its role in mediating activity-dependent circuit changes. These oxytocin-dependent changes occur at the synaptic level and consequently shape the cellular composition of circuits. Here we discuss recent advances that illustrate how oxytocin functions to reshape neural circuitry in response to environmental changes. Excitingly, recent findings pave the way for promising therapeutic applications of oxytocin to treat neurodevelopmental and neuropsychiatric diseases.
... Since microinjection of galanin into the VRC results in an inhibitory effect on ventilation (Abbott et al., 2009a), we hypothesized that there would be GalR1 and 3 present in the VRC, because they are Gi/Go coupled and mediate inhibitory actions of galanin (Ogren et al., 2010). The present study demonstrates the presence of >840 GalR1+ neurons in the BötC and preBötC area. ...
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Long-term hypercapnia is associated with respiratory conditions including obstructive sleep apnea, chronic obstructive pulmonary disease and obesity hypoventilation syndrome. Animal studies have demonstrated an initial (within hours) increase in ventilatory drive followed by a decrease in this response over the long-term (days–weeks) in response hypercapnia. Little is known about whether changes in the central respiratory chemoreflex are involved. Here we investigated whether central respiratory chemoreceptor neurons of the retrotrapezoid nucleus (RTN), which project to the respiratory pattern generator within the ventral respiratory column (VRC) have a role in the mechanism of neuroplasticity associated with long-term hypercapnia. Adult male C57BL/6 mice (n = 5/group) were used. Our aims were (1) to determine if galanin, neuromedin B and gastrin-releasing peptide gene expression is altered in the RTN after long-term hypercapnia. This was achieved using qPCR to measure mRNA expression changes of neuropeptides in the RTN after short-term hypercapnia (6 or 8 h, 5 or 8% CO2) or long-term hypercapnia exposure (10 day, 5 or 8% CO2), (2) in the mouse brainstem, to determine the distribution of preprogalanin in chemoreceptors, and the co-occurrence of the galanin receptor 1 (GalR1:Gi-coupled receptor) with inhibitory GlyT2 ventral respiratory column neurons using in situ hybridization (ISH) to better characterize galaninergic RTN-VRC circuitry, (3) to investigate whether long-term hypercapnia causes changes to recruitment (detected by cFos immunohistochemistry) of respiratory related neural populations including the RTN neurons and their galaninergic subset, in vivo. Collectively, we found that hypercapnia decreases neuropeptide expression in the RTN in the short-term and has the opposite effect over the long-term. Following long term hypercapnia, the number of RTN galanin neurons remains unchanged, and their responsiveness to acute chemoreflex is sustained; in contrast, we identified multiple respiratory related sites that exhibit blunted chemoreflex activation. GalR1 was distributed in 11% of preBötC and 30% of BötC glycinergic neurons. Our working hypothesis is that during long-term hypercapnia, galanin co-release from RTN neurons may counterbalance glutamatergic inputs to respiratory centers to downscale energetically wasteful hyperventilation, thereby having a role in neuroplasticity by contributing to a decrease in ventilation, through the inhibitory effects of galanin.
... Neuropeptides, the most common signaling molecules in the central nervous system, act as neurotransmitters, hormones, and neuromodulators and have been shown to participate in various physiological and pathologic processes, such as sleep, emotion, addiction, depression, anxiety, learning, and memory (Kirsz and Zieba 2011;Ogren et al. 2010;Portelli et al. 2012). Growing evidence suggests that neuropeptides regulate the withdrawal syndromes associated with several drugs, including morphine, alcohol, and cocaine (Leggio et al. 2011;Logrip et al. 2011;Picciotto 2010). ...
Article
The persistence of physical dependence and craving in addicts is considered to contribute to relapse. Increasing evidence indicates that neuropeptide systems are associated with several phases of drug addiction, but little is known about whether the neuropeptide trefoil factor affects withdrawal symptoms. This study aims to investigate the potential effects of the neuropeptide trefoil factor 3 (TFF3) on naloxone-precipitated withdrawal symptoms in morphine-dependent mice. Mice received increasing doses of morphine over 3 days. On day 4, the mice were injected with TFF3 (1.0 mg/kg, i.p.) 30 min after the last dose of morphine. Thirty minutes after TFF3 treatment, naloxone (1 mg/kg, i.p.) was injected, and body weight, jumping behavior, wet-dog shakes, and locomotor activity were assessed 30 min later. Naloxone caused significant weight loss and increased jumping behavior and wet-dog shakes in morphine-dependent mice. TFF3 (1.0 mg/kg) reversed these behavioral symptoms caused by morphine withdrawal, suggesting that TFF3 might ameliorate physical dependence associated with opiate addiction. Furthermore, TFF3 pretreatment significantly reduced morphine withdrawal-induced increases in plasma corticosterone and adrenocorticotropic hormone levels. The glucocorticoid receptor agonist RU486 blocked the behavioral effects of TFF3 on morphine withdrawal symptoms. Finally, Fos expression in the medial prefrontal cortex which was decreased during morphine withdrawal was increased by TFF3 pretreatment. These findings indicate that TFF3 might be a potential therapeutic candidate for opiate addiction by regulating glucocorticoid secretion and neuronal activation in the prefrontal cortex.
... Galanin is synthesised at high levels in the locus coeruleus and dorsal raphe nucleus (6), where galaninergic neurons project to regions of the forebrain to mediate a variety of physiological functions via binding to three identified receptor-subtypes (GALR1, GALR2, and GALR3) (7). Numerous experiments with rodents have confirmed a role for galanin in learning and memory (8), alcohol consumption, and general feeding behavior (9) as well as affective disorders (for reviews see 10,11). The exact receptor subtype(s) mediating these behaviors is yet to be elucidated, but the literature to date suggests GALR3 to be the most relevant in the context of alcohol consumption. ...
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The neuropeptide galanin has a role in promoting alcohol consumption and general feeding behavior. The galanin-3 receptor (GALR3) subtype is implicated in modulating the consumption of alcohol and has therefore been identified as a potential target for new pharmacotherapies to treat alcohol use disorders. We have previously shown that the selective GALR3 antagonist SNAP 37889 reduced voluntary alcohol consumption in iP (alcohol-preferring) rats. The present study firstly aimed to investigate the effect of GALR3 antagonism on the motivational properties of alcohol. Secondly, the potential of GALR3 as a therapeutic target in the prevention of relapse was investigated in response to alcohol-conditioned cues. Administration of SNAP 37889 (30 mg/kg, i.p.) significantly reduced the breakpoint for ethanol under a progressive-ratio operant responding schedule of reinforcement. SNAP 37889 also significantly reduced reinstatement of alcohol-seeking in response to re-exposure to conditioned cues that were previously associated with the availability of alcohol. Collectively, results from the current study provide new evidence of GALR3 involvement in cue-induced relapse and provide further evidence that GALR3 antagonism reduces the motivational drive to consume alcohol. These findings validate further research in to the potential use of SNAP 37889 and other GALR3 antagonists to treat alcohol abuse disorders in humans.
... Thereafter galanin biology has since the early 1990's been regularly summarized in books/journal from meetings (Hökfelt et al., 1991(Hökfelt et al., , 1998Hökfelt and Crawley, 2005;Hokfelt, 2010;Hokfelt and Tatemoto, 2010); and in peer-reviewed articles focusing on the nervous system (only such published after 2004, and not included in the books/journals cited above, are listed here) (Lundstrom et al., 2005;Holmes and Picciotto, 2006;Karlsson and Holmes, 2006;Ogren et al., 2006Ogren et al., , 2007Ogren et al., , 2010Robinson et al., 2006;Walton et al., 2006;Wrenn and Holmes, 2006;Lu et al., 2007;Tortorella et al., 2007;Picciotto, 2008;Robinson and Brewer, 2008;Butzkueven and Gundlach, 2010;Picciotto et al., 2010;Webling et al., 2012;Diaz-Cabiale et al., 2014;Freimann et al., 2015;Weinshenker and Holmes, 2016;Millon et al., 2017a;Genders et al., 2018a); and in some major comprehensive reviews (Lang et al., 2007(Lang et al., , 2015. ...
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Neuropeptides are auxiliary messenger molecules that always co-exist in nerve cells with one or more small molecule (classic) neurotransmitters. Neuropeptides act both as transmitters and trophic factors, and play a role particularly when the nervous system is challenged, as by injury, pain or stress. Here neuropeptides and coexistence in mammals are reviewed, but with special focus on the 29/30 amino acid galanin and its three receptors GalR1, -R2 and -R3. In particular, galanin’s role as a co-transmitter in both rodent and human noradrenergic locus coeruleus (LC) neurons is addressed. Extensive experimental animal data strongly suggest a role for the galanin system in depression–like behavior. The translational potential of these results was tested by studying the galanin system in postmortem human brains, first in normal brains, and then in a comparison of five regions of brains obtained from depressed people who committed suicide, and from matched controls. The distribution of galanin and the four galanin system transcripts in the normal human brain was determined, and selective and parallel changes in levels of transcripts and DNA methylation for galanin and its three receptors were assessed in depressed patients who committed suicide: upregulation of transcripts, e.g., for galanin and GalR3 in LC, paralleled by a decrease in DNA methylation, suggesting involvement of epigenetic mechanisms. It is hypothesized that, when exposed to severe stress, the noradrenergic LC neurons fire in bursts and release galanin from their soma/dendrites. Galanin then acts on somato-dendritic, inhibitory galanin autoreceptors, opening potassium channels and inhibiting firing. The purpose of these autoreceptors is to act as a ‘brake’ to prevent overexcitation, a brake that is also part of resilience to stress that protects against depression. Depression then arises when the inhibition is too strong and long lasting – a maladaption, allostatic load, leading to depletion of NA levels in the forebrain. It is suggested that disinhibition by a galanin antagonist may have antidepressant activity by restoring forebrain NA levels. A role of galanin in depression is also supported by a recent candidate gene study, showing that variants in genes for galanin and its three receptors confer increased risk of depression and anxiety in people who experienced childhood adversity or recent negative life events. In summary, galanin, a neuropeptide coexisting in LC neurons, may participate in the mechanism underlying resilience against a serious and common disorder, MDD. Existing and further results may lead to an increased understanding of how this illness develops, which in turn could provide a basis for its treatment.
Article
Dementia conditions and memory deficits of different origins (vascular, metabolic and primary neurodegenerative such as Alzheimer's and Parkinson's diseases) are getting more common and greater clinical problems recently in the aging population. Since the presently available cognitive enhancers have very limited therapeutical applications, there is an emerging need to elucidate the complex pathophysiological mechanisms, identify key mediators and novel targets for future drug development. Neuropeptides are widely distributed in brain regions responsible for learning and memory processes with special emphasis on the hippocampus, amygdala and the basal forebrain. They form networks with each other, and also have complex interactions with the cholinergic, glutamatergic, dopaminergic and GABA-ergic pathways. This review summarizes the extensive experimental data in the well-established rat and mouse models, as well as the few clinical results regarding the expression and the roles of the tachykinin system, somatostatin and the closely related cortistatin, vasoactive intestinal polypeptide (VIP) and pituitary adenylate-cyclase activating polypeptide (PACAP), calcitonin gene-related peptide (CGRP), neuropeptide Y (NPY), opioid peptides and galanin. Furthermore, the main receptorial targets, mechanisms and interactions are described in order to highlight the possible therapeutical potentials. Agents not only symptomatically improving the functional impairments, but also inhibiting the progression of the neurodegenerative processes would be breakthroughs in this area. The most promising mechanisms determined at the level of exploratory investigations in animal models of cognitive disfunctions are somatostatin sst4, NPY Y2, PACAP-VIP VPAC1, tachykinin NK3 and galanin GALR2 receptor agonisms, as well as delta opioid receptor antagonism. Potent and selective non-peptide ligands with good CNS penetration are needed for further characterization of these molecular pathways to complete the preclinical studies and decide if any of the above described targets could be appropriate for clinical investigations.
Article
Hippocampal neurogenesis is important for modulating the behavioural responses to stress and for certain forms of learning and memory. The mechanisms underlying the necessary coupling of neuronal activity to neural stem/progenitor cell (NSPC) function remain poorly understood. Within the dentate subgranular stem cell niche, local interneurons appear to play an important part in this excitation-neurogenesis coupling via GABAergic transmission, which promotes neuronal differentiation and integration. Neuropeptides such as neuropeptide Y (NPY), vasoactive intestinal peptide (VIP) and galanin have emerged as important mediators for signalling local and extrinsic interneuronal activity to subgranular zone precursors. Here we review the distribution of these neuropeptides and their receptors in the neurogenic area of the hippocampus and their precise effects on hippocampal neurogenesis. We also discuss neuropeptides' potential involvement in functional aspects of hippocampal neurogenesis particularly their involvement in the modulation of learning and memory and behavior responses.
Article
Galanin (Gal) and galanin-like peptide (GALP) may be involved in the mechanisms of the hypothalamo-neurohypophysial system. The aim of the present in vitro study was to compare the influence of Gal and GALP on vasopressin (AVP) and oxytocin (OT) release from isolated rat neurohypophysis (NH) or hypothalamo-neurohypophysial explants (Hth-NH). The effect of Gal/GALP on AVP/OT secretion was also studied in the presence of galantide, the non-selective galanin receptors antagonist. Gal at concentrations of 10(-10 )M and 10(-8 )M distinctly inhibited basal and K(+)-stimulated AVP release from the NH and Hth-NH explants, whereas Gal exerted a similar action on OT release only during basal incubation. Gal added to the incubation medium in the presence of galantide did not exert any action on the secretion of either neurohormone from NH and Hth-NH explants. GALP (10(-10 )M and 10(-9 )M) induced intensified basal AVP release from the NH and Hth-NH complex as well as the release of potassium-evoked AVP from the Hth-NH. The same effect of GALP has been observed in the presence of galantide. GALP added to basal incubation medium was the reason for stimulated OT release from the NH as well as from the Hth-NH explants. However, under potassium-stimulated conditions, OT release from the NH and Hth-NH complexes has been observed to be distinctly impaired. Galantide did not block this inhibitory effect of GALP on OT secretion. It may be concluded that: (i) Gal as well as GALP modulate AVP and OT release at every level of the hypothalamo-neurohypophysial system; (ii) Gal acts in the rat central nervous system as the inhibitory neuromodulator for AVP and OT release via its galanin receptors; (iii) the stimulatory effect of GALP on AVP and OT release is likely to be mediated via an unidentified specific GALP receptor(s).
Article
Memory is the ability to store, retrieve and use information that requires a progressive time-dependent stabilization process known as consolidation to be established. The hippocampus is essential for processing all the information that forms memory, especially spatial memory. Neuropeptide Y (NPY) affects memory, so in this study we investigated the participation and recruitment of NPY receptors during spatial memory consolidation in rats. Using the water maze test, we show that NPY (1 pmol) injected into the dorsal hippocampus impaired memory consolidation and that previous restraint stress (30 min) potentiates NPY effects, i.e. further impaired memory consolidation. Using selective antagonists for NPY Y1 and Y2 receptors we demonstrate that both receptors play a key role on spatial memory consolidation. Our data suggest that NPY modulates aversive and adaptive memory formation by NPY receptors activation.
Article
Neuropeptide AF (NPAF) is an amidated octadecapeptide, which is member of the RFamide peptide family. NPAF is encoded by the farp-1 gene and acts through the G protein coupled NPFF-1 and NPFF-2 receptors. NPAF is involved in several physiological functions of the central nervous system, however we have little evidence about the involvement of NPAF in learning and memory. Therefore, the aim of the present study was to investigate the action of NPAF on consolidation of memory in a passive avoidance learning paradigm in mice. We have also investigated the underlying neurotransmissions and the action of NPAF on β-amyloid-induced memory impairment. Accordingly, mice were pretreated with a nonselective muscarinic acetylcholine receptor antagonist, atropine, a non-selective 5-HT2 serotonergic receptor antagonist, cyproheptadine, a mixed 5-HT1/5-HT2 serotonergic receptor antagonist, methysergide, a D2, D3, D4 dopamine receptor antagonist, haloperidol, a non-selective opioid receptor antagonist, naloxone, a nitric oxide synthase inhibitor, nitro-l-arginine, a α1/α2β-adrenergic receptor antagonist, prazosin, a nonselective β-adrenergic receptor antagonist, propranolol or β-amyloid 25-35 in combination with NPAF administration. Our results demonstrate for the first time that NPAF improves the consolidation of passive avoidance learning. This effect is mediated through muscarinic cholinergic, 5HT1- and 5HT2-serotoninergic, dopaminergic, nitrergic and α- and β-adrenergic neurotransmissions, but not by opioid transmission, since atropine, cyproheptadine, methysergide, haloperidol, nitro-l-arginine, prazosin and propranolol reversed the action of NPAF, whereas naloxone was ineffective. The present study also shows that NPAF reverses the β-amyloid 25-35-induced memory impairment.
Article
Background: Galanin can promote skeletal muscle glucose transporter protein 4 membrane translocation and glucose clearance. Glucose transporter protein 4 is the main carrier of the movement to promote skeletal muscle glucose uptake, thereby increasing skeletal muscle glucose uptake and lowering blood sugar. Objective: To explore the combined effect of galanin and insulin on skeletal muscle glucose transporter protein 4 membrane displacement in diabetic rats. Methods: The first author searched PubMed database (1991-01/2011-12) (http://www.ncbi.nlm.nih.gov/PubMed) and Wanfang Database (1991-01/2011-12) (http://www.wanfangdata.com.cn) using the key words of "galanin, insulin" in English and "galanin, glucose transporter protein 4" in Chinese, respectively. Totally 143 papers were retrieved, and finally 37 articles were included that were related to clinical application and characteristics of galanin and insulin to improve skeletal muscle glucose uptake. Obsolete and duplicate papers were excluded, and articles published recently or in authorized journals were preferred. Results and Conclusion: Galanin is a widely distributed neuropeptide in the nervous system, with a wide range of neurological and biological functions. It has been recognized that the movement can promote plasma galanin concentration and galanin has a protective mechanism in type 2 diabetic patients. Both galanin and insulin can reduce blood glucose level, and diabetes mellitus is the result of the common barriers of galanin and insulin. Therefore, combination of galanin and insulin becomes a focus that whether the combination effects on skeletal muscle glucose transporter protein 4 membrane displacement is better than that of galanin or insulin alone.
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Pituitary adenylate cyclase activating polypeptide (PACAP) belongs to the vasoactive intestinal peptide-secretin-glucagon peptide family, isolated first from ovine hypothalamus. The diverse physiological effects of PACAP are known mainly from animal experiments, including several actions in endocrine glands. Alteration of PACAP expression has been shown in several tumors, but changes in expression of PACAP and its specific PAC1 receptor in human thyroid gland pathologies have not yet been investigated. Therefore, the aim of the present study was to investigate expression of PACAP and its PAC1 receptor in human thyroid papillary carcinoma, the most common endocrine malignant tumor. PACAP and PAC1 receptor expressions were investigated from thyroid gland samples of patients with papillary carcinomas. The staining intensity of follicular epithelial cells and thyroid colloid of tumor tissue was compared to that of tumor-free tissue in the same thyroid glands in a semi-quantitative way. Our results reveal that both PACAP(-like) and PAC1 receptor(-like) immunoreactivities are altered in papillary carcinoma. Stronger PACAP immunoreactivity was observed in active follicles. Colloidal PACAP immunostaining was either lacking or very weak, and more tumorous cells displayed strong apical immunoreactivity. Regarding PAC1 receptor, cells of the normal thyroid tissue showed strong granular expression, which was lacking in the tumor cells. The cytoplasm of tumor cells displayed weak, minimal staining, while in a few tumor cells we observed strong PAC1 receptor expression. This pattern was similar to that observed in the PACAP expression, but fewer in number. In summary, we showed alteration of PACAP and PAC1 receptor expression in human thyroid papillary carcinoma, indicating that PACAP regulation is disturbed in tumorous tissue of the thyroid gland. The exact role of PACAP in thyroid tumor growth should be further explored.
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The general limitations on liquid chromatographic performance in isocratic and gradient elution are now well understood. Many workers have contributed to this understanding and to developing graphical methods, or plots, to illustrate the capabilities of chromatographic systems over a wide range of values of operational parameters. These have been invaluable in getting a picture, in broad strokes, about the value of changing an operational parameter or the value of one separations approach over another. Here we present a plotting approach more appropriate for determining how to use chromatography most efficiently in one’s own laboratory. The axes are linear: column length vertical and mobile phase velocity horizontal. In this coordinate system, straight lines with intercept zero correspond to different values of t0. Hyperbolas correspond to values of pressure as the product of length and velocity is proportional to pressure. For a given relationship between theoretical plate height and velocity (e.g., van Deemter), the number of theoretical plates as a function of column length and mobile phase velocity is a surface (z direction) to the x and y of velocity and length. By representing the surface as contours, a two dimensional plot results. Any point along a constant pressure hyperbola represents the best one can do given the particle diameter, solute diffusion coefficient and temperature. The user can quickly see how to use the pressure for speed or for more theoretical plates. Sets of such plots allow for comparisons among particle diameters or temperatures. Analogous plots of peak capacity for gradient elution are equally revealing. The plots lead instantly to understanding liquid chromatographic optimization at a practical level. They neatly illustrate the value (or not) of changing pump pressure, particle diameter, or temperature, for fast or slow separations in either isocratic or gradient elution. They are illustrated with a focus on maximizing plate count with a given analysis time (isocratic), the effect of volume overload (isocratic), and separations of a limited number of peptides with a peak capacity requirement coming from statistical peak overlap theory (gradient).
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One important, however poorly understood, concept of Traditional Chinese Medicine (TCM) is that of hot, cold and neutral nature of its bioactive principles. In order to advance the field, in this study we analyzed Compound-nature pairs from TCM on a large scale (>23,000 structures) via chemical space visualizations to understand its physicochemical domain, and in silico target prediction to understand differences related to their Modes-of-Action (MoA) against proteins. We found that overall TCM natures spread into different sub-clusters with specific molecular patterns, as opposed to forming coherent global groups. Compounds associated with cold nature had a lower clogP and contain more aliphatic rings than the other groups and were found to control detoxification, heat-clearing, heart development processes and have sedative function, associated with "Mental and behavioural disorders" diseases. While compounds associated with hot nature were on average of lower molecular weight, had more aromatic ring systems than other groups, and frequently seemed to control body temperature, have cardio-protection function, improve fertility and sexual function, represents excitatory or activating effects, associated with "Endocrine, nutritional and metabolic diseases" and "Diseases of the circulatory system". Compounds associated with neutral nature had a higher Polar Surface Area and contain more cyclohexene moieties than other groups and seem to be related to memory function, suggesting that their nature may be a useful guide for their utility in neural degenerative diseases. We were hence able to elucidate the difference between different nature classes in TCM on the molecular level, and on a large dataset, for the first time, thereby helping a better understanding of TCM nature theory and bridging the gap between traditional medicine and our current understanding of the human body.
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Background The brain is extensively vascularized, useŝ20% of the body’s oxygen, and is highly sensitive to changes in oxygen. While synaptic plasticity and memory are impaired in healthy individuals by exposure to mild hypoxia, aged individuals appear to be even more sensitive. Aging is associated with progressive failure in pulmonary and cardiovascular systems, exposing the aged to both chronic and superimposed acute hypoxia. The HIF proteins, the “master regulators” of the cellular response to hypoxia, are robustly expressed in neurons and astrocytes. Astrocytes support neurons and synaptic plasticity via complex metabolic and trophic mechanisms. The activity of HIF proteins in the brain is diminished with aging, and the increased exposure to chronic and acute hypoxia with aging combined with diminished HIF activity may impair synaptic plasticity. Purpose Herein, we test the hypothesis that astrocyte HIF supports synaptic plasticity and learning upon hypoxia. Materials and Methods An Astrocyte-specific HIF loss-of-function model was employed, where knock-out of HIF-1α or HIF-2α in GFAP expressing cells was accomplished by cre-mediated recombination. Animals were tested for behavioral (open field and rotarod), learning (passive avoidance paradigm), and electrophysiological (long term potentiation) responses to mild hypoxic challenge. Results In an astrocyte-specific HIF loss-of-function model followed by mild hypoxia, we identified that the depletion of HIF-2α resulted in an impaired passive avoidance learning performance. This was accompanied by an attenuated response to induction in long-term potentiation (LTP), suggesting that the hippocampal circuitry was perturbed upon hypoxic exposure following HIF-2α loss in astrocytes, and not due to hippocampal cell death. We investigated HIF-regulated trophic and metabolic target genes and found that they were not regulated by HIF-2α, suggesting that these specific targets may not be involved in mediating the phenotypes observed. Conclusion Together, these results point to a role for HIF-2α in the astrocyte’s regulatory role in synaptic plasticity and learning under hypoxia and suggest that even mild, acute hypoxic challenges can impair cognitive performance in the aged population who harbor impaired HIF function.
Chapter
The noradrenergic system is located in both the central and peripheral nervous systems. In this chapter, only the central noradrenergic system is discussed with great emphasis on the molecular structure and mode of action of adrenergic receptors. The different neurotransmitters involved and the transporters responsible for the correct mechanism of release and uptake are also considered. The noradrenergic system is located in both the central and peripheral nervous systems. In this chapter, only the central noradrenergic system is discussed with great emphasis on the molecular structure and mode of action of adrenergic receptors. The different neurotransmitters involved and the transporters responsible for the correct mechanism of release and uptake are also considered.
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Rationale The neuropeptide galanin has been implicated in a wide range of pathological conditions in which frontal and temporal structures are compromised. It works through three subtypes of G-protein-coupled receptors. One of these, the galanin receptor 1 (Gal-R1) subtype, is densely expressed in the ventral hippocampus (vHC) and ventral prefrontal cortex (vPFC); two brain structures that have similar actions on behavioral control. We hypothesize that Gal-R1 contributes to cognitive-control mechanisms that require hippocampal-prefrontal cortical circuitry. Objective To examine the effect of local vHC and vPFC infusions of M617, a Gal-R1 agonist, on inhibitory mechanisms of response control. Methods Different cohorts of rats were implanted with bilateral guide cannulae targeting the vPFC or the vHC. Following infusion of the Gal-R1 agonist, we examined the animals’ behavior using a touchscreen version of the 5-choice reaction time task (5-choice task). Results The Gal-R1 agonist produced opposing behaviors in the vPFC and vHC, leading to disruption of impulse control when infused in the vPFC but high impulse control when infused into the vHC. This contrast between areas was accentuated when we added variability to the timing of the stimulus, which led to long decision times and reduced accuracy in the vPFC group but a general improvement in performance accuracy in the vHC group. Conclusions These results provide the first evidence of a selective mechanism of Gal-R1–mediated modulation of impulse control in prefrontal-hippocampal circuitry.
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In an ever‐changing environment, animals have to continuously adapt behavior. The ability to learn from experience is crucial for animals to increase their chances of survival. It is therefore not surprising that learning and memory evolved early in evolution and are mediated by conserved molecular mechanisms. A broad range of neuromodulators, in particular monoamines and neuropeptides, have been found to influence learning and memory, but our knowledge on their modulatory functions in learning circuits remains fragmentary. Many neuromodulatory systems are evolutionarily ancient and well‐conserved between vertebrates and invertebrates. Here, we highlight general principles and mechanistic insights on the actions of monoamines and neuropeptides in learning circuits that have emerged from invertebrate studies. Diverse neuromodulators have been shown to influence learning and memory in invertebrates, which can have divergent or convergent actions at different spatiotemporal scales. In addition, neuromodulators can regulate learning dependent on internal and external states, such as food and social context. The strong conservation of neuromodulatory systems, the extensive toolkit and compact learning circuits in invertebrate models makes these powerful systems to further deepen our understanding of neuromodulatory pathways involved in learning and memory.
Chapter
In Organismen, die aus mehr als einer Zelle bestehen, müssen diese sich so abstimmen, dass Struktur und Funktion der einzelnen Zelle für die arbeitsteilige Erfüllung ihrer Aufgaben im Sinn der Erhaltung und Funktion des Gesamtorganismus optimiert sind. Die interzelluläre Kommunikation kann durch direkte Zell-Zell-Kontakte erfolgen, was jedoch nur bei unmittelbar benachbarten Zellen möglich ist. Entfernt voneinander liegende Zellen kommunizieren daher entweder über neuronale Signalleitung (Fortleitung von Aktionspotenzialen, elektrische oder chemische Informationsübertragung an Synapsen) oder durch Hormone (Informationsübertragung von botenstoffproduzierenden Zellen auf Zielzellen durch chemische Botenstoffe, die mit den Körperflüssigkeiten transportiert werden). Je nach der Beziehung der hormonproduzierenden und der Zielzellen zueinander werden autokrine, parakrine und endokrine Hormonwirkungen unterschieden (◘ Abb. 14.1). Ist die botenstoffproduzierende und die empfangende Zelle identisch, spricht man von autokriner Hormonwirkung. Diffundieren die Botenstoffe über geringe Entfernungen und treffen noch im selben Gewebe auf Zielzellen, spricht man von einer parakrinen Signalübertragung. Werden die Botenstoffe mit dem Kreislaufsystem im gesamten Organismus verteilt und finden ihre Zielzellen in großer Entfernung vom Produktionsort, handelt es sich um eine endokrine Hormonwirkung.
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By using immunofluorescence methodology, extensive galanin (GAL) and GAL message-associated peptide (GMAP)-positive terminal networks were observed in the hippocampal formation. The majority of the GAL/GMAP fibers were dopamine β-hydroxylase- (DBH) positive, that is, they were noradrenergic. This finding was established with GAL/GMAP-DBH double-staining and with 6-hydroxy-dopamine treatment, which totally abolished all fibers in which GAL/GMAP and DBH coexisted. Also, reserpine treatment caused a marked depletion of GAL. No evidence for GAL/GMAP coexistence with 5-hydroxytryptamine was obtained. In the ventral hippocampus, GAL/GMAP-, DBH-negative fibers were seen in the stratum oriens, the anterior stratum radiatum, along the granule cell layer and in the strata oriens and alveus. In the locus coeruleus (LC), around 80% of the GMAP-positive neurons contained neuropeptide tyrosine (NPY), and about 40% of the NPY-positive neurons expressed GMAP. GAL-R1 receptor mRNA was expressed in Barrington's nucleus (close to the LC), but was not detected in the hippocampal formation/dorsal cortical areas. GAL-R2 receptor mRNA was found in the granule cell layer in the dentate gyrus.The present results show that most, but not all, immunohistochemically detectable GAL/GMAP in the hippocampal formation/dorsal cortex is present in noradrenergic nerve terminals originating in the LC, which has a robust GAL/GMAP synthesis. The functional role of GAL may be related to noradrenaline, possibly by a presynaptic action. However, the presence of GAL in other systems and of GAL-R2 receptor mRNA in granule cells also indicates other targets. J. Comp. Neurol. 392:227–251, 1998. © 1998 Wiley-Liss, Inc.
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Cognitive functions show large variation in elderly people and are substantially heritable. Animal studies revealed that dynorphins influence cognition and memory, especially in aged animals. Thus, we tested the effect of four SNPs (rs7272891, rs1997794, rs2235751 and rs910080) and the VNTR promoter polymorphism in the prodynorphin gene (PDYN) on episodic memory and verbal fluency in a large (n = 1619) sample of elderly people (mean age: 80 +/- 3.39 years; range 75-90 years) recruited through the German study on ageing, cognition and dementia in primary care patients (AgeCoDe). We found that carriers of the minor alleles of rs1997794 (P < 0.002) and rs910080 (P < 0.005) presented with higher episodic memory scores than homozygote carriers of the major allele. Also, a three marker haplotype including these two SNPs and rs2235751 was associated with better episodic memory scores. Verbal fluency scores were non-significantly better in carriers of these respective alleles. Thus, our results suggest a role of PDYN gene variations in determining memory function also in elderly humans.
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We tested a theoretical prediction that patterns of excitatory input activity that consistently fail to activate target neurons sufficiently to induce synaptic potentiation will instead cause a specific synaptic depression. To realize this situation experimentally, the Schaffer collateral projection to area CA1 in rat hippocampal slices was stimulated electrically at frequencies ranging from 0.5 to 50 Hz. Nine hundred pulses at 1-3 Hz consistently yielded a depression of the CA1 population excitatory postsynaptic potential that persisted without signs of recovery for greater than 1 hr after cessation of the conditioning stimulation. This long-term depression was specific to the conditioned input, ruling out generalized changes in postsynaptic responsiveness or excitability. Three lines of evidence suggest that this effect is accounted for by a modification of synaptic effectiveness rather than damage to or fatigue of the stimulated inputs. First, the effect was dependent on the stimulation frequency; 900 pulses at 10 Hz caused no lasting change, and at 50 Hz a synaptic potentiation was usually observed. Second, the depressed synapses continued to support long-term potentiation in response to a high-frequency tetanus. Third, the effects of conditioning stimulation could be prevented by application of NMDA receptor antagonists. Thus, our data suggest that synaptic depression can be triggered by prolonged NMDA receptor activation that is below the threshold for inducing synaptic potentiation. We propose that this mechanism is important for the modifications of hippocampal response properties that underlie some forms of learning and memory.
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The coexistence of galanin (GAL)-like immunoreactivity (LI) with markers for catecholamines, 5-hydroxytryptamine (5-HT), GABA, or some neuropeptides was mapped in the rat CNS by using adjacent sections, as well as by elution-restaining and double-labeling immunocytochemistry. Many instances of coexistence were observed, but there were also numerous GAL-positive cell body populations displaying distributions similar to those of these markers but without apparent coexistence. In the hypothalamic arcuate nucleus GAL-LI was found in a large proportion of tyrosine hydroxylase (TH)-positive cell bodies (A12 cells), both in the dorsomedial and ventrolateral subdivisions, with a higher number in the latter. GAL-LI coexisted in glutamic acid decarboxylase (GAD)-positive somata in the posterior aspects of the arcuate nucleus and at all rostrocaudal levels in fibers in the external layer of the median eminence. In the anterior hypothalamus, a large population of the cells of the parvocellular and magnocellular paraventricular nuclei contained both GAL-LI and vasopressin-LI. Moreover, somata containing both GAD- and GAL-LI were seen lateral to the mammillary recess in the tuberal and caudal magnocellular nuclei. Some of the neurons of the caudal group were shown to project to the occipital cortex using combined retrograde tracing and immunofluorescence. With regard to mesencephalic and medullary catecholamine neurons, GAL-LI coexisted in a large proportion of the noradrenergic locus coeruleus somata (A6 cell group) and in the A4 group dorsolateral to the fourth ventricle, as well as in the caudal parts of the A2 group in the dorsal vagal complex. However, in more rostral parts of the latter, especially in the medial subdivision of the solitary tract nucleus, a very large population of GAL-IR small cell bodies was seen intermingling with catecholamine neurons, but they did not contain TH-LI. Furthermore, GAL-IR cell bodies coextensive with, but not coexisting in, TH-IR somata were seen in the C1 (epinephrine) horea in the ventrolateral medulla at the level of area postrema and in the most rostral aspects of the C1 group. Finally, 5-HT-positive cell bodies of the mesencephalic and medullary raphe nuclei and a subpopulation of coarse 5-HT nerve fibers in the hippocampus co-contained GAL-LI. The present results demonstrate that a GAL-like peptide is present in many systems containing other neuroactive compounds, including dopamine, norepinephrine, 5-HT, GABA, and vasopressin.(ABSTRACT TRUNCATED AT 400 WORDS)
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Recent work has shown that the hippocampus contains a class of receptors for the excitatory amino acid glutamate that are activated by N-methyl-D-aspartate (NMDA) and that exhibit a peculiar dependency on membrane voltage in becoming active only on depolarization. Blockade of these sites with the drug aminophosphonovaleric acid (AP5) does not detectably affect synaptic transmission in the hippocampus, but prevents the induction of hippocampal long-term potentiation (LTP) following brief high-frequency stimulation. We now report that chronic intraventricular infusion of D,L-AP5 causes a selective impairment of place learning, which is highly sensitive to hippocampal damage, without affecting visual discrimination learning, which is not. The L-isomer of AP5 did not produce behavioural effects. AP5 treatment also suppressed LTP in vivo. These results suggest that NMDA receptors are involved in spatial learning, and add support to the hypothesis that LTP is involved in some, but not all, forms of learning.
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Antisera raised against synthetic dynorphin or [Leu5]enkephalin demonstrate immunostaining in hippocampal mossy fibers and in dentate granule cells. However, dynorphin immunoreactivity (ir) appears to be denser in immunocytochemical preparations and is quantitatively greater by radioimmunoassay than enkephalin-ir. Immunostaining with dynorphin antisera is eliminated by adsorption with 1-100 microM dynorphin-17 whereas immunostaining with enkephalin antisera is eliminated by adsorption with 1-100 microM [Leu5]enkephalin, dynorphin-17, dynorphin-(1-13), or alpha-neo-endorphin. Intrahippocampal colchicine injections, which selectively destroy dentate granule cells, significantly decrease the dynorphin-ir and enkephalin-ir levels in rat hippocampus. Intraventricularly administered kainic acid, which selectively destroys CA3-4 pyramidal cells, results in an increase of enkephalin immunostaining in mossy fibers and a significant increase in enkephalin-ir by radioimmunoassay in whole hippocampus. The enkephalin-ir cells and fibers in entorhinal/perirhinal cortex, which innervate rat hippocampus and dentate gyrus, do not contain dynorphin-ir.
Article
We tested a theoretical prediction that patterns of excitatory input activity that consistently fail to activate target neurons sufficiently to induce synaptic potentiation will instead cause a specific synaptic depression. To realize this situation experimentally, the Schaffer collateral projection to area CA1 in rat hippocampal slices was stimulated electrically at frequencies ranging from 0.5 to 50 Hz. Nine hundred pulses at 1-3 Hz consistently yielded a depression of the CA1 population excitatory postsynaptic potential that persisted without signs of recovery for greater than 1 hr after cessation of the conditioning stimulation. This long-term depression was specific to the conditioned input, ruling out generalized changes in postsynaptic responsiveness or excitability. Three lines of evidence suggest that this effect is accounted for by a modification of synaptic effectiveness rather than damage to or fatigue of the stimulated inputs. First, the effect was dependent on the stimulation frequency; 900 pulses at 10 Hz caused no lasting change, and at 50 Hz a synaptic potentiation was usually observed. Second, the depressed synapses continued to support long-term potentiation in response to a high-frequency tetanus. Third, the effects of conditioning stimulation could be prevented by application of NMDA receptor antagonists. Thus, our data suggest that synaptic depression can be triggered by prolonged NMDA receptor activation that is below the threshold for inducing synaptic potentiation. We propose that this mechanism is important for the modifications of hippocampal response properties that underlie some forms of learning and memory.
Article
Galanin is a neuroactive peptide that coexists with acetylcholine in the basal forebrain region. Galanin inhibits cholinergic functions in vitro and in vivo and has been shown to impair performance in some memory tasks. The present study compared the effects of galanin with the effects of scopolamine (a muscarinic antagonist) and ketamine and MK-801 (both NMDA receptor antagonists) on performance of an operant, spatial, delayed nonmatching-to-sample task in rats. Choice accuracy was impaired in a dose-dependent but delay-independent manner by galanin, scopolamine, and MK-801 but was not systematically influenced by ketamine. Measures of session duration, trials completed, discrimination accuracy, perseveration, within-trial error distribution, and operant lever pressing were also analyzed. These results support observations that galanin disrupts performance in memory tasks requiring delayed responding but that the disruption is not specific to mnemonic capabilities.
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The present article provides a brief overview of various aspects on neuropeptides, emphasizing their multitude and their wide distribution in both the peripheral and central nervous system. Interestingly, neuropeptides are also expressed in various types of glial cells under normal and experimental conditions. The recent identification of, often multiple, receptor subtypes for each peptide, as well as the development of peptide antagonists, have provided an experimental framework to explore functional roles of neuropeptides. A characteristic of neuropeptides is the plasticity in their expression, reflecting the fact that release has to be compensated by de novo synthesis at the cell body level. In several systems peptides can be expressed at very low levels normally but are upregulated in response to, for example, nerve injury. The fact that neuropeptides virtually always coexist with one or more classic transmitters suggests that they are involved in modulatory processes and probably in many other types of functions, for example exerting trophic effects. Recent studies employing transgene technology have provided some information on their functional role, although compensatory mechanisms in all probability could disguise even a well defined action. It has been recognized that both ‘old’ and newly discovered peptides may be involved in the regulation of food intake. Recently the first disease-related mutation in a peptidergic system has been identified, and clinical efficacy of a substance P antagonist for treatment of depression has been reported. Taken together it seems that peptides may play a role particularly when the nervous system is stressed, challenged or afflicted by disease, and that peptidergic systems may, therefore, be targets for novel therapeutic strategies.
Article
The neuropeptide galanin coexists in the medial septum and diagonal band of Broca with a population of acetylcholine neurons which project mainly to the ventral hippocampus. The present studies investigated the role of ventral hippocampal galanin in spatial learning in the male rat using a spatial learning task. In addition, the effects of galanin on cholinergic function were monitored by in vivo microdialysis and high-performance liquid chromatography. Bilateral microinjections of galanin (3 nmol/rat) via chronic cannulae placed into the ventral hippocampus (i.v.h.) produced a slight but significant impairment of acquisition of the spatial task, while the 1 nmol dose of galanin facilitated acquisition. The 6 nmol dose of galanin failed to affect performance. A trend for an impairment of long-term memory retention (examined seven days after the last training session) was observed after 3 nmol of galanin, while the 1 nmol dose facilitated retention performance. Scopolamine (0.1 mg/kg, s.c.) caused a marked impairment of aquisition. Galanin (3 nmol/rat) given i.v.h. failed to modify the acquisition impairment caused by scopolamine (0.1 mg/kg, s.c.). These results suggest that galanin given i.v.h. produces a biphasic dose-dependent effects on spatial learning. In freely moving rats, galanin (3 nmol/10 μl) given into the lateral ventricle (i.c.v.) did not affect basal acetylcholine release. In contrast, perfusion with 300 μM galanin (0.3 nmol/1.25 μl/min) but not with 100 μM through the ventral hippocampal probe resulted in a marked stimulation of basal acetlycholine release which was time dependent and reversible. Galanin given i.c.v. (3 nmol/10 μl) or through the probe (0.3 nmol/1.25 μl/min or 300 μM) did not attenuate the increase in acetylcholine release evoked by the muscarinic antagonist scopolamine (0.1 mg/kg, s.c.; 0.001 nmol/1.25 μl/min or 1 μM through the probe). Instead, the galanin plus scopolamine combinations produced an even higher increase in the extracellular acetylcholine concentrations than scopolamine alone. This suggests that the mechanism(s) behind scopolamine- and galanin-induced stimulation of acetylcholine differ.These results indicate that ventral hippocampal galanin plays a role in cognition and that it has a powerful and modulatory effect on cholinergic transmission. However, the effects of exogenous galanin on spatial learning cannot be directly related to changes in in vivo cholinergic transmission in the ventral hippocampus. These discrepancies may relate to effects on subtypes of galanin receptors with different functional coupling. In addition, other hippocampal neurotransmitter systems (e.g. noradrenergic neurons) important for cognitive functions may also be modulated by ventral hippocampal galanin.
Article
The galanin (GAL) containing peptide fiber system circuit which innervates acetylcholine containing basal forebrain neurons has been shown to hypertrophy and hyperinnervate remaining cholinergic Ch4 perikarya in Alzheimer's disease (AD). The present study examined whether a similar hyperinnervation occurs within the cholinergic vertical limb of the diagonal band nucleus (Ch2), a portion of the basal forebrain which, unlike Ch4, exhibits only modest degeneration in AD. Furthermore, we evaluated whether GAL hyperinnervation occurs within the basal forebrain in Down's syndrome, a genetic disorder with extensive AD-like pathology including cholinergic basal forebrain neuron degeneration. The present study revealed that virtually all Ch2 neurons were GAL immunonegative. However, this region was innervated by GAL immunoreactive (ir) interneurons and fibers associated with a major galaninergic pathway which travels through the substantia innominata enroute to the hypothalamus, bed nucleus of the stria terminalis as well as vertical limb of diagonal band nucleus. GAL-ir fibers coursing within this fiber bundle hypertrophied in AD relative to age matched controls and the Down's cases. Within the putative Ch2 terminal zones in AD, many of the remaining cholinergic neurons were hyperinnervated by GAL despite the modest reduction in Ch2 neurons. In contrast, GAL-ir fibers were not hypertrophied in Down's syndrome despite extensive cholinergic cell loss within Ch4. Taken together these findings suggest that extensive cholinergic basal forebrain cell loss alone is not sufficient to trigger the basal forebrain GAL plasticity response found in AD.Copyright © 1993 S. Karger AG, Basel
Article
This chapter reviews current knowledge of the distribution of GALRs with a particular focus on the rat CNS. Galanin is a 29 amino acid peptide that is widely distributed in central and peripheral tissues. Galanin is proposed to be involved in a broad spectrum of biological effects including neuroendocrine control, food intake, sensory transmission, memory and learning, central cardiovascular regulation and has been implicated in a variety of different diseases. Due to its wide range of actions and its potential for various therapeutic interventions, galanin research has attracted much interest since its discovery in the early 1980s. To date, three novel and distinct galanin receptor (GALR) subtypes have been cloned, each encoded by separate genes and located on different human chromosomes. Knowledge of their sequence has enabled the generation of receptor-specific probes for mRNA localization studies. The tissue distribution patterns of GALR1 and GALR2 are well characterized; however, localization of GALR3 is somewhat more controversial.
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The peptide nociceptin (also named orphanin FQ) acts in the brain to produce various pharmacological effects, including hyperalgesia and hypolocomotion. The nociceptin receptor uses guanine-nucleotide-binding proteins to mediate the inhibition of adenylyl cyclase, the activation of potassium channels and inhibition of calcium channels. It has been shown using knockout mice that the nociceptin receptor is not required for regulation of nociceptive responses or locomotion activity, but modulates the auditory function. Here we show that mice lacking the nociceptin receptor possess greater learning ability and have better memory than control mice. Histological analysis revealed the expression of both the nociceptin precursor and the nociceptin receptor in the hippocampus, thought to take part in aspects of learning and memory. Moreover, the receptor-deficient mice showed larger long-term potentiation in the hippocampal CA1 region than control mice, without apparent changes in presynaptic or postsynaptic electrophysiological properties. These results show that the loss of the nociceptin receptor results in a gain-of-function mutation in both the memory process and the long-term potentiation mechanism in CA1, perhaps as a result of altered intracellular signal transduction systems in neurons.
Article
This article summarizes our recent finding that the nociceptin system is involved in the regulation of learning and memory. The nociceptin-knockout mice show greater learning ability in the water maze task, an enhanced latent learning in the water finding task, better memory in the passive avoidance task, and further, larger long-term potentiation in the hippocampal CA1 region than wild-type mice. Nociceptin itself induces an impairment of passive avoidance task in wild-type mice, which is reversed by naloxone benzoylhydrazone (NalBzoH). Thus, the nociceptin system seems to play negative roles in learning and memory, and NalBzoH may act as a potent antagonist for the nociceptin receptor.
Article
Using iodinated human galanin and autoradiography, galanin binding sites were studied in cortical and hippocampal areas and in some brainstem nuclei in the brains of eight patients with senile dementia of the Alzheimer type (SDAT) and of nine matched control cases. The highest density of binding sites was found in the substantia nigra with a less intense labeling in the hippocampus and cortical regions. In the SDAT cases a significant increase in number of galanin binding sites was found in some hippocampal areas, a decrease in the caudate nucleus, and no significant changes in frontal and entorhinal cortices. These findings suggest that some central galanin systems may be deranged in SDAT.
Article
This paper presents evidence that galanin is a potent in vivo modulator of basal acetylcholine release in the rat brain with qualitatively and quantitatively differential effects in the dorsal and ventral hippocampus. Galanin perfused through the microdialysis probe decreased basal acetylcholine release in the ventral hippocampus, while it enhanced acetylcholine release in the dorsal hippocampus. Galanin (3 nmol/rat) infused into the ventral hippocampus impaired spatial learning acquisition, while it tended to facilitate acquisition when injected into the dorsal hippocampus. These effects appear to be related to activation of GAL-R1 (ventral hippocampus) and GAL-R2 (dorsal hippocampus) receptors, respectively. However, the effects of galanin on acetylcholine release and on spatial learning appear not to be directly related to cholinergic mechanisms, but they may also involve interactions with noradrenaline and/or glutamate transmission. Galanin administered into the lateral ventricle failed to affect acetylcholine release, while this route of administration produced a long-lasting reduction in 5-HT release in the ventral hippocampus, indicating that galanin is a potent inhibitor of mesencephalic 5-HT neurotransmission in vivo. Subsequent studies supported this hypothesis, showing that the effects on 5-HT release in vivo are most likely mediated by a galanin receptor in the dorsal raphe. The implications of these findings are discussed in relation to the role of acetylcholine in cognitive functions in the forebrain and the role of the raphe 5-HT neurons in affective disorders.
Article
The neuropeptide, galanin, and its receptors are localized in the cholinergic basal forebrain and its projection areas in mammalian brain. Centrally administered galanin inhibits acetylcholine release in the rat ventral hippocampus, and produces deficits in learning and memory tasks. In Alzheimer's disease, galanin is overexpressed in terminals innervating the nucleus basalis of Meynert cell bodies. Selective galanin receptor antagonists provide a novel approach for increasing cholinergic function, as a potential adjunct to the clinical treatment of dementias.
Article
The physiological role of the modulation via the nociceptin receptor is still unclear. Here we report the role of the nociceptin system in learning and memory. Nociceptin-knockout mice possess greater learning ability in the water maze task, show an enhanced latent learning in the water finding task, have better memory in the passive avoidance task, and further, show larger long-term potentiation in the hippocampal CA1 region than wild-type mice. Nociceptin itself induces an impairment of the passive avoidance task in wild-type mice. This impairment is reversed by naloxone benzoylhydrazone (NalBzoH), but not by other opioids in wild-type mice. Further, experiments on cultured cells transfected with nociceptin receptor cDNA show that NalBzoH competes []-nociceptin binding and attenuates the nociceptin-induced inhibition of cAMP accumulation induced by forskolin. These results demonstrate that the nociceptin system seems to play a negative role in learning and memory and that NalBzoH acts as a potent antagonist for the nociceptin receptor. In addition, the antagonists for the nociceptin receptor may be worth testing for alleviating memory disorders.
Article
Since the first description of their opioid properties three decades ago, dynorphins have increasingly been thought to play a regulatory role in numerous functional pathways of the brain. Dynorphins are members of the opioid peptide family and preferentially bind to kappa opioid receptors. In line with their localization in the hippocampus, amygdala, hypothalamus, striatum and spinal cord, their functions are related to learning and memory, emotional control, stress response and pain. Pathophysiological mechanisms that may involve dynorphins/kappa opioid receptors include epilepsy, addiction, depression and schizophrenia. Most of these functions were proposed in the 1980s and 1990s following histochemical, pharmacological and electrophysiological experiments using kappa receptor-specific or general opioid receptor agonists and antagonists in animal models. However, at that time, we had little information on the functional relevance of endogenous dynorphins. This was mainly due to the complexity of the opioid system. Besides actions of peptides from all three classical opioid precursors (proenkephalin, prodynorphin, proopiomelanocortin) on the three classical opioid receptors (delta, mu and kappa), dynorphins were also shown to exert non-opioid effects mainly through direct effects on NMDA receptors. Moreover, discrepancies between the distribution of opioid receptor binding sites and dynorphin immunoreactivity contributed to the difficulties in interpretation. In recent years, the generation of prodynorphin- and opioid receptor-deficient mice has provided the tools to investigate open questions on network effects of endogenous dynorphins.This article examines the physiological, pathophysiological and pharmacological implications of dynorphins in the light of new insights in part obtained from genetically modified animals.
Article
Homology cloning and, more recently, the sequencing of whole genomes, have identified many open reading frames encoding proteins of unknown function, in particular putative G protein-coupled membrane receptors. Identification of orphan receptors in this way has marked the advent of 'reverse pharmacology' to identify the corresponding physiological ligands. This approach has led to the discovery of the ORL1 (Opioid Receptor-Like 1) receptor, and of its natural ligand, nociceptin/orphanin FQ (noc/oFQ), the basic components of a new peptide-based signalling pathway in the nervous system. Based on genetic criteria, the ORL1 and opioid receptors belong to the same family, as do noc/oFQ and opioid peptides. The marked structural analogy between the ORLI and opioid receptors, especially the kappa-opioid receptor, and the noc/oFQ and opioid peptides, particularly dynorphin A, is not reflected anatomically since noc/oFQ and opioid peptides appear to be located in separate neuronal circuits. Noc/oFQ triggers the same G protein-mediated signalling pathways as do opioids, however, to produce pharmacological effects that sometimes differ from, and even oppose, those of opioids. Noc/oFQ stimulates an outward K+ current and/or inhibits voltage-gated Ca2+ channels, thereby reducing synaptic efficacy, i.e. neuronal activity. In the rat, noc/oFQ is endowed with supraspinal pronociceptive/anti-opioid properties (it suppresses opioid-mediated analgesia), while convergent electrophysiological and behavioural data indicate that the peptide is a spinal analgesic. Noc/oFQ has not yet been found to precipitate withdrawal in morphine-tolerant rats. Nor does it elicit motivational effects, suggesting it lacks abuse liability. Also, by acting supraspinally, noc/oFQ impairs motor performance, suppresses spatial learning, induces feeding, and regulates basal and stress-induced release of pituitary hormones. Noc/oFQ is also active when administered intravenously, exhibiting potent smooth muscle relaxant, diuretic, and antinatriuretic properties. Last but not least, noc/oFQ appears to regulate stimulated immune function, and to be involved in neuronal differentiation. The discovery of noc/oFQ, a neuropeptide with multiple functions, will certainly improve our knowledge of brain physiology, and may find therapeutic applications, for example in the management of pain or hyponatremic and water-retaining diseases. However, given the wide distribution of noc/oFQ and its receptor, the pharmacological profile of noc/oFQ is likely to be incomplete, and other as yet unknown functions of the peptide remain to be discovered. Most helpful in this respect will be the identification of new ligands of the ORL1 receptor, particularly antagonists. If research on noc/oFQ carries on unabated at the present pace, potentially clinically interesting new compounds could become available in the not too distant future.
Article
This study examines the effects of NOP agonists nociceptin/orphanin FQ (N/OFQ) and Ro 64-6198, NOP antagonists [Nphe(1)]N/OFQ(1-13)-NH(2) Nphe(1) and naloxone benzoylhydrazone (NalBzoH) on spatial memory in NMRI mice and pronociceptin (proNC) knockout (KO) mice using the water maze task. N/OFQ, administered i.c.v. (1, 5 and 10 nmol/mouse) and into hippocampal CA3 (1 nmol/mouse, bilaterally), impaired acquisition and retention in the maze. Impairments were blocked by pre-treatment with Nphe(1) (10 nmol, i.c.v.). Ro 64-6198 (0.1-0.3-1 mg/kg i.p.) also dose-dependently impaired learning. However, pre-treatment with NalBzoH (1 mg/kg, s.c.) failed to modify the effects of Ro 64-6198. Nphe(1) (10 nmol/mouse i.c.v.) and NalBzoH (1 mg/kg, s.c.) by themselves failed to affect maze performance, despite a tendency for enhanced performance. Prepro N/OFQ knockout (ppN/OFQ -/-) showed evidence of improved learning, evident at retention trials and in reversal training. ppN/OFQ -/- mice were not impaired by N/OFQ (10 nmol i.c.v.) in the task, suggesting that changes in postsynaptic NOP receptors may occur in such KO mice. It is concluded that N/OFQ and NOP receptors have an important role in hippocampus-dependent spatial learning and memory, probably by modulation of glutamatergic functions.
Article
Changes in the state of CREB phosphorylation and in LTP in the hippocampus have been associated with learning and memory. Here we show that galanin, the neuropeptide released in the hippocampal formation from cholinergic and noradrenergic fibers, that has been shown to produce impairments in memory consolidation in the Morris water maze task inhibits both LTP and CREB phosphorylation in the rat hippocampus in vivo. While there are many transmitters regulating CREB phosphorylation none has been shown to suppress behaviorally-induced hippocampal CREB phosphorylation as potently as galanin. The in vivo inhibition of dentate gyrus-LTP and of CREB phosphorylation by the agonist occupancy of GalR1 and GalR2-type galanin receptors provides strong in vivo cellular and molecular correlates to galanin-induced learning deficits and designates galanin as a major regulator of the memory consolidation process.
Article
The neuropeptide galanin coexists with acetylcholine (ACh) in the basal forebrain cholinergic neurons and modulates cholinergic activity in the forebrain. The cholinergic forebrain neurons appear to play a significant role in learning and memory, as suggested by a severe loss of these neurons in Alzheimer's disease. The involvement of endogenous galanin in learning is demonstrated here by the use of the recently synthesized high-affinity galanin antagonist M35 [galanin(1-13)-bradykinin(2-9) amide] (Kd = 0.1 nM). Intracerebroventricular (i.c.v.) administration of M35 (6 but not 3 nmol) produced a significant (P < 0.025) facilitation of acquisition in a spatial learning test (Morris swim maze) without any increase in swim speed. Thus, M35 (6 nmol) shortened the escape latency, reduced the number of failures to reach the platform, and shortened the path length to reach the hidden platform. M35 (3 and 6 nmol) tended to enhance retention performance seven days after the last training session. Receptor autoradiographic studies on the distribution of [125I]M35 following i.c.v. administration show that it binds preferentially in the periventricular regions including the hippocampus. These results suggest that galanin may modulate spatial learning and memory and that galanin antagonists may provide a new principle in the treatment of Alzheimer's disease.
Article
Galanin-like immunoreactivity (GAL-ir) was examined within the basal forebrain and adjacent regions of eight young adult New World monkeys (Cebus apella), one aged Old World monkey (Macaca mulatta), and eight humans without clinical or pathological evidence of neurological disease. All monkeys demonstrated similar patterns of immunoreactive profiles characterized by a continuum of GAL-ir magnocellular neurons located within the medial septum, diagonal band nuclei, and nucleus basalis. Colocalization experiments revealed that most (greater than 90%) of GAL-ir basal forebrain neurons also expressed the receptor for nerve growth factor (NGFR), an excellent marker for primate cholinergic basal forebrain neurons. A few smaller parvicellular GAL-ir neurons were also observed within the monkey basal forebrain. In contrast, identical cytochemical experiments revealed that virtually none of the magnocellular neurons within the basal forebrain of humans were GAL-ir. Rather, a network of GAL-containing fibers and terminal-like profiles were observed encompassing the magnocellular cholinergic neurons in humans. This immunohistochemical species difference does not appear to be mediated by procedural or technical factors since human brains contained numerous GAL-ir perikarya and fibers within adjacent regions including the bed nucleus of the stria terminalis and medial hypothalamus. These data demonstrate that there is a prominent phylogenetic transformation in primates with respect to the processing of GAL-mediated information. This species difference potentially relates to the severe basal forebrain degeneration reported in human dementias and illustrates the possible need for a reevaluation of the use of monkeys as an animal model of human basal forebrain-related cognitive dysfunction.
Article
The discovery in the late 1970s that cholinergic neurons in the basal forebrain degenerate in Alzheimer's disease (AD) greatly accelerated research on the role of cholinergic mechanisms in learning and memory. As is often the case in science, the early enthusiasm for the cholinergic hypothesis has been tempered by the results of subsequent research. Although there is substantial pharmacological evidence that unspecified cholinergic systems in the brain play important roles in some forms of learning and memory, recent findings in humans indicate that antimuscarinic drugs do not model the deficits seen in AD. In addition, the goal of elucidating the functions of these basal forebrain neurons in animals has proved to be difficult and is yet to be achieved. Despite substantial effort, therefore, the cognitive and behavioral consequences of cholinergic pathology in AD remain unknown. Under these circumstances, attempts to develop cholinergic pharmacotherapies for these deficits in AD are based on questionable assumptions.