Glutamatergic regulation of ghrelin-induced activation of the mesolimbic dopamine system

Recently, we demonstrated that the central ghrelin signalling system, involving the ghrelin receptor (GHS-R1A), is important for alcohol reinforcement. Ghrelin targets a key mesolimbic circuit involved in natural as well as drug-induced reinforcement, that includes a dopamine projection from the ventral tegmental area (VTA) to the nucleus accumbens. The aim of the present study was to determine whether it is possible to suppress ghrelin's effects on this mesolimbic dopaminergic pathway can be suppressed, by interrupting afferent inputs to the VTA dopaminergic cells, as shown previously for cholinergic afferents. Thus, the effects of pharmacological suppression of glutamatergic, orexin A and opioid neurotransmitter systems on ghrelin-induced activation of the mesolimbic dopamine system were investigated. We found in the present study that ghrelin-induced locomotor stimulation was attenuated by VTA administration of the N-methyl-D-aspartic acid receptor antagonist (AP5) but not by VTA administration of an orexin A receptor antagonist (SB334867) or by peripheral administration of an opioid receptor antagonist (naltrexone). Intra-VTA administration of AP5 also suppressed the ghrelin-induced dopamine release in the nucleus accumbens. Finally the effects of peripheral ghrelin on locomotor stimulation and accumbal dopamine release were blocked by intra-VTA administration of a GHS-R1A antagonist (BIM28163), indicating that GHS-R1A signalling within the VTA is required for the ghrelin-induced activation of the mesolimbic dopamine system. Given the clinical knowledge that hyperghrelinemia is associated with addictive behaviours (such as compulsive overeating and alcohol use disorder) our finding highlights a potential therapeutic strategy involving glutamatergic control of ghrelin action at the level of the mesolimbic dopamine system

Interactions of Dopamine D1 and N-methyl-D-Aspartate Receptors are Required for Acute Cocaine-Evoked Nitric Oxide Efflux in the Dorsal Striatum

Alterations in nitric oxide (NO) release in response to psychostimulants in the striatum cause a plastic change contributing to the development and expression of addiction. In this study, regulation of NO efflux evoked by acute cocaine in the dorsal striatum was investigated using real-time detection of NO in vivo. We found that acute systemic injection of cocaine (20 mg/kg) increased NO efflux, which was reduced by the intrastriatal infusion of the dopamine D1 receptor antagonist, SCH23390 (7.5 nmol), and the dopamine D2 receptor agonist, quinpirole (5 nmol). Increased levels of NO efflux by acute cocaine were also reduced by the intrastriatal infusion of the N-methyl-D-aspartate (NMDA) receptor antagonists, MK801 (2 nmol) and AP5 (2 nmol). These findings suggest that interactions of dopamine D1 receptors and NMDA receptors after acute exposure to cocaine participate in the upregulation of NO efflux in the dorsal striatum

A specific role for serotonin in overcoming effort cost

Serotonin is implicated in many aspects of behavioral regulation. Theoretical attempts to unify the multiple roles assigned to serotonin proposed that it regulates the impact of costs, such as delay or punishment, on action selection. Here, we show that serotonin also regulates other types of action costs such as effort. We compared behavioral performance in 58 healthy humans treated during 8 weeks with either placebo or the selective serotonin reuptake inhibitor escitalopram. The task involved trading handgrip force production against monetary benefits. Participants in the escitalopram group produced more effort and thereby achieved a higher payoff. Crucially, our computational analysis showed that this effect was underpinned by a specific reduction of effort cost, and not by any change in the weight of monetary incentives. This specific computational effect sheds new light on the physiological role of serotonin in behavioral regulation and on the clinical effect of drugs for depression

Nicotinic effects on midbrain dopamine neurons : a dual mechanism of action

The neurons of the mesocorticolimbic dopamine system are located in the ventral tegmental area (VTA) in the mesencephalon and send their projections to forebrain structures, such as the prefrontal cortex, the amygdala and the nucleus accumbens. The dopamine system is important in regulating mood and motivation as well as cognitive function and appear to be primarily involved in drug dependence, since most drugs abused by man stimulate this system. Nicotine stimulates dopamine neurons both by increasing their single spike activity and burst activity. Burst activity is characterized by action potentials fired rapidly in short episodes with longer intervals in between and is particularly effective in releasing dopamine in the terminal areas and increasing the postsynatic activation of the protoonco gene c-fos. Nicotine-induced dopamine release in the nucleus accumbens seems to be more or less exclusively dependent on the neuronal activation elicited via stimulation of nicotinic acetylcholine receptors (nAChRs) in the VTA. Burst firing of dopamine neurons is controlled by excitatory amino acids (EAAs) acting at NMDA receptors in the VTA. In many parts of brain, nicotine, instead of exciting neurons directly, as first thought, has been shown to act preferentially indirectly, i.e. by facilitating the release of EAAs. Recent evidence also suggests that nAChRs of the [alpha]7* subtype may be involved in presynaptic facilitation of EAA release. Therefore, the specific aim of the present project has been to analyze the role of EAAs in the stimulatory effects of nicotine on the mesocorticolimbic dopamine system and, in particular, the role of [alpha]7* nAChRs in this regard. Using microdialysis we found that the effect of nicotine (0.5 mg/kg s.c. free base) on dopamine release in the nucleus accumbens was attenuated by concomitant infusion in the VTA of the NMDA receptor antagonist AP-5, but not the AMPA/kainate receptor antagonist CNQX Nicotine also increased the levels of EAAs in the VTA an effect that was prevented by concomitant infusion of the 0 selective nAChR antagonist methyllycaconitine (MLA). Local infusion of MLA in the VTA also blocked nicotine-induced dopamine release in the nucleus accumbens. These data indicate that nicotine may act presynaptically at [alpha]7* nAChRs to stimulate the release of EAAs. Presynaptic [alpha]7* nAChRs may reside on [alpha]7* originating in the prefrontal cortex, since they provide an important source of glutamatergic [alpha]7* for dopamine neurons in the VTA. Therefore, excitotoxic lesions were made in the prefrontal cortex and autoradiography binding with nAChR ligands was performed on sections of the VTA. [alpha]-bungarotoxin binding, which represents binding to 0 nAChRs, was reduced by 30% in lesioned animals compared to controls, providing anatomical support for our notion. The postsynaptic consequences in the nucleus accumbens and medial prefrontal cortex of the corresponding pharmacological manipulations within the VTA was measured with Fos-immunohistochemistry. Nicotine increased Fos-expression in the nucleus accumbens and the medial prefrontal cortex. nAChR and NMDA receptor blockade in the VTA by mecamylamine or AP-5 prevented the effect of systemic nicotine on Fosexpression in the nucleus accumbens but not in the medial prefrontal cortex. MLA (6.0 mg/kg i.p.) antagonized the effect of nicotine on Fos expression both in the nucleus accumbens and the prefrontal cortex. MLA also inhibited nicotine-induced burst firing in dopamine neurons without affecting nicotine's effect on firing rate. In contrast the [alpha]4[beta]2 selective antagonist dihydro-[beta]-erythroidine [DH[beta]E, 1.0 mg/kg s.c.) prevented nicotine's effect on firing rate but did nor antagonize the nicotine-induced increase in burst firing. Accordingly, DH[beta]E did not affect the nicotine-induced Fos-expression in the nucleus accumbens and the prefrontal cortex. Also, we found that an 0 agonist (AR-R-17779) increased burst firing in dopamine neurons without affecting single spike activity, whereas an [alpha]4[beta]4[beta2 agonist (A-85380) increased single spike firing without affecting burst activity. These data suggest that [alpha]7* nAChRs are primarily involved in the burst firing enhancing effects of nicotine, whereas [alpha]4[beta]2 nAChRs appear to be primarily responsible for the nicotine-induced increase in single spike firing. Consequently, nicotine may activate dopamine neurons by two separate but convergent mechanisms. These mechanisms are both likely to contribute to different aspects of nicotine dependence. Selective ligands for nAChRs subtypes may be less dependence producing and might, therefore be used therapeutically since nicotine exerts several potentially beneficial effects on a number of CNS functions

”Miljön sänder budskap om vad som förväntas ske...” : Lärandemiljön i förskola och skola

I studien undersökte vi hur två förskolor och två skolor organiserat den fysiska lärandemiljön. Vårt syfte var att beskriva och analysera den fysiska lärandemiljön på två förskoleavdelningar och i två klassrum med avseende på möjligheter och hinder för relationer och aktiviteter. Vi använde oss av en kvalitativ datainsamlingsmetod med observationer där vi haft analysbegrepp, hämtade från ett postmodernt perspektiv som centrala utgångspunkter. Vi genomförde observationer i dessa fyra pedagogiska miljöer och analyserade dessa utifrån våra analysbegrepp och forskningsfrågor. I resultatet har det framkommit att det finns stora skillnader på utformningen av dessa fyra miljöer i form av möblering, placering och tillgänglighet av material. Resultatet antyder att en ökad medvetenhet om den fysiska miljöns betydelse kan bidra till ett mer reflekterat förhållningssätt när det gäller utformningen av lärandemiljöer

”En bild säger mer än tusen ord” - Föräldrars uppfattning av bildstöd vid vanligt förekommande procedurer : En enkätstudie inom barnsjukvården

Bakgrund: Barnperspektiv och barns perspektiv är grundläggande för ett barncentrerat förhållningssätt där barnet respekteras och tillåts vara delaktig. Vården ska utformas och genomföras i samråd med barnet och föräldrarna vilket ställer krav på vårdpersonalen att ge individanpassad information utifrån barnets förutsättningar. Syfte: Syftet var att utvärdera implementeringen av bildstöd vid vanligt förekommande procedurer på barnakuten och barnavdelning 64 i Västerås. Syftet var även att undersöka föräldrars uppfattning om bildstödet kan hjälpa barn vid procedurer som insättande av perifer venkateter och provtagning. Metod: Data insamlades genom att 57 föräldrar besvarade en enkät med slutna och öppna frågor. Kvantitativ data analyserades med beskrivande och jämförande statistik och de öppna frågorna analyserades med kvalitativ innehållsanalys. Resultat: Alla barn som planerades genomföra insättning av perifer venkateter eller provtagning erhöll information inför proceduren. Totalt fick 50 barn (88%) information med bildstöd och 7 barn (12%) erhöll endast muntlig information. Samband kunde ses mellan hur föräldrar skattade på en tiogradig skala att informationen var anpassad till barnets ålder och i vilken utsträckning de uppfattade att barnet förstått informationen i bildstödet (rs=0.396, p=0.008). Öppna frågorna resulterade i två huvudkategorier implementering av bildstöd och barns rättigheter inom sjukvården. Slutsats: Studien visade att bildstödet hade implementerats och att bildstöd kan hjälpa barn att förstå och ge dem möjlighet att vara involverade före och under proceduren. Det är viktigt att informationen är anpassad till barnets individuella förutsättningar och att föräldrarna kan delta i bedömningen av detta.Background: The child perspective is fundamental to a child-centered approach. The care must be provided by inviting the child and the parents to participate. This places demands on the healthcare professionals, who must provide information based on the child’s needs. Aim: To evaluate the use of picture support in procedures at the Children’s hospital in Västerås. A secondary aim was to investigate parents’ experiences of the use of picture support in procedures. Methods: Parents completed a questionnaire with multiple choice alternatives, ten-point scales questions and open-ended questions. Quantitative data were analyzed with descriptive and comparative statistics and the open-ended questions were analyzed with qualitative content analysis. Results: A total of 50 children (88%) who were planned to undergo peripheral venous catheters insertion or blood sampling received picture support prior to the procedure while 7 children (12%) received only verbal information. There was a correlation between how parents estimated that the information was adapted to the child's age and to what extent they perceived that the child understood the information in the picture support (rs=0.396, p=0.008). The open-ended questions resulted in two main categories, the implementation of visual support and children's rights in healthcare. Conclusion: The study showed that the picture support had been implemented and that picture support can help children understand and give them the opportunity to be involved before and during the procedure. It is important that the information is adapted to the child's conditions and the parents can be involved in the assessment of this

Antipsychotic-like effect by combined treatment with citalopram and WAY 100635: involvement ofthe 5-HT2C receptor.

Catalepsy occurs following high dopamine (DA) D2 blockade by typical antipsychotic drugs (APDs). We showed that a combination of a high dose of citalopram, a selective serotonin reuptake inhibitor (SSRI) and the selective 5-HT1A receptor antagonist WAY 100635 produces significant catalepsy in rats, similar to APDs. Here, we investigated the potential antipsychotic activity of lower doses of citalopram+WAY 100635, using the conditioned avoidance response (CAR) test. Cataleptogenic liability of the combination was evaluated with the catalepsy test. Citalopram and WAY 100635 in combination, but not when givenalone, prod uced a significant antipsychotic action in CAR without significant catalepsy, similar to the effect selective 5-HT2C receptor antagonist, SB , completely prevent 242084ed the citalopram/WAY 100635-induced suppression of CAR indicating an involvement of the 5-HT2C receptor. In summary, treatment with an SSRI/5-HT1A antagonist combination might prove beneficial in psychiatric disorders withpsychotic/depressive symptoms.

Adjunctive galantamine, but not donepezil, enhances the antipsychotic-like effect of raclopride in rats.

Acetylcholine (ACh) esterase inhibitors like galantamine and donepezil have been tested as adjunct treatment in schizophrenia. Although ACh esterase inhibition might confer some antipsychotic activity, the role of allosteric potentiation of nicotinic ACh receptors (nAChRs), which is an additional mechanism of galantamine, remains elusive. Therefore, the potential antipsychotic-like effects of galantamine and donepezil, respectively, alone, and in combination with the dopamine D2/3 receptor antagonist, raclopride, were tested in the conditioned avoidance response (CAR) test and extrapyramidal side-effect liability was assessed with the catalepsy test. Neither galantamine nor donepezil alone suppressed CAR selectively. Galantamine, but not donepezil, enhanced the raclopride-induced suppression of CAR, predicting augmentation of antipsychotic activity. In contrast to donepezil, galantamine did not increase catalepsy, alone or combined with raclopride. These data suggest that allosteric potentiation of nAChRs may mediate the antipsychotic-like effect of adjunctive galantamine and provide support for the development of α7 nAChR-selective allosteric potentiators for schizophrenia

Adjunctive galantamine, but not donepezil, enhances the antipsychotic-like effect of raclopride in rats

Abstract Acetylcholine (ACh) esterase inhibitors like galantamine and donepezil have been tested as adjunct treatment in schizophrenia. Although ACh esterase inhibition might confer some antipsychotic activity, the role of allosteric potentiation of nicotinic ACh receptors (nAChRs), which is an additional mechanism of galantamine, remains elusive. Therefore, the potential antipsychotic-like effects of galantamine and donepezil, respectively, alone, and in combination with the dopamine D 2/3 receptor antagonist, raclopride, were tested in the conditioned avoidance response (CAR) test and extrapyramidal side-effect liability was assessed with the catalepsy test. Neither galantamine nor donepezil alone suppressed CAR selectively. Galantamine, but not donepezil, enhanced the raclopride-induced suppression of CAR, predicting augmentation of antipsychotic activity. In contrast to donepezil, galantamine did not increase catalepsy, alone or combined with raclopride. These data suggest that allosteric potentiation of nAChRs may mediate the antipsychotic-like effect of adjunctive galantamine and provide support for the development of a 7 nAChR-selective allosteric potentiators for schizophrenia

The Importance of Ventral Hippocampal Dopamine and Norepinephrine in Recognition Memory

Dopaminergic neurons originating from the ventral tegmental area (VTA) and the locus coeruleus are innervating the ventral hippocampus and are thought to play an essential role for efficient cognitive function. Moreover, these VTA projections are hypothesized to be part of a functional loop, in which dopamine regulates memory storage. It is hypothesized that when a novel stimulus is encountered and recognized as novel, increased dopamine activity in the hippocampus induces long-term potentiation and long-term storage of memories. We here demonstrate the importance of increased release of dopamine and norepinephrinein the rat ventral hippocampus on recognition memory, using microdialysis combined to a modified novel object recognition test. We found that presenting rats to a novel object significantly increased dopamine and norepinephrine output in the ventral hippocampus. Two hours after introducing the first object, a second object (either novel or familiar) was placed in the same position as the first object. Presenting the animals to a second novel object significantly increased dopamine and norepinephrine release in the ventral hippocampus, compared to a familiar object. In conclusion, this study suggests that dopamine and norepinephrine output in the ventral hippocampus has a crucial role in recognition memory and signals novelty.De två sista författarna delar sistaförfattarskapet.</p