| 1. |
- Adermark, Louise, 1974, et al.
(författare)
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Temporal Rewiring of Striatal Circuits Initiated by Nicotine
- 2016
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Ingår i: Neuropsychopharmacology. - : Springer Science and Business Media LLC. - 0893-133X .- 1740-634X. ; 41:13, s. 3051-3059
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Tidskriftsartikel (refereegranskat)abstract
- Drug addiction has been conceptualized as maladaptive recruitment of integrative circuits coursing through the striatum, facilitating drug-seeking and drug-taking behavior. The aim of this study was to define temporal neuroadaptations in striatal subregions initiated by 3 weeks of intermittent nicotine exposure followed by protracted abstinence. Enhanced rearing activity was assessed in motor activity boxes as a measurement of behavioral change induced by nicotine (0.36 mg/kg), whereas electrophysiological field potential recordings were performed to evaluate treatment effects on neuronal activity. Dopamine receptor mRNA expression was quantified by qPCR, and nicotine-induced dopamine release was measured in striatal subregions using in vivo microdialysis. Golgi staining was performed to assess nicotine-induced changes in spine density of medium spiny neurons. The data presented here show that a brief period of nicotine exposure followed by abstinence leads to temporal changes in synaptic efficacy, dopamine receptor expression, and spine density in a subregion-specific manner. Nicotine may thus initiate a reorganization of striatal circuits that continues to develop despite protracted abstinence. We also show that the response to nicotine is modulated in previously exposed rats even after 6 months of abstinence. The data presented here suggests that, even though not self-administered, nicotine may produce progressive neuronal alterations in brain regions associated with goal-directed and habitual performance, which might contribute to the development of compulsive drug seeking and the increased vulnerability to relapse, which are hallmarks of drug addiction.
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| 2. |
- Danielsson, Johannes, et al.
(författare)
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Employing Futuristic Autobiographies to envision emerging human-agent interactions : The case of intelligent companions for stress management
- 2022
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Ingår i: ACM International Conference Proceeding Series. - New York, NY, USA : Association for Computing Machinery (ACM). - 9781450398084
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Konferensbidrag (refereegranskat)abstract
- Technology-supported stress management is one of the most promising and practically important application areas for intelligent companions, that is, digital assistants evoking empathy and personal attachment. In this paper, we employ the method of Futuristic Autobiographies (FABs) to elicit participants' attitudes and reflections regarding an imaginary digital assistant for stress management, implemented as an intelligent companion. For the purposes of the study, we developed six FABs, highlighting a range of potential issues related to the use of intelligent companions. The participants (N=17) provided their responses to the FABs by completing a survey, and a subset of the participants (N=5) also took part in follow-up online interviews. A thematic analysis of the results revealed six main themes: objectivity of the digital assistant, human-likeness, context-specificity of assistant's behavior, user's control, stress management, and user privacy. The themes, as well as the implications of the results for the design and use of intelligent stress management companions, are discussed.
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| 3. |
- Danielsson, Klara, et al.
(författare)
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Differential dopamine release by psychosis-generating and non-psychosis-generating addictive substances in the nucleus accumbens and dorsomedial striatum
- 2021
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Ingår i: Translational Psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Schizophrenia is associated with three main categories of symptoms; positive, negative and cognitive. Of these, only the positive symptoms respond well to treatment with antipsychotics. Due to the lack of effect of antipsychotics on negative symptoms, it has been suggested that while the positive symptoms are related to a hyperdopaminergic state in associative striatum, the negative symptoms may be a result of a reduced dopamine (DA) activity in the nucleus accumbens (nAc). Drug abuse is common in schizophrenia, supposedly alleviating negative symptomatology. Some, but not all, drugs aggravate psychosis, tentatively due to differential effects on DA activity in striatal regions. Here this hypothesis was tested in rats by using a double-probe microdialysis technique to simultaneously assess DA release in the nAc and associative striatum (dorsomedial striatum; DMS) following administration of the psychosis-generating substances amphetamine (0.5 mg/kg), cocaine (15 mg/kg) and Delta(9)-tetrahydrocannabinol (THC, 3 mg/kg), and the generally non-psychosis-generating substances ethanol (2.5 g/kg), nicotine (0.36 mg/kg) and morphine (5 mg/kg). The data show that amphetamine and cocaine produce identical DA elevations both in the nAc and DMS, whereas nicotine increases DA in nAc only. Ethanol and morphine both increased DMS DA, but weaker and in a qualitatively different way than in nAc, suggesting that the manner in which DA is increased might be important to the triggering of psychosis. THC elevated DA in neither region, indicating that the pro-psychotic effects of THC are not related to DA release. We conclude that psychosis-generating substances affect striatal DA release differently than non-psychosis-generating substances.
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| 4. |
- Danielsson, Klara
(författare)
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Dopaminergic lnterference for Treatment of Schizophrenia and Alcohol Use Disorder - an experimental study in rats
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The neurotransmitter dopamine is involved in several different physiological functions as well as pathological conditions. Two conditions that have been suggested to be related to a low dopaminergic tone in the ventral striatum are substance use disorder, and negative symptoms in schizophrenia, both of which are difficult to treat. In this thesis, we aimed to investigate in the rat the possibility of elevating dopamine in the ventral striatum (nucleus accumbens, nAc) in order to treat these conditions. To this end, we utilized in vivo microdialysis to sample and analyse extracellular dopamine, ex vivo electrophysiological field potential recordings to analyse effects on primarily excitatory neurotransmission, as well as behavioural methods to study ethanol consumption and behavioural sensitisation. In paper I, we show that the combination of the smoking cessation agent varenicline and the anti-depressant bupropion has an additive effect on nAc dopamine, and eliminates the alcohol deprivation effect in an ethanol consumption study. In paper II, we showcased the effects of protracted amphetamine treatment on both ventral and dorsal striatal (dorsomedial striatum, DMS) dopaminergic signalling. Results show that the nAc appears more sensitive to both acute and repeated amphetamine challenge, and that repeated amphetamine results in both reduced basal dopamine release and a qualitatively different signalling via dopamine D2 receptors in this region. In paper III, we investigated the effects of psychosis-generating and non-psychosis-generating addictive substances with regards of their effect on nAc and DMS dopamine. Key findings showed a distinct difference between amphetamine and cocaine, both strongly pro-psychotic, and nicotine, which has low psychosis-generating potential. Whereas amphetamine and cocaine both produced robust and similar elevations in dopamine in both the nAc and DMS, nicotine only had a noticeable effect in the nAc. In paper IV, findings from previous papers were combined in an effort to propose a way to selectively elevate dopamine in the nAc, without affecting DMS dopamine. We show that combining ethanol and nicotine produces an additive effect on nAc dopamine, with no marked interference on DMS dopamine, findings that we could then reproduce using varenicline and the glycine transport inhibitor Org24598. The combined findings presented in this thesis lend support to the possibility of raising nAc dopamine for treatment of alcohol use disorder and selectively raising nAc dopamine, for treatment of negative symptoms of schizophrenia.
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| 5. |
- Danielsson, Klara, et al.
(författare)
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Subregion-specific effects on striatal neurotransmission and dopamine-signaling by acute and repeated amphetamine exposure
- 2021
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Ingår i: Neuropharmacology. - : Elsevier BV. - 0028-3908. ; 194
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Tidskriftsartikel (refereegranskat)abstract
- Repeated administration of psychostimulants, such as amphetamine, is associated with a progressive increased sensitivity to some of the drug's effects, but tolerance towards others. We hypothesized that these adaptations in part could be linked to differential effects by amphetamine on dopaminergic signaling in striatal subregions. To test this theory, acute and long-lasting changes in dopaminergic neurotransmission were assessed in the nucleus accumbens (nAc) and the dorsomedial striatum (DMS) following amphetamine exposure in Wistar rats. By means of in vivo microdialysis, dopamine release induced by local administration of amphetamine was monitored in nAc and DMS of amphetamine naïve rats, and in rats subjected to five days of systemic amphetamine administration (2.0 mg/kg/day) followed by two weeks of withdrawal. In parallel, ex vivo electrophysiology was conducted to outline the effect of acute and repeated amphetamine exposure on striatal neurotransmission. The data shows that amphetamine increases dopamine in a concentration-dependent and subregion-specific manner. Furthermore, repeated administration of amphetamine followed by abstinence resulted in a selective decrease in baseline dopamine in the nAc, and a potentiation of the relative dopamine elevation after systemic amphetamine in the same area. Ex vivo electrophysiology demonstrated decreased excitatory neurotransmission in brain slices from amphetamine-treated animals, and a nAc selective shift in the responsiveness to the dopamine D2-receptor agonist quinpirole. These selective effects on dopamine signaling seen in striatal subregions after repeated drug exposure may partially explain why tolerance develops to the rewarding effects, but not towards the psychosis inducing properties of amphetamine. © 2021 The Author(s)
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| 6. |
- Lagström, Oona, et al.
(författare)
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Voluntary Ethanol Intake Produces Subregion-Specific Neuroadaptations in Striatal and Cortical Areas of Wistar Rats
- 2019
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Ingår i: Alcoholism: Clinical and Experimental Research. - : Wiley. - 0145-6008 .- 1530-0277. ; 43:5, s. 803-811
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Tidskriftsartikel (refereegranskat)abstract
- Background: Addiction has been conceptualized as a shift from controlled recreational use toward compulsive and habitual drug-taking behavior. Although the brain reward system is vital for alcohol reward and reinforcement, other neuronal circuits may be involved in controlling long-term alcohol-seeking and drug-taking behaviors. The aim of this study was to outline alcohol-induced neuroplasticity in defined cortical and striatal subregions, previously implicated in alcohol use disorder. Methods: Male Wistar rats were allowed to voluntarily consume ethanol (EtOH) in an intermittent manner for 2months, after which exvivo electrophysiological recordings were performed and data compared with isolated water controls housed in parallel. Results: Field potential recordings revealed an increase in field excitatory postsynaptic potentials (fEPSPs) in the dorsomedial striatum (DMS) of rats consuming EtOH, while a depression of evoked potentials was detected in the dorsolateral striatum (DLS). Mean activity in cortical (medial prefrontal cortex, lateral orbitofrontal cortex [OFC]), and accumbal regions (nucleus accumbens [nAc] core/shell) was not significantly altered as compared to water-drinking controls, but a correlation between the amount of alcohol consumed and evoked potentials could be found in both dorsal striatal subregions, OFC, and nAc core. Removal of EtOH for 1 to 2days was sufficient to restore neurotransmission in the DLS, while the increase in fEPSP amplitude sustained in the DMS. Conclusions: These preclinical findings are in line with clinical observations indicating that alcohol produces neurophysiological transformations in dorsal striatal circuits, which in turn may lead to disruptions in decision-making processes that could further promote alcohol misuse. © 2019 by the Research Society on Alcoholism
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| 7. |
- Olsson, Yasmin, et al.
(författare)
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Effects of systemic glycine on accumbal glycine and dopamine levels and ethanol intake in male Wistar rats
- 2021
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Ingår i: Journal of Neural Transmission. - : Springer Science and Business Media LLC. - 0300-9564 .- 1435-1463. ; 128, s. 83-94
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Tidskriftsartikel (refereegranskat)abstract
- Approved medications for alcohol use disorder (AUD) display modest effect sizes. Pharmacotherapy aimed at the mechanism(s) by which ethanol activates the dopamine reward pathway may offer improved outcomes. Basal and ethanol-induced accumbal dopamine release in the rat involve glycine receptors (GlyR) in the nucleus accumbens (nAc). Glycine transporter 1 (GlyT-1) inhibitors, which raise extracellular glycine levels, have repeatedly been shown to decrease ethanol intake in the rat. To further explore the rational for elevating glycine levels in the treatment of AUD, this study examined accumbal extracellular glycine and dopamine levels and voluntary ethanol intake and preference in the rat, after systemic treatment with glycine. The effects of three different doses of glycine i.p. on accumbal glycine and dopamine levels were examined using in vivo microdialysis in Wistar rats. In addition, the effects of the intermediate dose of glycine on voluntary ethanol intake and preference were examined in a limited access two-bottle ethanol/water model in the rat. Systemic glycine treatment increased accumbal glycine levels in a dose-related manner, whereas accumbal dopamine levels were elevated in a subpopulation of animals, defined as dopamine responders. Ethanol intake and preference decreased after systemic glycine treatment. These results give further support to the concept of elevating central glycine levels to reduce ethanol intake and indicate that targeting the glycinergic system may represent a pharmacologic treatment principle for AUD.
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| 8. |
- Söderpalm, Bo, 1959, et al.
(författare)
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Combined administration of varenicline and bupropion produces additive effects on accumbal dopamine and abolishes the alcohol deprivation effect in rats
- 2020
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Ingår i: Addiction Biology. - : Wiley. - 1355-6215 .- 1369-1600. ; 25:5
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Tidskriftsartikel (refereegranskat)abstract
- Alcohol use disorder (AUD) is detrimental to health and causes preterm death. Unfortunately, available pharmacological and nonpharmacological treatments have small effect sizes, and improved treatments are needed. Smoking and AUD share heritability and are pharmacologically associated, since drug-induced dopamine (DA) output in nucleus accumbens (nAc) involves nicotinic acetylcholine receptors (nAChRs) in both cases. Smoking therapy agents, such as the partial nAChR agonist varenicline or the DA/noradrenaline transporter inhibitor bupropion, could potentially also be used for AUD. To investigate this hypothesis, the effects of varenicline, bupropion, or a combination of the two on nAc DA levels, ethanol intake, and the alcohol deprivation effect (ADE) were examined. In vivo microdialysis showed that varenicline (1.5 mg/kg) and bupropion (2.5, 5, or 10 mg/kg) elevated nAc DA levels and that the combination produced additive effects. Five days treatment with varenicline, bupropion, or the combination did not suppress ethanol consumption, as compared with vehicle-treated control. However, combined administration of varenicline and bupropion completely blocked the ADE when readministering ethanol following 14 days of abstinence. Since ADE is considered highly predictive for the clinical outcome in man, our data suggest that the combination of varenicline and bupropion could be a promising treatment for AUD.
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| 9. |
- Abbafati, Cristiana, et al.
(författare)
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- 2020
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Tidskriftsartikel (refereegranskat)
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