| 1. |
- Adermark, Louise, 1974, et al.
(författare)
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Acute and chronic modulation of striatal endocannabinoid-mediated plasticity by nicotine.
- 2019
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Ingår i: Addiction biology. - : Wiley. - 1369-1600 .- 1355-6215. ; 24:3, s. 355-363
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Tidskriftsartikel (refereegranskat)abstract
- The endocannabinoid (eCB) system modulates several phenomena related to addictive behaviors, and drug-induced changes in eCB signaling have been postulated to be important mediators of physiological and pathological reward-related synaptic plasticity. Here, we studied eCB-mediated long-term depression (eCB-LTD) in the dorsolateral striatum, a brain region critical for acquisition of habitual and automatic behavior. We report that nicotine differentially affects ex vivo eCB signaling depending on previous exposure in vivo. In the nicotine-naïve brain, nicotine facilitates eCB-signaling and LTD, whereas tolerance develops to this facilitating effect after subchronic exposure in vivo. In the end, a progressive impairment of eCB-induced LTD is established after protracted withdrawal from nicotine. Endocannabinoid-LTD is reinstated 6months after the last drug injection, but a brief period of nicotine re-exposure is sufficient to yet again impair eCB-signaling. LTD induced by the cannabinoid 1 receptor agonist WIN55,212-2 is not affected, suggesting that nicotine modulates eCB production or release. Nicotine-induced facilitation of eCB-LTD is occluded by the dopamine D2 receptor agonist quinpirole, and by the muscarinic acetylcholine receptor antagonist scopolamine. In addition, the same compounds restore eCB-LTD during protracted withdrawal. Nicotine may thus modulate eCB-signaling by affecting dopaminergic and cholinergic neurotransmission in a long-lasting manner. Overall, the data presented here suggest that nicotine facilitates eCB-LTD in the initial phase, which putatively could promote neurophysiological and behavioral adaptations to the drug. Protracted withdrawal, however, impairs eCB-LTD, which may influence or affect the ability to maintain cessation.
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| 2. |
- Adermark, Louise, 1974, et al.
(författare)
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Age-contingent influence over accumbal neurotransmission and the locomotor stimulatory response to acute and repeated administration of nicotine in Wistar rats
- 2015
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Ingår i: Neuropharmacology. - : Elsevier BV. - 0028-3908. ; 97, s. 104-112
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Tidskriftsartikel (refereegranskat)abstract
- Nicotine addiction is one of the leading contributors to the global burden of disease, and early onset smokers report a more severe addiction with lower chance of cessation than those with a late onset. Preclinical research supports an age-dependent component to the rewarding and reinforcing properties of nicotine, and the aim of this study was to. define behavioral adaptations and changes in accumbal neurotransmission that arise over 15 days of intermittent nicotine treatment (0.36 mg/kg/day) in rats of three different ages (5 weeks, 10 weeks, 36 weeks old). Repeated treatment increased the locomotor stimulatory response to nicotine in all age groups, but significantly faster in the two younger groups. In addition, nicotine decreased rearing activity in a way that sustained even after repeated administration in aged rats but not in the younger age groups. Electrophysiological field potential recordings revealed a decline in input/output function in the nucleus accumbens (NAc) of animals intermittently treated with nicotine starting at 5 weeks of age, but not in older animals. In drug naive rats, acute administration of nicotine modulated both accumbal dopamine output and excitatory transmission in a partially age dependent manner. Fifteen days of intermittent nicotine treatment did not alter the acute effect displayed by nicotine on dopamine levels or evoked field potentials. The data presented here show that both acute and repeated nicotine administration modulates accumbal neurotransmission and behavior in an age-contingent manner and that these age-dependent differences could reflect important neurobiological underpinnings associated with the increased vulnerability for nicotine-addiction in adolescents. (C) 2015 Elsevier Ltd. All rights reserved.
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| 3. |
- 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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| 4. |
- Chau, Pei Pei, 1981, et al.
(författare)
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Acamprosate's ethanol intake-reducing effect is associated with its ability to increase dopamine
- 2018
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Ingår i: Pharmacology Biochemistry and Behavior. - : Elsevier BV. - 0091-3057. ; 175, s. 101-107
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Tidskriftsartikel (refereegranskat)abstract
- Previous studies indicate that the anti-craving substance acamprosate modulates nucleus accumbens (nAc) dopamine levels via a dopamine-controlling nAc-VTA-nAc neurocircuitry. It was demonstrated that glycine receptors in the nAc are involved both in the dopamine-elevating effect and the ethanol intake-reducing effect of the drug. Here we wanted to explore the interaction of ethanol and acamprosate on nAc dopamine and investigate whether dopaminergic transmission may be related to the ethanol intake-reducing effects. In three separate studies we investigated nAc extracellular dopamine levels by means of in vivo microdialysis after administration of acamprosate and ethanol in 1) naïve rats, 2) rats pre-treated with acamprosate for two days or 3) ethanol medium- and high-preferring rats receiving ten days of acamprosate pre-treatment. In the first two studies, acamprosate elevated dopamine and simultaneously prevented ethanol from further increasing dopamine output. In the third study, long-term acamprosate pre-treatment produced a loss of the ethanol intake-reducing as well as the dopamine-elevating effects of acamprosate, and the dopamine elevating property of ethanol was restored. We suggest that acamprosate may partly substitute for the dopamine-elevating effect of ethanol but once tolerance develops to this effect, the ability to decrease ethanol intake is lost.
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| 5. |
- Clarke, Rhona B. C., et al.
(författare)
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Involvement of Inhibitory Receptors in Modulating Dopamine Signaling and Synaptic Activity Following Acute Ethanol Exposure in Striatal Subregions
- 2015
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Ingår i: Alcoholism-Clinical and Experimental Research. - : Wiley. - 0145-6008 .- 1530-0277. ; 39:12, s. 2364-2374
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Tidskriftsartikel (refereegranskat)abstract
- Background: Alcohol acts on both inhibitory and excitatory receptor systems resulting in a net increase in dopamine output in the ventral striatum (nucleus accumbens [nAc]), which is implicated in drug reward. However, the dorsal striatum may also be involved in reward-related behaviors. The objectives of this study were to investigate the role of inhibitory receptors in modulating the acute effects of ethanol (EtOH) on dopamine release and synaptic activity in the shell region of the nAc (nAcS) and dorsolateral striatum (DLS). Methods: EtOH (300 mM) was administered via reversed microdialysis in the nAcS or DLS of Wistar rats following pretreatment with glycine or GABA(A) receptor antagonist strychnine and bicuculline, respectively. Dopamine content in dialysate samples was quantified using high-performance liquid chromatography. In addition, local field potential recordings were performed in the nAcS and DLS in slices from Wistar rats. Population spike (PS) amplitude was measured following treatment with EtOH (50 mM) in slices pretreated with strychnine or bicuculline. Results: Local EtOH increased dopamine levels in both regions, an effect that strychnine pretreatment inhibited in the nAcS. EtOH-induced increases in accumbal dopamine were not blocked by a low (5 mu M) concentration of bicuculline, but were inhibited by pretreatment with higher bicuculline concentrations. None of the antagonists administered in the DLS prevented the EtOH-induced dopamine increase. Field potential recordings in the nAcS showed that acute EtOH produced an increase in PS amplitude which was blocked by both strychnine and bicuculline. In the DLS, EtOH induced a decrease in PS amplitude which was not influenced by strychnine or bicuculline. Conclusions: The current results show that changes in striatal dopamine output and synaptic activity induced by acute EtOH administration are modulated by inhibitory receptors in a subregion-specific manner.
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| 6. |
- Ericson, Mia, 1970, et al.
(författare)
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Minor adaptations of ethanol-induced release of taurine following chronic ethanol intake in the rat
- 2017
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Ingår i: Advances in Experimental Medicine and Biology. - Dordrecht : Springer. - 0065-2598.
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Konferensbidrag (refereegranskat)abstract
- Alcohol dependence is a puzzling brain disorder causing enormous suffering and financial costs world-wide. One of the few common denominators of all addictive drugs is activation of the mesolimbic dopamine system resulting in increased dopamine levels in the nucleus accumbens. In order to understand the development of addiction and find new efficient treatment strategies we need to understand how addictive drugs increase dopamine following acute and chronic administration of drugs. In the search for mechanisms underlying ethanol’s ability to increase dopamine in the nucleus accumbens we have found taurine to be of major importance, although the complete picture remains to be disclosed. The aim of the present study was to explore whether chronic voluntary ethanol intake influences the ethanol-induced elevation of taurine. By means of in vivo micro-dialysis we found that voluntary intake of large amounts of ethanol for 12 weeks only had a modest influence on ethanol-induced elevations of taurine in the rat. © 2017, Springer Science+Business Media B.V.
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| 7. |
- Jayaram-Lindstrom, N., et al.
(författare)
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Naltrexone modulates dopamine release following chronic, but not acute amphetamine administration: a translational study
- 2017
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Ingår i: Translational Psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- The opioid antagonist naltrexone has been shown to attenuate the subjective effects of amphetamine. However, the mechanisms behind this modulatory effect are currently unknown. We hypothesized that naltrexone would diminish the striatal dopamine release induced by amphetamine, which is considered an important mechanism behind many of its stimulant properties. We used positron emission tomography and the dopamine D2-receptor radioligand [C-11]raclopride in healthy subjects to study the dopaminergic effects of an amphetamine injection after pretreatment with naltrexone or placebo. In a rat model, we used microdialysis to study the modulatory effects of naltrexone on dopamine levels after acute and chronic amphetamine exposure. In healthy humans, naltrexone attenuated the subjective effects of amphetamine, confirming our previous results. Amphetamine produced a significant reduction in striatal radioligand binding, indicating increased levels of endogenous dopamine. However, there was no statistically significant effect of naltrexone on dopamine release. The same pattern was observed in rats, where an acute injection of amphetamine caused a significant rise in striatal dopamine levels, with no effect of naltrexone pretreatment. However, in a chronic model, naltrexone significantly attenuated the dopamine release caused by reinstatement of amphetamine. Collectively, these data suggest that the opioid system becomes engaged during the more chronic phase of drug use, evidenced by the modulatory effect of naltrexone on dopamine release following chronic amphetamine administration. The importance of opioid-dopamine interactions in the reinforcing and addictive effects of amphetamine is highlighted by the present findings and may help to facilitate medication development in the field of stimulant dependence.
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| 8. |
- Jonsson, Susanne, 1980, et al.
(författare)
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Involvement of lateral septum in alcohol's dopamine-elevating effect in the rat
- 2017
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Ingår i: Addiction Biology. - : Wiley. - 1355-6215 .- 1369-1600. ; 22:1, s. 93-102
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Tidskriftsartikel (refereegranskat)abstract
- Drugs of abuse share the ability to increase extracellular dopamine (DA) levels in the mesolimbic DA system. This effect has been linked to positive and reinforcing experiences of drug consumption and is presumed to be of importance for continued use, as well as for the development of dependence and addiction. Previous rat studies from our lab have implicated a neuronal circuitry involving glycine receptors in nucleus accumbens (nAc) and, secondarily, nicotinic acetylcholine receptors in the ventral tegmental area (VTA) in ethanol's (EtOH) DA-elevating effect. The work presented here, performed in male Wistar rats, suggests that the lateral septum (LS), which has previously been associated with different aspects of EtOH-related behaviour, is involved as well. In vivo microdialysis methodology demonstrated that blocking the generation of action potentials in LS using tetrodotoxin prevented a DA increase in nAc after accumbal EtOH perfusion. Retrograde tracing and polymerase chain reaction (PCR) were used to identify and characterize cells projecting to VTA from nAc/LS and from LS to nAc. Based on the PCR results, cells projecting from both LS/nAc to anterior VTA and from LS to nAc were mainly GABAergic neurons expressing glycine receptors, and these cells are presumed to be involved in mediating the DA-elevating effect of EtOH. These results provide further evidence implicating LS in the reinforcing effects of EtOH. Additional studies are needed to investigate LS involvement in EtOH consumption behaviour and its potential role in the development of dependence and addiction.
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| 9. |
- Klawonn, Anna, et al.
(författare)
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The Sigma-2 Receptor Selective Agonist Siramesine (Lu 28-179) Decreases Cocaine-Reinforced Pavlovian Learning and Alters Glutamatergic and Dopaminergic Input to the Striatum
- 2017
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Ingår i: Frontiers in Pharmacology. - : Frontiers Media SA. - 1663-9812. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Drug addiction is a chronic, debilitating disease that affects millions of people around the world causing a substantial societal burden. Despite decades of research efforts, treatment possibilities remain limited and relapse represents the most treatmentresistant element. Neurosteroid sigma-1 receptors have been meticulously studied in psychostimulant reinforced Pavlovian learning, while the sigma-2 receptor subtype has remained unexplored. Recent development of selective sigma-2 receptor ligands have now made it possible to investigate if the sigma-2 receptor system is a potential target to treat drug addiction. We examined the effect of the sigma-2 receptor agonist Siramesine (Lu 28-179) on cocaine-associated locomotion, Pavlovian learning, and reward neurocircuitry using electrophysiology recordings and in vivo microdialysis. We found that Siramesine significantly attenuated conditioned place preference acquisition and expression, as well as it completely blocked cocaine-primed reinstatement. Siramesine, in a similar manner as the selective sigma-1 receptor antagonist BD 1063, decreased acute locomotor responses to cocaine. Immunohistochemistry suggests co-expression of progesterone receptor membrane component 1/sigma-2 receptors and vesicular glutamate transporter 1 in presynaptic boutons of the nucleus accumbens (NAc). Whole-cell voltage clamp recordings of neurons in the NAc indicated that Siramesine decreases the presynaptic release probability of glutamate. Further, we demonstrated, via in vivo microdialysis, that Siramesine significantly decreased cocaine-evoked dopamine release in the striatum of freely moving mice. Collectively, these findings demonstrate that sigma-2 receptors regulate neurocircuitry responsible for positive reinforcement and thereby play a role in cocaine-reinforced Pavlovian behaviors.
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| 10. |
- 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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