| 1. |
- Licheri, Valentina, et al.
(författare)
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Nicotine-induced neuroplasticity in striatum is subregion-specific and reversed by motor training on the rotarod.
- 2020
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Ingår i: Addiction biology. - : Wiley. - 1369-1600 .- 1355-6215. ; 25:3
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Tidskriftsartikel (refereegranskat)abstract
- Nicotine is recognized as one of the most addictive drugs, which in part could be attributed to progressive neuroadaptations and rewiring of dorsal striatal circuits. Since motor-skill learning produces neuroplasticity in the same circuits, we postulate that rotarod training could be sufficient to block nicotine-induced rewiring and thereby prevent long-lasting impairments of neuronal functioning. To test this hypothesis, Wistar rats were subjected to 15days of treatment with either nicotine (0.36mg/kg) or vehicle. After treatment, a subset of animals was trained on the rotarod. Ex vivo electrophysiology was performed 1week after the nicotine treatment period and after up to 3months of withdrawal to define neurophysiological transformations in circuits of the striatum and amygdala. Our data demonstrate that nicotine alters striatal neurotransmission in a distinct temporal and spatial sequence, where acute transformations are initiated in dorsomedial striatum (DMS) and nucleus accumbens (nAc) core. Following 3months of withdrawal, synaptic plasticity in the form of endocannabinoid-mediated long-term depression (eCB-LTD) is impaired in the dorsolateral striatum (DLS), and neurotransmission is altered in DLS, nAc shell, and the central nucleus of the amygdala (CeA). Training on the rotarod, performed after nicotine treatment, blocks neurophysiological transformations in striatal subregions, and prevents nicotine-induced impairment of eCB-LTD. These datasets suggest that nicotine-induced rewiring of striatal circuits can be extinguished by other behaviors that induce neuroplasticity. It remains to be determined if motor-skill training could be used to prevent escalating patterns of drug use in experienced users or facilitate the recovery from addiction.
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| 2. |
- Ademar, Karin, et al.
(författare)
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Acamprosate reduces ethanol intake in the rat by a combined action of different drug components
- 2023
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Ingår i: Scientific Reports. - 2045-2322. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Alcohol misuse accounts for a sizeable proportion of the global burden of disease, and Campral (R) (acamprosate; calcium-bis-(N-acetylhomotaurinate)) is widely used as relapse prevention therapy. The mechanism underlying its effect has in some studies been attributed to the calcium moiety and not to the N-acetylhomotaurine part of the compound. We recently suggested that the dopamine elevating effect of acamprosate is mediated both by N-acetylhomotaurine and calcium in a glycine receptor dependent manner. Here we aimed to explore, by means of in vivo microdialysis, if our previous study using local administration was functionally relevant and if systemic administration of the sodium salt of N-acetylhomotaurine (sodium acamprosate; 200 mg/kg, i.p.) enhanced the effects of calcium chloride (CaCl2; 73.5 mg/kg, i.p.) on nucleus accumbens (nAc) dopamine and/or taurine levels in male Wistar rats. In addition, we investigated the impact of regular acamprosate and the combination of CaCl(2 )and N-acetylhomotaurine on the alcohol deprivation effect (ADE). Finally, we assessed if N-acetylhomotaurine potentiates the ethanol-intake reducing effect of CaCl(2 )in a two-bottle choice voluntary ethanol consumption model followed by an ADE paradigm. Systemic administration of regular acamprosate, sodium acamprosate and CaCl(2 )all trended to increase nAc dopamine whereas the combination of CaCl(2)and sodium acamprosate produced a significant increase. Sodium acamprosate elevated extracellular taurine levels without additional effects of CaCl2. Ethanol intake was significantly reduced by systemic administration of CaCl(2 )without additional effects of the combination of CaCl(2 )and sodium acamprosate. Both acamprosate and CaCl(2 )combined with sodium acamprosate blocked the ADE following acute treatment. The data presented suggest that CaCl(2 )and N-acetylhomotaurine act in concert on a neurochemical level, but calcium appears to have the predominant effect on ethanol intake.
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| 3. |
- Ademar, Karin, et al.
(författare)
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Sodium acamprosate and calcium exert additive effects on nucleus accumbens dopamine in the rat
- 2022
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Ingår i: Addiction Biology. - : Wiley. - 1355-6215 .- 1369-1600. ; 27:5
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Tidskriftsartikel (refereegranskat)abstract
- Acamprosate (Campral (R) - calcium-bis[N-acetylhomotaurinate]) is one of few available pharmacotherapies for individuals suffering from alcohol use disorder. Previously, we suggested that acamprosate reduces ethanol intake by increasing dopamine in the nucleus accumbens (nAc), thereby partly substituting for alcohol's dopamine releasing effect. An experimental study suggested the calcium moiety of acamprosate to be the active component of the drug and to mediate the relapse preventing effect. The aim of the present study was to, by means of reversed in vivo microdialysis, elucidate if the dopamine elevating properties of acamprosate are mediated by N-acetylhomotaurine or by the calcium moiety. Male rats were equipped with a microdialysis probe in the nAc and received acute local treatment with regular acamprosate (CaAcamp 0.5 mM), calcium chloride (CaCl2 0.5 mM), sodium acamprosate (NaAcamp 0.5-1 mM), the glycine receptor (GlyR) antagonist strychnine (Stry 20 mu M), or vehicle. In all experiments, extracellular levels of dopamine and taurine were examined. We found that local perfusion with both CaAcamp and CaCl2 increased dopamine levels in a GlyR-dependent manner. NaAcamp did not influence dopamine levels, but concomitant administration with CaCl2 resulted in an additive dopamine output compared to the drugs administrated alone. We also found CaAcamp and the combination of CaCl2 and NaAcamp to increase accumbal taurine levels, suggesting that CaAcamp may act indirectly on GlyRs via taurine release. The present results indicate that both N-acetylhomotaurine and the calcium moiety of acamprosate have dopamine elevating properties within the nAc and that, in this respect, these substances are beneficial in combination.
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| 4. |
- 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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| 5. |
- 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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| 6. |
- Adermark, Louise, 1974, et al.
(författare)
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Astrocytes modulate extracellular neurotransmitter levels and excitatory neurotransmission in dorsolateral striatum via dopamine D2 receptor signaling
- 2022
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Ingår i: Neuropsychopharmacology. - : Springer Science and Business Media LLC. - 0893-133X .- 1740-634X. ; 47:8, s. 1493-1502
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Tidskriftsartikel (refereegranskat)abstract
- Astrocytes provide structural and metabolic support of neuronal tissue, but may also be involved in shaping synaptic output. To further define the role of striatal astrocytes in modulating neurotransmission we performed in vivo microdialysis and ex vivo slice electrophysiology combined with metabolic, chemogenetic, and pharmacological approaches. Microdialysis recordings revealed that intrastriatal perfusion of the metabolic uncoupler fluorocitrate (FC) produced a robust increase in extracellular glutamate levels, with a parallel and progressive decline in glutamine. In addition, FC significantly increased the microdialysate concentrations of dopamine and taurine, but did not modulate the extracellular levels of glycine or serine. Despite the increase in glutamate levels, ex vivo electrophysiology demonstrated a reduced excitability of striatal neurons in response to FC. The decrease in evoked potentials was accompanied by an increased paired pulse ratio, and a reduced frequency of spontaneous excitatory postsynaptic currents, suggesting that FC depresses striatal output by reducing the probability of transmitter release. The effect by FC was mimicked by chemogenetic inhibition of astrocytes using G(i)-coupled designer receptors exclusively activated by designer drugs (DREADDs) targeting GFAP, and by the glial glutamate transporter inhibitor TFB-TBOA. Both FC- and TFB-TBOA-mediated synaptic depression were inhibited in brain slices pre-treated with the dopamine D2 receptor antagonist sulpiride, but insensitive to agents acting on presynaptic glutamatergic autoreceptors, NMDA receptors, gap junction coupling, cannabinoid 1 receptors, mu-opioid receptors, P2 receptors or GABA(A) receptors. In conclusion, our data collectively support a role for astrocytes in modulating striatal neurotransmission and suggest that reduced transmission after astrocytic inhibition involves dopamine.
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| 7. |
- Adermark, Louise, 1974, et al.
(författare)
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Astrocytic Regulation of Endocannabinoid-Dependent Synaptic Plasticity in the Dorsolateral Striatum
- 2024
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Ingår i: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES. - 1661-6596 .- 1422-0067. ; 25:1
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Tidskriftsartikel (refereegranskat)abstract
- Astrocytes are pivotal for synaptic transmission and may also play a role in the induction and expression of synaptic plasticity, including endocannabinoid-mediated long-term depression (eCB-LTD). In the dorsolateral striatum (DLS), eCB signaling plays a major role in balancing excitation and inhibition and promoting habitual learning. The aim of this study was to outline the role of astrocytes in regulating eCB signaling in the DLS. To this end, we employed electrophysiological slice recordings combined with metabolic, chemogenetic and pharmacological approaches in an attempt to selectively suppress astrocyte function. High-frequency stimulation induced eCB-mediated LTD (HFS-LTD) in brain slices from both male and female rats. The metabolic uncoupler fluorocitrate (FC) reduced the probability of transmitter release and depressed synaptic output in a manner that was independent on cannabinoid 1 receptor (CB1R) activation. Fluorocitrate did not affect the LTD induced by the CB1R agonist WIN55,212-2, but enhanced CB1R-dependent HFS-LTD. Reduced neurotransmission and facilitated HFS-LTD were also observed during chemogenetic manipulation using Gi-coupled DREADDs targeting glial fibrillary acidic protein (GFAP)-expressing cells, during the pharmacological inhibition of connexins using carbenoxolone disodium, or during astrocytic glutamate uptake using TFB-TBOA. While pretreatment with the N-methyl-D-aspartate (NMDA) receptor antagonist 2-amino-5-phosphonopentanoic acid (APV) failed to prevent synaptic depression induced by FC, it blocked the facilitation of HFS-LTD. While the lack of tools to disentangle astrocytes from neurons is a major limitation of this study, our data collectively support a role for astrocytes in modulating basal neurotransmission and eCB-mediated synaptic plasticity.
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| 8. |
- Adermark, Louise, 1974, et al.
(författare)
-
Ethanol-induced modulation of synaptic output from the dorsolateral striatum in rat is regulated by cholinergic interneurons.
- 2011
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Ingår i: Neurochemistry international. - : Elsevier BV. - 1872-9754 .- 0197-0186. ; 58:6, s. 693-9
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Tidskriftsartikel (refereegranskat)abstract
- The striatum is the largest input nucleus to the basal ganglia and associated with reward-based behavior. We assessed whether acute ethanol (EtOH) exposure could modulate synaptic efficacy in the dorsolateral striatum of juvenile Wistar rats. Since acute EtOH administration can both increase and decrease the probability of release of different neurotransmitters from synaptic terminals, we used field potential recordings to evaluate the net effect of EtOH on striatal output. We showed that 50mM EtOH but not 20, 80 or 100mM, depresses population spike (PS) amplitude in the dorsolateral striatum. This depression of synaptic output is insensitive to the N-methyl-d-aspartic acid (NMDA) receptor inhibitor DL-2-amino-5-phosphonopentanoic acid (AP-5, 50μM), but is blocked in slices treated with glycine receptor antagonists (strychnine, 1μM; PMBA, 50μM), nicotinic acetylcholine receptor antagonists (mecamylamine, 10μM; methyllycaconitine citrate (MLA), 40nM), or GABA(A) receptor inhibitors (picrotoxin, 100μM; bicuculline, 2μM, 20μM). A long-term facilitation of synaptic output, which is more pronounced in slices from adult Wistar rats, is detected following EtOH washout (50, 80, 100mM). This long-term enhancement of PS amplitude is regulated by cholinergic interneurons and completely blocked by mecamylamine, MLA or the non-selective muscarinic antagonist scopolamine (10μM). Administration of 100mM EtOH significantly depresses PS amplitude in scopolamine-treated slices, suggesting that EtOH exerts dual actions on striatal output that are initiated instantly upon drug wash-on. In conclusion, EtOH modulates striatal microcircuitry and neurotransmission in a way that could be of importance for understanding the intoxicating properties as well as the acute reward sensation of EtOH.
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| 9. |
- Adermark, Louise, 1974, et al.
(författare)
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Implications for glycine receptors and astrocytes in ethanol-induced elevation of dopamine levels in the nucleus accumbens.
- 2011
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Ingår i: Addiction biology. - : Wiley. - 1369-1600 .- 1355-6215. ; 16:1, s. 43-54
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Tidskriftsartikel (refereegranskat)abstract
- ABSTRACT Elevated dopamine levels are believed to contribute to the rewarding sensation of ethanol (EtOH), and previous research has shown that strychnine-sensitive glycine receptors in the nucleus accumbens (nAc) are involved in regulating dopamine release and in mediating the reinforcing effects of EtOH. Furthermore, the osmoregulator taurine, which is released from astrocytes treated with EtOH, can act as an endogenous ligand for the glycine receptor, and increase extracellular dopamine levels. The aim of this study was to address if EtOH-induced swelling of astrocytes could contribute to elevated dopamine levels by increasing the extracellular concentration of taurine. Cell swelling was estimated by optical sectioning of fluorescently labeled astrocytes in primary cultures from rat, and showed that EtOH (25-150 mM) increased astrocyte cell volumes in a concentration- and ion-dependent manner. The EtOH-induced cell swelling was inhibited in cultures treated with the Na(+)/K(+)/2Cl(-) cotransporter blocker furosemide (1 mM), Na(+)/K(+)-ATPase inhibitor ouabain (0.1 mM), potassium channel inhibitor BaCl(2) (50 microM) and in cultures containing low extracellular sodium concentration (3 mM). In vivo microdialysis performed in the nAc of awake and freely moving rats showed that local treatment with EtOH enhanced the concentrations of dopamine and taurine in the microdialysate, while glycine and beta-alanine levels were not significantly modulated. EtOH-induced dopamine release was antagonized by local treatment with the glycine receptor antagonist strychnine (20 microM) or furosemide (100 microM or 1 mM). Furosemide also prevented EtOH-induced taurine release in the nAc. In conclusion, our data suggest that extracellular concentrations of dopamine and taurine are interconnected and that swelling of astrocytes contributes to the acute rewarding sensation of EtOH.
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| 10. |
- Adermark, Louise, 1974, et al.
(författare)
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Intermittent ethanol consumption depresses endocannabinoid-signaling in the dorsolateral striatum of rat.
- 2011
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Ingår i: Neuropharmacology. - : Elsevier BV. - 1873-7064 .- 0028-3908. ; https://gup.ub.gu.se/publications/sho61:7, s. 1160-1165
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Tidskriftsartikel (refereegranskat)abstract
- Recent research suggests that adaptations elicited by drugs of abuse share common features with traditional learning models, and that drugs of abuse cause long-term changes in behavior by altering synaptic function and plasticity. In this study, endocannabinoid (eCB) signaling in the dorsolateral striatum, a brain region vital for habit formation, was evaluated in acutely isolated brain slices from ethanol (EtOH)-consuming rats and control rats. EtOH-consuming rats had free access to a 20% EtOH solution for three 24hour sessions a week during seven weeks and consumed an average of 3.4g/kg per session. eCB-mediated long-lasting disinhibition (DLL) of population spike (PS) amplitude induced by moderate frequency stimulation was impaired in EtOH-consuming rats, and was not restored by the muscarinic receptor antagonist scopolamine (10μM). The lack of DLL could be linked to a reduced GABA(A) receptor tone, since bicuculline-mediated disinhibition of striatal output was significantly reduced in slices from EtOH-consuming rats. However, eCB signaling induced by high frequency stimulation (HFS) was also impaired in slices from EtOH-consuming rats and isolated control rats. Activation of presynaptic cannabinoid 1 receptors (CB1R) with WIN55,212-2 (250nM, 1μM) significantly modulated PS amplitude in slices from age-matched control rats while slices from EtOH-consuming rats remained unaffected, indicating that eCB signaling is inhibited at a level that is downstream from CB1R activation. Intermittent alcohol intake for seven weeks might thus be sufficient to modulate a presynaptic mechanism that needs to be synergized with CB1R activation for induction of long-term depression (LTD). In conclusion, alcohol consumption inhibits striatal eCB signaling in a way that could be of importance for understanding the neurological underpinnings of addictive behavior.
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