| 1. |
- Ademar, Karin, et al.
(author)
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Acamprosate reduces ethanol intake in the rat by a combined action of different drug components
- 2023
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In: Scientific Reports. - 2045-2322. ; 13:1
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Journal article (peer-reviewed)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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| 2. |
- Ademar, Karin, et al.
(author)
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Sodium acamprosate and calcium exert additive effects on nucleus accumbens dopamine in the rat
- 2022
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In: Addiction Biology. - : Wiley. - 1355-6215 .- 1369-1600. ; 27:5
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Journal article (peer-reviewed)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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| 3. |
- Adermark, Louise, 1974, et al.
(author)
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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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In: Neuropsychopharmacology. - : Springer Science and Business Media LLC. - 0893-133X .- 1740-634X. ; 47:8, s. 1493-1502
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Journal article (peer-reviewed)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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| 4. |
- Adermark, Louise, 1974, et al.
(author)
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Astrocytic Regulation of Endocannabinoid-Dependent Synaptic Plasticity in the Dorsolateral Striatum
- 2024
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In: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES. - 1661-6596 .- 1422-0067. ; 25:1
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Journal article (peer-reviewed)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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| 5. |
- Danielsson, Klara, et al.
(author)
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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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In: Translational Psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 11:1
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Journal article (peer-reviewed)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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| 6. |
- Danielsson, Klara, et al.
(author)
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Subregion-specific effects on striatal neurotransmission and dopamine-signaling by acute and repeated amphetamine exposure
- 2021
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In: Neuropharmacology. - : Elsevier BV. - 0028-3908. ; 194
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Journal article (peer-reviewed)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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| 7. |
- De Bejczy, Andrea, 1975, et al.
(author)
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A randomized, double-blind, placebo-controlled, multicentre trial on the efficacy of varenicline and bupropion in combination and alone for treatment of alcohol use disorder: Protocol for the COMB study
- 2024
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In: PLOS ONE. - 1932-6203. ; 19:1
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Journal article (peer-reviewed)abstract
- BackgroundAlcohol Use Disorder (AUD) is a major cause of premature death, disability and suffering. Available treatments are of modest efficacy and under-prescribed so there is a pressing need for a well-tolerated and effective treatment option for AUD. Dopamine is hypothesized to be involved in the development of alcohol dependence. To challenge the low-dopamine hypothesis of addiction, this randomized, double-blind, placebo-controlled, 13-week, multicentre clinical trial with four parallel arms is designed to evaluate the efficacy of two substances raising dopamine levels, varenicline and bupropion, alone and in combination vs. placebo on alcohol consumption in AUD. Varenicline, a partial agonist at brain nicotinic acetylcholine receptors increases dopamine release, whereas bupropion is a centrally-acting, norepinephrine-dopamine reuptake inhibitor. Varenicline is previously shown to reduce alcohol intake in individuals with AUD. We hypothesize that the effect size of a combination of two drugs affecting dopamine levels in the brain will exceed that of approved AUD therapies.MethodsConsenting individuals with AUD will be recruited via media advertisements. Those fulfilling the eligibility criteria (N = 380) will be randomized to one of four interventions (n = 95 per arm). Treatment will comprise one week of titration (varenicline 0.5-2 mg; bupropion SR 150-300 mg) plus 12 weeks at steady state. Efficacy will be evaluated using two primary endpoints of alcohol consumption: Heavy Drinking Days and blood levels of phosphatidylethanol. Secondary objectives, exploratory and subgroup analyses will be also performed. The modified Intention-to-Treat and Per Protocol datasets will be evaluated using Analysis of Covariance. Last patient out is estimated to occur in December, 2022.DiscussionThe COMB Study aims to evaluate the efficacy of the combination of varenicline and bupropion, two drugs affecting dopamine, on alcohol consumption, and to challenge the low-dopamine hypothesis of addiction.
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| 8. |
- Ericson, Mia, 1970, et al.
(author)
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Different dopamine tone in ethanol high- and low-consuming Wistar rats
- 2020
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In: Addiction Biology. - : Wiley. - 1355-6215 .- 1369-1600. ; 2019
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Journal article (peer-reviewed)abstract
- - Excessive alcohol use causes considerable morbidity and mortality worldwide. Changes in the mesolimbic dopamine system have been postulated as a neurobiological underpinning of excessive alcohol consumption, and recent research also suggests that the amino acid taurine plays a central role in ethanol-induced dopamine elevation. The aim of this study was to further outline the role of dopamine and taurine in regulating alcohol consumption. In this study, a choice between ethanol (20%) and water was administered to Wistar rats in an intermittent manner (three times/week) for seven consecutive weeks. In vivo microdialysis was used to explore baseline levels as well as ethanol-induced increases of extracellular dopamine and taurine, in the nucleus accumbens (nAc) of Wistar rats voluntarily consuming large or small amounts of ethanol. Basal levels of taurine were also measured in cerebrospinal fluid (CSF) and serum in a subset of rats. Ethanol-induced increases in nAc dopamine and taurine did not differ between alcohol-consuming and naïve rats. However, when categorized based on ethanol intake, rats consuming larger amounts of ethanol exhibited a lower dopamine tone in the nucleus accumbens and responded to ethanol with a slower elevation of extracellular taurine levels, as compared with low-consuming animals. Basal levels of taurine in nAc, CSF, or serum did not differ between ethanol high- and low-consuming rats. Our data support previous studies claiming an association between low endogenous dopamine levels and excessive alcohol intake. © 2019 Society for the Study of Addiction
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| 9. |
- Guiraud, J., et al.
(author)
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Sodium Oxybate for Alcohol Dependence: A Network Meta-Regression Analysis Considering Population Severity at Baseline and Treatment Duration
- 2023
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In: Alcohol and Alcoholism. - : Oxford University Press (OUP). - 0735-0414 .- 1464-3502. ; 58:2, s. 125-133
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Journal article (peer-reviewed)abstract
- Aims: The estimated effect of sodium oxybate (SMO) in the treatment of alcohol dependence is heterogeneous. Population severity and treatment duration have been identified as potential effect modifiers. Population severity distinguishes heavy drinking patients with <14 days of abstinence before treatment initiation (high-severity population) from other patients (mild-severity population). Treatment duration reflects the planned treatment duration. This study aimed to systematically investigate the effect of these potential effect moderators on SMO efficacy in alcohol-dependent patients. Methods: Network meta-regression allows for testing potential effect modifiers. It was selected to investigate the effect of the above factors on SMO efficacy defined as continuous abstinence (abstinence rate) and the percentage of days abstinent (PDA). Randomized controlled trials for alcohol dependence with at least one SMO group conducted in high-severity and mild-severity populations were assigned to a high-severity and mild-severity group of studies, respectively. Results: Eight studies (1082 patients) were retained: four in the high-severity group and four in the mild-severity group. The high-severity group was associated with larger SMO effect sizes than the mild-severity group: abstinence rate risk ratio (RR) 3.16, P = 0.004; PDA +26.9%, P < 0.001. For PDA, longer treatment duration was associated with larger SMO effect size: +11.3% per extra month, P < 0.001. In the high-severity group, SMO showed benefit: abstinence rate RR 2.91, P = 0.03; PDA +16.9%, P < 0.001. In the mild-severity group, SMO showed benefit only in PDA for longer treatment duration: +23.9%, P < 0.001. Conclusions: In the retained studies with alcohol-dependent patients, high-severity population and longer treatment duration were associated with larger SMO effect sizes.
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| 10. |
- Guiraud, J., et al.
(author)
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Treating alcohol dependence with an abuse and misuse deterrent formulation of sodium oxybate: Results of a randomised, double-blind, placebo-controlled study
- 2021
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In: European Neuropsychopharmacology. - : Elsevier BV. - 0924-977X. ; 52, s. 18-30
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Journal article (peer-reviewed)abstract
- Sodium oxybate (SMO) has been approved in Italy and Austria for the maintenance of abstinence in alcohol dependent (AD) patients. Although SMO is well tolerated in AD patients, cases of abuse and misuse have been reported outside the therapeutic setting. Here we report on a phase IIb double-blind, randomized, placebo-controlled trial for the maintenance of abstinence in AD patients with a new abuse and misuse deterrent formulation of SMO. A total of 509 AD patients were randomized to 12 weeks of placebo or one of four SMO doses (0.75, 1.25, 1.75 or 2.25 g t.i.d.) followed by a one-week medication-free period. The primary endpoint was the percentage of days abstinent (PDA) at end of treatment. An unexpectedly high placebo response (mean 73%, median 92%) was observed. This probably compromised the demonstration of efficacy in the PDA, but several secondary endpoints showed statistically significant improvements. A post-hoc subgroup analysis based on baseline severity showed no improvements in the mild group, but statistically significant improvements in the severe group: PDA: mean difference +15%, Cohen's d = 0.42; abstinence: risk difference +18%, risk ratio = 2.22. No safety concerns were reported. Although the primary endpoint was not significant in the overall population, several secondary endpoints were significant in the intent-to-treat population and post-hoc results showed that treatment with SMO was associated with a significant improvement in severe AD patients which is consistent with previous findings. New trials are warranted that take baseline severity into consideration. (C) 2021 The Authors. Published by Elsevier B.V.
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