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| 2. |
- 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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| 3. |
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| 4. |
- Chau, Pei Pei, 1981
(författare)
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Brain glycine receptors as a common target for alcohol and the relapse-preventing drug acamprosate - a preclinical study
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Alcohol abuse and dependence make up the most prevalent categories of substance use disorders in the world. Converging evidence from the current research group has identified two receptor populations, the glycine (GlyRs) and nicotinic acetylcholine receptors (nAChRs) in the mesolimbic dopamine system, as two potentially important targets for the development of new medication to treat alcohol dependence. It is suggested that ethanol primarily acts via GlyRs in the nucleus accumbens (nAc) with a secondary and indirect effect on nAChRs in the ventral tegmental area (VTA), subsequently activating dopaminergic neurons leading to an increase of extracellular dopamine in the nAc. Pharmacological modulation of these receptors alters the activity of the suggested nAc-VTA-nAc circuitry with prominent effects on ethanol-induced dopamine elevations as well as ethanol intake. The general aim of this thesis was to further investigate the role of these receptors for regulating ethanol-induced dopamine and consummatory actions, by using ethanol and substances with possible anti-alcohol effects in the rat. Measurements of extracellular dopamine and amino acid levels in the nAc were made using in vivo brain microdialysis in awake, freely-moving male Wistar rats. In addition, a voluntary ethanol consumption paradigm with limited access was used to measure ethanol intake. The results indicate that the anti-relapse substance acamprosate has a similar dopamine-modulating profile as previously observed with ethanol and the endogenous GlyR ligand taurine. The acamprosate-induced dopamine elevation was demonstrated to be inhibited by pre-treatment with GlyR or nAChR-antagonists (Paper I). At a behavioral level, the ethanol intake-reducing effect of acamprosate was reversed by GlyR antagonism in the nAc (Paper II). In addition, the loss of the ethanol intake-reducing effect of chronic administration of acamprosate is potentially linked with its’ dopamine-modulating property (Paper III). The influence of acamprosate-related substances, the metabotropic glutamate type 5 receptor (mGluR5) antagonist MPEP and taurine, were also investigated. We found that mGluR5 and GlyR may have a joint mechanism to activate the dopamine output (Paper IV). Also, an augmentation of extracellular taurine levels is required in order to obtain an ethanol-induced dopamine increase (Paper V). The findings of this thesis have revealed a new mechanism of action for the anti-relapse agent acamprosate. But, most importantly, the results have further confirmed the relevance of the nAc-VTA-nAc neuronal circuitry for alcohol addiction.
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| 5. |
- Chau, Pei Pei, 1981, et al.
(författare)
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Glycine Receptors in the Nucleus Accumbens Involved in the Ethanol Intake-Reducing Effect of Acamprosate.
- 2009
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Ingår i: Alcoholism, clinical and experimental research. - : Wiley. - 1530-0277 .- 0145-6008.
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Tidskriftsartikel (refereegranskat)abstract
- Background: We have previously demonstrated that strychnine-sensitive glycine receptors (GlyRs) in the nucleus accumbens (nAc) and nicotinic acetylcholine receptors (nAChRs) in the ventral tegmental area are involved in mediating ethanol (EtOH)-induced elevation of dopamine in the rat mesolimbic dopamine system. This neuronal circuitry was also demonstrated to mediate dopamine elevation in the nAc after both taurine, an endogenous agonist of GlyRs, and acamprosate, a synthetic derivate of homotaurine. The aim of this study was to investigate whether the EtOH intake-reducing effect of acamprosate involves accumbal GlyRs. Methods: For this purpose, we used a voluntary EtOH consumption model where EtOH medium- and high-preferring rats were implanted with guide cannulae in the nAc. The animals received daily injections of acamprosate or 0.9% NaCl before accessing a bottle of 6% EtOH and a bottle of water. After 2 days, a microinjection of strychnine or vehicle preceded the daily systemic injection and bottle-access period. Results: Acamprosate, but not saline, decreased EtOH intake. Pretreatment with Ringer in the nAc did not influence EtOH intake in saline or acamprosate-treated animals. Pretreatment with strychnine had no effect on EtOH intake in saline-treated animals, whereas it completely reversed the EtOH intake-reducing effect of acamprosate. Conclusions: Based on current and previous results, we suggest that acamprosate primarily interacts with accumbal GlyRs and secondarily with ventral tegmental nAChRs, in a similar manner to that previously observed with EtOH and taurine. The interaction between acamprosate and GlyRs does not only influence dopamine output in the nAc but also EtOH consumption, giving further support for our hypothesis that GlyRs are of importance in EtOH reinforcement.
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| 6. |
- Chau, Pei Pei, 1981, et al.
(författare)
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Glycine Receptors Involved in Acamprosate's Modulation of Accumbal Dopamine Levels: An In Vivo Microdialysis Study.
- 2009
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Ingår i: Alcoholism, clinical and experimental research. - : Wiley. - 1530-0277 .- 0145-6008.
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Tidskriftsartikel (refereegranskat)abstract
- Background: Glycine receptors (GlyRs) in the nucleus accumbens (nAc) and nicotinic acetylcholine receptors (nAChRs) in the ventral tegmental area (VTA) have been suggested to be involved in the positive reinforcing and dopamine elevating effects of ethanol. Recent studies have also shown that ethanol high-preferring rats substantially decrease their ethanol intake when treated with a glycine transporter 1 inhibitor (ORG 25935). Acamprosate, a drug used for relapse prevention in treatment of alcohol dependence, has also been demonstrated to elevate extracellular dopamine levels in the nAc. However, the underlying mechanism of action of acamprosate is not fully understood. Here we investigated whether acamprosate interferes with a neuronal circuitry that previously has been demonstrated to be involved in the dopamine elevating effects of ethanol and taurine. Methods: In vivo microdialysis in freely moving rats was used to assess accumbal dopamine levels before and during local (nAc) or systemic administration of acamprosate. Results: Perfusion of 0.5 mM acamprosate in the nAc significantly increased dopamine levels. Pretreatment either with 10 muM strychnine in the nAc or 100 muM mecamylamine in the VTA, completely antagonized the acamprosate-induced elevation of accumbal dopamine levels. Also, systemic acamprosate administration elevated accumbal dopamine output, an effect that was abolished by local (nAc) pretreatment with 10 muM strychnine. Conclusions: These results suggest that both systemic and local application of acamprosate elevate extracellular dopamine levels in the nAc by activating accumbal GlyRs, and, secondarily, tegmental nAChRs.
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| 7. |
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| 8. |
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| 9. |
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| 10. |
- Chau, Pei Pei, 1981, et al.
(författare)
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The mGluR5 antagonist MPEP elevates accumbal dopamine and glycine levels; interaction with strychnine-sensitive glycine receptors.
- 2011
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Ingår i: Addiction biology. - : Wiley. - 1369-1600 .- 1355-6215.
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Tidskriftsartikel (refereegranskat)abstract
- Studies have indicated that the metabotropic glutamate receptor 5 (mGluR5) antagonist 6-methyl-2-(phenylethynyl)-pyridine (MPEP) decreases ethanol self-administration, and the same receptor type was also suggested to be involved in the mechanism of action of the anti-craving substance acamprosate. Our previous research suggested that glycine receptors (GlyRs) in the nucleus accumbens (nAc) play a major part in mediating the dopamine-elevating properties of ethanol and are highly involved in the ethanol intake-reducing effect of acamprosate. The aim of this study was to examine if modulation of nAc dopamine via mGluR5 antagonism or GlyR agonism is a linked or separated phenomena. The extracellular levels of dopamine as well as of the GlyR ligands, glycine, taurine and β-alanine were measured in the nAc by means of microdialysis after local perfusion of MPEP (100 or 500µM) with or without pre-treatment with strychnine. MPEP increased dopamine levels, an effect that was blocked by pre-treatment with strychnine. In addition, the higher MPEP concentration increased glycine output, whereas no alterations of taurine or β-alanine were observed. These results indicate a relationship between the glutamatergic and glycinergic transmitter systems in regulating dopamine output, possibly via alteration of extracellular glycine levels. Taken together with our previous data demonstrating the importance of accumbal GlyRs both in ethanol-induced elevation of nAc dopamine and in ethanol consumption, it is plausible that the effects of MPEP treatment, on dopamine output and on ethanol intake, may be mediated via interaction with the same neuronal circuitry that previously has been demonstrated for ethanol, taurine and acamprosate.
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| 11. |
- Clarke, Rhona B. C., et al.
(författare)
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Increase in Nucleus Accumbens Dopamine Levels Following Local Ethanol Administration Is Not Mediated by Acetaldehyde
- 2014
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Ingår i: Alcohol and Alcoholism. - : Oxford University Press (OUP). - 0735-0414 .- 1464-3502. ; 49:5, s. 498-504
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Ethanol (EtOH) activates the mesolimbic dopamine system and increases dopamine levels in the nucleus accumbens (nAc), which is believed to underlie the rewarding effects of alcohol. Accumulating evidence now implicates that acetaldehyde, the first metabolite of EtOH, may play an important role in mediating some of the rewarding properties of its parent compound. The objective of this study was to investigate if the increase in accumbal dopamine output observed when administering EtOH locally in the nAc by reversed microdialysis is mediated by acetaldehyde. Methods: Acetaldehyde (1, 10, 100 or 200 mu M) or EtOH (300 mM) was administered via reversed microdialysis in the nAc of male Wistar rats. In a separate experiment, animals were administered EtOH (300 mM) in the nAc, following pre-treatment with the acetaldehyde-sequestering agent D-penicillamine (50 mg/kg injected intraperitoneally 60 min before drug challenge). Microdialysates from the nAc were collected every 20 min and dopamine content was quantified using high-performance liquid chromatography. Results: Acetaldehyde administered in the nAc did not influence accumbal dopamine levels at any of the concentrations applied, whereas EtOH induced a significant increase in accumbal dopamine. The dopamine-elevating properties of EtOH were not attenuated by pre-treatment with D-penicillamine. Conclusion: The current results show that EtOH administered in the nAc induces an elevation in accumbal dopamine levels, which is not mimicked by acetaldehyde alone, nor is it influenced by acetaldehyde sequestering. This would suggest that the increase in accumbal dopamine following nAc EtOH administration is not mediated by acetaldehyde.
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| 12. |
- Ericson, Mia, 1970, et al.
(författare)
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beta-alanine elevates dopamine levels in the rat nucleus accumbens: antagonism by strychnine.
- 2010
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Ingår i: Amino acids. - : Springer Science and Business Media LLC. - 1438-2199 .- 0939-4451. ; 38:4, s. 1051-1055
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Tidskriftsartikel (refereegranskat)abstract
- Glycine receptors (GlyRs) in the nucleus accumbens (nAc) have recently been suggested to be involved in the reinforcing and dopamine-elevating properties of ethanol via a neuronal circuitry involving the VTA. Apart from ethanol, both glycine and taurine have the ability to modulate dopamine output via GlyRs in the same brain region. In the present study, we wanted to explore whether yet another endogenous ligand for the GlyR, beta-alanine, had similar effects. To this end, we monitored dopamine in the nAc by means of in vivo microdialysis and found that local perfusion of beta-alanine increased dopamine output. In line with previous observations investigating ethanol, glycine and taurine, the competitive GlyR antagonist strychnine completely blocked the dopamine elevation. The present results suggest that beta-alanine has the ability to modulate dopamine levels in the nAc via strychnine-sensitive GlyRs, and are consistent with previous studies suggesting the importance of this receptor for modulating dopamine output.
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| 13. |
- Ericson, Mia, 1970, et al.
(författare)
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Nicotinic acetylcholine receptors in the anterior, but not posterior, ventral tegmental area mediate ethanol-induced elevation of accumbal dopamine levels.
- 2008
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Ingår i: The Journal of pharmacology and experimental therapeutics. - : American Society for Pharmacology & Experimental Therapeutics (ASPET). - 1521-0103 .- 0022-3565. ; 326:1, s. 76-82
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Tidskriftsartikel (refereegranskat)abstract
- Ethanol-induced elevations of accumbal dopamine levels have been linked to the reinforcing properties of the drug. However, it has not yet been demonstrated where the primary point of action of ethanol is in the mesolimbic dopamine system, and there appear to be conflicting findings depending on methodology (electrophysiology, microdialysis, or intracranial self-administration). We have suggested that ethanol acts in the nucleus accumbens (nAc), where it activates a neuronal loop involving ventral tegmental nicotinic acetylcholine receptors (nAChRs) to elevate dopamine levels in the nAc. Application of ethanol in the nAc results in elevated dopamine levels in the same brain region, whereas administration in the anterior ventral tegmental area (VTA) fails to influence dopamine output. In the present study, we were able to repeat these findings. In addition, application of ethanol in the posterior VTA also failed to influence nAc dopamine levels. Perfusion of the nAChR antagonist mecamylamine in the anterior VTA completely blocked the elevation of accumbal dopamine levels observed after ethanol perfusion in nAc, whereas mecamylamine in the posterior VTA had no effect. To detect a possible influence on phasic dopamine release, the dopamine transporter inhibitor nomifensine was included in the accumbal perfusate. In addition, under these conditions, ethanol in the anterior or posterior VTA failed to influence dopamine release in the nAc. These results support previous suggestions of distinct functions of the anterior and posterior VTA and give further evidence for our hypothesis of a nAc-anterior VTA-nAc neuronal circuitry involved in the dopamine-activating effects of ethanol.
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| 14. |
- Ericson, Mia, 1970, et al.
(författare)
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Rising taurine and ethanol concentrations in nucleus accumbens interact to produce dopamine release after ethanol administration.
- 2011
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Ingår i: Addiction biology. - : Wiley. - 1369-1600 .- 1355-6215. ; 16:3, s. 377-385
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Tidskriftsartikel (refereegranskat)abstract
- We have previously demonstrated that glycine receptors in the nucleus accumbens (nAc) are involved in modulating both basal and ethanol-induced dopamine output in the same brain region. Ethanol is known to induce a release of both taurine and dopamine in the nAc, but the relationship between these two neuromodulators has not been investigated thoroughly. In vivo microdialysis was used to measure the effects of systemic ethanol diluted in isotonic (0.9% NaCl) or hypertonic (3.6% NaCl) saline on accumbal taurine and dopamine levels. We found that ethanol given in a hypertonic solution, contrary to an isotonic solution, failed to increase concentrations both of taurine and dopamine in the nAc. However, a modest, non-dopamine elevating concentration of taurine in the nAc disclosed a dopamine-elevating effect of systemic ethanol also when given in a hypertonic solution. In a second experiment, we investigated the effects of ethanol on taurine and dopamine in normal rats and rats with decreased levels of endogenous taurine. Lowering the level of taurine, approximately 40% by adding 5% β-alanine in the drinking water, did not influence taurine or dopamine output over time. We conclude that the elevations of taurine and dopamine in the nAc are closely related, and that in order for ethanol to induce dopamine release, a simultaneous increase of extracellular taurine levels in the nAc is required. These data also provide support for the notion that the nAc is the primary target for ethanol in its dopamine-activating effect after systemic administration.
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| 15. |
- Ericson, Mia, 1970, et al.
(författare)
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Rising taurine and ethanol concentrations in nucleus accumbens interact to produce the dopamine-activating effects of alcohol
- 2013
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Ingår i: Advances in Experimental Medicine and Biology. - New York, NY : Springer New York. - 0065-2598. ; 775, s. 215-223
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Tidskriftsartikel (refereegranskat)abstract
- Alcohol misuse and addiction is a worldwide problem causing enormous individual suffering as well as financial costs for the society. To develop pharmacological means to reduce suffering, we need to understand the mechanisms underlying the effects of ethanol in the brain. Ethanol is known to increase extracellular levels of both dopamine and taurine in the nucleus accumbens (nAc), a part of the brain reward system, but the two events have not been connected. In previous studies we have demonstrated that glycine receptors in the nAc are involved in modulating both basal- and ethanol-induced dopamine output in the same brain region. By means of in vivo microdialysis in freely moving rats we here demonstrate that the endogenous glycine receptor ligand taurine mimics ethanol in activating the brain reward system. Furthermore, administration of systemic ethanol diluted in an isotonic (0.9% NaCl) or hypertonic (3.6% NaCl) saline solution was investigated with respect to extracellular levels of taurine and dopamine in the nAc. We found that ethanol given in a hypertonic solution, contrary to an isotonic solution, failed to increase concentrations of both taurine and dopamine in the nAc. However, a modest, non-dopamine elevating concentration of taurine in the nAc disclosed a dopamine elevating effect of systemic ethanol also when given in a hypertonic solution. We conclude that the elevations of taurine and dopamine in the nAc are closely related and that in order for ethanol to induce dopamine release, a simultaneous increase of extracellular taurine levels in the nAc is required. These data also provide support for the notion that the nAc is the primary target for ethanol in its dopamineactivating effect after systemic administration and that taurine is a prominent participant in activating the brain reward system. © Springer Science+Business Media New York 2013.
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| 16. |
- Löf, Elin, 1974, et al.
(författare)
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Ethanol-induced dopamine elevation in the rat--modulatory effects by subchronic treatment with nicotinic drugs.
- 2007
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Ingår i: European journal of pharmacology. - : Elsevier BV. - 0014-2999. ; 555:2-3, s. 139-47
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Tidskriftsartikel (refereegranskat)abstract
- Chronic nicotine administration is associated with increased ethanol consumption in laboratory animals and in humans. Some smokers report less sedation during acute ethanol intoxication after nicotine administration and the sedative effects from ethanol are mediated by inhibitory GABA(A)-receptors. In a series of in vivo microdialysis experiments we investigated whether subchronic pre-treatment with nicotinic drugs known to enhance ethanol consumption in the rat (nicotine or the peripheral nicotinic antagonist hexamethonium) could modulate the alterations in extracellular dopamine observed in response to administration of ethanol or the sedative GABA(A)-agonist diazepam. In the nucleus accumbens and the dorsal striatum, systemic and/or local ethanol administration resulted in transient increases in extracellular dopamine levels that returned to baseline before the local levels of ethanol started to decline. In hexamethonium pre-treated rats, however, the nucleus accumbens dopamine levels were time-locked to the ethanol levels in the same area after systemic or local ethanol administration. Perfusion of diazepam into the nucleus accumbens produced a significant reduction in nucleus accumbens dopamine in controls. Prior subchronic treatment with nicotine or hexamethonium abolished this effect. The present results suggest that subchronic treatment with the nicotinic acetylcholine receptor antagonist hexamethonium reduces a GABA(A)-R mediated counteraction of the nucleus accumbens dopamine response to ethanol. Additionally, we demonstrate that modulation of nicotinic receptors may reduce the sensitivity of GABA(A) receptors to benzodiazepines. These phenomena may offer a novel explanation to why nicotine and alcohol are often co-abused.
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| 17. |
- Pickering, Christopher, 1975, et al.
(författare)
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Ethanol and phencyclidine interact with respect to nucleus accumbens dopamine release: differential effects of administration order and pretreatment protocol.
- 2010
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Ingår i: Frontiers in behavioral neuroscience. - : Frontiers Media SA. - 1662-5153. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- Executive dysfunction is a common symptom among alcohol-dependent individuals. Phencyclidine (PCP) injection induces dysfunction in the prefrontal cortex of animals but little is known about how PCP affects the response to ethanol. Using the in vivo microdialysis technique in male Wistar rats, we investigated how systemic injection of 5 mg/kg PCP would affect the dopamine release induced by local infusion of 300 mM ethanol into the nucleus accumbens. PCP given 60 min before ethanol entirely blocked ethanol-induced dopamine release. However, when ethanol was administered 60 min before PCP, both drugs induced dopamine release and PCP's effect was potentiated by ethanol (180% increase vs 150%). To test the role of prefrontal cortex dysfunction in ethanol reinforcement, animals were pretreated for 5 days with 2.58 mg/kg PCP according to previously used 'PFC hypofunction protocols'. This, however, did not change the relative response to PCP or ethanol compared to saline-treated controls. qPCR illustrated that this low PCP dose did not significantly change expression of glucose transporters Glut1 (SLC2A1) or Glut3 (SLC2A3), monocarboxylate transporter MCT2 (SLC16A7), glutamate transporters GLT-1 (SLC1A2) or GLAST (SLC1A3), the immediate early gene Arc (Arg3.1) or GABAergic neuron markers GAT-1 (SLC6A1) and parvalbumin. Therefore, we concluded that PCP at a dose of 2.58 mg/kg for 5 days did not induce hypofunction in Wistar rats. However, PCP and ethanol do have overlapping mechanisms of action and these drugs differentially affect mesolimbic dopaminergic transmission depending on the order of administration.
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