1. |
- Adermark, Louise, 1974, et al.
(författare)
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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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2. |
- 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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3. |
- Adermark, Louise, 1974, et al.
(författare)
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Subregion-Specific Modulation of Excitatory Input and Dopaminergic Output in the Striatum by Tonically Activated Glycine and GABA(A) Receptors.
- 2011
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Ingår i: Frontiers in systems neuroscience. - : Frontiers Media SA. - 1662-5137. ; 5
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Tidskriftsartikel (refereegranskat)abstract
- The flow of cortical information through the basal ganglia is a complex spatiotemporal pattern of increased and decreased firing. The striatum is the biggest input nucleus to the basal ganglia and the aim of this study was to assess the role of inhibitory GABA(A) and glycine receptors in regulating synaptic activity in the dorsolateral striatum (DLS) and ventral striatum (nucleus accumbens, nAc). Local field potential recordings from coronal brain slices of juvenile and adult Wistar rats showed that GABA(A) receptors and strychnine-sensitive glycine receptors are tonically activated and inhibit excitatory input to the DLS and to the nAc. Strychnine-induced disinhibition of glutamatergic transmission was insensitive to the muscarinic receptor inhibitor scopolamine (10μM), inhibited by the nicotinic acetylcholine receptor antagonist mecamylamine (10μM) and blocked by GABA(A) receptor inhibitors, suggesting that tonically activated glycine receptors depress excitatory input to the striatum through modulation of cholinergic and GABAergic neurotransmission. As an end-product example of striatal GABAergic output in vivo we measured dopamine release in the DLS and nAc by microdialysis in the awake and freely moving rat. Reversed dialysis of bicuculline (50μM in perfusate) only increased extrasynaptic dopamine levels in the nAc, while strychnine administered locally (200μM in perfusate) decreased dopamine output by 60% in both the DLS and nAc. Our data suggest that GABA(A) and glycine receptors are tonically activated and modulate striatal transmission in a partially subregion-specific manner.
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4. |
- Clarke, Rhona B. C., et al.
(författare)
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Acute ethanol treatment prevents endocannabinoid-mediated long-lasting disinhibition of striatal output.
- 2009
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Ingår i: Neuropharmacology. - : Elsevier BV. - 1873-7064 .- 0028-3908.
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Tidskriftsartikel (refereegranskat)abstract
- Recent research has suggested that the neuronal circuit 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. Especially, the endocannabinoid (eCB) system appears to be involved in the neuronal circuitry regulating ethanol (EtOH) preference in rodent. The aim of this study was to evaluate if acute EtOH exposure could modulate eCB-mediated plasticity in the dorsolateral striatum. Our data show that EtOH (20 - 50mM) prevents eCB-mediated long-lasting disinhibition (DLL) of striatal output induced by a single stimulation train delivered at 5Hz for 60 s, and reduces long-term depression (LTD) induced by low frequency stimulation at inhibitory synapses. Acute EtOH-treatment also prevents DLL induced by the L-type calcium channel activator 2,5-dimethyl-4-[2-(phenylmethyl)benzoyl]-1H-pyrrole-3-carboxylic acid methylester (FPL64176; 500nM), or by the cannabinoid 1 receptor (CB(1)R) agonist WIN55,212-2 (300nM), indicating that EtOH affects eCB signaling at a stage that is downstream from eCB production and release. Importantly, high-frequency stimulation, or a higher concentration of WIN55,212-2 (1muM), induces EtOH-insensitive depression of striatal output, suggesting that EtOH affects CB(1)R-mediated signaling in a synapse-specific manner. Maintaining the balance between excitation and inhibition is vital for neuronal networks, and EtOH-mediated modulation of eCB-signaling might thus affect the stability and the fine-tuning of neuronal circuits in the striatum. Our data suggest that changes in eCB signaling could be involved in the physiological response to acute alcohol intoxication.
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5. |
- Clarke, Rhona B. C., et al.
(författare)
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Dopaminergic Regulation of Striatal Interneurons in Reward and Addiction: Focus on Alcohol
- 2015
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Ingår i: Neural Plasticity. - : Hindawi Limited. - 2090-5904 .- 1687-5443.
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Forskningsöversikt (refereegranskat)abstract
- Corticobasal ganglia networks coursing through the striatum are key structures for reward-guided behaviors. The ventral striatum (nucleus accumbens (nAc)) and its reciprocal connection with the ventral tegmental area (VTA) represent a primary component of the reward system, but reward-guided learning also involves the dorsal striatum and dopaminergic inputs from the substantia nigra. The majority of neurons in the striatum(>90%) are GABAergic medium spiny neurons (MSNs), but both the input to and the output from these neurons are dynamically controlled by striatal interneurons. Dopamine is a key neurotransmitter in reward and reward-guided learning, and the physiological activity of GABAergic and cholinergic interneurons is regulated by dopaminergic transmission in a complex manner. Here we review the role of striatal interneurons in modulating striatal output during drug reward, with special emphasis on alcohol.
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6. |
- Clarke, Rhona B. C.
(författare)
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Ethanol-induced modulation of dopamine transmission and synaptic activity in striatal subregions - focus on inhibitory receptors
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Alcoholism is a chronic brain disease, affecting neurocircuitries involved in reward and learning. The rewarding effects of alcohol (ethanol) are believed to result from increased dopamine levels in the nucleus accumbens (nAc) via the mesolimbic system. The exact mechanisms through which this occurs are debated, but evidence from the current research group suggests that ethanol activates the mesolimbic system via a reciprocal connection between the nAc and the ventral tegmental area (VTA), involving the activation of glycine receptors (GlyRs) in the nAc. Research from other groups suggests that ethanol may activate the mesolimbic system via its primary metabolite, acetaldehyde, through direct actions in the VTA. The effects of acetaldehyde in the nAc-VTA-nAc neuronal circuitry however, have not been investigated. Dopamine signaling is also important in the dorsolateral striatum (DLS), an area involved in habit formation. The effects of ethanol on dopamine levels in this region are poorly understood, as are the roles of inhibitory GlyRs and γ-amino-butyric acid type A (GABAA) receptors, in mediating these effects. Aims: To explore the effects of ethanol (or acetaldehyde) on dopamine transmission and synaptic activity in the nAc and DLS. Special emphasis is placed on the involvement of GlyRs and GABAA receptors. Methods: Dopamine transmission was studied using in vivo microdialysis in awake, adult Wistar rats. This method was also used for local administration of relevant drugs/substances. Synaptic activity was measured by in vitro field-potential recordings in coronal brain slices from juvenile and adult Wistar rats. All animals were alcohol-naïve. Results: Local acetaldehyde administration did not increase nAc dopamine levels, nor did sequestering of ethanol-derived acetaldehyde affect the dopamine-elevating properties of ethanol. Results also showed that the dopamine-enhancing effects of ethanol were mediated by GlyRs in the nAc, but neither by GlyRs nor GABAA receptors in the DLS. Ethanol produced both enhancing and depressing effects on synaptic activity, which were dependent on the region studied, the age of the animal, as well as the concentration applied. The relative involvement of inhibitory receptors also differed in an age and region-specific manner. Conclusions: The results in this thesis indicate that acetaldehyde is not involved in the dopamine-enhancing effects of ethanol that are mediated via the reciprocal nAc-VTA-nAc neuronal circuitry. Furthermore, it is shown that changes in dopamine and synaptic activity induced by acute ethanol administration are modulated by inhibitory receptors in a region and age-specific manner. By pinpointing similarities and differences in response to alcohol between reward-related and habit-related parts of the brain this research may contribute to furthering the knowledge of how alcohol addiction develops and progresses.
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7. |
- 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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8. |
- 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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9. |
- 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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10. |
- 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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