1. |
|
|
2. |
|
|
3. |
- Chau, Pei Pei, 1981, et al.
(författare)
-
Glycine Receptors in the Nucleus Accumbens Involved in the Ethanol Intake-Reducing Effect of Acamprosate.
- 2009
-
Ingår i: Alcoholism, clinical and experimental research. - : Wiley. - 1530-0277 .- 0145-6008.
-
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.
|
|
4. |
- Chau, Pei Pei, 1981, et al.
(författare)
-
Glycine Receptors Involved in Acamprosate's Modulation of Accumbal Dopamine Levels: An In Vivo Microdialysis Study.
- 2009
-
Ingår i: Alcoholism, clinical and experimental research. - : Wiley. - 1530-0277 .- 0145-6008.
-
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.
|
|
5. |
|
|
6. |
|
|
7. |
|
|
8. |
- Ericson, Mia, 1970, et al.
(författare)
-
Acute ethanol exposure elevates muscarinic tone in the septohippocampal system.
- 2009
-
Ingår i: Journal of neurophysiology. - : American Physiological Society. - 1522-1598 .- 0022-3077. ; 103:1, s. 290-296
-
Tidskriftsartikel (refereegranskat)abstract
- The septohippocampal system has been implicated in the cognitive deficits associated with ethanol consumption, but the cellular basis of ethanol action awaits full elucidation. In the MS/DB, a muscarinic tone, reflective of firing activity of resident cholinergic neurons, regulates that of their non-cholinergic, putatively GABAergic, counterparts. Here we tested the hypothesis that ethanol alters this muscarinic tone. The spontaneous firing activity of cholinergic and non-cholinergic MS/DB neurons were monitored in acute MS/DB slices from C57Bl/6 mice. Exposing the entire slice to ethanol increased firing in both cholinergic and non-cholinergic neurons. However, applying ethanol focally to individual MS/DB neurons increased firing only in cholinergic neurons. The differential outcome suggested different mechanisms of ethanol action on cholinergic and non-cholinergic neurons. Indeed, with bath-perfused ethanol, the muscarinic antagonist methyl scopolamine prevented the increase in firing in non-cholinergic, but not cholinergic, MS/DB neurons. Thus, the effect on non-cholinergic neuronal firing was secondary to ethanol's direct action of acutely increasing muscarinic tone. We propose that the acute ethanol-induced elevation of muscarinic tone in the MS/DB contributes to the altered net flow of neuronal activity in the septohippocampal system that underlies compromised cognitive function.
|
|
9. |
- Ericson, Mia, 1970, et al.
(författare)
-
Nicotinic acetylcholine receptors in the anterior, but not posterior, ventral tegmental area mediate ethanol-induced elevation of accumbal dopamine levels.
- 2008
-
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
-
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.
|
|
10. |
- Ericson, Mia, 1970, et al.
(författare)
-
Taurine elevates dopamine levels in the rat nucleus accumbens; antagonism by strychnine.
- 2006
-
Ingår i: The European journal of neuroscience. - : Wiley. - 0953-816X .- 1460-9568. ; 23:12, s. 3225-9
-
Tidskriftsartikel (refereegranskat)abstract
- The mesolimbic dopamine (DA) system, projecting from the ventral tegmental area (VTA) to the nucleus accumbens (nAcc), is involved in reward-related behaviours and addictive processes, such as alcoholism and drug addiction. It was recently suggested that strychnine-sensitive glycine receptors (GlyR) in the nAcc regulate both basal and ethanol-induced mesolimbic DA activity via a neuronal loop involving endogenous activation of nicotinic acetylcholine receptors (nAChR) in the VTA. However, as the nAcc appears to contain few glycine-immunoreactive cell bodies or fibres, the question as to what may be the endogenous ligand for GlyRs in this brain region remains open. Here we have investigated whether the amino acid taurine could serve this purpose using in vivo microdialysis in awake, freely moving male Wistar rats. Local perfusion of taurine (1, 10 or 100 mm in the perfusate) increased DA levels in the nAcc. The taurine (10 mm)-induced DA increase was, similarly to that previously observed after ethanol, completely blocked by (i) perfusion of the competitive GlyR antagonist strychnine in the nAcc, (ii) perfusion of the nAChR antagonist mecamylamine (100 microm) in the VTA, and (iii) systemic administration of the acetylcholine-depleting drug vesamicol (0.4 mg/kg, i.p). The present results suggest that taurine may be an endogenous ligand for GlyRs in the nAcc and that the taurine-induced elevation of DA levels in this area, similarly to that observed after local ethanol, is mediated via a neuronal loop involving endogenous activation of nAChRs in the VTA.
|
|