| 1. |
- Andersson, Niklas, 1970, et al.
(författare)
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Investigation of central versus peripheral effects of estradiol in ovariectomized mice
- 2005
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Ingår i: J Endocrinol. - : Bioscientifica. - 0022-0795 .- 1479-6805. ; 187:2, s. 303-9
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Tidskriftsartikel (refereegranskat)abstract
- It is generally believed that estrogens exert their bone sparing effects directly on the cells within the bone compartment. The aim of the present study was to investigate if central mechanisms might be involved in the bone sparing effect of estrogens. The dose-response of central (i.c.v) 17beta-estradiol (E2) administration was compared with that of peripheral (s.c.) administration in ovariectomized (ovx) mice. The dose-response curves for central and peripheral E2 administration did not differ for any of the studied estrogen-responsive tissues, indicating that these effects were mainly peripheral. In addition, ovx mice were treated with E2 and/or the peripheral estrogen receptor antagonist ICI 182,780. ICI 182,780 attenuated most of the estrogenic response regarding uterus weight, retroperitoneal fat weight, cortical BMC and trabecular bone mineral content (P<0.05). These findings support the notion that the primary target tissue that mediates the effect of E2 on bone is peripheral and not central.
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| 2. |
- 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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| 3. |
- deBejczy, Andrea, et al.
(författare)
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Varenicline for Treatment of Alcohol Dependence: A Randomized, Placebo-Controlled Trial
- 2015
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Ingår i: Alcoholism-Clinical and Experimental Research. - : Wiley. - 0145-6008 .- 1530-0277. ; 39:11, s. 2189-2199
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundAlcohol dependence is a devastating illness affecting a large population, and new pharmacological treatments with good efficacy are greatly needed. One potential candidate is varenicline, a smoking cessation agent with partial agonist action at (42) nicotinic acetylcholine receptors. MethodsA total of 160 subjects, 30 to 70years of age, fulfilling DSM-IV criteria for alcohol dependence without any serious physical or mental disorders, were recruited through advertisement at 3 university clinics in Sweden during March 2009 to January 2011. After a 2-week placebo run-in period, subjects received 2mg varenicline daily (titrated from 0.5mg during first week) or placebo for 12weeks in a double-blind manner. ResultsThe primary outcome was the proportion of heavy drinking days, measured by self-reported alcohol consumption. Primary and secondary outcomes were calculated as a mean over the 10-week steady-state active treatment period. In the primary outcome analysis, no effect of varenicline over placebo was found (p=0.73 for the intention to treat [ITT] and 0.92 for per protocol [PP]). Secondary outcome analysis found a significant reduction of specific alcohol marker phosphatidylethanol (PEth) in the blood in the varenicline group compared to placebo (p=0.02 ITT). Craving (p=0.048 PP) and Alcohol Use Disorders Identification Test (AUDIT) scores (p=0.015 ITT) were also reduced in the active treatment group. PEth more strongly correlated with self-reported alcohol consumption than carbohydrate-deficient ttransferrin and -glutamyl transferase, and correlation coefficients were higher in the varenicline group than in the placebo group for all markers. ConclusionsAlthough the results of the main outcome of this study did not support an effect of varenicline in alcohol-dependent individuals, the secondary analyses of PEth, craving and AUDIT score support an effect of varenicline on alcohol consumption. The disclosure of a treatment effect and the lack of a clear placebo effect when using PEth as outcome variable, together with a nonsymmetric bias associated with self-reported data, strongly argue for using the specific biomarker PEth in studies of treatments of alcohol dependence.
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| 4. |
- Ericson, Mia, 1970, et al.
(författare)
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Ethanol elevates accumbal dopamine levels via indirect activation of ventral tegmental nicotinic acetylcholine receptors.
- 2003
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Ingår i: European journal of pharmacology. - 0014-2999. ; 467:1-3, s. 85-93
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Tidskriftsartikel (refereegranskat)abstract
- It was previously demonstrated that the central nicotinic acetylcholine receptor antagonist mecamylamine perfused in the ventral tegmental area (VTA) counteracts the elevation of extracellular dopamine levels in the nucleus accumbens after systemic ethanol, as measured by in vivo microdialysis. In the present study we investigated the effect of different concentrations of ethanol perfused locally in the VTA or in the nucleus accumbens on extracellular accumbal dopamine levels. Ethanol (10-1000 mM) perfused in the VTA did not influence dopamine output in the nucleus accumbens. However, ethanol (300 mM) perfused in the nucleus accumbens increased accumbal dopamine levels to approximately the same extent (30%) as observed after systemic ethanol, whereas ethanol (1000 mM) decreased the dopamine output by approximately 50%. Next, the hypothesis that endogenous acetylcholine is required for the increased accumbal dopamine levels after ethanol was challenged. It was shown that in animals pre-treated with vesamicol, a potent inhibitor of vesicular acetylcholine storage, ethanol (300 mM) in the nucleus accumbens failed to elevate extracellular accumbal dopamine levels. Similarly, in animals perfused with mecamylamine in the VTA, but not in the nucleus accumbens, ethanol in the nucleus accumbens (300 mM) failed to increase accumbal dopamine levels. However, whereas dihydro-beta-erythroidine (antagonist for the nicotinic receptor subtype alpha4beta2) perfused in the VTA prevented the increase in accumbal dopamine after systemic nicotine, the antagonist was unable to prevent the dopamine elevating effects of ethanol. Finally, to investigate whether mecamylamine exerts its antagonizing effect of ethanol induced accumbal dopamine levels through an interaction with the NMDA receptor MK-801, the effects of the prototypic NMDA receptor antagonist were examined and compared to those of mecamylamine. After perfusion in the VTA, MK-801 enhanced accumbal dopamine levels by itself but did not antagonize the enhancing effect of ethanol. The present set of experiments indicate that the mesolimbic dopamine activating effects of ethanol may be due to an indirect rather than direct activation of ventral tegmental nicotinic acetylcholine receptors of a subtype composition different from the alpha4beta2. Furthermore, it is argued that the primary site of action of ethanol in its accumbal dopamine elevating effect may be located to the nucleus accumbens or nearby regions.
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| 5. |
- 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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| 6. |
- Ericson, Mia, 1970, et al.
(författare)
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The smoking cessation medication varenicline attenuates alcohol and nicotine interactions in the rat mesolimbic dopamine system.
- 2009
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Ingår i: The Journal of pharmacology and experimental therapeutics. - : American Society for Pharmacology & Experimental Therapeutics (ASPET). - 1521-0103 .- 0022-3565. ; 329:1, s. 225-30
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Tidskriftsartikel (refereegranskat)abstract
- Varenicline was recently approved as an aid for smoking cessation. Patients treated with varenicline have reported a concomitant reduction in their alcohol consumption. This compound has also been demonstrated to reduce alcohol seeking and consumption in alcohol high-preferring rats. Based on the extensive coabuse of nicotine and alcohol, the aim of the present study was to explore whether interactions among varenicline, nicotine, and ethanol in the brain reward system could indicate the use of varenicline also for alcohol dependence. Using the in vivo microdialysis method, we investigated the effects of systemic injections of varenicline on the extracellular accumbal dopamine levels in response to a systemic challenge of ethanol, nicotine, or the combination of nicotine and ethanol in the experimental rat. Acute systemic coadministration of varenicline and ethanol counteracted each others' respective enhancing effect on dopamine levels in the nucleus accumbens. However, after 5 days of varenicline pretreatment, acute combined varenicline and ethanol administration raised dopamine levels to the same extent as either drug alone. Furthermore, after varenicline pretreatment an acute injection of varenicline antagonized the dopamine stimulatory effect of acute nicotine as well as that of systemic coadministration of ethanol and nicotine. In contrast, a pronounced additive dopamine increase was observed when nicotine and ethanol were coadministered in vehicle-pretreated rats. The antismoking agent varenicline exhibits properties with respect to its interaction with ethanol and nicotine in the brain reward system that may be beneficial for treating patients with alcohol dependence with (and possibly also without) concomitant nicotine dependence.
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| 7. |
- Löf, Elin, 1974, et al.
(författare)
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Characterization of ethanol-induced dopamine elevation in the rat nucleus accumbens.
- 2007
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Ingår i: European journal of pharmacology. - : Elsevier BV. - 0014-2999. ; 555:2-3, s. 148-55
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Tidskriftsartikel (refereegranskat)abstract
- Ethanol-induced accumbal dopamine elevations have been linked to ethanol consumption. It is unclear, however, where along the mesolimbic dopamine system this effect is initiated and why the ethanol-induced dopamine elevations are transient, returning to pre-drug baseline before brain and blood ethanol levels decline. Using in vivo microdialysis, Experiment 1 investigated the effect of local ethanol application in the nucleus accumbens, the ventral tegmental area and the nucleus accumbens+the ventral tegmental area, on accumbal dopamine. Experiment 2 examined whether the rapid withdrawal of dopamine response to ethanol involves activation of GABA(A)-receptors, by analyzing the effect of accumbal co-perfusion of picrotoxin and ethanol. In Experiment 1, ethanol perfusion into the ventral tegmental area alone did not affect accumbal dopamine. Ethanol co-perfusion of one of the tested doses into the ventral tegmental+the nucleus accumbens produced higher dopamine levels than ethanol perfusion into the nucleus accumbens alone during 120-160 min following perfusion onset. In Experiment 2, accumbal ethanol perfusion caused a transient increase in nucleus accumbens dopamine. Co-perfusion of ethanol and picrotoxin produced a sustained dopamine elevation. These data support the hypothesis that the primary effect of ethanol on accumbal dopamine is in the nucleus accumbens, but that a secondary effect of nucleus accumbens ethanol perfusion, such as release of acetylcholine in the ventral tegmental area, enables ethanol to act as a nicotinic acetylcholine receptor co-agonist in this area. Moreover, recruitment of GABA(A)-receptor activity appears responsible for the second, declining phase with respect to dopamine levels following ethanol administration.
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| 8. |
- Löf, Elin, 1974
(författare)
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Conditional and non-conditional reward-related responses to alcohol. Nicotinic mechanisms
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The mesolimbic dopamine system is believed to mediate the positive reinforcing and rewarding effects of addictive drugs by increasing dopamine levels in its terminal area, the nucleus accumbens (nAc). Nicotinic acetylcholine receptors (nAChRs) within this system appear important for the pharmacological actions of both alcohol and nicotine, which may explain the frequent co-abuse of these two drugs. Despite available pharmacological and psychological therapies, most addicts relapse to smoking and alcoholism, often due to the impact of drug-associated stimuli (cues) on craving and compulsive drug-seeking.The first part of this thesis investigated the role of nAChRs in the effects of alcohol-associated as well as sucrose-associated cues on mesolimbic dopamine activity and/or behaviors related to drug-seeking (responding with conditioned reinforcement) in the rat. In the second part, in vivo microdialysis was utilized to characterize the ethanol-induced dopamine elevation in the rat nAc and the consequences thereon by subchronic pre-treatment with nicotinic drugs. The data demonstrate that antagonism of ventral tegmental area (VTA) nAChRs abolishes the ethanol cue-induced dopamine elevations in the nAc and the conditioned reinforcing properties of ethanol cues. Moreover, nAChRs appear to mediate responding with conditioned reinforcement to sucrose. The results also indicate that the most important site of interference for ethanol-induced dopamine elevations is in the nAc, but that once the ethanol action is present in this brain region, ethanol may act also in the VTA to produce add-on effects. Furthermore, the decline in dopamine that is observed following the initial elevation after ethanol administration may be due to recruitment of dopamine inhibitory GABAA receptors in the nAc, as demonstrated by the ability of a GABAA antagonist to attenuate this effect. Pretreatment with a nicotinic drug abolished the dopamine declining phase. We hypothesize a novel mechanism by which alcohol-associated cues stimulate mesolimbic dopamine activity and promote drug-seeking behavior by activation of VTA alpha3beta2* and/or alpha6* nAChRs. Interestingly, the same nAChR subtypes were previously demonstrated to mediate the pharmacological effects of ethanol. This coincidence may play a critical role in the well known phenomenon of ¡§loss of control¡¨ of drinking, a hallmark of alcoholism. Pharmacological manipulations of specific nAChR subtypes may thus be possible treatment strategies to prevent cue-induced relapse to alcoholism. The demonstration that nAChRs mediate responding with conditioned reinforcement also to sucrose, may explain the enhanced sugar intake associated with smoking cessation and alcohol abstinence. The second part of the thesis suggests that recruitment of GABAA-receptor activity is responsible for the second, declining phase with respect to nAc dopamine levels following ethanol administration and that pre-treatment with nicotinic drugs produces tolerance to this effect in the nAc and other brain regions. This phenomenon could be part of the explanation to why the sedative effects of ethanol are reduced in some nicotine users. These results contribute with novel explanations for the common co-abuse of nicotine and alcohol and suggest specific nAChRs as potential targets for novel pharmacological interventions aimed at reducing cue-induced craving and relapse in alcoholism.
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| 9. |
- 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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| 10. |
- Löf, Elin, 1974, et al.
(författare)
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Nicotinic acetylcholine receptors are required for the conditioned reinforcing properties of sucrose-associated cues.
- 2010
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Ingår i: Psychopharmacology. - : Springer Science and Business Media LLC. - 1432-2072 .- 0033-3158. ; 212:3, s. 321-328
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Tidskriftsartikel (refereegranskat)abstract
- RATIONALE: We recently demonstrated that blocking specific nicotinic acetylcholine receptors (nAChRs) abolishes the conditioned reinforcing properties of ethanol-associated cues in rat, suggesting nAChRs as promising pharmacological targets for prevention of cue-induced relapse. OBJECTIVES: The present study investigated the involvement of nAChR subtypes in the conditioned reinforcing properties of stimuli associated with a natural reward (sucrose). METHODS: Water-deprived rats were trained to associate a tone + light stimulus (CS) with the presentation of a 0.1 M sucrose solution for 10 consecutive days. On the subsequent day, the animals were tested on the stringent acquisition of a new instrumental response with conditioned reinforcement, following a systemic injection of the nonselective nAChR antagonist mecamylamine (MEC) or the selective alpha7 and alpha6/alpha3beta2beta3* nAChR antagonist methyllycaconitine (MLA). At testing, the rats were presented with two novel levers. Responding on the lever assigned as active (CR lever) resulted in a presentation of the CS alone, while pressing the inactive lever (NCR lever) had no programmed consequences. RESULTS: Control animals pressed the CR lever significantly more than the NCR lever, demonstrating that the CR had acquired conditioned reinforcing properties. Systemic MEC as well as MLA reduced the CR lever responses to the same level as for the NCR lever. CONCLUSIONS: These results demonstrate a role for the alpha7 and/or alpha6/alpha3beta2beta3* nAChRs in conditioned reinforcement to a natural reward and suggest neuronal nAChRs as common mediators of the impact of cues on incentive processes.
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