| 1. |
- Birzniece, Vita
(författare)
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Neuroactive steroids and rat CNS
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Several studies suggest profound effects on mood and cognition by neuroactive steroids. Estrogen alone or in combination with antidepressant drugs affecting the serotonin system has been used to treat mood disorders. On the other hand, progesterone is related to negative effects on mood and memory. A major part of the progesterone effects on the brain can be mediated by its metabolite allopregnanolone, which is also de novo synthesized in the brain, and affects the GABAA receptors. It would be of great importance to find a substance that antagonize allopregnanolone adverse effects. To investigate how long term supplementation of estradiol and progesterone, resembling postmenopausal hormone replacement therapy, affects serotonin receptors in different brain areas important for mood and memory functions, we used ovariectomized female rats. After 2 weeks of supplementation with 17β-estradiol alone or in combination with progesterone, or placebo pellets, estradiol alone decreases but estradiol supplemented together with progesterone increases 5HT1A mRNA expression in the hippocampus. Estradiol decreases the 5HT2C receptor gene expression, while estradiol in combination with progesterone increases the 5HT2A mRNA expression in the ventral hippocampus. Thus, estradiol alone has opposite effects compared to the estradiol/progesterone combination. To detect if acute tolerance develops to allopregnanolone, an EEG method was used where male rats by continuous allopregnanolone infusion were kept on anesthesia level of the silent second (SS). After different time intervals (first SS, 30 min or 90 min of anesthesia) several GABAA receptor subunit mRNAs were measured for detecting if changed expression of any GABAA receptor subunits is involved in development of acute tolerance. There is development of acute tolerance to allopregnanolone and brain regions of importance are hippocampus, thalamus and hypothalamus. The GABAA receptor alpha4 subunit in thalamus and alpha2 subunit in the dorsal hippocampus are related to development of acute tolerance. For assessing allopregnanolone behavioral effects, we studied how this neurosteroid affects spatial learning in the Morris water maze task Allopregnanolone inhibits spatial learning short after the injection and shows a specific behavioral pattern with swimming close to the pool wall. The steroid UC1011 can inhibit the increase in chloride ion uptake induced by allopregnanolone. UC1011 decreases allopregnanoloneinduced impairment of spatial learning in the water maze, as well as the specific behavioral swim pattern. In conclusion, the present work demonstrates that neuroactive steroids affect the 5HT and GABA systems in a brain region specific way. GABAA receptor subunit changes in hippocampus and thalamus are related to acute allopregnanolone tolerance. Allopregnanolone induces cognitive deficits, like spatial learning impairment and UC1011 can inhibit allopregnanolone-induced effects in vitro and in vivo. Key words: Estradiol, progesterone, HRT, allopregnanolone, UC1011, serotonin receptor, GABAA receptor, mRNA, Morris water maze, silent second, tolerance.
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| 2. |
- Bohlooly-Yeganeh, Mohammad, 1966, et al.
(författare)
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Enhanced spontaneous locomotor activity in bovine GH transgenic mice involves peripheral mechanisms
- 2001
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Ingår i: Endocrinology. ; 142:10, s. 4560-4567
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Tidskriftsartikel (refereegranskat)abstract
- Clinical and experimental studies indicate a role for GH in mechanisms related to anhedonia/hedonia, psychic energy, and reward. Recently we showed that transgenic mice with general overexpression of bovine GH display increased spontaneous locomotor activity. In the present study, we investigated whether this behavioral change is owing to a direct action of GH in the central nervous system or to peripheral GH actions. A transgenic construct, containing the glial fibrillary acidic protein promoter directing specific expression of bovine GH to the central nervous system, was designed. The central nervous system-specific expression of bovine GH in the glial fibrillary acidic protein-bovine GH transgenic mice was confirmed, but no effect on spontaneous locomotor activity was observed. Serum bovine GH levels were increased in glial fibrillary acidic protein-bovine GH transgenic mice but clearly lower than in transgenic mice with general overexpression of bovine GH. In contrast to the transgenic mice with general overexpression of bovine GH, glial fibrillary acidic protein-bovine GH mice did not display any difference in serum IGF-I levels. The levels of free T(3) and the conversion of the free T(4) to free T(3) were only increased in transgenic mice with general overexpression of bovine GH, but serum corticosterone levels were similarly increased in both transgenic models. These results suggest that free T(3) and/or IGF-I, affecting dopamine and serotonin systems in the central nervous system, may mediate the enhanced locomotor activity observed in transgenic mice with general overexpression of bovine GH.
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| 3. |
- 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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| 4. |
- Larsson, Anna, 1973, et al.
(författare)
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Is an alpha-conotoxin MII-sensitive mechanism involved in the neurochemical, stimulatory, and rewarding effects of ethanol?
- 2004
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Ingår i: Alcohol. ; 34:2-3, s. 239-250
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Tidskriftsartikel (refereegranskat)abstract
- Ethanol and nicotine are the most commonly abused drugs among human beings, and a large body of evidence, from both epidemiologic and preclinical studies, indicates that there is a positive correlation between intake of both drugs. Findings of studies from our research group have demonstrated that nicotinic acetylcholine receptors, especially those located in the ventral tegmental area, are important for the stimulatory, rewarding, and dopamine-enhancing effects of ethanol. Furthermore, results of recent work indicate that the alpha4beta2* and the alpha7* receptor subunits of the nicotinic acetylcholine receptors do not seem to be involved in the neurochemical and behavioral effects of ethanol in rodents. The aim of the current study was to investigate further the role of different nicotinic acetylcholine receptor subunits in the stimulatory, dopamine-enhancing, and rewarding effects of ethanol in rodents by using the peptide alpha-conotoxin MII (5 nmol; an antagonist of the alpha3beta2*, beta3*, and alpha6* subunits of the nicotinic acetylcholine receptor) administered locally into the ventral tegmental area. A significant reduction of ethanol-induced accumbal dopamine overflow, measured by means of in vivo microdialysis, and of locomotor stimulation was observed in mice. Furthermore, alpha-conotoxin MII was demonstrated to reduce voluntary ethanol intake significantly in both rats and mice. These results indicate that alpha-conotoxin MU-sensitive receptors may be important in mediating the stimulatory, dopamine-enhancing, and rewarding effects of ethanol, and that alpha-conotoxin MII-sensitive receptors may constitute targets for development of new adjuvant for treatment of ethanol dependence.
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| 5. |
- Larsson, Anna, 1973, et al.
(författare)
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Role of different nicotinic acetylcholine receptors in mediating behavioral and neurochemical effects of ethanol in mice.
- 2002
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Ingår i: Alcohol. ; 28:3, s. 157-167
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Tidskriftsartikel (refereegranskat)abstract
- Ethanol and nicotine are the most abused drugs, and it is well known that co-abuse of ethanol and nicotine is frequent in human beings. We have previously obtained results indicating that the ethanol-induced stimulation of both the mesolimbic dopamine system and locomotor activity may involve activation of central nicotinic acetylcholine receptors (nAChRs), especially those located in the ventral tegmental area. Different subpopulations of nAChRs have been identified, and, in the present series of experiments, we have studied the effects of various nAChR antagonists on the stimulation of dopamine overflow in the nucleus accumbens and on locomotor activity induced by ethanol in male mice. Ethanol (2.0 g/kg, i.p.) enhanced dopamine overflow in the nucleus accumbens by approximately 40%, measured by means of in vivo microdialysis in awake, freely moving mice. Mecamylamine (negative allosteric modulator of nAChR; 2.0 mg/kg, i.p.) blocked the ethanol-induced stimulation of both locomotor activity and accumbal dopamine overflow. Methyllycaconitine citrate (alpha(7) antagonist; 2.0 mg/kg, i.p.) and dihydro-beta-erythroidine (competitive and selective alpha(4)beta(2) antagonist; 0.5 mg/kg, s.c.), in doses that had no marked effects per se, did not significantly reduce the behavioral and neurochemical stimulation caused by ethanol. The present results support the suggestion that the stimulatory effects of ethanol on locomotor activity and dopamine release do not involve the alpha(4)beta(2) or alpha(7) subunit compositions of the nAChR and that the effects of mecamylamine are mediated through a site not directly associated with the alpha(4)beta(2) or alpha(7) nAChR subunits.
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| 6. |
- Lê, A D, et al.
(författare)
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Neurobiological processes in alcohol addiction.
- 2001
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Ingår i: Alcoholism, clinical and experimental research. - 0145-6008. ; 25:5 Suppl ISBRA
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Forskningsöversikt (refereegranskat)abstract
- This article represents the proceedings of a symposium at the ISBRA Meeting in Yokohama, Japan. The chairs were A. D. Lê and K. Kiianmaa. The presentations were (1) Alcohol reward and aversion, by C. L. Cunningham; (2) The role of sensitization of neuronal mechanisms in ethanol self-administration, by J. A. Engel, M. Ericson, and B. Söderpalm; (3) Alcohol self-administration in dependent animals: Neurobiological mechanisms, by G. F. Koob, A. J. Roberts, and F. Weiss; (4) Stress and relapse to alcohol, by A. D. Lê; (5) Alcohol-preferring AA and alcohol-avoiding ANA rats differ in locomotor activation induced by repeated morphine injections, by P. Hyytiä, S. Janhunen, J. Mikkola, P. Bäckström, and K. Kiianmaa; and (6) Initial sensitivity and acute functional tolerance to the hypnotic effects of ethanol in mice genetically selected for mild and severe ethanol withdrawal convulsions, by I. Ponomarev and J. C. Crabbe.
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| 7. |
- Narahashi, T, et al.
(författare)
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Mechanisms of alcohol-nicotine interactions: alcoholics versus smokers.
- 2001
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Ingår i: Alcoholism, clinical and experimental research. - 0145-6008. ; 25:5 Suppl ISBRA
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Forskningsöversikt (refereegranskat)abstract
- This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The chairs were Toshio Narahashi and Bo Söderpalm. The presentations were (1) Nicotinic mechanisms and ethanol reinforcement: Behavioral and neurochemical studies, by Bo Söderpalm, M. Ericson, P. Olausson, and J. A. Engel; (2) Chronic nicotine and ethanol: Differential regulation in gene expression of nicotinic acetylcholine receptor subunits, by X. Zhang and A. Nordberg; (3) Nicotine-ethanol interactions at neuronal nicotinic acetylcholine receptors, by Toshio Narahashi, William Marszalec, and Gary L. Aistrup; (4) Relapse prevention in alcoholics by cigarette smoking? Treatment outcome in an observational study with acamprosate, by L.G. Schmidt, U. Kalouti, M. Smolka, and M. Soyka; and (5) Effect of nicotine on voluntary ethanol intake and development of alcohol dependence in male rats, by L. Hedlund and G. Wahlström.
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| 8. |
- Olausson, Peter, 1971, et al.
(författare)
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Nicotine-induced behavioral disinhibition and ethanol preference correlate after repeated nicotine treatment.
- 2001
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Ingår i: European journal of pharmacology. - 0014-2999. ; 417:1-2, s. 117-23
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Tidskriftsartikel (refereegranskat)abstract
- This study investigated the effects of repeated daily nicotine (0.35 mg/kg; 15 days) treatment on behavioral inhibition and locomotor activity in the elevated plus-maze and on voluntary ethanol consumption. When challenged with nicotine before the test, rats pretreated with repeated nicotine spent more time on and made more entries onto the open arms of an elevated plus-maze than did vehicle-pretreated animals. The ethanol preference and intake, measured during 3 h after a nicotine injection, was also higher in the nicotine-pretreated animals. In ethanol consumption experiments, there was a positive correlation between the % time and % entries made onto open arms vs. the ethanol preference and intake. However, no correlation between the total number of entries made in the elevated plus-maze and the measures of ethanol consumption was observed. These findings suggest that the ability of repeated nicotine administration to increase ethanol consumption is related to development of a nicotine-induced reduction of inhibitory control rather than development of locomotor sensitization.
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| 9. |
- Svensson, Anders I, 1969, et al.
(författare)
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Disinhibitory behavior and GABA(A) receptor function in serotonin-depleted adult male rats are reduced by gonadectomy.
- 2000
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Ingår i: Pharmacology, biochemistry, and behavior. - 0091-3057. ; 67:3, s. 613-20
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Tidskriftsartikel (refereegranskat)abstract
- Impulsive and aggressive behaviors in, e.g., personality or substance abuse disorders in man and corresponding behaviors in rats may involve serotonin (5-HT), gamma-amino-butyric acid(A)/benzodiazepine receptor complexes (GABA(A)/BDZ-RC) and steroid hormones, e.g., testosterone. Here, we studied the effect of gonadectomy on disinhibitory behavior in individually housed 5-HT-depleted rats and on GABA(A)/BDZ-RC function in vitro, in corticohippocampal synaptoneurosomes prepared from the brain of these animals. 5-HT depletion by intracerebroventricular 5,7-dihydroxytryptamine (5,7-DHT)-induced disinhibitory behavior in a shock-induced behavioral inhibition model (punished conflict model) 14 days after operation. Gonadectomy in connection with the 5-HT depletion reduced the disinhibitory behavior and testosterone substitution prevented this effect. Shock threshold and drinking motivation were not affected by gonadectomy and/or 5-HT depletion. The relative epididymides weight was increased in 5-HT-depleted as compared to sham-operated rats. However, the serum concentrations of testosterone and the relative testes weights were not different in 5-HT-depleted rats as compared to controls. GABA-induced (30, 100, 300 microM) 36Cl(-)-uptake into synaptoneurosomes was lower in 5,7-DHT+gonadectomized rats compared to the control group. This effect was reversed by substitution with testosterone. These results demonstrate that gonadectomy reduces disinhibitory behavior in 5-HT-depleted rats and that GABA(A)/BDZ-RC may be involved in this effect.
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| 10. |
- Svensson, Anders I, 1969, et al.
(författare)
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Gonadectomy enhances shock-induced behavioral inhibition in adult male rats: implications for impulsive behavior.
- 2000
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Ingår i: Pharmacology, biochemistry, and behavior. - 0091-3057. ; 65:4, s. 731-6
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Tidskriftsartikel (refereegranskat)abstract
- The effects of gonadectomy on shock-induced behavioral inhibition in a modified Vogel's drinking conflict model and on diazepam-induced disinhibition and sedation were investigated in adult male rats. Gonadectomy enhanced shock-induced behavioral inhibition when determined 9, 21, 45, and 65 days, but not 3 days, after operation, without affecting shock sensitivity or drinking motivation. Testosterone-substitution for 21 days following gonadectomy prevented this enhanced inhibition without significantly affecting the behavior in sham-operated rats. Diazepam produced behavioral disinhibition both in sham-operated and gonadectomized rats. However, after the highest dose (16 mg/kg, IP) the disinhibited behavior decreased only in sham-operated animals, most likely due to sedation. Moreover, whereas there was no difference in basal rotarod-performance between controls and gonadectomized rats, the latter animals were less sensitive to diazepam-induced disruption of rotarod walking ability. Sham-operated or gonadectomized animals did not differ with respect to serum diazepam levels at the postinjection times used in the behavioral tests. Taken together, gonadectomized rats were less sensitive towards diazepam-induced sedation, possibly due to a subsensitivity at or beyond GABA(A)/benzodiazepine receptors. Furthermore, the finding that lack of testosterone enhanced shock-induced inhibition could be interpreted to reflect increased impulse control and may involve an altered activation of GABA(A)/benzodiazepine receptors.
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