Browsing by Subject "ethanol"

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  • Grotell, Milo; den Hollander, Bjornar; Jalkanen, Aaro; Törrönen, Essi; Ihalainen, Jouni; de Miguel, Elena; Dudek, Mateusz; Kettunen, Mikko I.; Hyytiä, Petri; Forsberg, Markus M.; Kankuri, Esko; Korpi, Esa R. (2021)
    Mephedrone (4-MMC), despite its illegal status, is still a widely used psychoactive substance. Its effects closely mimic those of the classical stimulant drug methamphetamine (METH). Recent research suggests that unlike METH, 4-MMC is not neurotoxic on its own. However, the neurotoxic effects of 4-MMC may be precipitated under certain circumstances, such as administration at high ambient temperatures. Common use of 4-MMC in conjunction with alcohol raises the question whether this co-consumption could also precipitate neurotoxicity. A total of six groups of adolescent rats were treated twice daily for four consecutive days with vehicle, METH (5 mg/kg) or 4-MMC (30 mg/kg), with or without ethanol (1.5 g/kg). To investigate persistent delayed effects of the administrations at two weeks after the final treatments, manganese-enhanced magnetic resonance imaging brain scans were performed. Following the scans, brains were collected for Golgi staining and spine analysis. 4-MMC alone had only subtle effects on neuronal activity. When administered with ethanol, it produced a widespread pattern of deactivation, similar to what was seen with METH-treated rats. These effects were most profound in brain regions which are known to have high dopamine and serotonin activities including hippocampus, nucleus accumbens and caudate-putamen. In the regions showing the strongest activation changes, no morphological changes were observed in spine analysis. By itself 4-MMC showed few long-term effects. However, when co-administered with ethanol, the apparent functional adaptations were profound and comparable to those of neurotoxic METH.
  • Jaatinen, Pia; Sarviharju, Maija; Raivio, Noora; Eriksson, Peter; Hervonen, Antti; Kiianmaa, Kalervo (2013)
  • Törrönen, Essi (Helsingin yliopisto, 2020)
    4-Methylmethcathinone (Mephedrone) is one of the the most prevalent synthetic cathinones that bears close structural similarity to amphetamines. Like other stimulants, mephedrone is often used with alcohol (ethanol). In animal studies ethanol has been observed to potentiate the neurotoxicity of amphetamine-type stimulants, and same has been observed when mephedrone and alcohol is combined. The long-term effects of mephedrone have still remained largely elusive. The aim of this thesis is to study the effects of mephedrone, methamphetamine, and ethanol on dendritic spine density and morphology in the hippocampus, nucleus accumbens and caudate putamen, and compare the spine densities with changes in brain activation observed in manganese-enhanced magnetic resonance imaging (MEMRI). Dendritic spines are small membranous protrusions on dendrites that act as the post-synaptic sites for most of the excitatory synapses. Amphetamine and methamphetamine have been shown to affect the density and morphology of the spines. The goal of this thesis was to investigate the long-term effect of binge-like (two times a day, four consecutive days) stimulant treatment on dendritic spines using Golgi-stained rat brain sections. The brains of 48 male Wistar rats were imaged using AxioImager Z2 microscope and the number and the size of the spines was analyzed using Reconstruct software. In this thesis no effect on dendritic spines was observed in the hippocampus and nucleus accumbens in animals treated with mephedrone, methamphetamine, ethanol or combination of them. In the caudate putamen significant increase in the total density of dendritic spines and in the density of filopodia-like spines was observed in mephedrone-treated animals. Other treatments showed no observable effect. These results were conflicting with previous studies where amphetamine-type stimulants have been shown to increase the spine density in the nucleus accumbens and the hippocampus and increase the density of branched spines. In the caudate putamen methamphetamine has been observed to decrease the spine density. There was no correlation between spine densities and brain activation observed in MEMRI. To my best knowledge this is the first time when the effect of mephedrone on dendritic spines has been studied. It is possible that the treatment regimen used here was not strong enough to produce marked long-term changes on dendritic spines. It is also possible, that mephedrone is not as neurotoxic as other amphetamine-type stimulants, which may explain why the effects remained limited and conflicting. More research is still required to establish the long-term structural effects of mephedrone.
  • Östergen, Olof; Korhonen, Kaarina; Gustafsson, Nina-Katri; Martikainen, Pekka (2021)
    Background Most first-generation migrants have lower mortality compared to the native population. Finnish-born migrants in Sweden instead have higher mortality; possibly because of health behaviours established before migration. To increase our understanding of this excess mortality, we compared the cause-specific mortality of Finnish migrants in Sweden to both the native population of Sweden and the native Finnish population residing in Finland. Methods We used Swedish and Finnish register data, applying propensity score matching techniques to account for differences in sociodemographic characteristics between the migrants, Swedes and Finns. The index population were Finnish migrants aged 40–60, residing in Sweden in 1995. We compared patterns of all-cause, alcohol- and smoking-related, and cardiovascular disease mortality across the groups in the period 1996–2007. Results Finnish migrant men in Sweden had lower all-cause mortality compared to Finnish men but higher mortality compared to the Swedish men. The same patterns were observed for alcohol-related, smoking-related and cardiovascular disease mortality. Among women, all three groups had similar levels of all-cause mortality. However, Finnish migrant women had higher alcohol-related mortality than Swedish women, similar to Finnish women. Conversely, migrant women had similar levels of smoking-related mortality to Swedish women, lower than Finnish women. Conclusions Finnish-born migrants residing in Sweden have mortality patterns that are typically in between the mortality patterns of the native populations in their country of origin and destination. Both the country of origin and destination need to be considered in order to better understand migrant health.
  • Nieminen, Mikko T.; Salaspuro, Mikko (2018)
    The resident microbiome plays a key role in exposure of the upper gastrointestinal (GI) tract mucosa to acetaldehyde (ACH), a carcinogenic metabolite of ethanol. Poor oral health is a significant risk factor for oral and esophageal carcinogenesis and is characterized by a dysbiotic microbiome. Dysbiosis leads to increased growth of opportunistic pathogens (such as Candida yeasts) and may cause an up to 100% increase in the local ACH production, which is further modified by organ-specific expression and gene polymorphisms of ethanol-metabolizing and ACH-metabolizing enzymes. A point mutation in the aldehyde dehydrogenase 2 gene has randomized millions of alcohol consumers to markedly increased local ACH exposure via saliva and gastric juice, which is associated with a manifold risk for upper GI tract cancers. This human cancer model proves conclusively the causal relationship between ACH and upper GI tract carcinogenesis and provides novel possibilities for the quantitative assessment of ACH carcinogenicity in the human oropharynx. ACH formed from ethanol present in “non-alcoholic” beverages, fermented food, or added during food preparation forms a significant epidemiologic bias in cancer epidemiology. The same also concerns “free” ACH present in mutagenic concentrations in multiple beverages and foodstuffs. Local exposure to ACH is cumulative and can be reduced markedly both at the population and individual level. At best, a person would never consume tobacco, alcohol, or both. However, even smoking cessation and moderation of alcohol consumption are associated with a marked decrease in local ACH exposure and cancer risk, especially among established risk groups.
  • Grotell, Milo; Abdurakhmanova, Shamsiiat; Elsilä, Lauri V.; Korpi, Esa R. (2021)
    In the brain, extrasynaptically expressed ionotropic, delta subunit-containing gamma-aminobutyric acid A-type receptors (delta-GABA(A)Rs) have been implicated in drug effects at both neuronal and behavioral levels. These alterations are supposed to be caused via drug-induced modulation of receptor ionophores affecting chloride ion-mediated inhibitory tonic currents. Often, a transgenic mouse model genetically lacking the delta-GABA(A)Rs (delta-KO) has been used to study the roles of delta-GABA(A)Rs in brain functions, because a specific antagonist of the delta-GABA(A)Rs is still lacking. We have previously observed with these delta-KO mice that activation of delta-GABA(A)Rs is needed for morphine-induced conditioning of place preference, and others have suggested that delta-GABA(A)Rs act as targets selectively for low doses of ethanol. Furthermore, activation of these receptors via drug-mediated agonism induces a robust increase in the slow-wave frequency bands of electroencephalography (EEG). Here, we tested delta-KO mice (compared to littermate wild-type controls) for the pharmaco-EEG responses of a broad spectrum of pharmacologically different drug classes, including alcohol, opioids, stimulants, and psychedelics. Gaboxadol (THIP), a known superagonist of delta-GABA(A)Rs, was included as the positive control, and as expected, delta-KO mice produced a blunted pharmaco-EEG response to 6 mg/kg THIP. Pharmaco-EEGs showed notable differences between treatments but also differences between delta-KO mice and their wild-type littermates. Interestingly mephedrone (4-MMC, 5 mg/kg), an amphetamine-like stimulant, had reduced effects in the delta-KO mice. The responses to ethanol (1 g/kg), LSD (0.2 mg/kg), and morphine (20 mg/kg) were similar in delta-KO and wild-type mice. Since stimulants are not known to act on delta-GABA(A)Rs, our findings on pharmaco-EEG effects of 4-MMC suggest that delta-GABA(A)Rs are involved in the secondary indirect regulation of the brain rhythms after 4-MMC.
  • Ojanen, Sami (2006)
    Repeated use of drugs of abuse induces permanent changes in the brain that together with environmental factors can promote the development of addiction. Addiction to alcohol or drugs is a chronic disease that is characterized by a compulsion to seek and take the drug, loss of control in limiting intake, continued use despite obvious harm, and recurrent relapses. Behavioral animal models of addiction are invaluable tools for evaluating the neuroadaptations underlying these behaviors. Behavioral sensitization is a form of neuronal plasticity where repeated administration of drugs induces a progressive and enduring enhancement in their behavioral and neurochemical effects. The aim of this study was to investigate differences in susceptibility to morphine-induced behavioral and neurochemical sensitization in alcohol-preferring AA and alcohol-avoiding ANA rat lines, and to clarify its role on voluntary intake of ethanol. In vivo microdialysis was used to examine dopaminergic, glutamatergic and GABAergic neurotransmission in the brain. Interactions between behavioral sensitization and voluntary ethanol intake were assessed in AA rats during and after the rats were sensitized to morphine. The results showed that AA rats are more susceptible to morphine-induced behavioral sensitization than ANA rats. Neurochemical studies indicated a dissociation between the locomotor stimulant effects of morphine and extracellular levels of dopamine in the nucleus accumbens. In addition, sensitization to morphine affected glutamatergic transmission in the ventral tegmental area differently in AA and ANA rats. In contrast, extracellular levels of GABA differed neither between the lines nor between morphine- sensitized rats and controls. Glutamatergic transmission is therefore potentially involved in the higher susceptibility to morphine-induced sensitization in AA rats relative to ANAs, but the role of GABA remains unclear. Morphine-induced behavioral sensitization or other long-term adaptations in the brain induced by repeated morphine administration were not critically involved in the regulation of voluntary ethanol drinking. Opioid receptor activation with morphine injection, however, was shown to dramatically increase ethanol drinking in morphine-sensitized AA rats. Thus, the neuronal mechanisms underlying behavioral sensitization to morphine probably are distinct from those mediating ethanol reinforcement. In contrast, when given an additional morphine injection, reinforcing effects of ethanol were enhanced in AA rats sensitized to morphine.
  • Asamoah, Benjamin O.; Salmi, Pauliina; Räty, Jukka; Ryymin, Kalle; Talvitie, Julia; Karjalainen, Anna K.; Kukkonen, Jussi V. K.; Roussey, Matthieu; Peiponen, Kai-Erik (MDPI, 2021)
    Polymers 13: 6
    The abundance of microplastics (MPs) in the atmosphere, on land, and especially in water bodies is well acknowledged. In this study, we establish an optical method based on three different techniques, namely, specular reflection to probe the medium, transmission spectroscopy measurements for the detection and identification, and a speckle pattern for monitoring the sedimentation of MPs filtrated from wastewater sludge and suspended in ethanol. We used first Raman measurements to estimate the presence and types of different MPs in wastewater sludge samples. We also used microscopy to identify the shapes of the main MPs. This allowed us to create a teaching set of samples to be characterized with our optical method. With the developed method, we clearly show that MPs from common plastics, such as polypropylene (PP), polyethylene terephthalate (PET), polystyrene (PS), and polyethylene (PE), are present in wastewater sludge and can be identified. Additionally, the results also indicate that the density of the plastics, which influences the sedimentation, is an essential parameter to consider in optical detection of microplastics in complex natural environments. All of the methods are in good agreement, thus validating the optics-based solution.
  • Jin, Zhe; Bhandage, Amol K.; Bazov, Igor; Kononenko, Olga; Bakalkin, Georgy; Korpi, Esa R.; Birnir, Bryndis (2014)
  • Hellström, Per M.; Hendolin, Panu; Kaihovaara, Pertti; Kronberg, Leif; Meierjohann, Axel; Millerhovf, Anders; Paloheimo, Lea; Sundelin, Heidi; Syrjanen, Kari; Webb, Dominic-Luc; Salaspuro, Mikko (2017)
    Introduction: Helicobacter-induced atrophic gastritis with a hypochlorhydric milieu is a risk factor for gastric cancer. Microbes colonising acid-free stomach oxidise ethanol to acetaldehyde, a recognised group 1 carcinogen. Objective: To assess gastric production of acetaldehyde and its inert condensation product, non-toxic 2-methyl-1,3-thiazolidine-4-carboxylic acid (MTCA), after alcohol intake under treatment with slow-release L-cysteine or placebo. Methods: Seven patients with biopsy-confirmed atrophic gastritis, low serum pepsinogen and high gastrin-17 were studied in a cross-over single-blinded design. On separate days, patients randomly received 200 mg slow-release L-cysteine or placebo with intragastric instillation of 15% (0.3 g/kg) ethanol. After intake, gastric concentrations of ethanol, acetaldehyde, L-cysteine and MTCA were analysed. Results: Administration of L-cysteine increased MTCA (p <.0004) and decreased gastric acetaldehyde concentrations by 68% (p <.0001). The peak L-cysteine level was 7552 +/- 2687 mu mol/L at 40 min and peak MTCA level 196 +/- 98 mu mol/L at 80 min after intake. Gastric L-cysteine and MTCA concentrations were maintained for 3 h. The AUC for MTCA was 11-fold higher than acetaldehyde, indicating gastric first-pass metabolism of ethanol. With placebo, acetaldehyde remained elevated also at low ethanol concentrations representing 'non-alcoholic' beverages and food items. Conclusions: After gastric ethanol instillation, slow-release L-cysteine eliminates acetaldehyde to form inactive MTCA, which remains in gastric juice for up to 3 h. High acetaldehyde levels indicate a marked gastric first-pass metabolism of ethanol resulting in gastric accumulation of carcinogenic acetaldehyde. Local exposure of the gastric mucosa to acetaldehyde can be mitigated by slow-release L-cysteine capsules.
  • Harkki, Juliana Sade Maria (Helsingin yliopisto, 2020)
    Background: Alcohol dependence is a chronic severe substance use disorder that has devastating personal and public health consequences. The efficacy of the current pharmacotherapy options for the treatment of alcohol dependence are modest at best, therefore better alternatives are greatly needed. Lysergic acid diethylamide (LSD) has shown promise in treatment of alcohol dependence in several clinical trials. A sigle high dose of LSD has been suggested to have a treatment effect that last for at least six months, indicating a remarkably better efficacy than the currently available methods. LSD itself has been reported to have a low addiction potential. In mouse models, acute LSD has been demonstrated to reduce ethanol consumption. Yet, the mechanism of action behind these effects has remained largely unknown. LSD is an agonist of serotonin’s 5-HT2A and 5-HT2C receptors which have been shown to modulate the dopaminergic activity of the reward circuitry, a crucial brain area in the initiation of addiction. Intracranial self-stimulation (ICSS) is a procedure for a quantitative assessment of reward behavior in animal models. In ICSS, laboratory rodents self-administer electric stimulation to the dopaminergic pathways of the reward circuitry inducing a reinforcing effect similar to drug reward. Aim: The aim of the current body of work was to use ICSS to assess the acute effects of LSD on reward behavior in C57BL/6JRj mice. This was done to improve the understanding of the mechanism of action of LSD and to evaluate whether the ethanol-consumption-reducing effect of LSD in mice is mediated through the reward mechanism. Methods: Bipolar electrodes targeting the medial forebrain bundle were implanted in the brains of C57BL/6JRj mice in a stereotaxic surgery. The animals were trained to acquire the self-stimulation in the discrete-trial current-intensity procedure. First, the possible dose-dependent acute effects were tested with three different doses of LSD. Next, the acute effect of LSD on amphetamine-induced changes in ISCC were tested. Lastly, a small preliminary test on the effects of LSD on lipopolysaccharide (LPS) -induced changes on ICSS were conducted. Results and conclusions: Acute LSD did not affect reward behavior in ICSS on any of the tested doses. Accordingly, LSD did not affect the facilitation of ICSS induced by acute amphetamine. The results of the LPS experiment were likely to be skewed by the development of tolerance to LPS, therefore the evaluation of the possible effect of LSD was not possible. These findings suggest that the previously reported LSD-induced reduction in ethanol consumption in mice, is not mediated through alteration of the reward mechanism. At the same time, these findings provide further evidence supporting the suggestion that LSD itself does not induce facilitation of the reward circuitry needed for the development of addiction.
  • Ylitalo, Merja (Helsingfors universitet, 2016)
    Ethanol intake and the use of several drugs of abuse lead to the activation of the endogenous opioid system which has an important role in reward and reinforcement. Ethanol can affect also many other neurotransmitter systems, for example the dopaminergic, GABAergic and glutamatergic systems. The ability of opioid antagonists to decrease ethanol intake refers to the important role of the opioidergic system in mediating the reinforcement from ethanol. Important brain areas in the mesolimbic reward system are the ventral tegmental area, nucleus accumbens and ventral pallidum. The ventral pallidum is regarded as the endpoint of the mesolimbic reward system and as the cross point of the motivational circuit and reward circuit. The role of the ventral pallidum and its GABAergic and opioidergic systems in ethanol reinforcement has been proven in many studies. This review goes through the brain areas involved in the reward circuit and ethanol's effects on the neurotransmitter systems connected to the reward system. This review concentrates especially on the opioidergic system and on the role of the ventral pallidum in ethanol reinforcement. The aim of this study was to research the role µ-opioid receptors in the ventral pallidum on ethanol intake using an ethanol-preferring AA (Alko, Alcohol) rat line. The hypothesis of the study was that local inhibition of the ventral pallidum with an excess of µ-opioid receptors effects ethanol intake. We infused µ-opioid receptor gene overexpressing viral vectors (AAV-MOR), control vectors or vehicle into the ventral pallidum of rats. Ethanol drinking of the rats was examined in the limited access paradigm. After the ethanol drinking study rats received injections of an opioid receptor antagonist, naltrexone (0.1 mg/kg and 0.3 mg/kg, s.c) and an opioid receptor agonist, morphine (3 mg/kg, repeatedly, s.c) before the ethanol drinking session to see what effect the drugs have on ethanol drinking. The biological activity of the viral vectors was confirmed with immunohistochemical staining and qPCR. In the ethanol drinking study there were no statistically significant differences between the groups. Naltrexone 0.1 mg/kg dose decreased statistically significantly ethanol drinking only in AAV-MOR group and caused statistically significant difference in ethanol drinking between the AAV-MOR and control vector groups when proportionate to the control. These results suggest that possibly part of to that naltrexone's ethanol intake decreasing effects are mediated via the ventral pallidum. Morphine did not cause statistically significant differences in ethanol drinking between the groups. The results of this study do not exclude the role of the ventral pallidum in controlling ethanol drinking.