Browsing by Subject "alcohol addiction"

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  • Suo-Yrjö, Ville (Helsingfors universitet, 2010)
    Nearly all drugs that are abused release dopamine in the nucleus accumbens, the end point structure of mesolimbic dopamine pathway. This why effect of those drugs is closely attached to dopaminergic system. It seems that function of mesolimbic dopamine pathway is necessary for rewarding effects of drugs as cocaine and amphetamine. However rewarding effects of ethanol seems to mediate routes despite of mesolimbic dopamine pathway. This conclusion is a result of several studies that have showed that destruction of synapses of in nucleus accumbens have no effect on ethanol drinking of rats. So it might be that the possible place were effects of ethanol mediate beside of straight stimulation of nucleus accumbens, are GABA- and opioidergic medium spiny neurons that project from nucleus accumbens to ventral pallidum and also from ventral pallidum back to nucleus accumbens. Ventral pallidum is the structure of brain that is thought to be the last common pathway of brain reward circuitry. Ventral pallidum is also found to mediate reinforcement of pleasure of natural rewarders and also drugs that are abused. Meaning of this study was to find how opioidreceptors in ventral pallidum control the drinking of ethanol. The method of study was observe how opioidergic drugs (µ-, δ-, κ-agonist and -antagonist) that are microinjected in brain of AA-rats mediate voluntary ethanol drinking of these animals. Hypothesis of this study was that activation of opioidreceptors in ventral pallidum leads to lower consumption of ethanol and inactivation of these receptors leads to higher consumption of ethanol. Study was performed in National institute for health and welfare, Department of Alcohol, Drugs an Addiction, in research group of Kalervo Kiianmaa. There were used ethanol prefering AA-rats which were microinjected in ventral pallidum with opioidergic drugs. Study involved 72 male rats form generation F99. There were six groups and each had 12 rats. Before the actual trial rats were taught to drink 10 % ethanol/water-solution voluntary. Surgery and placement of canulaes were done with stereotactic device. Bilateral guide canulaes were placed above the ventral pallidum. Each drug was given in three different size doses and also ringer's solution was given as a control. Volume on injections were in each drug and with the ringer's solution 0,3 µl and rate of injection was 0,3 µl/min. Total trial involved four experiment days (three with the drugs and one with the ringer's solution). Injections were given in mixed order. Immediately after injection rats were moved in their homecages and they were given drinking bottle which was filled with ethanol. The consumption of ethanol was observed in time of 10, 20, 30, 50, 70 and 90 minutes. After all experiment's were done rats were decapitated and the places of injections were checked from brain slices that were stained with thionine. Results were analyzed with repeated measures ANOVA and if difference between groups were found the post hoc test were done with Dunnett's test. If the statistical difference were found with repeated measures ANOVA the result were analyzed also in exact time point with ANOVA and Dunnett's test. The only significant result was found with µ-opioidreceptoragonist (DAMGO). It lowered the ethanol consumption significantly. The drop in ethanol consumption was dose dependent and was seen with two highest doses of DAMGO. Clearest difference was seen at the first 50 minutes after rats had started drinking ethanol. The second highest dose of µ-opioidreceptorantagonist (CTOP) had a little tendency to elevate ethanol consumption and was near to be a significant (p=0.08). There were found no effects with other drugs. The main conclusion of this study was that activation of µ-opioidreceptors in the ventral pallidum lowers consumption of ethanol in AA-rats. Inhibition the µ-opioidreceptors had a mild effect of elevating ethanol consumption but this could not be taken as reliable and more studies are needed to be done. δ- and κ-opioidreceptor activation or inhibition had no effect in ethanol consumption in these rats. Conclusions made by these results give support to the theory of role of ventral pallidum as a part of brain reward circuitry. When these results are compared to studies were GABAergic drugs are injected in ventral pallidum and ethanol consumption is observed and also with the knowledge of how these drugs affect the cell's membrane potential, there can be made conclusion that inhibition the activity of ventral pallidum has effects that block pleasure mechanisms that interface with ethanol.
  • Eteläinen, Tony (Helsingfors universitet, 2017)
    lcohol addiction is a significant public health problem worldwide, and its treatment is extremely challenging. One major problem in the treatment of alcohol addiction are the later relapses to uncontrollable drinking. Approximately 60-70 % of addicts relapse to drinking within a year from the beginning of the treatment. The current treatment of alcohol addiction is based on a combined psychotheraphy and pharmacological treatments, but even at the best the efficacy remains quite modest. This is why further studies on the underlying mechanisms behind alcohol addiction and development of more effective pharmaceuticals to treat it are an important field of research. Chronic exposure to the rewarding effects of alcohol causes neurochemical adaptations in the brain reward system. These adaptations strive to restrain the recurring rewarding signals caused by alcohol and lead eventually to increased reward thresholds in the reward system. As the reward thresholds increase, the individual develops tolerance to the rewarding effects of alcohol, but also craving for the substance and a dysphoric mental state which are highlighted especially during periods of abstinence. It is known that the increase in reward thresholds is an important factor leading to relapses, but the exact nature of the neurochemical adaptations behind it are not known. According to recent studies dynorphin -peptides (DYN) and κ-opioid receptors (KOR) of the endogenous opioid system seem to have an important role in these neurochemical adaptations. It has been shown that chronic alcohol exposure increases the activity of DYN/ KOR -system especially within the nucleus accumbens (NAc), which is an essential structure of the brain reward system. The increased activity of the DYN/ KOR -system in the NAc has been shown to inhibit the development of rewarding signals. Previous studies have shown that inhibiting the increased activity of the DYN/ KOR -system with a selective KOR-antagonist, reduces voluntary alcohol intake and relapse-like alcohol seeking behavior during periods of abstinence, especially in physically addicted animals. In this study we studied the relapse-like alcohol drinking of Long-Evans rats in the alcohol deprivation effect (ADE) model. The effects of selective and long-acting KOR-antagonists, JDTic and nor-BNI, were tested on the ADE-effect which occurs after a period of deprivation. The ADE is defined as a transient increase in alcohol intake after a forced period of abstinence and it has been shown both in rodents with a history of alcohol consumption, and human alcohol addicts. In this study the rats were allowed to consume alcohol (10% ethanol-water solution) voluntarily during 90 minutes for 10 consecutive days after which followed a six days long deprivation period. According to results, both intra-accumbally (15 µg/ 0,3 µl/min/ site) or subcutaneously (10 mg/kg) administered JDTic decreased the ADEeffect significantly compared to vehicle, when administered 24 hours prior the end of the deprivation period. Also intra-accumbally administered nor-BNI (3 µg/0,3 µl/min/site) decreased the ADE-effect significantly compared to vehicle when administered 24 hour prior the end of deprivation. The results are in line with the theory that alcohol induces sensitization of the DYN/ KOR -system within the brain structures involved in reward. In theory it can be speculated that by suppressing the activity of the DYN/ KOR -system, KOR-antagonists can relieve craving for alcohol. This can be seen as a decrease in relapse-like consumption of alcohol. In conclusion, it can be suggested that by suppressing the increased activity of the DYN/ KOR -system induced by chronic alcohol exposure with a selective KOR-antagonist, like JDTic or nor-BNI, it could be possible to reduce the risk of relapse during abstinence and thus improve the efficacy of treatments for alcohol addiction.