Browsing by Subject "ethanol"

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.

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.

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.