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Research on ghrelin mechanisms for the prevention of relapse in cannabinoid addiction
Charalambous, Chrysostomos ; Šustková, Magdaléna (advisor) ; Vaculín, Šimon (referee) ; Rudá, Jana (referee)
Background: Cannabis and cannabinoids are frequently used for recreational and therapeutic purposes, but people tend to overlook the associated risks that comes with them. Cannabinoid- associated use disorders and dependence are alarmingly increasing, and an effective treatment is currently lacking. Recently, the growth hormone secretagogue receptor (GHSR1A) antagonism was proposed as a promising mechanism for drug addiction therapy. However, the role of GHS- R1A and its endogenous ligand ghrelin in cannabinoid abuse remains unclear. Aim: The principal aim of this research thesis was to further investigate whether the GHS-R1A antagonist JMV2959 could reduce the WIN55,212-2 intravenous self-administration (IVSA) and the tendency to relapse, but also reduce the tetrahydrocannabinol (THC)-induced conditioned place preference (CPP). Methods: In a rat model, the intravenous self-administration directly measured the rat's response to the reinforcement effects of WIN55,212-2 as spontaneous drug-seeking and consumption with pretreatments of GHS-R1A antagonist/JMV2959 or saline. Further, the behavioural changes in rats were observed on the conditioned place preference apparatus which monitored the influence of JMV2959 on the THC effects. Findings: Following the ongoing WIN55,212-2 self-administration,...
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Investigation of the involvement of central ghrelin signalling in methamphetamine dependence using behavioural and molecular methods
Lapka, Marek ; Šustková, Magdaléna (advisor) ; Votava, Martin (referee) ; Amchová, Petra (referee)
v anglickém jazyce Interest in appetite-inducing peptide hormones, such as ghrelin, is gradually increasing. There is a growing number of publications dealing with the involvement of this orexigenic peptide in the mechanisms of obesity and various addictive behaviours, not excluding addiction to stimulant substances including methamphetamine. Central ghrelin signaling appears to play an important role in addictive behavior, and in the processing of memory traces. Recently, antagonism of the ghrelin receptor for growth hormone secretion (GHS-R1A) has been proposed as a promising tool for the still unsatisfactory treatment of methamphetamine addiction. Premedication with a commonly used experimental GHS-R1A antagonist, the triazole derivative, JMV2959, significantly reduced the rewarding and reinforcing effects of methamphetamine in several animal models of addiction. However, the molecular aspects of GHS-R1A involvement in specific brain regions related to the addiction process remain unclear. This work demonstrates that acute and subchronic (4 days) administration of JMV2959 alone, at doses significantly effective in addiction models (1 and 3 mg/kg intraperitoneally), had no effect on memory functions tested in the Morris water maze in rats, as well as no significant effects on molecular markers...
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The effect of selected cannabinoids on quantitative EEG, behaviour, and their therapeutic potential
Uttl, Libor ; Páleníček, Tomáš (advisor) ; Šlamberová, Romana (referee) ; Šustková, Magdaléna (referee)
Cannabinoids and especially CBD are these days a highly discussed topic with a huge overlap in the media space. Their ability to interact not only with cannabinoid receptors, but also with other pathways, in combination with a huge "hype", leads, despite the not very strong evidence of their effects in clinical practice, to the testing of cannabinoids in a broad spectrum of indications. Nowadays, we have more than 150 isolated cannabinoids, but the research is focused only on the main cannabinoids like for example THC, CBD, cannabigerol, cannabichromen or hexahydrocannabinol. For our research, we have chosen the two most well- known cannabinoids THC and CBD, and our key question was not only what is the role of these cannabinoids individually, but, also, how do they interact when administered together, how do they influence behaviour and how do they interact in dependence on the method of administration. All these questions were addressed within our rat experiments. Somewhat surprisingly, we did not observe the typical cannabinoid tetrad (decreased sensitivity to painful stimuli, hypothermia, catalepsy, and overall decrease in motor activity) after the THC administration, so we wondered what would happen if we used more potent and selective synthetic cannabinoids JWH- 073, JWH-210, instead of THC....
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The role of ghrelin signalling in the neurobiological mechanisms of rewarding effects of cannabinoids and opioids
Charalambous, Chrysostomos ; Šustková, Magdaléna (advisor) ; Rudá, Jana (referee) ; Petrásek, Tomáš (referee)
Background: Ghrelin, an orexigenic appetite stimulating peptide, in addition to promoting energy balance, contributes to the rewarding effects associated with overeating. It also seems to play an important role in the rewarding/reinforcing effects of alcohol and addictive stimulants. The involvement of the ghrelin mechanisms in cannabinoid and opioid misuse and addiction have been under-researched. Aims: The principal aim of this research thesis was to investigate whether the pretreatment with the growth hormone secretagogue receptor 1A (GHS-R1A) antagonist (JMV2959) could reduce the cannabinoid receptor type 1 (CB1R) agonist WIN55,212-2-induced dopamine efflux in the nucleus accumbens shell (NACSh), which is considered a crucial trigger impulse of the addiction process. Also, test whether JMV2959 can influence the WIN55,212-2 and fentanyl-induced effects on the endocannabinoids N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG) and the gama-aminobutyric acid (GABA) content in the NACSh, and in extend, to specify the involvement of GHS-R1A located in the ventral tegmental area (VTA) and the NACSh in the observed accumbens changes. Furthermore, to test whether the JMV2959 pretreatment could reduce the cannabinoid [tetrahydrocannabinol (THC) and WIN55,212-2] induced behavioural...
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Research into the mechanisms of methamphetamine dependence
Havlíčková, Tereza ; Šustková, Magdaléna (advisor) ; Šlamberová, Romana (referee) ; Petrásek, Tomáš (referee)
The presented dissertation deals with the issue of methamphetamine dependence. The first part focuses on a research that seeks a new promising possibilities of using ghrelin antagonist to reduce the potentiating effects of methamphetamine, with the intent of a more effective approach/treatment in current unsatisfactory approach in methamphetamine dependence. Furthermore, it summarizes the already available knowledge that deals with the possibilities of influencing the mechanisms of substance abuse through ghrelin antagonism, and especially focuses on our own experimental work. We tested the efficacy of the GHS- R1A receptor antagonist, JMV2959, in experimental models of methamphetamine dependence. There is only a minimum of work dealing with this issue yet. The experimental part summarizes the results of our two studies examining the effect of a ghrelin antagonist on the development of addictive reinforcing mechanisms, methamphetamine intake itself and the tendency to relapse behavior. Using the drug conditioned place preference (CPP) method in rats, we demonstrated in two experimental settings a significant effect of ghrelin antagonism on the development of methamphetamine binding to the environment and on the already induced search for a drug-related environment. We have shown that a GHS-R1A...
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Research of the role of ghrelin/GHS-R1A in the cannabinoid addiction
Hronec, Martin ; Šustková, Magdaléna (advisor) ; Vaculín, Šimon (referee)
Background: Cannabinoids are the most widely used illicit substances. Cannabis strains with high THC content, which are currently the most common, are linked to higher risk of addiction development. Studies proved the role of ghrelin and it's receptor GHS-R1A in the brain reward system, which is crucial for reinforcing effects of palatable food and drugs of abuse. Because the role of ghrelin in rewarding effects of cannabinoids wasn't widely studied, we tested this relationship using the conditioned place preference (CPP) method. Aim: Using the rat model, to find out if: (A) acute premedication with GHS-R1A antagonist influences the manifestation of THC-induced place preference; (B) co- administration of the GHS-R1A antagonist together with THC during conditioning suppresses the development of CPP. Methods: Male rats (Wistar) were separated into three groups for both experimental arrangements (JMV2959 dosage of 0, 1 or 3 mg/kg). First day we determined natural preference of the rats for one of the compartments (20 min). 2-9th day the conditioning took place, where THC (0,3 mg/kg i.p.) in the less preferred compartment and saline in the preferred compartment were administered. 10th day we again observed preference of the rats for one of the compartments. In arrangement (A) acute application of...
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Comparison of reflex-based and operant methods when evaluating effects of treatment on pain in experimetnal models
Panušková, Kristýna ; Vaculín, Šimon (advisor) ; Šustková, Magdaléna (referee)
Pharmacological treatment of neuropathic pain is still insufficient. Methylphenidate, a psychostimulant that increases the dopamine and noradrenaline levels, is commonly used for treating ADHD. There have been reports of changes in patients pain thresholds by ADHD patients treated with methylphenidate. The aim of the study is to examine if methylphenidate can affect peripheral neuropathic pain. Neuropathic pain has been modelled on laboratory rats by chronic constriction of the ischiatic nerve. The effect of methylphenidate on the evoked pain component was evaluated on control animals and on animals with neuropathic pain using reflex (plantar test, vonFrey test) and operanting test (thermal place preference). The effect of methylphenidate on the spontaneous components of pain was evaluated using the methods of conditioned place preference. This study has proven that methylphenidate in an applicable dose of 1 mg/kg has an antialodynic effect but does not act antinociceptively. This study further confirms that methylphenidate in low doses does not act as attractant and has no effect on spontaneous pain. The last part of the study compares the different methods for pain measurement and comes to the conclusion that the plantar test is not an adequate method for evaluating the effect of analgesics...
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Disposition and metabolism of cannabinoids.
Hložek, Tomáš ; Balíková, Marie (advisor) ; Miovský, Michal (referee) ; Šustková, Magdaléna (referee)
This thesis describes in the form of a commentary on own original publications research on the problems of cannabinoids, ie. phytocannabinoids and some synthetic cannabinoids, their pharmacokinetics and effects. The work consists of four thematic areas: the pharmacokinetics of delta-9- tetrahydrocannabinol (THC) and cannabidiol (CBD) in rats, depending on the route of administration; THC concentration time profile in humans (after inhalation) and implications for transport safety; the pharmacokinetic profile of synthetic cannabinoids in rats; extraction and determination of phytocannabinoids in plant material. The first part of the thesis was to determine pharmacokinetic profiles of THC, CBD and combination thereof (1:1 weight ratio) in rats with respect to administration common in humans, i.e. inhalation, oral and subcutaneous administration. THC, its metabolites (11-hydroxy-tetrahydrocannabinol, 11-OH-THC; 11-nor-delta-9- carboxytetrahydrocannabinol, THCOOH) and CBD concentrations in serum and brains of animals were monitored at the 24 hours experimental interval during the study. Except for inhalation administration, co-administration of CBD inhibited THC metabolism (after both oral and subcutaneous), resulting in an increase in THC concentrations in both serum and brain of the rats relative to...
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Possible perspective use of ghrelin mechanisms in the treatment of opioid addiction
Jeřábek, Pavel ; Šustková, Magdaléna (advisor) ; Šlamberová, Romana (referee) ; Petrásek, Tomáš (referee)
This dissertation deals with the narrow issue of the new perspective research direction, which is research of the possibility of using ghrelin antagonism in the treatment of opioid addiction, which has been rarely studied yet. It summarizes the general principles of neurobiological mechanisms of drug addiction as well as treatment guidelines and procedures based on these findings. The definition of addiction as a disease together with the factors contributing to its formation and course, are presented in this dissertation. The definition includes individual repetitive phases (cycles) of the substance addiction, along with a description of the anticipated involvement of individual brain structures and basic neuromediators involved in these phases, including references to the most important literary findings on the role of ghrelin in the mechanisms of addiction, focused on mechanism of action of ghrelin in the opioid addiction. In the experimental part, the results of the CNS microdialysis experiments in rats, using the GHS-R1A antagonist (JMV2959 pretreatment), were presented in both acute single dose morphine experiment and sub-chronic experiment in which morphine was administered in increasing doses for five consecutive days. The results are presented in relation to changes in the level of...
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Disposition of New Synthetic Drugs in The Organism. Pharmacokinetics and Biotransformation Study. Toxicological Detection in Biological Materials.
Židková, Monika ; Balíková, Marie (advisor) ; Šustková, Magdaléna (referee) ; Šanda, Miloslav (referee)
The object of this thesis was the study on the pharmacokinetics and biotransformation of selected abused new synthetic drugs, specifically belonging to cathinone and aminoindane groups, in experimental rats. This work consisted of two parts: a biotransformation study of mephedrone, methylone, 5,6-methylenedioxy-2- aminoindane (MDAI) and a distribution profile study of mephedrone, methylone, MDAI and naphyrone. This document is presented as a commentary to the original papers, which were published in peer reviewed journals. The samples of blood and tissue (brain, lungs, liver) were taken at specific times after a subcutaneous single bolus dose of the studied drugs. The urine samples for the biotransformation studies were collected over a 24-hour period following the sc. dose. The LC/HRMS method was used for metabolite detection and quantitative analysis. Our findings not only included testing metabolites of the aforementioneddrugs against the synthesized reference standards, but also discovering previously unknown metabolites of these drugs. Ten phase I and five phase II metabolites aside from the parent drug were identified in urine after mephedrone administration by comparison of their spectra against those of reference standards and/or MS2 spectra of previously identified metabolites. The main...
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