| 1. |
- Aranäs, Cajsa, et al.
(författare)
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Salmon Calcitonin Attenuates Some Behavioural Responses to Nicotine in Male Mice
- 2021
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Ingår i: Frontiers in Pharmacology. - : Frontiers Media SA. - 1663-9812. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- The behavioural responses to nicotine involve appetite-regulatory hormones; however, the effects of the anorexigenic hormone amylin on reward-related behaviours induced by nicotine remain to be established. Previous studies have shown that the amylinergic pathway regulates behavioural responses to alcohol, amphetamine and cocaine. Here, we evaluated the effects of salmon calcitonin (sCT), an amylin and calcitonin receptor (CTR) agonist, on nicotine-induced locomotor stimulation and sensitisation as well as dopamine release in the nucleus accumbens (NAc) shell. Moreover, we investigated the effects of sCT on the acquisition and expression of nicotine-induced reward in the conditioned place preference (CPP) paradigm. Finally, we performed Western Blot experiments in an attempt to identify the levels of the amylin receptor components CTRa, CTRb, and RAMP1 in reward-related areas of mice responding differently to repeated injections of sCT and nicotine in the locomotor sensitisation test. We found that sCT blocked nicotine's stimulatory and dopamine-releasing effects and prevented its ability to cause locomotor sensitisation. On the other hand, sCT did not alter nicotine-induced acquisition and expression of CPP. Lastly, sCT-nicotine treated mice from the locomotor sensitisation experiment displayed higher levels of total CTR, i.e. CTRa and CTRb together, in the reward-processing laterodorsal tegmental area (LDTg) of the brain compared to mice treated with vehicle-nicotine. Overall, the present data reveal that activation of CTR or/and amylin receptors attenuates certain nicotine-induced behaviours in male mice, further contributing to the understanding of appetite-regulatory peptides in reward regulation.
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| 2. |
- Kalafateli, Aimilia Lydia, 1987, et al.
(författare)
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A cannabinoid receptor antagonist attenuates ghrelin-induced activation of the mesolimbic dopamine system in mice
- 2018
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Ingår i: Physiology and Behavior. - : PERGAMON-ELSEVIER SCIENCE LTD. - 0031-9384 .- 1873-507X. ; 184, s. 211-219
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Tidskriftsartikel (refereegranskat)abstract
- Ghrelin has been attributed various physiological processes including food intake and reward regulation, through activation of the mesolimbic dopamine system. Reward modulation involves the mesolimbic dopamine system, consisting of the ventral tegmental area (VTA) dopamine neurons targeting nucleus accumbens (NAc), a system that ghrelin activates through VTA-dependent mechanisms. In the first study, we found that systemic intraperitoneal (ip) administration of rimonabant attenuated intracerebroventricular (icv) ghrelins ability to cause locomotor stimulation and NAc dopamine release in mice. Ghrelin-induced (icv) chow intake was not altered by rimonabant administration (ip). Finally, we showed that bilateral VTA administration of rimonabant blocks the ability of intra-VTA administered ghrelin to increase locomotor activity, but does not affect food intake in mice. Collectively, these data indicate clear dissociation between regulation of food intake and activation of the mesolimbic dopamine system.
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| 3. |
- Kalafateli, Aimilia Lydia, 1987, et al.
(författare)
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Activation of amylin receptors attenuates alcohol-mediated behaviours in rodents.
- 2019
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Ingår i: Addiction biology. - : Wiley. - 1369-1600 .- 1355-6215. ; 24:3, s. 388-402
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Tidskriftsartikel (refereegranskat)abstract
- Alcohol expresses its reinforcing properties by activating areas of the mesolimbic dopamine system, which consists of dopaminergic neurons projecting from the ventral tegmental area to the nucleus accumbens. The findings that reward induced by food and addictive drugs involve common mechanisms raise the possibility that gut-brain hormones, which control appetite, such as amylin, could be involved in reward regulation. Amylin decreases food intake, and despite its implication in the regulation of natural rewards, tenuous evidence support amylinergic mediation of artificial rewards, such as alcohol. Therefore, the present experiments were designed to investigate the effect of salmon calcitonin (sCT), an amylin receptor agonist and analogue of endogenous amylin, on various alcohol-related behaviours in rodents. We showed that acute sCT administration attenuated the established effects of alcohol on the mesolimbic dopamine system, particularly alcohol-induced locomotor stimulation and accumbal dopamine release. Using the conditioned place preference model, we demonstrated that repeated sCT administration prevented the expression of alcohol's rewarding properties and that acute sCT administration blocked the reward-dependent memory consolidation. In addition, sCT pre-treatment attenuated alcohol intake in low alcohol-consuming rats, with a more evident decrease in high alcohol consumers in the intermittent alcohol access model. Lastly, sCT did not alter peanut butter intake, blood alcohol concentration and plasma corticosterone levels in mice. Taken together, the present data support that amylin signalling is involved in the expression of alcohol reinforcement and that amylin receptor agonists could be considered for the treatment of alcohol use disorder in humans.
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| 4. |
- Kalafateli, Aimilia Lydia, 1987, et al.
(författare)
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Activation of the amylin pathway modulates cocaine-induced activation of the mesolimbic dopamine system in male mice
- 2021
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Ingår i: Hormones and Behavior. - : Elsevier BV. - 0018-506X. ; 127:January
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Tidskriftsartikel (refereegranskat)abstract
- Besides food intake reduction, activation of the amylin pathway by salmon calcitonin (sCT), an amylin and calcitonin receptor agonist, inhibits alcohol-mediated behaviors in rodents. This involves brain areas processing reward, i.e. the laterodorsal (LDTg), ventral tegmental area (VTA) and nucleus accumbens (NAc). However, the effects of stimulation of the amylin pathway on behaviors caused by cocaine and the brain areas involved in these processes have not yet been investigated. We therefore explored in male mice, the effects of systemic administration of sCT on cocaine-induced locomotor stimulation, dopamine release in the NAc and cocaine reward, as well as reward-dependent memory of cocaine, in the conditioned place preference (CPP) paradigm. Moreover, the outcome of systemic sCT and cocaine co-administration for five days on locomotor activity was investigated. Lastly, the impact of sCT infusions into the LDTg, VTA, NAc shell or core on cocaine-evoked locomotor stimulation was explored. We found that sCT attenuated cocaine-induced locomotor stimulation and accumbal dopamine release, without altering cocaine's rewarding properties or reward-dependent memory retrieval in the CPP paradigm. Five days of cocaine administration caused locomotor stimulation in mice pre-treated with vehicle, but not with sCT. In mice infused with vehicle into the aforementioned reward-related areas, cocaine caused locomotor stimulation, a response that was not evident following sCT infusions. The current findings suggest a novel role for the amylinergic pathway as regulator of cocaine-evoked activation of the mesolimbic dopamine system, opening the way for the investigation of the amylin signalling in the modulation of other drugs of abuse. © 2020
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| 5. |
- Kalafateli, Aimilia Lydia, 1987, et al.
(författare)
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An amylin analogue attenuates alcohol-related behaviours in various animal models of alcohol use disorder.
- 2019
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Ingår i: Neuropsychopharmacology. - : Springer Science and Business Media LLC. - 0893-133X .- 1740-634X. ; 44:6, s. 1093-1102
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Tidskriftsartikel (refereegranskat)abstract
- Recent findings have identified salmon calcitonin (sCT), an amylin receptor agonist and analogue of endogenous amylin, as a potential regulator of alcohol-induced activation of the mesolimbic dopamine system and alcohol consumption. Providing that the role of amylin signalling in alcohol-related behaviours remains unknown, the present experiments investigate the effect of sCT on these behaviours and the mechanisms involved. We showed that repeated sCT administration decreased alcohol and food intake in outbred rats. Moreover, single administration of the potent amylin receptor antagonist, AC187, increased short-term alcohol intake in outbred alcohol-consuming rats, but did not affect food intake. Acute administration of sCT prevented relapse-like drinking in the "alcohol deprivation effect" model in outbred alcohol-experienced rats. Additionally, acute sCT administration reduced operant oral alcohol self-administration (under the fixed ratio 4 schedule of reinforcement) in selectively bred Sardinian alcohol-preferring rats, while it did not alter operant self-administration (under the progressive ratio schedule of reinforcement) of a highly palatable chocolate-flavoured beverage in outbred rats. Lastly, we identified differential amylin receptor expression in high compared to low alcohol-consuming rats, as reflected by decreased calcitonin receptor and increased receptor activity modifying protein 1 expression in the nucleus accumbens (NAc) of high consumers. Collectively, our data suggest that amylin signalling, especially in the NAc, may contribute to reduction of various alcohol-related behaviours.
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| 6. |
- Kalafateli, Aimilia Lydia, 1987, et al.
(författare)
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An amylin and calcitonin receptor agonist modulates alcohol behaviors by acting on reward-related areas in the brain.
- 2021
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Ingår i: Progress in neurobiology. - : Elsevier BV. - 1873-5118 .- 0301-0082. ; 200
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Tidskriftsartikel (refereegranskat)abstract
- Alcohol causes stimulatory behavioral responses by activating reward-processing brain areas including the laterodorsal (LDTg) and ventral tegmental areas (VTA) and the nucleus accumbens (NAc). Systemic administration of the amylin and calcitonin receptor agonist salmon calcitonin (sCT) attenuates alcohol-mediated behaviors, but the brain sites involved in this process remain unknown. Firstly, to identify potential sCT sites of action in the brain, we used immunohistochemistry after systemic administration of fluorescent-labeled sCT. We then performed behavioral experiments to explore how infused sCT into the aforementioned reward-processing brain areas affects acute alcohol-induced behaviors in mice and chronic alcohol consumption in rats. We show that peripheral sCT crosses the blood brain barrier and is detected in all the brain areas studied herein. sCT infused into the LDTg attenuates alcohol-evoked dopamine release in the NAc shell in mice and reduces alcohol intake in rats. sCT into the VTA blocks alcohol-induced locomotor stimulation and dopamine release in the NAc shell in mice and decreases alcohol intake in rats. Lastly, sCT into the NAc shell prevents alcohol-induced locomotor activity in mice. Our data suggest that central sCT modulates the ability of alcohol to activate reward-processing brain regions.
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| 7. |
- Kalafateli, Aimilia Lydia, 1987, et al.
(författare)
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Effects of a selective long-acting amylin receptor agonist on alcohol consumption, food intake and body weight in male and female rats
- 2021
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Ingår i: Addiction Biology. - : Wiley. - 1355-6215 .- 1369-1600. ; 26:2
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Tidskriftsartikel (refereegranskat)abstract
- Alcohol use disorder is a complex neuropsychiatric disorder affecting both males and females worldwide; however, the efficacy of current pharmacotherapies varies. Recent advances show that gut-brain peptides, like amylin, regulate alcohol behavioural responses by acting on brain areas involved in alcohol reward processes. Thus, the activation of amylin receptors (AMYRs) by salmon calcitonin (sCT) decreases alcohol behaviours in male rodents. Given that sCT also activates the sole calcitonin receptor (CTR), studies of more selective AMYR agonists in both male and female rodents are needed to explore amylinergic modulation of alcohol behaviours. Therefore, we investigated the effects of repeated administration of a selective long-acting AMYR agonist, NNC0174-1213 (AM1213), on alcohol, water and food intake, as well as body weight in male and female rats chronically exposed to alcohol. We confirm our previous studies with sCT in male rats, as repeated AM1213 administration for 2 weeks initially decreased alcohol intake in both male and female rats. However, this reduction ceases in both sexes on later sessions, accompanied by an increase in males. AM1213 reduced food intake and body weight in both male and female rats, with sustained body weight loss in males after discontinuation of the treatment. Moreover, AM1213 administration for 3 or 7 days, differentially altered dopamine, serotonin and their metabolites in the reward-related areas in males and females, providing tentative, but different, downstream mechanism through which selective activation of AMYR may alter alcohol intake. Our data provide clarified insight into the importance of AMYRs for alcohol intake regulation in both sexes.
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| 8. |
- Kalafateli, Aimilia Lydia, 1987, et al.
(författare)
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Effects of sub-chronic amylin receptor activation on alcohol-induced locomotor stimulation and monoamine levels in mice
- 2020
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Ingår i: Psychopharmacology. - : Springer Science and Business Media LLC. - 0033-3158 .- 1432-2072. ; 237, s. 3249-3257
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Tidskriftsartikel (refereegranskat)abstract
- Rationale Amylin receptors consist of the calcitonin receptor (CTR) and one of three receptor activity-modifying proteins (RAMPs). The identification of amylin receptors in areas processing reward, namely laterodorsal tegmental area (LDTg), ventral tegmental area (VTA), and nucleus accumbens (NAc), has attributed them a role as reward regulators. Indeed, acute activation of amylin receptors by the amylin receptor agonist salmon calcitonin (sCT) attenuates alcohol-induced behaviours in rodents. Objectives The effects of long-term administration of sCT on alcohol-related behaviours and the molecular mechanisms underlying these processes are not yet elucidated. To fill this knowledge gap, we investigated the effects of sub-chronic sCT treatment on the locomotor stimulatory responses to alcohol in mice and the molecular pathways involved. Methods We assessed the behavioural effects of sub-chronic sCT treatment by means of locomotor activity experiments in mice. We used western blot to identify changes of the CTR levels and ex vivo biochemical analysis to detect changes in monoamines and their metabolites. Results After discontinuation for 5 days of sCT treatment, alcohol did not induce locomotor stimulation in mice pre-treated with sCT when compared with vehicle, without altering secondary behavioural parameters of the locomotor activity experiment or the protein levels of the CTR in reward-related areas in the same set of animals. Moreover, repeated sCT treatment altered monoaminergic neurotransmission in various brain areas, including increased serotonin and decreased dopamine turnover in the VTA. Lastly, we identified a differential effect of repeated sCT and acute alcohol administration on alcohol-induced locomotion in mice, where sCT initially attenuated and later increased this alcohol response. It was further found that this treatment combination did not affect secondary behavioural parameters measured in this locomotor activity experiments. Conclusions These data suggest that sub-chronic sCT treatment differentially alters the ability of alcohol to cause locomotor stimulation, possibly through molecular mechanisms involving various neurotransmitter systems and not the CTR levels per se.
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| 9. |
- Kalafateli, Aimilia Lydia, 1987
(författare)
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The gut-brain axis and alcohol-mediated behaviours: the amylin story
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Alcohol use disorder (AUD) is a complex neuropsychiatric disorder with high rates of mortality and morbidity. The currently available pharmacotherapies show varied efficacy, leading to the investigation of new neurochemical targets for alcohol. Recently, gut-brain hormones involved in appetite regulation have been shown to modulate alcohol-mediated behaviours. However, the role of the anorexigenic gut-brain hormone amylin in such behaviours was until recently unknown. Therefore, this thesis aims at identifying how amylin signalling regulates behavioural responses to alcohol and suggests the underlying mechanisms of this modulation. The studies in this thesis present novel data that, firstly, amylin receptor (AMYR) activation by the amylin analogue salmon calcitonin (sCT) attenuates the established acute effects of alcohol to increase locomotion and dopamine release in the nucleus accumbens (NAc) in mice. Secondly, acute sCT administration decreases alcohol consumption and alcohol relapse drinking in rats chronically exposed to alcohol. Notably, the gene expression of the AMYR components is different in the NAc of high, compared to low alcohol-consuming rats. In selectively bred Sardinian alcoholpreferring rats, sCT decreases the number of lever presses for alcohol reward in an operant self-administration paradigm. Thirdly, sCT crosses the blood-brain barrier and reaches reward-related areas, including the laterodorsal tegmental area, the ventral tegmental area and the NAc, whereby activates local AMYRs to decrease acute alcohol behaviours in mice and chronic in rats. Fourthly, repeated sCT treatment decreases alcohol-induced locomotion even after discontinuation of sCT administration and alters the levels of neurotransmitters in reward-related areas. Lastly, a selective AMYR synthetic amylin analogue decreases alcohol consumption in both male and female rats and alters monoamine levels in reward-related brain areas in both sexes. The thesis attributes an entire new role to the amylin signalling, that of the regulator of alcohol-mediated behaviours. The commercial availability of amylin analogues for the treatment of other disorders could set the ground for the development of targeted pharmacotherapies for AUD and potentially for other addictive disorders.
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| 10. |
- Vallöf, Daniel, 1988, et al.
(författare)
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Brain region specific glucagon-like peptide-1 receptors regulate alcohol-induced behaviors in rodents.
- 2019
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Ingår i: Psychoneuroendocrinology. - : Elsevier BV. - 0306-4530 .- 1873-3360. ; 103, s. 284-295
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Tidskriftsartikel (refereegranskat)abstract
- Glucagon-like peptide 1 (GLP-1), an incretin hormone that reduces food intake, was recently established as a novel regulator of alcohol-mediated behaviors. Clinically available analogues pass freely into the brain, but the mechanisms underlying GLP-1-modulated alcohol reward remains largely unclear. GLP-1 receptors (GLP-1R) are expressed throughout the nuclei of importance for acute and chronic effects of alcohol, such as the laterodorsal tegmental area (LDTg), the ventral tegmental area (VTA) and the nucleus accumbens (NAc). We therefore evaluated the effects of bilateral infusion of the GLP-1R agonist exendin-4 (Ex4) into NAc shell, anterior (aVTA), posterior (pVTA) or LDTg on the acute alcohol-induced locomotor stimulation and memory of alcohol reward in the conditioned place preference (CPP) model in mice, as well as on alcohol intake in rats consuming high amounts of alcohol for 12 weeks. Ex4 into the NAc shell blocks alcohol-induced locomotor stimulation and memory of alcohol reward as well as decreases alcohol intake. The GLP-1R expression in NAc is elevated in high compared to low alcohol-consuming rats. On the contrary, GLP-1R activation in the aVTA does not modulate alcohol-induced behaviors. Ex4 into the pVTA prevents alcohol-induced locomotor simulation, but does neither modulate CPP-dependent alcohol memory nor alcohol intake. Intra-LDTg-Ex4 attenuates alcohol-induced locomotor stimulation and reduces alcohol intake, but does not affect memory of alcohol reward. Collectively, these data provide additional knowledge of the functional role of GLP-1R in reward-related areas for alcohol-mediated behaviors and further support GLP-1R as a potential treatment target for alcohol use disorder.
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