An amylin analogue attenuates alcohol-related behaviours in various animal models of alcohol use disorder

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.

Effects of sub-chronic amylin receptor activation on alcohol-induced locomotor stimulation and monoamine levels in mice

“…Therefore, the locomotor differences noted in the present locomotion experiments could be associated with altered RAMP levels; the lack of data thereof can be considered as a limitation, and future studies are warranted. Although differential expression of the calcitonin receptor gene is detected in the NAc of high compared with low alcoholconsuming rats chronically exposed to alcohol (Kalafateli et al 2019a), the lack of effect on the protein levels of this receptor in the present could be a result of chronic alcohol exposure in rats, which is not the case in the present conditions in mice. Additionally, previous studies have showed differences in amylin-mediated behaviours between the subregions of the NAc (Baldo and Kelley 2001;Mietlicki-Baase et al 2015b).…”

“…The agonist was administered 30 min prior to alcohol administration in the experimental setup, where alcohol was administered the same day with sCT. This dose of sCT was used, as we have previously established that this dose attenuates alcohol-mediated behaviours in rodents (Kalafateli et al 2019a ; Kalafateli et al 2019b ). Moreover, this sCT dose, at least acutely, does not affect blood alcohol concentration (Kalafateli et al 2019b ), rendering the possibility of pharmacokinetic interaction between the two drugs less likely.…”

“…Recent data suggest that activation of amylin receptors by sCT attenuates alcohol-mediated behaviours in rodents (Kalafateli et al 2019a ; Kalafateli et al 2019b ) and that the gene expression of amylin receptor components in the NAc is differential in low compared with high alcohol-consuming rats (Kalafateli et al 2019a ). In particular, acute sCT decreases alcohol-induced locomotor stimulation, accumbal dopamine release, and alcohol-induced CPP in mice.…”

Palatable food access impacts expression of amylin receptor components in the mesocorticolimbic system

“…We also characterized fully all components of the AmyR in the mPFC and CeA. Previous research has demonstrated expression of a subset of AmyR components in these nuclei (Kalafateli et al., 2019), but here we expand upon these earlier data by investigating both subtypes of CTR and all three types of RAMP , in addition to the impact of access to fat on expression of these components. Our data indicate that all CTR and RAMP subtypes are expressed in the mPFC and CeA.…”

“…The CTRs and RAMPs can dimerize in different combinations to form AmyRs of varying degrees of sensitivity and selectivity to amylin (Christopoulos et al., 1999; Hay, Christopoulos, Christopoulos, & Sexton, 2004; Muff, Buhlmann, Fischer, & Born, 1999). One paper showed that some components of the AmyR are expressed in PFC and CeA (Kalafateli et al., 2019) but did not fully characterize expression of all potential AmyR components within these nuclei. Thus, the particular components of the AmyR that are expressed in these sites are not completely resolved.…”