Activation of amylin receptors attenuates alcohol‐mediated behaviours in rodents

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.

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

“…In contrast to an attenuation of alcohol-induced locomotor stimulation as previously observed (Kalafateli et al 2019b), we here notice that the alcohol response is greater in sCTtreated mice compared with that in vehicle-treated mice. However, co-administration of sCT and alcohol for 5 days did not alter any secondary behavioural parameters as measured in this locomotor activity experiments.…”

“…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.…”

“…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. Alcohol (95%, Solveco AB; Stockholm, Sweden) was diluted in vehicle (0.9% sodium chloride solution) to 15% v /v and was administered at a dose of 1.75 g/kg, IP, for all experiments.…”

“…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.…”

Dose Frequency Optimization of the Dual Amylin and Calcitonin Receptor Agonist KBP-088: Long-Lasting Improvement in Food Preference and Body Weight Loss

“…Though the mechanism facilitating the improved food preference is unknown, we speculate that KBP-088 acts centrally as amylin agonism is known to affect dopamine release in the hypothalamus (Brunetti et al, 2002), which affects the feeding patterns (Szczypka et al, 1999(Szczypka et al, , 2000. This is supported by the observation that the DACRA, salmon calcitonin (sCT), reduces fat intake and to some extent sucrose intake possibly via the ventral tegmental area and/or the area postrema (Mietlicki-Baase et al, 2017;Whiting et al, 2017), and have been suggested to be involved in blocking the reward mechanism normally induced by alcohol (Kalafateli et al, 2018). Hence, it is likely that KBP-088 influences food preference via central mechanisms.…”