Salmon Calcitonin Attenuates Some Behavioural Responses to Nicotine in Male Mice

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

Appetite-regulating peptides and natural rewards: emphasis on ghrelin and glucagon-like peptide-1

Evolutionary conserved natural behaviors, such as foraging and sexual behaviors, are strongly associated with reward processes. Brain areas important for reward processes include, but are not limited to, the nucleus accumbens (NAc) shell, the ventral tegmental area (VTA), the laterodorsal tegmental area (LDTg) and the nucleus of the solitary tract (NTS). The mechanisms that control natural rewards are complex, and appetite-regulating peptides, such as ghrelin and glucagon-like peptide-1 (GLP-1), have recently been identified as substrates involved in reward processes. The aim of the present thesis is therefore to elucidate the involvement of ghrelin and GLP-1 in natural rewards, by assessing how they mediate two different natural rewards, i.e. skilled reach foraging from the feeding-related domain and sexual behaviors from the social behavior domain, in preclinical behavioral models. We showed in paper I that repeated treatment with a ghrelin receptor antagonist decreases the motivation of skilled reach foraging in rats with an acquired skilled reach performance tentatively through suppression of ghrelin receptors within the NAc shell. Repeated ghrelin increases, whereas a ghrelin receptor antagonist reduces, the motivation and learning of skilled reach foraging in rats during acquisition of this behavior. In paper II, we further established that GLP-1, as ghrelin, modulates the motivation and learning of skilled reach foraging. Indeed, the GLP-1 receptor (GLP-1R) agonists, exendin-4 and liraglutide, decrease the motivation of skilled reach foraging in rats with an acquired skilled reach performance whereas another GLP-1R agonist, dulaglutide, increases the learning of this complex behavior. When it comes to GLP-1 and sexual behaviors we demonstrated in paper III that a systemic exendin-4 injection decreases social behaviors, mounting behaviors and self-grooming behaviors but does not influence preference for females or female odors in sexually naïve male mice. We also identified that activation of GLP-1R within the NTS suppresses social behaviors, mounting behaviors and self-grooming behaviors in sexually naïve male mice. In addition, in paper IV we further identified that activation of GLP-1R within the LDTg or the posterior VTA suppresses social behaviors and mounting behaviors whereas activation of GLP-1R within the NAc shell only reduces social behaviors, but not mounting behaviors, in sexually naïve male mice. Collectively, these data support the emerging literature suggesting that ghrelin increases whereas GLP-1 decreases natural rewards, by showing that these peptides via reward-related areas modulate natural rewards from both the feeding-related and the social behavior domains of natural rewards. Keywords: Reward, Gut-brain axis, Sexual behaviors, Skilled reach foraging ISBN: 978-91-7833-962-4 (PRINT) ISBN: 978-91-7833-963-1 (PDF

The Anorexigenic Peptide Neuromedin U (NMU) Attenuates Amphetamine-Induced Locomotor Stimulation, Accumbal Dopamine Release and Expression of Conditioned Place Preference in Mice.

Amphetamine dependence, besides its substantial economical consequence, is a serious cause of mortality and morbidity. By investigations of the neurochemical correlates through which addictive drugs, such as amphetamine, activate the mesoaccumbal dopamine system unique targets for treatment of drug addiction can be identified. This reward link consists of a dopamine projection from the ventral tegmental area to the nucleus accumbens (NAc) suggesting that these brain areas are important for reward. The physiological function of gut-brain peptides has expanded beyond food intake modulation and involves regulation of drug reinforcement. A novel candidate for reward regulation is the anorexigenic peptide neuromedin U (NMU). We therefore investigated the effects of intracerebroventricular (icv) administration of NMU on amphetamine's well-documented effects on the mesoaccumbal dopamine system, i.e. locomotor stimulation and accumbal dopamine release in mice. In addition, the effect of accumbal NMU administration on locomotor activity was examined. The effect of NMU, icv or intra-NAc, on the expression of conditioned place preference (CPP) was elucidated. Firstly, we showed that icv administration of NMU attenuate the amphetamine-induced locomotor stimulation, accumbal dopamine release and expression of CPP in mice. Secondly, we found that a lower dose of NMU (icv) reduce the amphetamine-induced locomotor stimulation in mice. Thirdly, we demonstrated that NMU administration into the NAc block the ability of amphetamine to cause a locomotor stimulation in mice. However, accumbal NMU administration did not attenuate the amphetamine-induced expression of CPP in mice. Our novel data suggest that central NMU signalling is involved in development of amphetamine dependence

Accumbal administration of NMU attenuates amphetamine-induced locomotor stimulation, but does not affect the expression of conditioned place preference in mice.

<p>(A) Amphetamine-induced (2 mg/kg, ip) locomotor stimulation was attenuated by an accumbal injection of NMU (62.5 ng per side). Accumbal NMU administration had no effect <i>per se</i> on locomotor activity. (B) Accumbal NMU (62.5 ng per side, Amph-NMU) administration did not attenuate amphetamine-induced (2 mg/kg, ip, Amph-Veh) expression of CPP in mice. Data are presented as mean ± SEM (n.s. P>0.05, *P<0.05).</p

Central (1 μg, icv) administration of NMU attenuates amphetamine-induced locomotor stimulation, accumbal dopamine release and expression of conditioned place preference in mice.

<p>(A) Amphetamine-induced (2 mg/kg, ip) locomotor stimulation was blocked by a central injection of NMU (1 μg, icv) at time point 15–35 minutes. Central NMU administration had no effect <i>per se</i> on locomotor activity. (B) NMU (1 μg, icv) attenuated amphetamine (2 mg/kg, ip) induced increase in accumbal dopamine release at time point 40–80 minutes. (C) Central NMU (1 μg, icv, Amph-NMU) administration prevented the amphetamine (2 mg/kg, Amph-Veh) induced expression of conditioned place preference (CPP). Data are presented as mean ± SEM (*P<0.05, **P<0.01, ***P<0.001 for Veh-Veh versus Veh-Amph and # P<0.05, ## P<0.01, ### P<0.001 for Veh-Amph versus NMU-Amph).</p

Central (0.3 μg, icv) administration of NMU reduces amphetamine-induced locomotor stimulation in mice.

<p>Amphetamine-induced (2 mg/kg, ip) locomotor stimulation was reduced, but not blocked, by a central injection of a lower does of NMU (0.3 μg, icv). Central administration of this lower dose of NMU had no effect <i>per se</i> on locomotor activity. Data are presented as mean ± SEM (n.s. P>0.05, *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001 compared to vehicle-vehicle treatment).</p