The CB1 receptor as an important mediator of hedonic reward processing

Abstract

The endocannabinoid (ECB) system has emerged recently as a key mediator for reward processing. It is well known that cannabinoids affect appetitive learning processes and can induce reinforcing and rewarding effects. However, the involvement of the ECB system in hedonic aspects of reward-related behavior is not completely understood. With the present study, we investigated the modulatory role of the ECB system on hedonic perception, measured by the pleasure attenuated startle (PAS) paradigm for a palatable food reward. Here, a conditioned odor is thought to induce a pleasant affective state that attenuates an aversive reflex-the acoustic startle response. Modulatory effects of the CB1 receptor antagonist/inverse agonist SR1411716 and the cannabinoid agonist WIN 55 212-2 on PAS were examined in rats. PAS was also measured in CB1 receptor knockout (KO) and wild-type (WT) mice. Pharmacological inhibition as well as the absence of CB1 receptors was found to reduce PAS, whereas WIN 55 212-2 administration increased PAS. Finally, presentation of a conditioned reward cue was found to induce striatal FosB/ΔFosB expression in WT mice, but not in KO mice, indicating a reduced stimulation of reward-related brain regions in conditioned KO mice by odor presentation. We here show that in addition to our previous studies in rats, PAS may also serve as a valuable and suitable measure to assess hedonic processing in mice. Our data further indicate that the ECB system, and in particular CB1 receptor signaling, appears to be highly important for the mediation of hedonic aspects of reward processing.

Figure 1

Effects of SR141716 (SR) and WIN 55 212-2 (WIN) on pleasure attenuated startle (PAS) in rats. Percentage change from baseline acoustic startle response (ASR) by odor presentation was assessed in trained animals and untrained controls after chronic SR/vehicle (a) and WIN/vehicle (b) treatment. PAS was significantly affected in rats that received chronic SR (1 mg/kg) treatment during appetitive odor conditioning compared with trained, vehicle-treated controls (p=0.038). No significant treatment differences could be observed between SR and untrained, vehicle-treated animals (p>0.05). Vehicle-treated animals that underwent reward-association training also differed significantly from their untrained, vehicle-treated controls (p=0.021). Furthermore, chronic WIN (0.3 mg/kg) treatment during reward conditioning was found to increase PAS compared with vehicle-treated controls (p=0.008). Chronic WIN treatment per se did not affect percentage ASR reduction in untrained animals (p>0.05), and in trained, vehicle-treated animals showed a significantly higher PAS than untrained, vehicle-treated controls (p=0.023). Data are expressed as means±SEM (p<0.05 is indicated by asterisks) (SR experiment—trained: SR n=16, vehicle n=12, untrained: SR n=6, vehicle n=7; WIN experiment: trained: WIN n=9, vehicle n=12, untrained: WIN n=6, vehicle n=9).

Figure 2

Pleasure attenuated startle (PAS), acoustic startle response (ASR), and sweetened condensed milk (SCM) intake in CB1 knockout (KO) and wild-type (WT) mice. We observed a stable PAS response in WT mice; however, PAS was found to be almost absent in CB1 KO mice (a). To control for potential variances in startle habituation between the test sessions, a second cohort of KO and WT mice underwent a sham training procedure without odor-reward association and were tested according the PAS protocol. No differences could be observed between the genotypes, indicating a similar ASR reponse after repeated testing in CB1 KO and WT animals (b). The conditioned odor-cue attenuated the ASR magnitude in WT animals during the second startle session (c), whereas no such reduction could be observed in CB1 KO mice (d). Accordingly, the time course in percentage PAS was significantly lower in CB1 KO mice throughout the whole test session (e). Finally, free SCM intake was reduced in CB1 KO mice compared with WT controls (f). Data are expressed as means±SEM (p<0.05 is indicated by asterisks) (WT and CB1 KO: n=11; sham training conditions—WT and CB1 KO: n=7).

Figure 3

Odor preference in CB1 knockout (KO) and wild-type (WT) mice. Both genotypes showed a similar preference for the scented object during odor discrimination testing, indicating a comparable ability for odor perception in CB1 KO and WT animals. Data are expressed as means±SEM (WT and CB1 KO: n=11).

Figure 4

Striatal sampling sites and exemplary FosB/ΔFosB staining. The schematic coronal brain section illustrates the steady position of sampling graticules (500 × 500 μm²) for the dorsal striatum (dStr) and nucleus accumbens (NAC) at a section plane corresponding to +1.45 to +1.35 from Bregma. Representative FosB/ΔFosB stainings of the dStr from sham- and odor-trained mice of both genotypes are shown on the right side.

Figure 5

FosB/ΔFosB stimulation by appetitive odor-cue presentation in CB1 knockout (KO) and wild-type (WT) mice. The conditioned odor cue was found to significantly enhance FosB/ΔFosB expression in trained WT animals in the nucleus accumbens (NAC) (a) and dorsal striatum (dStr) (b) compared to sham-trained controls. No such increased expression could be observed for CB1 KO mice, neither in the NAC (c) nor the dStr (d). Data are expressed as means±SEM (p<0.05 is indicated by asterisks) (WT: trained and sham-trained: n=5; CB1 KO: trained n=4, sham-trained n=5).