Voluntary exercise and sucrose consumption enhance cannabinoid CB1 receptor sensitivity in the striatum

Valentina De Chiara, Francesco Errico, Alessandra Musella, Silvia Rossi, Giorgia Mataluni, Lucia Sacchetti, Alberto Siracusano, Maura Castelli, Francesca Cavasinni, Giorgio Bernardi, Alessandro Usiello, Diego Centonze, Valentina De Chiara, Francesco Errico, Alessandra Musella, Silvia Rossi, Giorgia Mataluni, Lucia Sacchetti, Alberto Siracusano, Maura Castelli, Francesca Cavasinni, Giorgio Bernardi, Alessandro Usiello, Diego Centonze

Abstract

The endogenous cannabinoid system is involved in the regulation of the central reward pathway. Running wheel and sucrose consumption have rewarding and reinforcing properties in rodents, and share many neurochemical and behavioral characteristics with drug addiction. In this study, we investigated whether running wheel or sucrose consumption altered the sensitivity of striatal synapses to the activation of cannabinoid CB1 receptors. We found that cannabinoid CB1 receptor-mediated presynaptic control of striatal inhibitory postsynaptic currents was remarkably potentiated after these environmental manipulations. In contrast, the sensitivity of glutamate synapses to CB1 receptor stimulation was unaltered, as well as that of GABA synapses to the stimulation of presynaptic GABAB receptors. The sensitization of cannabinoid CB1 receptor-mediated responses was slowly reversible after the discontinuation of running wheel or sucrose consumption, and was also detectable following the mobilization of endocannabinoids by metabotropic glutamate receptor 5 stimulation. Finally, we found that the upregulation of cannabinoid transmission induced by wheel running or sucrose had a crucial role in the protective effects of these environmental manipulations against the motor and synaptic consequences of stress.

Figures

Figure 1
Figure 1
Running wheel and sucrose consumption potentiate the effects of HU210 on striatal sIPSCs. (a) The graph shows that HU210-induced reduction of sIPSC frequency was normal after 1 and 3 days of exposure to sucrose-containing solution. Conversely, the effects of HU210 on sIPSCs were potentiated after 7 and 15 days of sucrose exposure. (b) Preincubation with the CB1 receptor antagonist AM251 prevented the depressant action of HU210 both in control mice and in sucrose-exposed mice. The electrophysiological traces in the bottom are examples of voltage–clamp recordings before and during the application of HU210 in control and sucrose (7 days)-exposed mice. (c) The graph shows that the HU210-induced reduction on sIPSC frequency was normal after 1, 3, and 7 days of wheel running. Instead, the effects of HU210 on sIPSCs were potentiated after 15 and 30 days of exposure to running wheel. (d) Preincubation with AM251 prevented the depressant action of HU210 in both control mice and running wheel-exposed mice. The electrophysiological traces on the bottom are examples of voltage–clamp recordings before and during the application of HU210 in control and running wheel (15 days)-exposed mice. *p<0.05 compared with control.
Figure 2
Figure 2
Running wheel and sucrose consumption potentiate the effects of HU210 through a presynaptic action. (a and b) The activation of CB1 receptors with HU210 reduced mIPSC frequency but not amplitude in control and in rewarded mice. In sucrose (7 days)-receiving mice (a) and in wheel (15 days)-exposed mice (b), the effect of HU210 was potentiated. (c–e) Cumulative distribution of mIPSC inter-event interval recorded before and during HU210 application from control mice (c), sucrose (7 days)-receiving mice (d), and wheel (15 days)-exposed mice (e). (f) HU210 enhanced PPR of eIPSCs in neurons recorded from control and rewarded mice. Samples of PPR recordings before and during the application of HU210 in control (upper traces) and sucrose (7 days)-receiving mice (lower traces) are shown on the right. *p<0.05 compared with control, #p<0.05 compared with pre-drug values.
Figure 3
Figure 3
Hedonic effect of sucrose in C57BL/6J mice. Two-bottle free-choice sucrose preference test, carried out in control mice (n=11 per sucrose concentration), indicates that both 0.75 and 3% concentrations exert similar rewarding responses. Preference for sucrose, expressed in percentage, was used as dependent variable. ***p<0.0001, compared with control water bottle (Fisher's post-hoc comparison). All values are expressed as mean±SEM.
Figure 4
Figure 4
Cannabinoid receptor activity after running wheel or sucrose consumption. The histogram shows the dose–response relationship for HU210 effects in rewarded and control mice. *p<0.05.
Figure 5
Figure 5
Effects of time on running wheel- and sucrose-induced sensitization of cannabinoid receptors. (a) The graph shows that the depressant effects of HU210 on sIPSC frequency were still potentiated in mice exposed for 7 days to sucrose-containing solution and recorded 1 day after. In mice recorded 3 and 7 days after the last exposure to sucrose, HU210 produced normal effects. (b) The depressant effects of HU210 on sIPSC frequency were still potentiated in mice exposed to running wheel for 15 days and recorded 1 and 3 days after. In mice recorded 7 days after the last exposure to running wheel, HU210 produced normal effects. *p<0.05 compared with control.
Figure 6
Figure 6
Running wheel and sucrose consumption potentiate the effects of HU210 on striatal sIPSC through a specific pre-synaptic action. (a and b) The depressant effect of baclofen (3 and 10 μM) on sIPSC frequency was similar in control mice, in sucrose (7 days)-receiving mice (a) and in wheel (15 days)-exposed mice (b).
Figure 7
Figure 7
Effects of DHPG on striatal mIPSCs. (a) The reduction of mIPSC frequency after the application of the group I mGlu receptor agonist DHPG was potentiated in sucrose (7 days)-treated mice. (b) Preincubation with the CB1 receptor antagonist AM251 prevented the depressant action of DHPG in control and sucrose (7 days)-receiving mice. Traces in the bottom are voltage–clamp recordings before and during the application of DHPG in control and sucrose (7 days)-treated mice. (c) The graph shows that the reduction of mIPSC frequency after the application of DHPG was increased by running wheel (15 days). (d) Preincubation with AM251 prevented the depressant action of DHPG in control and in running wheel (15 days)-exposed mice. The traces on the bottom are examples of voltage–clamp recordings before and during the application of DHPG in control and in running wheel (15 days)-exposed mice.
Figure 8
Figure 8
Effects of HU210 on striatal glutamatergic transmission. (a) The depressant effects of HU210 on sEPSC frequency were similar in control and in mice exposed to sucrose (7 days)-containing solution. The electrophysiological traces on the right are examples of sEPSCs before and during the application of HU210 in control and sucrose (7 days)-exposed mice. (b) The depressant effects of HU210 on sEPSC frequency were comparable in control and in running wheel (15 days)-exposed animals. The electrophysiological traces on the right are examples of voltage–clamp recordings before and during the application of HU210 in control and running wheel (15 days)-exposed mice.
Figure 9
Figure 9
Running wheel and sucrose consumption protect mice from the behavioral effect of social defeat stress. Mice were allowed to explore an open-field box for 30 min. (a) Total distance traveled by mice subjected to social stress was significantly reduced compared with non-stressed animals. On the contrary, mice previously exposed to 15 days of running wheel or to 7 days of sucrose consumption showed a locomotor activity comparable with controls. (b) Similar results were obtained by recording the profile of locomotion over successive 10-min intervals. (c) The distance covered in the center compared with the total distance was used as a parameter of anxiety-related behavior. In accordance to motor activity, this index of emotionality showed that running wheel and sucrose rewards are able to prevent stress-induced anxiety. Indeed, mice exposed to natural rewards before stress showed distance ratios comparable with those of their control non-stressed littermates. (d) The graph shows the protective action of natural rewards from the synaptic consequences of stress: sucrose (7 days) treatment and running wheel (15 days) exposure were able to rescue the effect of HU210 on sIPSC frequency. *p<0.05 compared with control mice. **p<0.01 compared with control mice.
Figure 10
Figure 10
Behavioral effects of AM251 in mice exposed to running wheel or to sucrose before the stress procedure. (a and b) Blockade of CB1 receptors prevented the protective action of both running wheel and sucrose consumption on the motor effect of stress.

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