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, 6 (11), e26617

Circuit Specific Functions of Cannabinoid CB1 Receptor in the Balance of Investigatory Drive and Exploration


Circuit Specific Functions of Cannabinoid CB1 Receptor in the Balance of Investigatory Drive and Exploration

Martin Häring et al. PLoS One.


Well balanced novelty seeking and exploration are fundamental behaviours for survival and are found to be dysfunctional in several psychiatric disorders. Recent studies suggest that the endocannabinoid (eCB) system is an important control system for investigatory drive. Pharmacological treatment of rodents with cannabinergic drugs results in altered social and object investigation. Interestingly, contradictory results have been obtained, depending on the treatment, drug concentration and experimental conditions. The cannabinoid type 1 (CB1) receptor, a central component of the eCB system, is predominantly found at the synapses of two opposing neuronal populations, i.e. on inhibitory GABAergic and excitatory glutamatergic neurons. In the present study, using different transgenic mouse lines, we aimed at investigating the impact of CB1 receptor inactivation in glutamatergic or GABAergic neurons on investigatory behaviour. We evaluated animate (interaction partner) and inanimate (object) exploratory behaviour in three different paradigms. We show that exploration was increased when CB1 receptor was deleted from cortical and striatal GABAergic neurons. No effect was observed when CB1 receptor was deleted specifically from dopamine receptor D1-expressing striatal GABAergic medium spiny neurons. In contrast, deletion of CB1 receptor from cortical glutamatergic neurons resulted in a decreased exploration. Thus, our results indicate that exploratory behaviour is accurately balanced in both, the social and non-social context, by the eCB system via CB1 receptor activation on cortical glutamatergic and GABAergic neurons. In addition, the results could explain the contradictory findings of previous pharmacological studies and could further suggest a possibility to readjust an imbalance in exploratory behaviour observed in psychiatric disorders.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.


Figure 1
Figure 1. Inanimate exploration in the novel object recognition task.
(A–C) Total time of exploration of two identical objects (O1, both on left and right side) during the training session for three conditional CB1 receptor mutant lines (Glu-CB1 [n = 23+13], GABA-CB1 [n = 18+23], D1-CB1 [12+12]) and their wild-type control littermates. (D–F) Total time of exploration of familiar object (O1) and novel object (O2 or O3) during the retention session after 2 h or 24 h (G–I). Glu-CB1−/− mice displayed a reduced exploration, while GABA-CB1−/− mice showed an increased exploration both in the training and retention session when compared to their wild-type littermate controls. No significant genotype differences were observed in the D1-CB1 mutant line. 2-way ANOVA (genotype differences) *p<0.05, ***p<0.001; t-test (discrimination index DI) #p<0.05.
Figure 2
Figure 2. Animate vs. inanimate exploration in the sociability test.
(A–C) Comparison of animate (mouse) and inanimate (object, “empty”) exploration for the three mutants lines (Glu-CB1 [n = 22+13], GABA-CB1 [n = 18+23], D1-CB1 [16+16]) and their wild-type littermate controls during the sociability phase. (D–F) Exploration of the familiar and the novel interaction partner for during the social novelty phase. Glu-CB1−/− mice displayed no significant change in the exploration session, where there was a choice between the object and the interaction partner. In the social novelty phase, however, the interaction with a novel interaction partner was decreased when compared with their wild-type littermate controls. GABA-CB1−/− mice showed an increased social interaction in both sessions. In the D1-CB1 mutant line, no genotype differences were observed neither in the sociability nor in the social novelty phase. n = 11–20 animals; t-test *p<0.05, **p<0.01.
Figure 3
Figure 3. Animate exploration in the resident-intruder test.
(A–C) Social interaction with an unknown, younger intruder for all three mutant lines (Glu-CB1 [n = 23+13], GABA-CB1 [n = 18+23], D1-CB1 [n = 16+16]). (D–E) Number of fights induced by the resident is shown for all three mutant lines. Glu-CB1−/− mice showed a significantly reduced exploration during the first 5 min observation period and an increased aggression towards the intruder when compared to wild-type littermate controls. GABA-CB1−/− mice displayed an increased interaction with the intruder, but no difference in aggressive behaviour. D1-CB1−/− mice showed no behavioural changes as compared to their wild-type littermate controls. t-test *p<0.05, **p<0.01.

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