Abstract
Although cannabinoid CB1 receptors (CB1Rs) are densely expressed in neurons expressing dopamine D1 receptors (D1Rs), it is not fully understood to what extent they modulate emotional behaviors. We used conditional CB1R knock-out animals lacking CB1Rs in neurons expressing D1R (D1–CB1−/−) in order to answer this question. To elucidate the behavioral effects of CB1R deficiency in this specific neuronal subpopulation, we subjected D1–CB1−/− mice to a battery of behavioral tests which included exploration-based tests, depressive-like behavioral tests, social behavior, and fear-related memory paradigms. D1–CB1−/− did not show any difference in the exploration-based paradigms such as open field, elevated plus maze, or novel object investigation test, except for an increase in novelty-induced grooming. By contrast, they showed a mild anhedonia-like state as described by the slightly decreased preference for sweet solution, as compared to wild-type control group. This decrease, however, could be observed only during the first day of exposure, thus suggesting increased neophobia as an alternative explanation. Accordingly, mutant mice performed normally in the forced swim test, a procedure widely used for evaluating behavioral despair in rodents. However, weak- to moderate anxiety-like phenotypes were evident when D1–CB1−/− mice were tested for social behavior. Most strikingly, D1–CB1−/− mice exhibited significantly increased contextual and auditory-cued fear, with attenuated within session extinction, suggesting that a specific reduction of endocannabinoid signaling in neurons expressing dopamine D1Rs is able to affect acute fear adaptation. These results provided first direct evidence for a cross-talk between dopaminergic D1Rs and endocannabinoid system in terms of controlling negative affect.
Highlights
In the central nervous system (CNS), endogenous cannabinoids compounds activate cannabinoid CB1 receptors (CB1Rs), which are located pre-synaptically in several brain regions such as prefrontal cortex, hippocampus, amygdala, and basal ganglia
The dopamine D1 receptors (D1Rs), which belong to the “D1-like” group, are expressed in brain regions involved in aversive learning and memory such as nucleus accumbens, hippocampus, and amygdala. (Kamei et al, 1995; Bernabeu et al, 1997; El-Ghundi et al, 2001; Nagai et al, 2007)
In the present study we provide first evidence that the genetic deletion of cannabinoids CB1Rs in dopamine D1Rs-expressing neurons is able to affect the emotional behavior in mice in highly selective manner
Summary
In the central nervous system (CNS), endogenous cannabinoids compounds activate cannabinoid CB1 receptors (CB1Rs), which are located pre-synaptically in several brain regions such as prefrontal cortex, hippocampus, amygdala, and basal ganglia. They act as inhibitory retrograde signaling messengers at glutamatergic and GABAergic synapses, modulating the release of several neurotransmitters such as acetylcholine or dopamine (DA) (Marsicano and Lutz, 1999; Piomelli, 2003). It has been suggested that CB1R signaling modulates DAergic pathways by influencing directly or indirectly the activity of DAergic neurons through either post- or pre-synaptic mechanisms (Laviolette and Grace, 2006) Both the mechanisms through which DAergic and EC signaling cross-talk and the role played by the dopamine D1 receptor positive neurons still remain unclear. The colocalization of CB1Rs with D1Rs indicates that these receptors may interact by potentially modifying their respective functions with important behavioral and pharmacological consequences (Hermann et al, 2002)
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