Cannabinoid type-1 receptor signaling in dopaminergic Engrailed-1 expressing neurons modulates motivation and depressive-like behavior
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Abstract
The endocannabinoid system comprises highly versatile signaling functions
within the nervous system. It is reported to modulate the release of several
neurotransmitters, consequently affecting the activity of neuronal circuits.
Investigations have highlighted its roles in numerous processes, including
appetite-stimulating characteristics, particularly for palatable food. Moreover,
endocannabinoids are shown to fine-tune dopamine-signaled processes
governing motivated behavior. Specifically, it has been demonstrated that
excitatory and inhibitory inputs controlled by the cannabinoid type 1 receptor
(CB1) regulate dopaminergic neurons in the mesocorticolimbic pathway. In the
present study, we show that mesencephalic dopaminergic (mesDA) neurons
in the ventral tegmental area (VTA) express CB1, and we investigated the
consequences of specific deletion of CB1 in cells expressing the transcription
factor Engrailed-1 (En1). To this end, we validated a new genetic mouse line EN1-
CB1-KO, which displays a CB1 knockout in mesDA neurons beginning from their
differentiation, as a tool to elucidate the functional contribution of CB1 in mesDA
neurons. We revealed that EN1-CB1-KO mice display a significantly increased
immobility time and shortened latency to the first immobility in the forced swim
test of adult mice. Moreover, the maximal effort exerted to obtain access to
chocolate-flavored pellets was significantly reduced under a progressive ratio
schedule. In contrast, these mice do not differ in motor skills, anhedonia- or
anxiety-like behavior compared to wild-type littermates. Taken together, these
findings suggest a depressive-like or despair behavior in an inevitable situation
and a lack of motivation to seek palatable food in EN1-CB1-KO mice, leading
us to propose that CB1 plays an important role in the physiological functions
of mesDA neurons. In particular, our data suggest that CB1 directly modifies
the mesocorticolimbic pathway implicated in depressive-like/despair behavior
and motivation. In contrast, the nigrostriatal pathway controlling voluntary
movement seems to be unaffected.
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Frontiers in molecular neuroscience, 17, Frontiers Media Foundation, Lausanne, 2024, https://doi.org/10.3389/fnmol.2024.1379889