Lack of Cannabinoid Receptor Type-1 Leads to Enhanced Age-Related Neuronal Loss in the Locus Coeruleus

Abstract

Our laboratory and others have previously shown that cannabinoid receptor type-1 (CB1r) activity is neuroprotective and a modulator of brain ageing; a genetic disruption of CB1r signaling accelerates brain ageing, whereas the pharmacological stimulation of CB1r activity had the opposite effect. In this study, we have investigated if the lack of CB1r affects noradrenergic neurons in the locus coeruleus (LC), which are vulnerable to age-related changes; their numbers are reduced in patients with neurodegenerative diseases and probably also in healthy aged individuals. Thus, we compared LC neuronal numbers between cannabinoid 1 receptor knockout (Cnr1−/−) mice and their wild-type littermates. Our results reveal that old Cnr1−/− mice have less noradrenergic neurons compared to their age-matched wild-type controls. This result was also confirmed by the analysis of the density of noradrenergic terminals which proved that Cnr1−/− mice had less compared to the wild-type controls. Additionally, we assessed pro-inflammatory glial activity in the LC. Although the density of microglia in Cnr1−/− mice was enhanced, they did not show enhanced inflammatory profile. We hypothesize that CB1r activity is necessary for the protection of noradrenergic neurons, but its anti-inflammatory effect probably only plays a minor role in it.