Abstract
Neurocognitive effects of cannabinoids have been extensively studied with a focus on CB1 cannabinoid receptors because CB1 receptors have been considered the major cannabinoid receptor in the nervous system. However, recent discoveries of CB2 cannabinoid receptors in the brain demand accurate determination of whether and how CB2 receptors are involved in the cognitive effects of cannabinoids. CB2 cannabinoid receptors are primarily involved in immune functions, but also implicated in psychiatric disorders such as schizophrenia and depression. Here, we examined the effects of CB2 receptor knockout in mice on memory to determine the roles of CB2 receptors in modulating cognitive function. Behavioral assays revealed that hippocampus-dependent, long-term contextual fear memory was impaired whereas hippocampus-independent, cued fear memory was normal in CB2 receptor knockout mice. These mice also displayed enhanced spatial working memory when tested in a Y-maze. Motor activity and anxiety of CB2 receptor knockout mice were intact when assessed in an open field arena and an elevated zero maze. In contrast to the knockout of CB2 receptors, acute blockade of CB2 receptors by AM603 in C57BL/6J mice had no effect on memory, motor activity, or anxiety. Our results suggest that CB2 cannabinoid receptors play diverse roles in regulating memory depending on memory types and/or brain areas.
Highlights
Neuropsychiatric effects of cannabinoids, including endocannabinoids and cannabis ingredients, have been primarily studied in relation to CB1 cannabinoid receptors (CB1Rs) because CB1R has been considered the major, if not the only, cannabinoid receptor in the nervous system
Contextual, but Not Cued, Fear Memory Is Impaired in CB2R KO Mice
CB2R wild type (WT) and KO mice were presented with a 30 s tone and a 2 s electric foot shock, 3 times every 2 min (Figure 1(a))
Summary
Neuropsychiatric effects of cannabinoids, including endocannabinoids and cannabis ingredients, have been primarily studied in relation to CB1 cannabinoid receptors (CB1Rs) because CB1R has been considered the major, if not the only, cannabinoid receptor in the nervous system. In situ hybridization studies show that CB2R mRNAs are expressed in neurons in the cerebellum [5], globus pallidus, cerebral cortex, hippocampus [6, 7], ventral tegmental area [8], nucleus accumbens, and dorsal striatum [9] in rodents and macaque. These data have been supported by negative control experiments with CB2R knockout (KO) mice [8] or sense probes [5, 7, 8]. The expression of CB2Rs in microglia can be induced under pathological conditions for neuroprotective immune responses (for review, see [14])
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