Peripheral CB1 receptor blockade acts as a memory enhancer through an adrenergic-dependent mechanism

Abstract

Peripheral inputs to the brain continuously shape its function and adjust non-emotional memory, but the mechanisms involved are not fully understood. Cannabinoid type-1 receptors (CB1Rs), widely distributed in the organism, are well recognized players in memory performance and their systemic modulation significantly influence memory function. By assessing non-emotional memory in mice, we found a relevant role of peripheral CB1R in memory persistence. Indeed, peripherally restricted CB1R antagonist AM6545 showed a mnemonic effect occluded in adrenalectomized mice, after peripheral adrenergic blockade, or when vagus nerve was chemogenetically inhibited. Genetic CB1R deletion in dopamine β-hydroxylase-expressing cells enhanced memory persistence, supporting a role of peripheral CB1Rs modulating the adrenergic tone. Notably, while brain connectivity was slightly affected by peripheral CB1R inhibition, locus coeruleus activity and extracellular norepinephrine in the hippocampus, were increased, and intra-hippocampal β-adrenergic blockade prevented AM6545 mnemonic effects. Together, we disclose a novel peripheral mechanism relevant for non-emotional memory persistence modulation.

Sub-chronic peripheral CB1R inhibition enhances cognitive performance and induces hippocampal synaptic plasticity changes in naïve mice

“…Regarding emotional memory, we reported that a single administration of AM6545 after the first extinction session in the context fear conditioning, promoted freezing behavior when memory was assessed the next day. However, freezing behavior was reduced when assessed during the subsequent extinction sessions (Martínez-Torres et al, 2023). In the present study, we showed that administering AM6545 after every extinction session maintains high freezing levels across days, pointing to a persistent effect of the repeated exposure to AM6545 in emotional memory.…”

“…Our previous research showed that AM6545-memory improvement after a single administration was dependent on an adrenergic mechanism given that AM6545 mnemonic effect was prevented by the peripherally restricted β-adrenergic antagonist sotalol (Martínez-Torres et al, 2023). The fact that here sotalol pretreatment significantly reduced the mnemonic effect of sub-chronic AM6545 points to a relevant role of the peripheral adrenergic tone.…”

“…Here, we demonstrated that no tolerance develops after repeated treatment as object-recognition memory persistence was significantly enhanced in both male and female mice when the test was performed 48 h after training. We used the period of 48 h as we previously revealed that at this time point control mice naturally show reduced novel object discrimination and hence low discrimination indexes (Martínez-Torres et al, 2023). Moreover, we also observed that the repeated AM6545 treatment improved learning in both sexes when NORT was modified by reducing the training period to 3 min, compared to the 9 min in standard conditions.…”

“…We performed a sub-chronic treatment with AM6545 for 7 days to assess whether tolerance to the mnemonic effects of acute AM6545 previously described (Martínez-Torres et al, 2023) was developed after repeated treatment. We tested memory at 48 h as we previously demonstrated that object-recognition memory is significantly reduced at this time point after training, which makes it a suitable interval to assess memory persistence (Martínez-Torres et al, 2023). We observed that sub-chronic AM6545 treatment potentiated memory recall at this time point in the NORT in both male (Student's t-test: p = 0.002) (Figure 1A) and female (Student's t-test: p = 0.001) mice (Figure 1B), indicating the lack of tolerance to the mnemonic effect of AM6545.…”

“…Interestingly, it was previously demonstrated that the acute inhibition of peripheral CB1R from dopamine β-hydroxylase (DBH+) cells from adrenal glands triggers an adrenergic mechanism that derives in an enhancement in memory persistence that involves the vagus nerve. This cognitive enhancement is accompanied by changes in functional brain connectivity as well as an increase in hippocampal extracellular noradrenaline (Martínez-Torres et al, 2023).…”