Endocannabinoid Modulation of Cortical Up-States and NREM Sleep

Abstract

Up-/down-state transitions are a form of network activity observed when sensory input into the cortex is diminished such as during non-REM sleep. Up-states emerge from coordinated signaling between glutamatergic and GABAergic synapses and are modulated by systems that affect the balance between inhibition and excitation. We hypothesized that the endocannabinoid (EC) system, a neuromodulatory system intrinsic to the cortical microcircuitry, is an important regulator of up-states and sleep. To test this hypothesis, up-states were recorded from layer V/VI pyramidal neurons in organotypic cultures of wild-type or CB1R knockout (KO) mouse prefrontal cortex. Activation of the cannabinoid 1 receptor (CB1) with exogenous agonists or by blocking metabolism of endocannabinoids, anandamide or 2-arachidonoyl glycerol, increased up-state amplitude and facilitated action potential discharge during up-states. The CB1 agonist also produced a layer II/III-selective reduction in synaptic GABAergic signaling that may underlie its effects on up-state amplitude and spiking. Application of CB1 antagonists revealed that an endogenous EC tone regulates up-state duration. Paradoxically, the duration of up-states in CB1 KO cultures was increased suggesting that chronic absence of EC signaling alters cortical activity. Consistent with increased cortical excitability, CB1 KO mice exhibited increased wakefulness as a result of reduced NREM sleep and NREM bout duration. Under baseline conditions, NREM delta (0.5–4 Hz) power was not different in CB1 KO mice, but during recovery from forced sleep deprivation, KO mice had reduced NREM delta power and increased sleep fragmentation. Overall, these findings demonstrate that the EC system actively regulates cortical up-states and important features of NREM sleep such as its duration and low frequency cortical oscillations.

Revealing the role of the endocannabinoid system modulators, SR141716A, URB597 and VDM-11, in sleep homeostasis

“…For example, preceding studies have demonstrated that administrations of SR141716A promote waking and diminish SWS and REMS (Santucci et al, 1996;Murillo-Rodrı´guez et al, 2001. Furthermore, the CB 1 cannabinoid receptor KO mice show a reduction in SWS during sleep recovery period (Pava et al, 2014;Silvani et al, 2014). However, evidence showing an apparent opposite modulatory role of the CB 1 cannabinoid receptor in sleep modulation has been published as well.…”

Integrating Endocannabinoid Signaling and Cannabinoids into the Biology and Treatment of Posttraumatic Stress Disorder

“…Several reports have suggested that AEA signaling may be involved in sleep induction (Mechoulam et al, 1997;Murillo-Rodriguez et al, 2003;Murillo-Rodriguez et al, 2001). Similarly, augmentation of eCB signaling alters sleep architecture to promote time spent in NREM sleep and less time in wakefulness (Huitron-Resendiz et al, 2004;Pava et al, 2014Pava et al, , 2016. Consistent with this, disruption of CB1 receptor signaling is known to increase EEG measures of arousal, reduce time spent sleeping, increase wakefulness, and alter sleep architecture, with some evidence suggesting that impairments in CB1 receptor signaling favor an increase in time spent in REM sleep (Pava et al, 2014(Pava et al, , 2016Santucci et al, 1996;Silvani et al, 2014).…”

Dose-dependent cannabis use, depressive symptoms, andFAAHgenotype predict sleep quality in emerging adults: a pilot study

“…CB1 receptor antagonists increase wakefulness and reduce rapid eye movement (REM) time in animal studies (5–8). In addition, CB1 knockout mice experience increased wakefulness (9). The relationship between CB1 receptor inactivation and wakefulness is likely related to anandamide (AEA), an endogenous cannabinoid that, like THC, binds to the CB1 receptor and promotes sleep, including increased slow wave sleep (SWS) and REM time (6, 10–13).…”