Repeated Stress Impairs Endocannabinoid Signaling in the Paraventricular Nucleus of the Hypothalamus

Abstract

Endocannabinoids (eCBs) are ubiquitous retrograde signaling molecules in the nervous system that are recruited in response to robust neuronal activity or the activation of postsynaptic G-protein-coupled receptors. Physiologically, eCBs have been implicated as important mediators of the stress axis and they may contribute to the rapid feedback inhibition of the hypothalamic-pituitary-adrenal axis (HPA) by circulating corticosteroids (CORTs). Understanding the relationship between stress and eCBs, however, is complicated by observations that eCB signaling is itself sensitive to stress. The mechanisms that link stress to changes in synaptic eCB signaling and the impact of these changes on CORT-mediated negative feedback have not been resolved. Here, we show that repetitive immobilization stress, in juvenile male rats, causes a functional downregulation of CB 1 receptors in the paraventricular nucleus of the hypothalamus (PVN). This loss of CB 1 receptor signaling, which requires the activation of genomic glucocorticoid receptors, impairs both activity and receptordependent eCB signaling at GABA and glutamate synapses on parvocellular neuroendocrine cells in PVN. Our results provide a plausible mechanism for how stress can lead to alterations in CORT-mediated negative feedback and may contribute to the development of plasticity of HPA responses.

Endocannabinoid-mediated retrograde modulation of synaptic transmission

“…Conversely, stress-induced HPA axis activity alters the endocannabinoid system, either positively or negatively depending on the brain region, age and conditions of stress, in several brain regions including the hippocampus, amygdala, hypothalamus, nucleus accumbens and prefrontal cortex [6,37,51]. For example, repetitive immobilization stress impaired DSI/DSE by down-regulating CB 1 receptors in the paraventricular nucleus of the hypothalamus [52], whereas chronic stress enhanced DSI partially by down-regulating MGL in the basolateral amygdala [53]. Interestingly, in vivo recordings of medial prefrontal cortex (mPFC)-evoked spike probability from the bed nucleus of the stria terminalis showed that acute restraint stress switched CB 1 -dependent plasticity from LTD to LTP, and that the stress-elicited shift in plasticity was controlled by CB 1 receptors on excitatory terminals [54].…”

Novel Aspects of Glucocorticoids Actions on Energy Homeostasis and Hydromineral Balance

“…According to these findings, these authors proposed that the CB1R-mediated signaling is required for glucocorticoid negative feedback, but not for the initial HPA axis response to restraint. In addition, a downregulation of CB1R and an impaired glucocorticoid-mediated inhibition of excitatory inputs to parvocellular PVN neurons were observed in hypothalamic slices from rats submitted to repeated immobilization stress (Wamsteeker et al, 2010). Interestingly, application of a CB1R agonist to the bath did not suppress the excitatory inputs onto PVN neurons, suggesting that the CB1R-mediated signaling may be disrupted after prolonged exposure to stress.…”

Neuromodulators, stress and plasticity: a role for endocannabinoid signalling

“…This postsynaptic depolarization causing a transient suppression of GABA or glutamate release is termed depolarization-induced suppression of inhibition (DSI) (Pitler and Alger, 1992) or excitation (DSE), respectively (Kodirov et al, 2010;Kreitzer and Regehr, 2001b). This method is used to measure retrograde eCB production and signalling, and has been shown to occur in core regions implicated in the stress response, including the hippocampus (Pitler and Alger, 1992), amygdala (Kodirov et al, 2010), prefrontal cortex (Yoshino et al, 2011 and hypothalamus (Wamsteeker et al, 2010).Interestingly, induction of DSI in one cell can inhibit nearby synapses as well ). Application of the group I mGluR agonist DHPG causes a comparable suppression of evoked inhibitory postsynaptic currents (eIPSCs), through enhanced production of eCBs, confirmed by occlusion with the CB1R agonist WIN55,212-2 (WIN) (Neu et al, 2007;Maejima et al, 2001).…”

“…The role of voltagesensitive calcium channels is confirmed by occlusion of CB1R agonist actions by the application of an N-type Ca 2+ channel blocker ). This eCB-induced depression of eIPSCs is accompanied by an inhibition of spontaneous IPSC (sIPSC) frequency, and in some cases sIPSC amplitude (Pitler and Alger, 1992;Wamsteeker et al, 2010;). This reduction in sIPSC frequency appears to be directly proportionate to eIPSC inhibition (J. I. Wamsteeker, personal communication).…”

“…2). This effect requires the activation of the genomic GC receptor as it is prevented by intraperitoneal injections of the GC receptor antagonist RU486 prior to stress (Wamsteeker et al, 2010). Furthermore, this loss of eCB signalling is due to compromised function of the CB1R and not to an inability of this system to produce eCBs.…”