Cannabinoids Ameliorate Impairments Induced by Chronic Stress to Synaptic Plasticity and Short-Term Memory

Abstract

Repeated stress is one of the environmental factors that precipitates and exacerbates mental illnesses like depression and anxiety as well as cognitive impairments. We have previously shown that cannabinoids can prevent the effects of acute stress on learning and memory. Here we aimed to find whether chronic cannabinoid treatment would alleviate the long-term effects of exposure to chronic restraint stress on memory and plasticity as well as on behavioral and neuroendocrine measures of anxiety and depression. Late adolescent rats were exposed to chronic restraint stress for 2 weeks followed each day by systemic treatment with vehicle or with the CB1/2 receptor agonist WIN55,212-2 (1.2 mg/kg). Thirty days after the last exposure to stress, rats demonstrated impaired long-term potentiation (LTP) in the ventral subiculum-nucleus accumbens (NAc) pathway, impaired performance in the prefrontal cortex (PFC)-dependent object-recognition task and the hippocampal-dependent spatial version of this task, increased anxiety levels, and significantly reduced expression of glucocorticoid receptors (GRs) in the amygdala, hippocampus, PFC, and NAc. Chronic WIN55,212-2 administration prevented the stress-induced impairment in LTP levels and in the spatial task, with no effect on stress-induced alterations in unconditioned anxiety levels or GR levels. The CB1 antagonist AM251 (0.3 mg/kg) prevented the ameliorating effects of WIN55,212-2 on LTP and short-term memory. Hence, the beneficial effects of WIN55,212-2 on memory and plasticity are mediated by CB1 receptors and are not mediated by alterations in GR levels in the brain areas tested. Our findings suggest that cannabinoid receptor activation could represent a novel approach to the treatment of cognitive deficits that accompany a variety of stress-related neuropsychiatric disorders.

Cannabinoid Receptor Activation Prevents the Effects of Chronic Mild Stress on Emotional Learning and LTP in a Rat Model of Depression

“…We found that chronic WIN55,212-2 administration in proximity to chronic (ie, 2 weeks) restraint stress prevented the stress-induced impairment in LTP in the vSub-NAc pathway and performance in a non-aversive spatial task (Abush and Akirav, 2013). In that study (Abush and Akirav, 2013), chronic restraint stress did not result in 'classic' depressionlike symptoms such as alterations in anhedonia and coping with stress behavior, and the drug treatment was applied throughout the 2 weeks of the stress period at a high dose (1.2 mg/kg).…”

“…LTP was measured as an increase in the amplitude and slope of the evoked field potentials. Potentiation was measured as a percentage of change from the average of the 30 min baseline before HFS (Abush and Akirav, 2013). The amplitude was measured by peak-to-peak values based on the previous findings of LTP in the vSub-NAc pathway (Abush and Akirav, 2012;Dong et al, 2007).…”

“…The amplitude was measured by peak-to-peak values based on the previous findings of LTP in the vSub-NAc pathway (Abush and Akirav, 2012;Dong et al, 2007). However, it is the slope that is considered to reflect LTP (ie, the strengthening of existing synaptic contacts), whereas the amplitude may also reflect the activity of the cells (Abush and Akirav, 2013).…”

“…We have recently suggested that cannabinoid receptor activation, using the CB1/2 receptor agonist WIN55,212-2, could represent a novel approach to the treatment of cognitive deficits that accompany a variety of stress-related neuropsychiatric disorders (Abush and Akirav, 2013). We found that chronic WIN55,212-2 administration in proximity to chronic (ie, 2 weeks) restraint stress prevented the stress-induced impairment in LTP in the vSub-NAc pathway and performance in a non-aversive spatial task (Abush and Akirav, 2013).…”

Cannabidiol as a Potential Treatment for Anxiety Disorders

“…Genetic manipulations that impede CB 1 R activation are anxiogenic [35], and individuals with eCB system gene polymorphisms that reduce eCB tonefor example, FAAH gene polymorphisms-exhibit physiological, psychological, and neuroimaging features consistent with impaired fear regulation [36]. Reduction of AEA-CB 1 R signaling in the amygdala mediates the anxiogenic effects of corticotropin-releasing hormone [37], and CB 1 R activation is essential to negative feedback of the neuroendocrine stress response, and protects against the adverse effects of chronic stress [38,39]. Finally, chronic stress impairs eCB signaling in the hippocampus and amygdala, leading to anxiety [40,41], and people with PTSD show elevated CB 1 R availability and reduced peripheral AEA, suggestive of reduced eCB tone [42].…”