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. 2013 Jul;38(8):1521-34.
doi: 10.1038/npp.2013.51. Epub 2013 Feb 20.

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

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

Hila Abush et al. Neuropsychopharmacology. .
Free PMC article

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.

Figures

Figure 1
Figure 1
The effects of chronic exposure to restraint stress and WIN55,212-2 on synaptic plasticity in the ventral subiculum-nucleus accumbens pathway. (a) The Stress-Vehicle group demonstrates reduced amplitude levels compared with the Stress-WIN and No Stress-Vehicle groups (**p<0.01). (b) The Stress-Vehicle group demonstrates reduced slope levels compared with the Stress-WIN and No Stress-Vehicle groups (#p=0.053, **p<0.01). (c) Representative traces in the NAc taken before (black) and 1 hr after (gray) HFS to the vSub (calibration: 0.2 mV, 10 ms). Up: the Stress-Vehicle group; Down: the Stress-WIN group. (d) The Stress-Vehicle group demonstrates reduced amplitude levels compared with the Stress-WIN and No Stress-Vehicle groups (*p<0.05; **p<0.01). (e) The Stress-Vehicle group demonstrates reduced slope levels compared with the No Stress-Vehicle and Stress-WIN groups, and the Stress-AM+WIN group demonstrates reduced slope levels compared with the No Stress-Vehicle group (#p=0.055; *p<0.05; **p<0.01).
Figure 2
Figure 2
The effects of chronic exposure to restraint stress and WIN55,212-2 on short-term memory. (a) In the object-location task, rats in the Stress-Vehicle group spend significantly less time exploring the new location compared with rats in the No Stress-Vehicle group. (**p<0.01). (b) In the object-location task, the Stress-Vehicle and Stress-AM+WIN groups spend significantly less time exploring the new object compared with rats in the Stress-WIN and No Stress-Vehicle groups (*p<0.05). (c) In the object-recognition task, rats in the No Stress-Vehicle group spend significantly more time exploring the new object compared with rats in the Stress-Vehicle and No stress-WIN groups (*p<0.05; **p<0.01).
Figure 3
Figure 3
The effects of chronic exposure to restraint-stress and WIN55,212-2 on performance in the open field. (a) Rats in the Stress groups spend significantly less time in the center of the open field than rats in the No Stress groups (*p<0.05; **p<0.01). (b) Rats in the WIN groups demonstrate significantly more rearing than rats in the Vehicle groups (*p<0.05; **p<0.01). (c) Rats in the No Stress-WIN group cover more distance in the open field than rats in the No Stress-Vehicle group (*p<0.05).
Figure 4
Figure 4
The effects of chronic exposure to restraint-stress and WIN55,212-2 on performance in the forced-swim test. (a) Thirty days after stress and drug injections, rats in the Stress-WIN group spend significantly less time swimming than rats in the Stress-Vehicle and No Stress-Vehicle groups (*p<0.05). (b) Twenty-four hours after stress and drug injections, rats in the Stress-Vehicle group spend significantly more time climbing than rats in the No Stress-WIN group. Rats in the No Stress-WIN group spend significantly more time immobile than rats in the Vehicle groups (**,p<0.01). (c) Ten days after stress and drug injections, there are no significant differences between the groups.
Figure 5
Figure 5
The effects of chronic exposure to restraint-stress and WIN55,212-2 on sucrose consumption and weight gain. (a) There are no significant differences between the groups in the sucrose consumption test. (b) Rats in the stress groups demonstrate lower weight gain rate compared with the non-stressed groups (**p<0.01; ***p<0.001).
Figure 6
Figure 6
The effects of chronic exposure to restraint stress and WIN55,212-2 on GR levels. Representative bands (taken from different gels) for the expression of GR and β-actin (upper panel) and quantitative analysis result (lower panel) of GR expression. (a) In the NAc, rats in the stress groups demonstrate significantly lower GR expression levels compared with rats in the non-stressed groups. Rats in the No Stress-Vehicle group demonstrate significantly lower GR expression levels compared with rats in the No Stress-WIN group (**p<0.01; ***p<0.001). (b) In the BLA, rats in the stress groups demonstrate significantly lower GR expression levels compared with rats in the non-stressed groups (*p<0.05; **p<0.01; ***p<0.001). (c) In the PFC, rats in the stress groups demonstrate significantly lower GR expression levels compared with rats in the non-stressed groups (***p<0.001). (d) In the CA1, rats in the Stress-Vehicle group demonstrate significantly lower GR expression levels compared with rats in non-stressed groups. Rats in the Stress-WIN group demonstrate significantly lower GR expression levels compared with rats in the No Stress-WIN group (*p<0.05; **p<0.01). (e) In the vSub, rats in the stress groups demonstrate significantly lower GR expression levels compared with rats in the non-stressed groups (**p<0.01; ***p<0.001).

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