Cannabinoid receptor activation prevents the effects of chronic mild stress on emotional learning and LTP in a rat model of depression

Abstract

Most psychiatric disorders are characterized by emotional memory or learning disturbances. Chronic mild stress (CMS) is a common animal model for stress-induced depression. Here we examined whether 3 days of treatment using the CB1/2 receptor agonist WIN55,212-2 could ameliorate the effects of CMS on emotional learning (ie, conditioned avoidance and extinction), long-term potentiation (LTP) in the hippocampal-accumbens pathway, and depression-like symptoms (ie, coping with stress behavior, anhedonia, and weight changes). We also examined whether the ameliorating effects of WIN55,212-2 on behavior and physiology after CMS are mediated by CB1 and glucocorticoid receptors (GRs). Rats were exposed to CMS or handled on days 1-21. The agonist WIN55,212-2 or vehicle were administered on days 19-21 (IP; 0.5 mg/kg) and behavioral and electrophysiological measures were taken on days 23 and 28. The CB1 receptor antagonist AM251 (IP; 0.3 mg/kg) or the GR antagonist RU-38486 (IP; 10 mg/kg) were co-administered with WIN55,212-2. Our results show that CMS significantly modified physiological and behavioral reactions, as observed by the impairment in avoidance extinction and LTP in the hippocampal-accumbens pathway, and the alterations in depression-like symptoms, such as coping with stress behavior, weight gain, and sucrose consumption. The most significant effect observed in this study was that 3 days of WIN55,212-2 administration prevented the CMS-induced alterations in emotional memory (ie, extinction) and plasticity. This effect was mediated by CB1 receptors as the CB1 receptor antagonist AM251 prevented the ameliorating effects of WIN55,212-2 on extinction and LTP. The GR antagonist RU-38486 also prevented the CMS-induced alterations in extinction and plasticity, and when co-administered with WIN55,212-2, the preventive effects after CMS were maintained. The findings suggest that enhancing cannabinoid signaling could represent a novel approach to the treatment of cognitive deficits that accompany stress-related depression.

Figure 1

WIN55,212-2 prevents the CMS-induced impairment in extinction. (a) When tested on day 23, the No CMS-Veh group demonstrated decreased latency compared with all the groups on Ext1. On Ext2, Ext3, and Ext4, the No CMS-Veh and CMS-WIN groups demonstrated decreased latency compared with the CMS-Veh and CMS-WIN+AM groups. On Ext5, the No CMS+Veh group demonstrated decreased latency compared with the CMS+Veh and CMS+WIN+AM groups (*p<0.05; **p<0.01). (b) When tested on day 28, the CMS-WIN group demonstrated decreased latency compared with the CMS-Veh and CMS+WIN+AM group on Ext1. On Ext2, the No CMS+Veh group demonstrated decreased latency compared with the CMS-Veh. On Ext3, Ext4, and Ext5, the No CMS+Veh and CMS+WIN groups demonstrated decreased latency compared with the CMS-Veh and CMS+WIN+AM groups (*p<0.05; **p<0.01; ***p<0.001). (c) When the drugs were injected with no stress exposure 2 days before conditioning, the Vehicle group demonstrated decreased latency compared with the other groups on Cond and increased latency on Ext1 and Ext2 (*p<0.05; **p<0.01; ***p<0.001). (d) When WIN55,212-2 or AM251were injected without stress exposure a week before conditioning, conditioned avoidance and extinction levels were not significantly different from the vehicle-treated rats. (e) When tested on day 23, the No CMS-Veh group demonstrated decreased latency compared with the CMS-Veh and CMS-RU groups on Cond. On Ext2, the CMS-Veh group demonstrated increased latency compared with the No CMS-Veh and CMS-RU groups. On Ext3 and Ext4, the CMS-Veh group demonstrated increased latency compared with all the groups (*p<0.05; **p<0.01).

Figure 2

WIN55,212-2 prevents the CMS-induced impairment in LTP in the vSub-NAc pathway. (a) When tested on day 23, the CMS-Veh and CMS-AM+WIN groups demonstrated significantly reduced amplitude compared with the No CMS-Veh and CMS-WIN groups post HFS (*p<0.05). (b) When tested on day 23, the CMS-Veh and CMS-AM+WIN groups demonstrated significantly reduced slope compared with the CMS-WIN group post HFS. Also the CMS-WIN+AM showed reduced slope compared with the No CMS-Veh group post HFS (*p<0.05). (c) When tested on day 28, all the groups demonstrated similar amplitude, suggesting intact LTP. (d) When tested on day 28, all the groups demonstrated similar slope, suggesting intact LTP. (e) Representative traces in the NAc taken before (continuous line) and 1 h after (broken line) HFS to the vSub (calibration: 0.2 mV, 10 msec).

Figure 3

RU-38486 prevents the CMS-induced impairment in LTP in the vSub-NAc pathway. (a) When tested on day 23, the CMS-Veh group demonstrated significantly reduced amplitude compared with all groups post HFS (*p<0.05). (b) When tested on day 23, the CMS-Veh group demonstrated significantly reduced slope compared with all the groups post HFS (*p<0.05; **p<0.01). (c) When the drugs were injected without stress exposure, the RU group demonstrated reduced amplitude compared with the Vehicle and AM groups, and the WIN group demonstrated reduced amplitude compared with the AM group (*p<0.05; **p<0.01; ***p<0.001). (d) When the drugs were injected without stress exposure, the RU group demonstrated reduced slope compared with the Vehicle and WIN groups (*p<0.05; **p<0.01).

Figure 4

The effects of CMS and WIN55,212-2 on stress-coping behavior in the forced swim test. (a) When tested on day 23, the No CMS-Veh group demonstrated less immobility compared with the CMS-Veh and CMS-WIN groups. Also, the No CMS-Veh and No CMS-WIN groups demonstrated more swimming compared with the CMS-Veh and CMS-WIN groups (*p<0.05; **p<0.01). (b) When microinjected into the BLA, the CMS-Veh group demonstrated increased immobility and reduced swimming compared with the No CMS-Veh and CMS-WIN groups. Also, the No CMS-Veh group demonstrated more climbing compared with the CMS-Veh and CMS-WIN groups (*p<0.05; **p<0.01). (c) Representative schematic drawings of cannulae tip positions in the BLA. A coronal view at position 3.14 and 3.30 mm posterior to bregma. (d) When coping behavior was tested on day 28, there were no differences between the groups in immobility, climbing, or swimming. (e) When WIN was injected systemically after pretest with no CMS exposure, the WIN group demonstrated less immobility and more climbing than the Vehicle group (*p<0.05).

Figure 5

The effects of CMS and WIN55,212-2 on sucrose intake and weight gain. (a) The CMS-Veh and CMS-WIN groups demonstrated reduced sucrose intake compared with the No CMS-Veh group on days 7, 14, and 28 (*p<0.05; **p<0.01). (b) The CMS-Veh and CMS-WIN groups demonstrated lower weight gain compared with the No CMS-Veh group on days 7, 14, 21, and 28 (*p<0.05; averaged baseline weight: 397.37±33.86).