Changes in the Brain Endocannabinoid System in Rat Models of Depression

Abstract

A growing body of evidence implicates the endocannabinoid (eCB) system in the pathophysiology of depression. The aim of this study was to investigate the influence of changes in the eCB system, such as levels of neuromodulators, eCB synthesizing and degrading enzymes, and cannabinoid (CB) receptors, in different brain structures in animal models of depression using behavioral and biochemical analyses. Both models used, i.e., bulbectomized (OBX) and Wistar Kyoto (WKY) rats, were characterized at the behavioral level by increased immobility time. In the OBX rats, anandamide (AEA) levels were decreased in the prefrontal cortex, hippocampus, and striatum and increased in the nucleus accumbens, while 2-arachidonoylglycerol (2-AG) levels were increased in the prefrontal cortex and decreased in the nucleus accumbens with parallel changes in the expression of eCB metabolizing enzymes in several structures. It was also observed that CB₁ receptor expression decreased in the hippocampus, dorsal striatum, and nucleus accumbens, and CB₂ receptor expression decreased in the prefrontal cortex and hippocampus. In WKY rats, the levels of eCBs were reduced in the prefrontal cortex (2-AG) and dorsal striatum (AEA) and increased in the prefrontal cortex (AEA) with different changes in the expression of eCB metabolizing enzymes, while the CB₁ receptor density was increased in several brain regions. These findings suggest that dysregulation in the eCB system is implicated in the pathogenesis of depression, although neurochemical changes were linked to the particular brain structure and the factor inducing depression (surgical removal of the olfactory bulbs vs. genetic modulation).

Keywords: Animal model of depression; Endocannabinoid system; Olfactory bulbectomy; Wistar Kyoto.

Fig. 1

Changes in the eCBs levels; AEA (a) and 2-AG (b) in brain structures from OBX and WKY rats. AEA anandamide, 2-AG 2-arachidonoylglycerol, PFCTX prefrontal cortex, FCTX frontal cortex, HIP hippocampus, DSTR dorsal striatum, NAc nucleus accumbens, CER cerebellum, OBX bulbectomized rats, WKY Wistar Kyoto rats. All data are expressed as mean ± SEM. N = 8 rats/group. *p < 0.05; **p < 0.01; ***p < 0.001 vs SHAM-operated or Wistar rats

Fig. 2

Changes in the expression of metabolizing enzymes of AEA synthetizing enzyme—NAPE-PLD (a) and degrading enzyme—FAAH (b) in brain structures from OBX and WKY rats. AEA anandamide, NAPE-PLD N-acyl phosphatidylethanolamine phospholipase D, FAAH fatty acid amide hydrolase, PFCTX prefrontal cortex, FCTX frontal cortex, HIP hippocampus, DSTR dorsal striatum, NAc nucleus accumbens, CER cerebellum, OBX bulbectomized rats, WKY Wistar Kyoto rats. All data are expressed as mean ± SEM. N = 8 rats/group. *p < 0.05; **p < 0.01 vs SHAM-operated or Wistar rats

Fig. 3

Changes in the expression of metabolizing enzymes of 2-AG synthetizing enzyme—DAGLα (a) and degrading enzyme—MAGL (b) in brain structures from OBX and WKY rats. 2-AG 2-arachidonoylglycerol, DAGLα diacylglycerol lipase α, MAGL monoacylglycerol lipase, PFCTX prefrontal cortex, FCTX frontal cortex, HIP hippocampus, DSTR dorsal striatum, NAc nucleus accumbens, CER cerebellum, OBX bulbectomized rats, WKY Wistar Kyoto rats. All data are expressed as mean ± SEM. N = 8 rats/group. *p < 0.05; **p < 0.01; ***p < 0.001 vs SHAM-operated or Wistar rats

Fig. 4

Changes in the expression of CB receptors CB₁ (a) and CB₂ (b) in brain structures from OBX and WKY rats. PFCTX prefrontal cortex, FCTX frontal cortex, HIP hippocampus, DSTR dorsal striatum, NAc nucleus accumbens, CER cerebellum, OBX bulbectomized rats, WKY Wistar Kyoto rats. All data are expressed as mean ± SEM. N = 8 rats/group. *p < 0.05; **p < 0.01 vs SHAM-operated or Wistar rats