Changes in the Brain Endocannabinoid System in Rat Models of Depression

Irena Smaga,Beata Bystrowska,Żaneta Broniowska,Małgorzata Filip,Magdalena Zaniewska,Dawid Gawliński,Joanna Jastrzębska,Agata Faron-Górecka,Joanna Miszkiel

doi:10.1007/s12640-017-9708-y

Irena Smaga, Beata Bystrowska + Show 7 more

Open Access

https://doi.org/10.1007/s12640-017-9708-y

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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).

Highlights

At present, depression is one of the most common psychiatric disorders, but its pharmacotherapy and pathophysiology are still unclear
3 Laboratory of Biochemical Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, PL 31-343 Kraków, Poland 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, neurochemical changes were linked to the particular brain structure and the factor inducing depression
after: anandamide (AEA) When comparing the OBX to the SHAM rats (Fig. 2a), we found a significant reduction of the AEA levels in the prefrontal cortex (t = 4.487; df = 14; p = 0.0005), hippocampus (t = 5.405; df = 14; p < 0.0001), and dorsal striatum (t = 3.328; df = 14; p = 0.005)

Summary

Introduction

Depression is one of the most common psychiatric disorders, but its pharmacotherapy and pathophysiology are still unclear. The facilitation of eCB signaling exerts antidepressant-like behavioral responses in rodents, which were observed after: anandamide (AEA) administration (Umathe et al 2011), AEA uptake inhibition (Hill and Gorzalka 2005; Adamczyk et al 2008; Mannucci et al 2011; Umathe et al 2011), eCB degrading enzyme inhibition (Gobbi et al 2005; Adamczyk et al 2008), or by direct CB1 agonists (Bambico et al 2007; Haring et al 2013; Smaga et al 2014b). Augmentation of eCB signaling evoked different changes implicated in antidepressant effects, such as modulation of neurotransmitter release, regulation of the stress axis, promotion of neurogenesis, and normalization of the excitation state (Smaga et al 2014a, b)

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