Antidepressant-like effects of Δ9-tetrahydrocannabinol and rimonabant in the olfactory bulbectomised rat model of depression

Abstract

The endocannabinoid signalling system is widely accepted to play a role in controlling the affective state. Plant cannabinoids are well known to have behavioural effects in animals and humans and the cannabinoid CB(1) receptor antagonist rimonabant has recently been shown to precipitate depression-like symptoms in clinical trial subjects. The aim of the present study was to investigate the behavioural and neurochemical effects of chronic administration of Δ⁹-tetrahydrocannabinol (THC) and rimonabant on intact and olfactory bulbectomised (OB) rats used as a model of depression. As expected, OB rats were hyperactive in the open field. Repeated THC (2 mg/kg, i.p. once every 48 h for 21 days) and rimonabant (5 mg/kg, i.p. once every 48 h for 21 days) reduced this hyperactivity, which is typical of clinically effective antidepressant drugs. In intact animals, chronic THC increased brain derived neurotrophic factor (BDNF) expression levels in the hippocampus and frontal cortex but rimonabant had no effect. Rimonabant increased the levels of phosphorylated extracellular signal regulated kinases (p-ERKs(1/2)) in the hippocampus and prefrontal cortex and THC also increased expression in frontal cortex. OB did not affect BDNF or p-ERK(1/2) expression in the hippocampus or frontal cortex and in, contrast to the intact animals, neither THC nor rimonabant altered expression in the OB rats. These findings indicate antidepressant-like behavioural properties of both THC and rimonabant in OB rats although additional studies are required to clarify the relationship between the chronic effects of cannabinoids in other pre-clinical models and in human depression.

Role of the Endocannabinoid System in Depression: from Preclinical to Clinical Evidence

“…5.1) to endocannabinoid enhancers have been evaluated in several in vitro and in vivo studies to assess their therapeutic potential in stress-related neuropsychiatric disorders [23] (Table 5.4). Based on the hypothesis that a reduction of endocannabinoid signaling could underlie depressive disorders, it has been seen that acute or repeated treatment with different compounds which activate directly cannabinoid receptors, such as the main pharmacologically active principle of Cannabis sativa ∆9-THC [98,[127][128][129][130], the endogenous cannabinoid AEA [131,132], the synthetic nonspecific CB1/CB2 receptor agonists CP55,940 [133], WIN55,212-2 [134,135] and HU-210 [136][137][138][139] or the selective CB1 receptor agonist arachidonoyl 2'-chloroethylamide (ACEA) [140,141] elicited antidepressant-like effects through CB1 and 5-HTergic or NEergic receptor-mediated mechanisms.…”

“…12). Although the CB1 receptor antagonist rimonabant, which was introduced into clinical practice as antiobesity agent, was withdrawn from the market due to the higher incidence of psychiatric side effects [147], preclinical studies have reported an antidepressant-like activity of rimonabant in rodents [129,130,[148][149][150][151]. Using a genetic approach controversial results regarding the effects of CB1 receptor signaling inhibition on stress coping behaviour have been obtained indicating that they could depend on specific deletion of CB1 receptors in some neuronal subpopulations [129,152,153].…”

Endocannabinoid Signaling in the Etiology and Treatment of Major Depressive Illness

“…Cannabinoids increase the expression of hippocampal BDNF [253, 254] and chronic cannabinoid treatment of both adult and aged rats increases neurogenesis in the hippocampus [255, 256]. FAAH null mice exhibit increased cell proliferation in the hippocampus [257].…”

“…However, CB1R antagonists can also have antidepressant effects in the FST [208, 209, 275]. Similarly, rimonabant reduces hyperactivity in OBX rats, a hallmark of antidepressant efficacy [254]. On the other hand, chronic rimonabant does not increase hippocampal BDNF in normal rats, while CB1R agonists do [254] suggesting that CB1R blockade is not as robust an antidepressant therapy as CB1R activation.…”

Endocannabinoids and neuropathic pain: focus on neuron–glia and endocannabinoid–neurotrophin interactions

“…By contrast, endocannabinoids can transactivate Trkb receptors during interneuron migration and morphogenesis or contribute to BDNF overexpression, which is induced during neuron excitotoxicity (Berghuis et al, 2005;Aguado et al, 2007). Indeed, the endocannabinoid system seems to play a crucial role during stress-induced and BDNF-mediated adult neurogenesis, and ensuing inhibition of depressive-like symptoms (Aso et al, 2008;Steiner et al, 2008;Elbatsh et al, 2012). Also in the case of BDNF there exist several examples of reciprocal regulation with endocannabinoids, the neurotrophin having been shown to, for example: (1) stimulate neuronal sensitivity to endocannabinoids during development (Maison et al, 2009); (2) release endocannabinoids at layer 2/3 inhibitory synapses in the neocortex (Lemtiri-Chlieh & Levine, 2010); and (3) inhibit CB 1 function in the striatum, through a mechanism mediated by altered cholesterol metabolism and membrane lipid raft function, and restricted to CB 1 receptors controlling GABA-mediated inhibitory postsynaptic current (De Chiara et al, 2010).…”