Pregnenolone blocks cannabinoid-induced acute psychotic-like states in mice

Abstract

Cannabis-induced acute psychotic-like states (CIAPS) represent a growing health issue, but their underlying neurobiological mechanisms are poorly understood. The use of antipsychotics and benzodiazepines against CIAPS is limited by side-effects and/or by their ability to tackle only certain aspects of psychosis. Thus, safer wide-spectrum treatments are currently needed. Although the blockade of cannabinoid type-1 receptor (CB1) had been suggested as a therapeutical means against CIAPS, the use of orthosteric CB1 receptor full antagonists is strongly limited by undesired side effects and low efficacy. The neurosteroid pregnenolone has been recently shown to act as a potent endogenous allosteric signal-specific inhibitor of CB1 receptors. Thus, we tested in mice the potential therapeutic use of pregnenolone against acute psychotic-like effects of Δ9-tetrahydrocannabinol (THC), the main psychoactive component of cannabis. We found that pregnenolone blocks a wide spectrum of THC-induced endophenotypes typically associated with psychotic-like states, including impairments in cognitive functions, somatosensory gating and social interaction. In order to capture THC-induced positive psychotic-like symptoms (e.g. perceptual delusions), we adapted a behavioral paradigm based on associations between different sensory modalities and selective devaluation, allowing the measurement of mental sensory representations in mice. Acting at hippocampal CB1 receptors, THC impaired the correct processing of mental sensory representations (reality testing) in an antipsychotic- and pregnenolone-sensitive manner. Overall, this work reveals that signal-specific inhibitors mimicking pregnenolone effects can be considered as promising new therapeutic tools to treat CIAPS.

Hippocampal CB1 Receptors Control Incidental Associations

“…Our previous data revealed that extended preconditioning training (six odor-taste pairings instead of three) suppresses mediated learning, installing the so-called ''reality testing,'' through which the animals are able to successfully discriminate between stimuli that they initially reacted to in the same way (Busquets-Garcia et al, 2017b;McLaren and Mackintosh, 2002). Notably, extended training also normalizes the hippocampal expression of CB 1 R. Thus, it will be extremely interesting to investigate the causes and the consequences of these molecular adaptations in the training-dependent behavioral switch from mediated learning to ''reality testing'' responses (McDannald and Schoenbaum, 2009).…”

“…***p < 0.001 (vehicle-versus Rimonabant-treated mice). For statistical details and n, see Tables S1 and S2. taste aversion (Busquets-Garcia et al, 2017b), suggesting that CB 1 R activation is specifically required for the formation of incidental associations, but not for the expression of mediated aversion.…”

“…Immunoblotting experiments revealed that 3 odor-taste pairings, but not the same number of presentations of odor alone, taste alone, or unpaired odor-taste, specifically resulted in enhanced hippocampal expression of CB 1 R protein ( Figures 5A, S5A, and S5B). Extended preconditioning training is known to suppress the expression of mediated learning (Busquets-Garcia et al, 2017b), suggesting that increasing the number of stimuli associations could trigger cellular and molecular changes. Intriguingly, we observed that hippocampal CB 1 R expression was normalized by extended preconditioning training (six odor-taste pairings) ( Figures 5A and S5B), further suggesting that increased levels of hippocampal CB 1 R protein are reliably associated to the expression of mediated learning.…”

“…As previously described (Chevaleyre and Castillo, 2003), we observed that the application of two HFS trains induced a reliable I-LTD in 71% of pyramidal neurons from naive control mice ( Figures 5D and 5E). Odor-taste preconditioning procedures involve limited access to water (1 hr per day; Busquets-Garcia et al, 2017a, 2017bsee Star Methods). Surprisingly, only 26% of pyramidal neurons in hippocampal slices from water-restricted control mice only exposed to plain water underwent I-LTD after HFS ( Figure 5E), indicating an impact of limited access to water on this form of synaptic plasticity.…”

Modulation of CB1 cannabinoid receptor by allosteric ligands: Pharmacology and therapeutic opportunities

“…PSNCBAM-1, for example, elicits acute hypophagic effects (Horswill et al, 2007) and antagonizes neuronal excitability (Wang et al, 2010), properties which may lead to treatments of obesity and some central nervous system (CNS) disorders. Pregnenolone has demonstrated promise in blocking the psychotic-like symptoms such as THC-impaired cognitive function (Busquets-Garcia et al, 2017). Lipoxin A4 has been shown to protect neuronal cells from β-amyloid-induced neurotoxicity (Pamplona et al, 2012), thus demonstrating possible therapeutic potential for the treatment of Alzheimer’s disease.…”