Distinct Neurobehavioural Effects of Cannabidiol in Transmembrane Domain Neuregulin 1 Mutant Mice

Abstract

The cannabis constituent cannabidiol (CBD) possesses anxiolytic and antipsychotic properties. We have previously shown that transmembrane domain neuregulin 1 mutant (Nrg1 TM HET) mice display altered neurobehavioural responses to the main psychoactive constituent of cannabis, Δ9-tetrahydrocannabinol. Here we investigated whether Nrg1 TM HET mice respond differently to CBD and whether CBD reverses schizophrenia-related phenotypes expressed by these mice. Adult male Nrg1 TM HET and wild type-like littermates (WT) received vehicle or CBD (1, 50 or 100 mg/kg i.p.) for 21 days. During treatment and 48 h after withdrawal we measured behaviour, whole blood CBD concentrations and autoradiographic receptor binding. Nrg1 HET mice displayed locomotor hyperactivity, PPI deficits and reduced 5-HT2A receptor binding density in the substantia nigra, but these phenotypes were not reversed by CBD. However, long-term CBD (50 and 100 mg/kg) selectively enhanced social interaction in Nrg1 TM HET mice. Furthermore, acute CBD (100 mg/kg) selectively increased PPI in Nrg1 TM HET mice, although tolerance to this effect was manifest upon repeated CBD administration. Long-term CBD (50 mg/kg) also selectively increased GABAA receptor binding in the granular retrosplenial cortex in Nrg1 TM HET mice and reduced 5-HT2A binding in the substantia nigra in WT mice. Nrg1 appears necessary for CBD-induced anxiolysis since only WT mice developed decreased anxiety-related behaviour with repeated CBD treatment. Altered pharmacokinetics in mutant mice could not explain our findings since no genotype differences existed in CBD blood concentrations. Here we demonstrate that Nrg1 modulates acute and long-term neurobehavioural effects of CBD, which does not reverse the schizophrenia-relevant phenotypes.

Neuregulin-1 and schizophrenia in the genome-wide association study era

“…Both younger and older mice also showed modest increases in NMDAR binding in sensory, motor and cingulate cortices. These findings contrast with two other studies that used the same Nrg1 model, but found no genotype related differences in NMDAR binding in adult (20-27 weeks) mice (Dean et al 2008;Long et al 2012), although variable levels of environmental enrichment, which has been found to affect NMDAR subunit expression (Guilarte et al 2003), may have been a factor in these studies. Two further studies employing the TM Nrg1 model found reduced NMDAR subunit phosphorylation in both hippocampus (Bjarnadottir et al 2007) and prelimbic (i.e.…”

mGluR2/3 agonist LY379268 rescues NMDA and GABAA receptor level deficits induced in a two-hit mouse model of schizophrenia

“…GABAA-R expression level differences vary between receptor subtypes and brain regions in individuals with schizophrenia (Benes et al, 1996a(Benes et al, , 1996bDuncan et al, 2010). The reduction in NMDA-R and GABAA-R binding supports our two-hit modelling strategy as neither NRG1 HET mice nor chronic PCP treatment alone showed such robust impairments in the present study or in previously published experiments (Beninger et al, 2010;Bullock et al, 2009;Dean et al, 2008;Hanania et al, 1999;Lindahl and Keifer, 2004;Long et al, 2013Long et al, , 2012Newell et al, 2013;Stefansson et al, 2002;Wang et al, 2005). Cognitive and memory functions rely on balanced glutamatergic and GABAergic neurotransmission (Klausberger and Somogyi, 2008).…”

Does cannabidiol have a role in the treatment of schizophrenia?

“…Chronic CBD treatment (50, 100 mg/kg) attenuated hyperactivity in NRG1 mutant mice (Long et al, 2012) and interestingly, this inhibitory effect of CBD was still present two days after treatment had ceased. NRG1 mutant mice did not display any deficits in social behaviour but chronic CBD treatment induced an increase in active social interaction.…”