Background Individuals with schizophrenia have high rates of comorbid substance use problems. One potential explanation for this comorbidity is similar neuropathophysiology in substance use and schizophrenia, which may arise from shared genetic risk factors between the two disorders. Here we investigated if genetic risk for schizophrenia could affect drug reward and reinforcement for cocaine in an established mouse model of genetic risk for schizophrenia, the neuregulin 1 transmembrane domain heterozygous (Nrg1 TM HET) mouse. Methods We examined drug-induced locomotor sensitization and conditioned place preference for several cocaine doses (5, 10, 20, 30 mg/kg) in male adult Nrg1 TM HET and wild-type-like (WT) littermates. We also investigated intravenous self-administration of and motivation for cocaine (doses 0.1, 0.5, 1 mg/kg/infusion), as well as extinction and cue-induced reinstatement of cocaine. In a follow-up experiment, we examined self-administration, extinction and cue-induced reinstatement of a natural reward, oral sucrose. Results Cocaine preference was similar between Nrg1 TM HET mice and WT littermates at all doses tested. Locomotor sensitization to cocaine was not affected by Nrg1 genotype at any dose. Although self-administration and motivation for cocaine was unaffected, extinction of cocaine self-administration was impaired in Nrg1 TM HET compared to WT controls, and cue-induced reinstatement was greater in Nrg1 mutants in the middle of the reinstatement session. Sucrose self-administration and extinction thereof was not affected by genotype, but inactive lever responding was elevated during cue-induced reinstatement for operant sucrose in Nrg1 TM HET mice compared to WTs. Discussion These results suggest impaired response inhibition for cocaine in Nrg1 TM HET mice and suggests Nrg1 mutation may contribute to behaviours which can limit control over cocaine use.

Cannabidiol (CBD) is a non-intoxicating cannabinoid with antipsychotic-like properties, however it’s potential to prevent schizophrenia development has not been thoroughly investigated. Brain maturation during adolescence creates a window where CBD could potentially limit the development of schizophrenia. The neuregulin 1 transmembrane domain heterozygous (Nrg1 TM HET) mutant mouse shows face, predictive, and construct validity for schizophrenia. Here we sought to determine if CBD given in adolescence could prevent the development of the schizophrenia-relevant phenotype, as well as susceptibility to the psychoactive cannabinoid Δ9-tetrahydrocannabinol (THC) in Nrg1 TM HET mice. Adolescent male Nrg1 mutants and wild type-like (WT) animals were administered 30 mg/kg CBD i.p. daily for seven weeks, and were tested for locomotion, social behavior, sensorimotor gating and cognition, and sensitivity to acute THC-induced behaviors. GAD67, GluA1, and NMDAR1 protein levels were measured in the hippocampus, striatum, and prefrontal cortex. Chronic adolescent CBD increased locomotion in animals regardless of genotype, was anxiolytic, and increased social behavior when animals were tested for their acute THC response. CBD did not alleviate the schizophrenia-relevant hyperlocomotive phenotype of Nrg1 mutants, nor deficits in social behaviors. Nrg1 mutant mice treated with CBD and THC showed no habituation to a startle pulse, suggesting CBD increased vulnerability to the startle habituation-reducing effects of THC in mutant mice. CBD increased levels of GluA1, but reduced levels of GAD67 in the hippocampus of Nrg1 mutants. These results suggest adolescent CBD is not effective as a preventative of schizophrenia-relevant behavioral deficits in mutants and may actually contribute to pathological changes in the brain that increase sensitivity to THC in particular behavioral domains.

Background Schizophrenia is caused by interactions between genes of predisposition and environmental insults. The main pharmacological treatments for schizophrenia are antipsychotic drugs; however, these are associated with a range of side effects (weight gain, metabolic disease, diabetes), have limited treatment compliance, and do not work for approximately 30% of patients. Cannabidiol (CBD) is a non-psychoactive cannabinoid that has shown promise as an antipsychotic-like drug in both human and rodent studies, however its potential as a preventative drug via anti-inflammatory pathways has not yet been investigated. Brain maturation during adolescent development creates a window where CBD could potentially reverse later behavioural deficits via pathways such as anti-inflammation, and reverse the deficits caused by Δ⁹-tetrahydrocannabinol (THC), a psychoactive compound of the cannabis plant linked to the development of schizophrenia. Here we investigated the therapeutic potential of CBD administered in adolescence to protect against the development of schizophrenia-like behaviours, as well as whether CBD could protect against later sensitivity to THC. For this study we used a well-established genetic mouse model of schizophrenia (Nrg1 TM HET) that shows face, construct, and predictive validity for schizophrenia, and is also more susceptible to the effects of cannabinoids. Methods In this study, male Nrg1 TM HET mice and wild type (WT) mice were treated with 30 mg/kg of CBD or vehicle intraperitoneally for three weeks during adolescence (PND 35–60). Mice were tested CBD-free in adulthood (5–6 mo) in the open field task, which measures locomotion and anxiety (related to positive symptoms in schizophrenia); social interaction, which measures mouse interactions (relevant to negative symptoms); pre-pulse inhibition (PPI), which measures sensorimotor gating (deficits also found in schizophrenia patients); and fear conditioning, which measures associative learning and memory. Mice were then treated after one week washout with either 3 mg/kg of THC or vehicle, and run in a battery of open field, social interaction, and PPI tests. Brains and bloods were collected to investigate neuroinflammation after another week of washout. Western blots were used to investigate Iba1 levels, while ELISA was used to investigate levels of cytokines IL-10, IL-1B, and TNF-a. Results CBD treatment significantly reduced anxiety in Nrg1 TM HET mice but not WT mice, however it had no effect on locomotion in either group in the open field task. CBD treatment lowered the frequency of total social interaction in both genotypes, and reduced the frequency of social interactions of Nrg1 TM HET to WT levels. CBD reduced PPI in Nrg1 TM HET mice but not WT mice, and Nrg1 TM HET mice had lower overall PPI than WT mice. There was no effect of CBD on fear-associated memory. CBD effects on THC sensitivity in these mice are ongoing, as are brain cytokine and protein analyses. Discussion These results suggest that Nrg1 TM HET mice are more susceptible to the effects of chronic CBD in adolescence, despite a significant washout. This confirms previous data from our laboratory demonstrating increased susceptibility of Nrg1 TM HET male mice to cannabinoid constituents, and suggests persistent brain changes following adolescent exposure to CBD. Potential reasons for these persistent changes include an altered neuroinflammatory profile in Nrg1 TM HET mice. CBD has previously been shown to be anxiolytic in other studies and our results confirm its potential as an anxiolytic, particularly in our model of schizophrenia.