Effects of cannabinoid drugs on the deficit of prepulse inhibition of startle in an animal model of schizophrenia: the SHR strain

Abstract

Clinical and neurobiological findings suggest that the cannabinoids and the endocannabinoid system may be implicated in the pathophysiology and treatment of schizophrenia. We described that the spontaneously hypertensive rats (SHR) strain presents a schizophrenia behavioral phenotype that is specifically attenuated by antipsychotic drugs, and potentiated by proschizophrenia manipulations. Based on these findings, we have suggested this strain as an animal model of schizophrenia. The aim of this study was to evaluate the effects of cannabinoid drugs on the deficit of prepulse inhibition (PPI) of startle, the main paradigm used to study sensorimotor gating impairment related to schizophrenia, presented by the SHR strain. The following drugs were used: (1) WIN55212,2 (cannabinoid agonist), (2) rimonabant (CB1 antagonist), (3) AM404 (anandamide uptake inhibitor), and (4) cannabidiol (CBD; indirect CB1/CB2 receptor antagonist, among other effects). Wistar rats (WRs) and SHRs were treated with vehicle (VEH) or different doses of WIN55212 (0.3, 1, or 3 mg/kg), rimonabant (0.75, 1.5, or 3 mg/kg), AM404 (1, 5, or 10 mg/kg), or CBD (15, 30, or 60 mg/kg). VEH-treated SHRs showed a decreased PPI when compared to WRs. This PPI deficit was reversed by 1 mg/kg WIN and 30 mg/kg CBD. Conversely, 0.75 mg/kg rimonabant decreased PPI in SHR strain, whereas AM404 did not modify it. Our results reinforce the role of the endocannabinoid system in the sensorimotor gating impairment related to schizophrenia, and point to cannabinoid drugs as potential therapeutic strategies.

Cannabidiol effects in the prepulse inhibition disruption induced by amphetamine

“…These animals exhibit behavioral changes such as a basal disruption in PPI that have been associated with schizophrenia, since they are reversed by clozapine (Levin et al 2011). Similar to antipsychotic drugs, CBD also increases the PPI response in these (Levin et al 2014). In contrast to our results, these authors also found that anandamide uptake inhibitor did not modify PPI response in SHR strain.…”

Differential Pharmacological Regulation of Sensorimotor Gating Deficit in CB1 Knockout Mice and Associated Neurochemical and Histological Alterations

“…These discrepancies could be attributed to different genetic manipulation processes to obtain the deletion of CB1r and, most probably, to the use of mice with different genetic backgrounds (CBA/J-C57BL/10 and CD1 strains). In addition, another study showed that the CB1r antagonist rimonabant (SR141716, 0.75 mg/kg) significantly reduced PPI in SHR rats (Levin et al, 2014). Accordingly, in the present study WT mice treated with the highest dose of AM251 (3 mg/kg) showed significantly lower PPI in comparison with control animals (see Supplementary Tables S5 and S6).…”

Cannabidiol as a Potential New Type of an Antipsychotic. A Critical Review of the Evidence

“…These rats show impaired social interaction (Calzavara et al, 2011; Almeida et al, 2014) and reduced PPI (Levin et al, 2011, 2014) as compared to Wistar rats. In addition, antipsychotic drugs reduced abnormalities in contextual fear conditioning (Calzavara et al, 2009), social interaction (Calzavara et al, 2011) as well as PPI (Levin et al, 2011).…”

“…In Sprague Dawley rats, cannabidiol reduced startle amplitude (3 and 10 but not 30 mg/kg) and PPI (10 mg/kg only) in a dose-dependent manner (Gururajan et al, 2011), whereas the startle amplitude of Wistar rats was not influenced by acute cannabidiol (15, 30, 60 mg/kg) treatment, while higher dosages of cannabidiol (30, 60 mg/kg) seemed to increase PPI (Levin et al, 2014). …”