This study shows that CBD attenuates the PPI disruption induced by amphetamine. Moreover, our data suggests that CBD infusion into the nucleus accumbens seems to be sufficient for the attenuation of PPI disruption. However, these results do not exclude the potential role of other structures in the CBD effects. In addition, we found that the FAAH inhibitor, similar to CBD, attenuated the amphetamine-induced PPI deficit. These results allow the suggestion that CBD action mechanism may be related to the facilitation of endocannabinoid-mediated neurotransmission through anandamide increase. Further studies are required to describe CBD mechanisms of action in the PPI modulation.

The present results agree with previous reports of CBD effects in predictive models for antipsychotic effects based on the dopamine hypothesis of schizophrenia. For example, CBD and haloperidol attenuated apomorphine-induced stereotypy in rats, but only the latter produced catalepsy, a model associated with extrapyramidal side effects induced by typical antipsychotics (Carlsson 1998; Howes and Kapur 2009; Zuardi et al. 1991). Additionally, Moreira and Guimarães (2005) observed that CBD decreased amphetamine-induced hyperlocomotion in mice. These effects were observed at the dose of 60 mg/kg, the same dose that attenuated the PPI disruption induced by amphetamine in our study.

CBD was also able to attenuate the hyperlocomotion induced by ketamine, extending its antipsychotic-like effects to schizophrenia models based on the glutamatergic system (Moreira and Guimarães 2005). In the same study, similar to clozapine, CBD did not induce catalepsy. These results corroborate the hypothesis that CBD may act as an atypical antipsychotic. In agreement with this possibility, Long and colleagues (2006) found that CBD (5 mg/kg), similar to clozapine (4 mg/kg), reversed the PPI impairment induced by MK-801 (1 mg/kg). Since it also improved the reduced social interaction caused by this treatment, it was suggested that CBD could attenuate both the positive and negative symptoms of schizophrenia (Long et al. 2006; Gururajan et al. 2011).

Together, these preclinical results indicate that CBD possesses antipsychotic properties. This was recently confirmed in spontaneously hypertensive rats (SHRs). 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 animals (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. This pharmacological approach was not tested in the amphetamine-induced PPI disruption.

The antipsychotic properties of CBD are also confirmed by clinical studies. For example, it prevented the psychotomimetic effects of high doses of delta-9-tetrahydrocannabinol (Zuardi et al. 1982; Englund et al. 2013). Also, the symptom improvement induced by CBD in schizophrenic patients was initially detected in open studies with small samples (for review see Zuardi et al. 2012). It was recently confirmed in a double-blind study that CBD was as effective as amisulpride but did not induce common antipsychotic undesirable effects such as extrapyramidal symptoms, prolactin increase, and weight gain (Leweke et al. 2012).

The brain sites of the antipsychotic-like effect of CBD had not yet been investigated but could involve the nucleus accumbens, an area proposed to mediate the effects of antipsychotic drugs on the positive symptoms of schizophrenia (for review, see Seeman et al. 2002). In a previous study, CBD, at doses similar to those used in the present work, increased neuronal activation measured by cFos expression in the nucleus accumbens (Guimarães et al. 2004). In addition, even if other regions such as the prefrontal cortex could also be involved (Csernasnky et al. 1993; Swerdlow et al. 2001), several pieces of evidence indicate that the nucleus accumbens is an essential structure in PPI modulation (Swerdlow et al. 2001).

The nucleus accumbens receives a dense dopaminergic innervation from the midbrain ventral tegmental area and contains several neurotransmitters that regulate PPI (Koch et al. 1999). Facilitation of dopamine-mediated neurotransmission in this structure impairs PPI (Swerdlow et al. 1992, 2001; Wan et al. 1994) whereas dopamine receptor antagonists reverse PPI deficits induced by dopamine direct or indirect agonists (Swerdlow et al. 1990, 1994; Wan et al. 1994). A similar effect was found after nucleus accumbens dopamine depletion after the use of the neurotoxin 6-OHDA (Zhang et al. 2000). Our results corroborate the proposed central role of the nucleus accumbens in the control of sensory-motor filter and suggest that CBD action in this brain region is important for its ability to decrease the effects of amphetamine on PPI.

The pharmacological mechanisms involved in the antipsychotic effects of CBD remain unclear. CBD has a lower affinity for CB1 and CB2 receptors but can indirectly increase endocannabinoid tonus by decreasing anandamide reuptake/metabolism (Bisogno et al. 2001). In fact, it has been suggested that CBD antipsychotic profile may be related to its ability to increase the availability of anandamide (Schubart et al. 2013). In a clinical study conducted by Giuffrida and coworkers (2004), schizophrenic patients were compared to healthy controls, and it was observed that the first group had higher concentrations of anandamide in cerebrospinal fluid, and this concentrations were negatively correlated with psychotic symptoms. This data may suggest that the increase of anandamide involves a negative feedback response in order to counteract the psychotic symptoms, and the D2 receptor hiperactivation.

In a complementary study conducted by Leweke and coworks (2012), a significant association between anandamide levels and the improvement of psychotic symptoms was found. These authors also found that the same CBD concentration that inhibits, in vitro, anandamide metabolism does not interact with receptors commonly associated with schizophrenia such as dopamine, GABA, serotonin, and glutamate. Moreover, facilitation of CB1-mediated neurotransmission by CBD also increases adult hippocampal neurogenesis (Campos et al. 2013), a mechanism that could be involved in cognitive deficits observed in schizophrenic patients (Zuardi et al. 2011). CBD and anandamide can also activate TRPV1 channels, which could result in facilitation of glutamate presynaptic release (Zygmunt et al. 1999). This mechanism has been related to CBD blockade of PPI disruption induced by MK-801, a NMDA receptor antagonist (Long et al. 2006). Corroborating the hypothesis that anandamide has a role in the CBD antipsychotic-like effects, we provide the first demonstration that URB597, a known potent and selective inhibitor of the enzyme which catalyzes the hydrolysis of anandamida (Piomelli et al. 2006), has similar effects to CBD in the PPI test. The same action mechanism was found to attenuate the hyperactivity induced by dopamine D2/D3 agonism (Luque-Rojas et al. 2013). In addition, in rats, the properties of the anandamide transport inhibitor N-(4-hydroxyphenyl)-arachidonamide (AM404) counteracting behavioral responses associated with activation of dopamine D2 family receptors were demonstrated (Beltrano et al. 2000). The property of the endocannabinoid system as a relevant negative modulator of both D1 and D2 receptor–mediated behaviors was also demonstrated by Martín and coworkers (2008).

Furthermore, CBD also possesses several other mechanisms such as facilitation of 5HT1A receptor–mediated neurotransmission (an effect shared by the atypical antipsychotic aripiprazol) or anti-inflammatory/neuroprotective properties (for review see Campos et al. 2012) that could help to explain its antipsychotic effects. Further investigation is required.

In conclusion, the present study found that CBD attenuates PPI disruption induced by amphetamine. Moreover, we showed that this effect could be mediated by CBD direct action in the nucleus accumbens. Together, the results support the hypothesis that CBD might be a useful antipsychotic drug.