Preclinical literature concerning the effects of SNP in schizophrenia is outlined in Table 1. Intraperitoneal (i.p.) administration of SNP (0.3–3 mg/kg) did not affect rats’ attentional skills evaluated in the prepulse inhibition (PPI) test [45]. By contrast, acute application of SNP (2–6 mg/kg, i.p.) attenuated hyperactivity, stereotypies and c-fos expression, which is a metabolic marker of neuronal activation, in cortical areas caused by the NMDA receptor antagonist phencyclidine (PCP) (5 mg/kg, i.p.) in the rat [46]. A subsequent study, revealed that SNP given acutely (0.3–1 mg/kg, i.p.), reversed recognition memory deficits induced by the D₁/D₂ DAergic receptor agonist apomorphine (1 mg/kg, i.p.) evidenced in the object recognition task (ORT) in the rat [47]. Issy and colleagues [48] reported that a single injection of SNP (2.5 mg/kg, i.p.) reduced attentional impairments produced by the enhancer of DA release amphetamine (10 mg/kg, i.p.) in the PPI procedure in mice.

Additionally, in line with previous findings [46] pretreatment with SNP (4 mg/kg, i.p.) was efficient in counteracting hyperlocomotion and bizarre behaviour (stereotypies) caused by another NMDA receptor antagonist (ketamine, 25 mg/kg, i.p.) in mice [49]. Further, subsequent results of the same group of researchers showed that posttreatment with SNP (5 mg/kg, i.p.) reduced ketamine (30 mg/kg, i.p.)-induced hypermotility in the rat. It is important to emphasize, however, that this dose of SNP (5 mg/kg) caused hypomotility by itself [50]. It is difficult, therefore, to exclude whether or not sedation might has confounded the effects of SNP on ketamine-induced hyperactivity [50].

ORT and social interaction test (SIT) were used to assess in rats the ability of SNP (0.3–1 mg/kg, i.p.) to attenuate the detrimental action of ketamine on recognition memory and social withdrawal, the latter being a model of negative symptoms of schizophrenia. Acute administration of SNP (0.3–1 mg/kg) counteracted recognition memory deficits induced by ketamine (3 mg/kg, i.p.). Interestingly, SNP (1 mg/kg, i.p.) attenuated the social isolation produced by sub-chronic treatment with ketamine (8 mg/kg, i.p.) [51].

In a rat model mimicking working memory deficits [the trial-unique-delayed nonmatching to location test (TUNLT)] SNP (2–5 mg/kg, i.p.) failed to reduce disruption of working memory caused by treatment with the NMDA receptor antagonist MK-801 (0.05–0.1 mg/kg, i.p.). In spite of it, SNP (2 mg/kg, i.p.) exerted some minor beneficial effects on task accuracy and reduced perseverative behaviour [52].

In a non-pharmacological animal model of schizophrenia, the spontaneously hypertensive (SHR) rat, the effects of administration of SNP were tested using behavioural models resembling positive symptoms, cognitive impairments and negative symptoms of schizophrenia. SNP given chronically (30 days, 0.5–2.5 mg/kg, i.p.) but not acutely (0.5–5 mg/kg, i.p.) reduced hyperactivity and social isolation. Moreover, SNP, at the same dose range, attenuated contextual fear conditioning deficits [53].

In a subsequent study, the potential synergistic effects of administration of sub-threshold doses SNP and the atypical neuroleptic clozapine were tested on schizophrenia-like behaviour induced by MK-801 and amphetamine in mice. Combination of inactive doses of SNP (1 mg/kg, i.p.) and clozapine (1 mg/kg, i.p.) reduced attentional deficits induced by amphetamine (1 mg/kg, i.p.) but not MK-801 (0.5 mg/kg, i.p.) in the PPI test. Interestingly, SNP (2.5–4 mg/kg, i.p.) failed to attenuate the disruption of mice performance caused by MK-801 (0.5 mg/kg, i.p.) in the PPI test. It has also been evidenced that SNP attenuated the amphetamine-induced increase of cAMP in the striatum [54].

In addition, SNP (2.5 mg/kg, i.p., acutely) reduced hypermotility caused by MK-801 (0.4 mg/kg, i.p., acutely) but did not reverse attentional and memory deficits induced by the same dose of MK-801 in rats [55]. It cannot be ruled out, however, that this apparent failure of SNP to counteract behavioural impairments caused by MK-801 might resides to the especially high dose of MK-801 utilized in the present study (0.4 mg/kg) respect to what is commonly applied (0.05–0.25 mg/kg) (for review see [56]).

Finally, it has recently been reported that a combination of SNP (2.5 mg/kg, i.p., acutely) and the second generation antipsychotic risperidone (0.25 mg/kg, i.p., acutely) facilitated rats’ performance in the conditioned avoidance response test (CART) and enhanced the risperidone-induced release of DA from PFC [57].

In summary, SNP seems to attenuate psychotomimetic effects and cognitive deficits evaluated across different animal pharmacological models of schizophrenia reflecting malfunction of the DAergic and the glutamatergic system respectively. Similar results were obtained when the SHR rat model was used. Further, the combination of SNP with atypical antipsychotics (clozapine or risperidone) was also demonstrated fruitful. In spite of it, information is incomplete since is not yet examined whether a potential antipsychotic profile of SNP could also be emerged from other than pharmacological preclinical models (e.g., neurodevelopmental, genetic, etc.).

A summary of the literature dealing with the clinical effects of administration of SNP in schizophrenia is provided in Table 2. Initial findings reported were promising. In a randomized, double-blind, placebo-controlled trial conducted on 20 schizophrenics (aged from 19 to 40 years) who were in the first 5 years of disease and receiving appropriate medication, a single SNP 4 h infusion [0.5 μg/min intravenous, (i.v.)] attenuated positive, negative, anxiety and depression symptoms [58]. Interestingly, it has been reported that these effects of SNP lasted for 4 weeks following infusion [58]. A subsequent clinical study performed by the same group of researchers confirmed the effectiveness of SNP previously observed. SNP administered at the same treatment schedule of the first here reported study [59], reduced cognitive disorders such as executive functions (selective attention and working memory), a typical feature usually disrupted in patients suffering from schizophrenia [59].

Subsequent research, however, did not replicate the above described promising results [60,61,62,63]. Specifically, Stone and colleagues, by using the same treatment scheme of the previous studies [58,59] did not detect a beneficial impact of SNP on psychotic symptoms and spatial working memory abilities of schizophrenics [60]. Authors of this latter study, hypothesized that SNP might be effective in patients with a shorter history of pathology, or with more acute exacerbation of symptoms [60]. Repeated administration of SNP (twice, at seven days interval) also failed to decrease psychotic symptoms and improve cognitive functions in patients with schizophrenia [61]. A trial carried out in treatment-resistant outpatients also did not reveal a beneficial effect of acute challenge with SNP [62]. Finally, repeated challenge with SNP was unable to improve symptoms in treatment resistant chronic schizophrenia subjects. Reportedly, in this context, authors suggest that SNP’s presumed antipsychotic effects might have limited to the initial phase of this psychiatric disorder [63].

Overall, the exciting results of the first set of studies [58,59] were not reproduced by subsequent clinical research [60,61,62,63]. This inconsistency might depend on important differences in experimental protocols. Specifically, in studies in which the antipsychotic effects of SNP were revealed, participants were young subjects, no cigarette smokers, displaying serious negative symptoms and with relative short illness course [58,59]. Conversely, SNP was unable to express an antipsychotic profile in clinical trials in which patients were older, cigarette smokers, presenting less serious negative symptoms and with longer disease course respect to the studies in which the efficacy of SNP was revealed [60,61,62,63]. The role of nicotine as a critical factor of the ineffectiveness of SNP should also be considered since it interferes with NO and reduces SNP efficacy [64]. It can be thus hypothesized that SNP seem to improve schizophrenia symptoms when is administered in young patients, no smokers and having a short history of the disease. It is important to underline finally, that in all the aforementioned clinical studies designed to test the effectiveness of SNP as antipsychotic agent, this NO donor was well tolerated and no adverse side effects were reported [58,59,60,61,62,63].

There is scant evidence concerning the clinical efficacy of other NO modulators in schizophrenia and the results reported are contradictory. Specifically, in randomized, double-blind, placebo-controlled studies either the NO precursor L-arginine (repeatedly administered in patients under medication) [64] or the NO donor glyceryl trinitrate (GTN) (chronically administered in first-episode unmedicated patients) [65] failed to improve schizophrenia symptoms. Both studies were conducted in a small size of participants and only one dose of compound was used.

Recently, however, promising results were obtained following administration of the NO donor isosorbide mononitrate (ISMN). In a randomized, double-blind, placebo-controlled preliminary trial performed in 24 schizophrenics under medication, repeated treatment with ISMN exerted a beneficial effect on positive symptoms and functioning. In spite of it, important limitations characterize this interesting study including the sample size, the absence of healthy controls and the investigation of a single dose of ISMN [66]. Future research is mandatory to evaluate the efficacy of this NO donor as a potential antipsychotic agent.

The mechanism(s) by which SNP might reduce psychotic symptoms is not yet fully elucidated. SNP is a fast, short-acting vasodilator agent and seems to stimulate cerebral perfusion and consequently might alleviate cerebral hypoperfusion, a common feature of schizophrenia patients [67]. Further, SNP appears to exert a tonic effect on the NMDA-nNOS-cGMP pathway [58] which functionality is compromised in schizophrenia.

Several lines of evidence suggest that SNP reversed schizophrenia-like symptoms in rodents induced by pharmacological manipulation of the glutamatergic and DAergic system respectively [45,46,47,48,49,50,51,52,53,54,55,56,57]. In this context, it has been demonstrated that SNP counteracted psychotomimetic effects caused by hypofunction of the glutamatergic system by blocking PCP-induced brain c-fos expression [46], promoting a feedback inhibition of NOS [58] and normalizing the up-regulation of NOS-expressing neurons in the rat hippocampus following ketamine administration [68].

In line with the above, SNP attenuated cognitive deficits associated with abnormal DAergic transmission. It has been shown that the impairing effect exerted by apomorphine on memory is mediated by the activation of the D₂ DA receptor in PFC [69]. It has been proposed that SNP attenuated the amnestic effects of apomorphine probably by blocking the stimulatory action of this DAergic agonist on the D₂ DA receptor [47]. Additionally, it has been reported that apomorphine inhibits the induction of long-term potentiation (LTP), which is considered an electrophysiological marker of learning [70], while SNP promotes its formation [71]. Regarding the mechanism that might underlie the efficacy of SNP in counteracting attentional deficits induced by enhancers of DAergic transmission as are apomorphine and amphetamine, the implication of the nucleotide cAMP in this matter might be critical [48,54]. Interestingly, the ability of SNP to amplify the stimulatory action of risperidone on DA release in PFC has recently been reported and this action may be of relevance for the relief of cognitive impairments and negative symptoms in schizophrenics [57].

A relationship between oxidative stress and schizophrenia is well-documented [5]. In this context, it has been reported that both ketamine [72] and apomorphine [73] were found to increase oxidative stress in rodent’s brain. Taken the above into account, the potent antioxidant properties of SNP revealed in various experimental models of neurodegenerative diseases [44] may also represent a plausible explanation of SNP’s effects. Further research is required aiming to elucidate this important issue. A summary of the potential mechanism(s) of action of SNP in schizophrenia is provided in Table 3.