T109. MODULATORY ACTIVITY OF THE NOVEL DRUG SEP-363856 ON BRAIN FUNCTION: POTENTIAL APPLICATION FOR THE TREATMENT OF SCHIZOPHRENIA

Abstract

Background: Schizophrenia is a complex and heterogeneous psychiatric disorder. The core features comprise positive and negative symptoms, including hallucinations and impaired motivation, as well as cognitive impairment. Current evidence implicates dysfunctions of different brain circuits, involving several neurotransmitters, among which dopamine and glutamate may play a prominent role. So far, the main treatment approach consists of antipsychotic drugs, mostly dopamine/serotonin antagonists, although there is an active search for drugs with novel mechanisms of action. In this regard, the drug SEP-363856 has demonstrated broad antipsychotic activity in preclinical models. The mechanism of action of SEP-363856 is distinct from currently available antipsychotics as it does not have affinity for D2 or 5-HT2A receptors, but it acts as an agonist at 5-HT1A and trace amine-associated (TAAR1) receptors. The aim of the present study was to investigate the ability of SEP-363856 to modulate the functional activity of selected brain areas relevant for schizophrenia and to test its potential in counteracting behavioural and molecular alterations induced by acute phencyclidine (PCP) administration, to mimic a condition of hypo-glutamatergia in the rat. Methods: In order to investigate brain region-specific transcriptional mechanisms, adult male Sprague Dawley rats were treated with vehicle or SEP- 363856 (1, 3 or 10 mg/kg, PO) and sacrificed 1h later for the dissection of brain areas for molecular analysis. In order to test the ability of SEP- 363856 to correct the alterations under a condition of reduced glutamate activity, adult female Lister Hooded rats were pre-treated with the drug (1, 3 or 10 mg/kg, PO) 60 minutes before an acute injection of PCP (2 mg/kg, i.p). Locomotor activity was analysed during the following 90 minutes before sacrifice for the molecular analyses. Results: We found that the prefrontal cortex (PFC) showed the most significant changes in response to acute administration of SEP-363856. Indeed, the drug induced a significant up-regulation of a number of activity-dependent genes, such as Arc, Zif268, c-Fos and Npas4. We also found that the expression of the pool of BDNF transcripts with the long 3'UTR, characterized by a prominent dendritic localisation, was significantly increased within the PFC of animals treated with SEP-363856. The prominent activation of PFC was associated with a significant increase of signalling pathways associated with glutamatergic and dopaminergic activity, including the phosphorylation levels of AMPA receptor subunit 1 (GluA1), protein kinase B (Akt) and, to a lesser extent, the MAP kinases ERK1/2. When investigating the activity of the drug in the acute PCP model, we found that SEP-363856 at all doses attenuated PCP-induced hyperlocomotion. At the molecular level, we found that acute PCP injection up-regulated mRNA levels of activity-dependent genes (Arc, Zif268, c-Fos and Npas4) as well as of BDNF within PFC and these changes were also prevented by SEP- 363856 at all doses. Discussion: In summary, the results of our studies indicate that SEP-363856 has a rather selective activity on prefrontal cortex, by promoting rapid transcriptional mechanisms that may be related to its ability in modulating glutamatergic as well as dopaminergic pathways. Moreover, we found that SEP-363856 was able to counteract the behavioural and molecular effects induced by NMDA receptor antagonism. Further studies will investigate its ability to restore cognitive functions known to be impaired in schizophrenia.