Contents lists available at ScienceDirect Neuropeptides journal homepage: www.elsevier.com/locate/npep Effects of non-peptide nociceptin/orphanin FQ receptor ligands on methylphenidate-induced hyperactivity in mice: Implications for bipolar disorders Laila Asth a , Pamella R.F. Tiago a , Layse R.F. Costa a , Victor A.D. Holanda a , Salvatore Pacifico b , Nurulain T. Zaveri c , Girolamo Calo' d , Chiara Ruzza d,e , Elaine C. Gavioli a, ⁎ a Department of Biophysics and Pharmacology, Federal University of Rio Grande do Norte, Natal, Brazil b Department of Chemical and Pharmaceutical Sciences, University of Ferrara, 44121 Ferrara, Italy c Astraea Therapeutics, LLC., 320 Logue Avenue, Mountain View, CA 94043, United States d Department of Medical Sciences, Section of Pharmacology, University of Ferrara, 44121 Ferrara, Italy e Technopole of Ferrara, LTTA Laboratory for Advanced Therapies, Ferrara, Italy ARTICLE INFO Keywords: Nociceptin/orphanin FQ NOP receptor Mania Methylphenidate Hyperlocomotion Mouse ABSTRACT Bipolar disorder is a psychiatric pathology characterized by biphasic mood episodes of mania or hypomania and depression. The pharmacotherapy of bipolar disorder has significant adverse effects impairing treatment ad- herence and patient quality of life. The N/OFQ-NOP receptor system has been widely implicated with mood disorders. Clinical and preclinical findings suggest antidepressants actions for NOP antagonists. More recently, the administration of NOP agonists has shown to promote depressant states. The present study aimed to in- vestigate the effects of non-peptide NOP ligands in methylphenidate-induced manic-like behavior in mice. The NOP agonist Ro 65–6570 (0.01–1 mg/kg, ip), at the higher dose, did not affect spontaneous locomotion per se, but prevented the methylphenidate (10 mg/kg, sc)-induced hyperlocomotion. The NOP partial agonist AT-090 (0.001–0.03 mg/kg, ip) and the NOP antagonist SB-612111 (1–10 mg/kg, ip) did not significantly affect the psychostimulant-induced hyperactivity. Experiments performed with mice lacking the NOP receptor (NOP (-/-)) demonstrated that the treatment with methylphenidate induced similar hyperlocomotion in NOP (-/-) and NOP(+/+) mice. In conclusion, these findings suggest a potential role for NOP agonists in the prevention of manic states, especially by counteracting the hyperactivity symptom of bipolar patients. However, more studies are necessary in order to evaluate these compounds in other features of bipolar disorder. 1. Introduction Bipolar disorder is a multicomponent psychiatric illness character- ized by biphasic mood episodes of mania or hypomania and depression (Vieta et al., 2018). It is one of the leading causes of disability world- wide (Krahn, 2011), and is associated with high rates of premature mortality from both suicide and medical comorbidities (Crump et al., 2013; Hayes et al., 2015). The Diagnostic and Statistical Manual of Mental Disorders in its last edition (i.e., DSM-V) classified the bipolar disorder in an exclusive category, ‘Bipolar and Related Disorders’ (APA, 2013). In addition, the bipolar disorder in the DSM-V is subclassified as bipolar I disorder and bipolar II disorder, depending on the severity and duration of manic (or hypomanic, that is a milder and shorter form of mania) and depressive episodes (APA, 2013). During manic episodes, hyperactivity, increased self-esteem, grandiosity, reduced need for sleep, expansive mood and behavior and psychotic symptoms are common, whereas during depressive episodes, decreased energy, sad- ness, social withdrawal, hypersomnia and low self-esteem are the car- dinal features (Vieta et al., 2018). Bipolar disorder affects around 1% of the global population (Merikangas et al., 2011). The prevalence of bipolar I disorder is similar in men and women, but bipolar II disorder is more common in females (Nivoli et al., 2011). Pharmacological treatment for bipolar disorder is complex and includes lithium, some atypical antipsychotics and antic- onvulsant drugs that can be used to distinctly treat acute phases in manic (or hypomanic) and in depressive episodes, and in long-term therapy to prevent episode recurrence (Vieta et al., 2018). These medications have different tolerability profiles and are associated with https://doi.org/10.1016/j.npep.2020.102059 Received 24 March 2020; Received in revised form 9 June 2020; Accepted 9 June 2020 ⁎ Corresponding author at: Behavioral Pharmacology Laboratory, Department of Biophysics and Pharmacology, Federal University of Rio Grande do Norte, Av. Sen. Salgado Filho, s/n – Campus Universitário Lagoa Nova, Natal, Brazil. E-mail address: elainegavioli@gmail.com (E.C. Gavioli). Neuropeptides 82 (2020) 102059 Available online 15 June 2020 0143-4179/ © 2020 Elsevier Ltd. All rights reserved. T