Lithium and valproate prevent methylphenidate-induced mania-like behaviors in the hole board test.

Manic bipolar is diagnosed by psychomotor agitation, increased goal-directed activity, insomnia, grandiosity, excessive speech, and risky behavior. Animal studies aimed to modeling mania are commonly based in psychostimulants-induced hyperlocomotion. The exploration of other behaviors related with mania is mandatory to investigate this phase of bipolar disorder in animals. In this study, the hole board apparatus was suggested for evaluating mania-like behaviors induced by the psychostimulant methylphenidate. The treatment with methylphenidate (10mg/kg, ip) increased locomotion in the open field test. The pretreatment with lithium (50mg/kg, ip) and valproate (400mg/kg, ip) significantly prevented the hyperlocomotion. In the hole-board test, methylphenidate increased interactions with the central and peripheral holes and the exploration of central areas. Lithium was more effective than valproate in preventing all the behavioral manifestations induced by the psychostimulant. These findings were discussed based on the ability of methylphenidate-treated mice mimicking two symptoms of mania in the hole board test: goal-directed action and risk-taking behavior. In conclusion, the results point to a new approach to study mania through the hole board apparatus. The hole board test appears to be a sensitive assay to detect the efficacy of antimanic drugs.

Beta-arrestin 2 rather than G protein efficacy determines the anxiolytic-versus antidepressant-like effects of nociceptin/orphanin FQ receptor ligands.

BACKGROUND AND PURPOSE: Nociceptin/orphanin FQ (N/OFQ) receptor (NOP) agonists produce anxiolytic-like effects in rodents while antagonists promote antidepressant-like effects. The aim of this study was to investigate the effect on anxiety and depression of NOP receptor partial agonists such as the peptides [F/G]N/OFQ(1-13)NH2 and UFP-113 and the non-peptide AT-090. EXPERIMENTAL APPROACH: In vitro AT-090, UFP-113, and [F/G]N/OFQ(1-13)NH2 were tested for their ability to promote NOP/G-protein and NOP/ß-arrestin 2 interaction, using a bioluminescence resonance energy transfer assay. In vivo, they were tested in mice in the elevated plus maze (EPM) and in the forced swim (FST) tests. NOP partial agonists effects were systematically compared to those of full agonists (N/OFQ and Ro 65-6570) and antagonists (UFP-101 and SB-612111). KEY RESULTS: In vitro, AT-090, UFP-113, and [F/G]N/OFQ(1-13)NH2 promoted NOP/G protein interaction, with maximal effects lower than those evoked by N/OFQ and Ro 65-6570. AT-090 behaved as a NOP partial agonist also in inducing ß-arrestin 2 recruitment, while UFP-113 and [F/G]N/OFQ(1-13)NH2 were inactive in this assay. In vivo, AT-090 induced anxiolytic-like effects in the EPM but was inactive in the FST. Opposite results were obtained with UFP-113 and [F/G]N/OFQ(1-13)NH2. CONCLUSIONS AND IMPLICATIONS: NOP ligands producing similar effects on NOP/G protein interaction (partial agonism) but showing different effects on ß-arrestin 2 recruitment (partial agonism vs antagonism) elicited different actions on anxiety and mood. These results suggest that the action of a NOP ligand on emotional states is better predicted based on its ß-arrestin 2 rather than G-protein efficacy.