Central adenosine A 2A receptor is a promising target for drugs to treat Parkinson's disease (PD), and the central blockade of adenosine A 1 receptor improves cognitive function. In the present study, we investigated the effect of a novel adenosine A 1 and A 2A dual antagonist, 5-[5-amino-3-(4-fluorophenyl) pyrazin-2-yl]-1-isopropylpyridine-2(1H)-one (ASP5854), in animal models of PD and cognition. The binding affinities of ASP5854 for human A 1 and A 2A receptors were 9.03 and 1.76 nM, respectively, with higher specificity and no species differences. ASP5854 also showed antagonistic action on A 1 and A 2A agonist-induced increases of intracellular Ca 2ϩ concentration. ASP5854 ameliorated A 2A agonist 2-[p-(2-carboxyethyl) phenethylamino]-5Ј-N-ethylcarboxamidoadenosine (CGS21680)-and haloperidol-induced catalepsy in mice, with the minimum effective doses of 0.32 and 0.1 mg/kg, respectively, and it also improved haloperidol-induced catalepsy in rats at doses higher than 0.1 mg/kg. In unilateral 6-hydroxydopamine-lesioned rats, ASP5854 significantly potentiated l-dihydroxyphenylalanine (L-DOPA)-induced rotational behavior at doses higher than 0.032 mg/kg. ASP5854 also significantly restored the striatal dopamine content reduced by 1-metyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment in mice at doses higher than 0.1 mg/ kg. Furthermore, in the rat passive avoidance test, ASP5854 significantly reversed the scopolamine-induced memory deficits, whereas the specific adenosine A 2A antagonist 8-((E)-2-(3,4-dimethoxyphenyl)ethenyl)-1,3-diethyl-7-methyl-3,7-dihydro-1H-purine-2,6-dione (KW-6002; istradefylline) did not. Scopolamine-or 5H-dibenzo [a,d]cyclohepten-5,10-imine (dizocilpine maleate) (MK-801)-induced impairment of spontaneous alternation in the mouse Y-maze test was ameliorated by ASP5854, whereas KW-6002 did not exert improvement at therapeutically relevant dosages. These results demonstrate that the novel, selective, and orally active dual adenosine A 1 and A 2A receptors antagonist ASP5854 improves motor impairments, is neuroprotective via A 2A antagonism, and also enhances cognitive function through A 1 antagonism.Adenosine is a ubiquitous neuromodulator in the central nervous system. Its major role in the central nervous system is to modulate neurotransmitter release, the postsynaptic components, and also the nonsynaptic components such as glial cell signaling. Adenosine exerts these diverse physiological actions through activation of specific G protein-coupled receptors termed A 1 , A 2A , A 2B , and A 3 (Fredholm et al., 1994).Adenosine A 2A receptors are specifically localized in the striatum (Svenningsson et al., 1999), where they are coexpressed with dopamine D 2 receptors in the GABAergic striaArticle, publication date, and citation information can be found at http://jpet.aspetjournals.org. doi:10.1124/jpet.107.121962. ABBREVIATIONS:CGS21680, 2-[p-(2-carboxyethyl)phenethylamino]-5Ј-N-ethylcarboxamidoadenosine; NECA, N-ethylcarboxamidoadenosine; KW-6002, 7-methyl-3,7-dihydro-1H-purine-2,6-dion...

Abstract. Adenosine A 1 receptors in the brain are believed to play an important role in brain functioning. We have discovered a novel adenosine A 1 receptor antagonist, FR194921 (2-(1-methyl-4-piperidinyl)-6-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-3(2H)-pyridazinone), and characterized the pharmacological activity in the present study. FR194921 showed potent and selective affinity for the adenosine A 1 receptor without affinity for A 2A and A 3 receptors and did not show any species differences in binding affinity profile among human, rat, and mouse. Pharmacokinetic study in rats revealed that FR194921 was orally active and highly brain penetrable. Oral administration of FR194921 dose-dependently ameliorated the hypolocomotion induced by the A 1 receptor agonist N 6 -cyclopentyladenosine in rats, indicating this compound exerts A 1 -antagonistic action in vivo. In the passive avoidance test, scopolamine (1 mg / kg)-induced memory deficits were significantly ameliorated by FR194921 (0.32, 1 mg / kg). In two animal models of anxiety, the social interaction test and elevated plus maze, FR194921 showed specific anxiolytic activity without significantly influencing general behavior. In contrast, FR194921 did not show antidepressant activity even at a dose of 32 mg / kg in the rat forced swimming test. These results indicate that the novel, potent, and selective adenosine A 1 receptor antagonist FR194921 exerts both cognitive-enhancing and anxiolytic activity, suggesting the therapeutic potential of this compound for dementia and anxiety disorders.

The auditory steady-state response (ASSR) has been used to detect auditory processing deficits in patients with psychiatric disorders. However, the methodology of ASSR recording from the brain surface has not been standardized in preclinical studies, limiting its use as a translational biomarker. The sites of maximal ASSR in humans are the vertex and/or middle frontal area, although it has been suggested that the auditory cortex is the source of the ASSR. We constructed and validated novel methods for ASSR recording using a switchable pedestal which allows ASSR recording alternatively from temporal or parietal cortex with a wide range of frequencies in freely moving rats. We further evaluated ASSR as a translational tool by assessing the effect of ketamine. The ASSR measured at parietal cortex did not show clear event-related spectral perturbation (ERSP) or inter-trial coherence (ITC) in any frequency bands or a change with ketamine. In contrast, the ASSR at temporal cortex showed clear ERSP and ITC where 40 Hz was maximal in both gamma-band frequencies. Ketamine exerted a biphasic effect in ERSP at gamma bands. These findings suggest that temporal cortex recording with a wide frequency range is a robust methodology to detect ASSR, potentially enabling application as a translational biomarker in psychiatric and developmental disorders.

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Standard dopamine therapies for schizophrenia are not efficacious for negative symptoms of the disease, including asociality. This reduced social behavior may be due to glutamatergic dysfunction within the amygdala leading to increased fear and social anxiety. Several studies have demonstrated the pro-social effects of oxytocin in schizophrenia patients. Therefore, this study evaluates the effect of sub-chronic oxytocin on electroencephalographic (EEG) activity in amygdala of mice during performance of the three chamber social choice and open field tests following acute ketamine as a model of glutamatergic dysfunction. Oxytocin did not restore social deficits introduced by ketamine, but did significantly increase sociality in comparison to the control group. Ketamine had no effect on time spent in the center during the open field trials, while oxytocin increased overall center time across all groups, suggesting a reduction in anxiety. Amygdala activity was consistent across all drug groups during social and nonsocial behavioral trials. However, oxytocin reduced overall amygdala EEG power during the two behavioral tasks. Alternatively, ketamine did not significantly affect EEG power throughout the tasks. Decreased EEG power in the amygdala, as caused by oxytocin, may be related to both reduced anxiety and increased social behaviors. Data suggest that separate pro-social and social anxiety pathways may mediate social preference.