Pharmacology, biochemistry, and behavior
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Pharmacol. Biochem. Behav. · Aug 2015
Pharmacological evaluation of a novel phosphodiesterase 10A inhibitor in models of antipsychotic activity and cognition.
In this study, we report the pharmacological effects of a novel PDE10A inhibitor, SEP-39. SEP-39 is a potent (1.0nM) inhibitor of human PDE10A in vitro, with good selectivity (>16000-fold) against other PDEs. In an in vivo occupancy study, the RO50 value was determined to be 0.7mg/kg (p.o.), corresponding to plasma and brain exposures of 28ng/mL and 43ng/g, respectively. ⋯ We also demonstrate the procognitive effects of SEP-39 in the rat novel object recognition assay. These effects appear to require less PDE10A inhibition than the reversal of PCP-induced hyperlocomotion or EEG effects, as improvements in recognition index were seen at doses of 0.3mg/kg and above. Our data demonstrate that SEP-39 is a potent, orally active PDE10A inhibitor with therapeutic potential in a number of psychiatric indications.
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Pharmacol. Biochem. Behav. · Aug 2015
Antinociceptive and hypnotic activities of pregabalin in a neuropathic pain-like model in mice.
To evaluate the antinociceptive and hypnotic effects of pregabalin, we established a neuropathic pain-like model in mice using partial sciatic nerve ligation (PSNL), and examined thermal hyperalgesia, mechanical allodynia, electroencephalogram, rota-rod testing, and c-Fos expression in the anterior cingulate cortex. Gabapentin was used as a reference drug in the study. Pregabalin administered i.g. at 12.5 and 25mg/kg prolonged the duration of thermal latencies by 1.4- and 1.6-fold and increased the mechanical threshold by 2.2- and 3.1-fold 3h after administration, respectively, but did not affect motor coordination in PSNL mice, compared with vehicle control. ⋯ However, pregabalin (25mg/kg) given at 20:30 did not alter the sleep pattern in normal mice. Immunohistochemical study showed that PSNL increased c-Fos expression in the neurons of anterior cingulate cortex by 2.1-fold, which could be reversed by pregabalin. These results indicate that pregabalin is an effective treatment for both neuropathic pain and sleep disturbance in PSNL mice.
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Pharmacol. Biochem. Behav. · Aug 2015
Activation of P2X7 receptors in the midbrain periaqueductal gray of rats facilitates morphine tolerance.
Opiates such as morphine exhibit analgesic effect in various pain models, but repeated and chronic morphine administration may develop resistance to antinociception. The purinergic signaling system is involved in the mechanisms of pain modulation and morphine tolerance. This study aimed to determine whether the P2X7 receptor in the ventrolateral midbrain periaqueductal gray (vlPAG) is involved in morphine tolerance. ⋯ AS ODN (15nmol/0.3μL) against the P2X7 receptor reduced the development of chronic morphine tolerance in rats. These results suggest that the development of antinociceptive tolerance to morphine is partially mediated by activating the vlPAG P2X7 receptors. The present data also suggest that the P2X7 receptors may be a therapeutic target for improving the analgesic effect of morphine in treatments of pain when morphine tolerance occurs.
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Pharmacol. Biochem. Behav. · Jul 2015
Intrathecal injection of KN93 attenuates paradoxical remifentanil-induced postoperative hyperalgesia by inhibiting spinal CaMKII phosphorylation in rats.
Remifentanil is a short-acting and highly selective mu opiate agonist that is used in many clinical surgical situations for intraoperative pain relief. Under certain conditions, remifentanil can produce "paradoxical" hyperalgesia. This study aims to investigate mechanisms of actions mediating this "paradoxical" effect. ⋯ Intrathecal injection of KN93 attenuates postoperative hyperalgesia induced by intraoperative infusion of remifentanil in rats through inhibiting spinal CaMKII phosphorylation.
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Pharmacol. Biochem. Behav. · Jul 2015
Flavonoid Chrysin prevents age-related cognitive decline via attenuation of oxidative stress and modulation of BDNF levels in aged mouse brain.
In this study, the effect of Chrysin (5,7-dihydroxyflavone), an important member of the flavonoid family, on memory impairment, oxidative stress and BDNF reduction generated by aging in mice were investigated. Young and aged mice were treated daily per 60days with Chrysin (1 and 10mg/kg; per oral, p.o.) or veichle (10ml/kg; p.o.). Mice were trained and tested in Morris Water Maze task. ⋯ Moreover, Chrysin marked mitigated the decrease of BDNF levels in the PFC and HC of aged mice. These results demonstrated that flavonoid Chrysin, an antioxidant compound, was able to prevent age-associated memory probably by their free radical scavenger action and modulation of BDNF production. Thus, this study indicates that Chrysin may represent a new pharmacological approach to alleviate the age-related declines during normal age, acting as an anti-aging agent.