A novel NMDA receptor modulator:antidepressant ef-fect and mechanism of GW043 / 中国药理学与毒理学杂志

OBJECTIVE The N-methyl-D-aspartate(NMDA)receptor has been shown to be strongly associ-ated with rapid antidepressant effects.GW043 is a com-pound with a novel structure that we designed and syn-thesized to act on the NMDA receptor(NMDAR).METH-ODS In this study,we first confirmed the target of GW043 using a receptor binding assay.We observed the effect of GW043 on NMDAR currents in vivo and in vitro assays using a membrane clamp technique with a view to characterizing the function of GW043.We investi-gated the antidepressant effect of GW043 in rodent behavioral models such as FST,TST and CUMS.Fur-thermore,we explored the mechanism of GW043 onset using Western blotting,BrdU staining,Golgi staining and electrophysiological techniques.RESULTS GW043 interacts with high affinity only at the NMDAR.Electro-physiological studies have indicated that GW043 is a par-tial agonist of NMDAR.Meanwhile,behavioral experi-ments were conducted to confirm the antidepressant effect of GW043 in rodents.The mechanism study found that GW043 regulate synaptic plasticity through LTP and BDNF/mTOR pathways and increase the number of new-born neurons to cause antidepressant effects.GW043,a partial agonist of NMDAR,reversed depression-like behav-ior in rats by modulating synaptic plasticity,suggesting an antidepressant effect.CONCLUSION The results suggest that GW043 is a partial agonist of NMDA recep-tors and has significant antidepressant effects.

Pathological Gambling Due to Aripiprazole: Two Cases

ABSTRACT Aripiprazole is an atypical antipsychotic agent which has a partial agonistic effect on dopamine D2 and D3 receptors. It is effective in the treatment of schizophrenia and bipolar disorder. Owing to its partial agonistic effect, hyperactivity of dopamine may occur in the mesolimbic pathway. In the literature, there are few case reports about pathological gambling due to aripiprazole. In this article, there are two case reports of patients who showed pathological gambling behaviour and alcohol abuse and who were under treatment with aripiprazole. The patient had a history of gambling in the past. With the use of aripiprazole, pathological gambling behaviour occurred quickly and with discontinuation of aripiprazole it ended completely. Aripiprazole causes pathological gambling by forming a hyperdopaminergic condition in the mesolimbic dopaminergic pathway. Aripiprazole should be recommended cautiously and carefully to patients who are impulsive and have a history of alcohol/substance abuse.

PPARγ non-agonist ligand:the structure optimization based on PPARγ partial agonist / 药学学报

Recent studies indicate that insulin-sensitizing activity of TZDs occurs through the inhibition of PPARγ Ser273 phosphorylation mediated by cyclin-dependent kinase 5(Cdk5), which is resulted from the binding activity for PPARγ. While, the side effects of TZDs may be related to the agonistic potency for PPARγ. In this article, 15 target compounds were designed and synthesized based on the structure of PPAR γ partial agonist INT131, with the aim of maintaining the insulin-sensitizing activity and reducing the side effects of INT131. The structures of these compounds were confirmed by 1H NMR and ESI-MS, and their binding activities and agonistic potencies for PPARγ were measured. The binding activity of compound 15 is 88.47% of rosiglitazone, which is similar to INT131 (98.55%), but the agonistic potency of compound 15 is 1.41% of rosiglitazone, obviously lower than INT131 (15.18%).

Two Cases of Hypersexuality Probably Associated with Aripiprazole

Sexual dysfunction is a common side effect in patients treated with antipsychotics but significant differences exist across different compounds. We report hypersexuality symptoms in two female patients with schizophrenia who were receiving treatment with aripiprazole. The patients experienced more frequent sexual desire and greater sexual preoccupation after taking aripiprazole. We discuss the potential neuro-chemical mechanisms for this and argue that aripiprazole's unique pharmacological profile, partial agonism with high affinity at dopamine D2-receptor, may have contributed to the development of these symptoms.

Varenicline - A New Pharmacotherapy For Smoking Cessation: Implication For Smokers With Mental Health Problems

Objective: The smoking rate among patients with mental health problem is higher than in the general population. Effective pharmacotherapy to treat nicotine addiction is thus needed to reduce the morbidity and mortality associated with cigarette smoking among these patients. This article reviews the literature on the suitability of varenicline for smokers with mental health problems. Methods: A search of the literature was conducted using PubMed from year 2001 to July 2009 using key words varenicline alone and varenicline and mental health. Articles chosen were narrowed to those published in English. The type of articles chosen included clinical trials, meta-analyses, case reports, and review articles. Results: The search produced a total of 322 articles on varenicline and 14 articles on varenicline and mental health. Varenicline, a new drug for smoking cessation is an α4β2 partial agonist and partial antagonist at nicotinic acetylcholine receptor. As a partial agonist, varenicline relieves craving and withdrawal symptoms that occur during smoking abstinence and also reduce the rewarding effects of smoking in patients who relapse. However, at present, there is concern regarding the neuropsychiatric side effects such as aggressive behaviour, suicidal ideation, mania and depression associated with varenicline use in patients with mental health problems, but these reports did not show a causal-link or lack of link between these symptoms and varenicline. Conclusion: Current available data support the effectiveness of varenicline to treat nicotine dependence. However its safety among smokers with mental health problems remains to be elucidated. At present, further safety assessment is needed in this patient population. Until new data is available regarding the safety of varenicline in these populations, psychiatrists and physicians prescribing this medication should be extra cautious and monitor for possible psychiatric side effects when prescribing this medication to patients with pre-existing psychiatric disorders or have vulnerability to psychoses.