2-3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline and Depressive-Disorder

Ketamine has been shown to induce a rapid antidepressant effect on patients with depression. In many animal models, both rapid and sustained antidepressant activities were also found in response to an antagonist of group II metabotropic glutamate receptors, LY341495, and its mechanism of action seemed to be similar in many ways to the action of ketamine. It has also been found that LY341495 enhanced the antidepressant-like activity of sub-effective doses of ketamine in rats without inducing adverse effects. Here, we investigated the role of AMPA receptor and TrkB receptor activation in the antidepressant-like effects of ketamine (3 mg/kg) co-administered with LY341495 (0.1 mg/kg), in the forced swim test in rats, at three time points (40 min, 3 h and 24 h) after joint administration of the tested compounds. It was found that the AMPA receptor antagonist NBQX (10 mg/kg) reversed the antidepressant effect of ketamine co-administered with LY341495 at all tested time points, whereas the TrkB receptor antagonist ANA-12 contributed to blockade of the effect of ketamine and LY341495 3 h after their joint administration. These results indicate that activation of AMPA receptor and BDNF-related signaling may play a role in the mechanism of antidepressant action of ketamine co-administered with LY341495.

Topics: Amino Acids; Animals; Antidepressive Agents; Azepines; Benzamides; Depression; Depressive Disorder; Excitatory Amino Acid Antagonists; Ketamine; Male; Prefrontal Cortex; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptor, trkB; Receptors, AMPA; Receptors, Metabotropic Glutamate; Signal Transduction; Xanthenes

Conventional antidepressants lack efficacy for many patients (treatmentresistant depression or TRD) and generally take weeks to produce full therapeutic response in others. Emerging data has identified certain drugs such as ketamine as rapidly-acting antidepressants for major depressive disorder and TRD. Scopolamine, a drug used to treat motion sickness and nausea, has also been demonstrated to function as a rapidly-acting antidepressant. The mechanisms associated with efficacy in TRD patients and rapid onset of action have been suggested to involve a-Amino-3-hydroxy- 5-methyl-4-isoxazolepropionic acid (AMPA) receptor and mammalian target of rapamycin (mTOR) signaling. Since the work on these mechanisms with scopolamine has been limited, the present set of experiments was designed to further explore these mechanisms of action.. Male, NIH Swiss mice demonstrated a robust and immediate antidepressant signature with ketamine or scopolamine when studied under the forced-swim test.. The AMPA receptor antagonist NBQX prevented this antidepressant-like effect of scopolamine and ketamine. An orally-bioavilable mTOR inhibitor (AZD8055) also attenuated the antidepressant- like effects of scopolamine and ketamine. Scopolamine was also shown to augment the antidepressant- like effect of the selective serotonin reuptake inhibitor citalopram. When given in combination, scopolamine and ketamine acted synergistically to produce antidepressant-like effects. Although drug interaction data suggested that additional mechanisms might be at play, metabolomic analysis of frontal cortex and plasma from muscarinic M1+/+ and M1 -/- mice given scopolamine or vehicle did not reveal any hints as to the nature of these additional mechanisms of action.. Overall, the data substantiate and extend the idea that AMPA and mTOR signaling pathways are necessary for the antidepressant-like effects of scopolamine and ketamine, mechanisms that appear to be of general significance for TRD therapeutic agents.

Topics: Animals; Antidepressive Agents; Citalopram; Depressive Disorder; Drug Interactions; Drug Therapy, Combination; Excitatory Amino Acid Antagonists; Frontal Lobe; Ketamine; Male; Metabolome; Mice, Inbred C57BL; Mice, Knockout; Morpholines; Quinoxalines; Receptor, Muscarinic M1; Receptors, AMPA; Scopolamine; Selective Serotonin Reuptake Inhibitors; TOR Serine-Threonine Kinases

Clinical studies have shown that the muscarinic receptor antagonist scopolamine induces a potent and rapid antidepressant effect relative to conventional antidepressants. However, potential undesirable effects, including memory impairment, partially limit the use of scopolamine in psychiatry. In the present study, we propose to overcome these limitations and enhance the therapeutic effects of scopolamine via administration in combination with the group II metabotropic glutamate (mGlu) receptor antagonist, LY341495. Joint administration of sub-effective doses of scopolamine (0.03 or 0.1 mg/kg, i.p.) with a sub-effective dose of LY341495 (0.1 mg/kg, i.p.) induced a profound antidepressant effect in the tail suspension test (TST) and in the forced swim test (FST) in mice. This drug combination did not impair memory, as measured using the Morris water maze (MWM), and did not influence the locomotor activity of mice. Furthermore, we found that an AMPA receptor antagonist, NBQX (10 mg/kg), completely reversed the antidepressant-like activity of a mixture of scopolamine and LY341495 in the TST. However, this effect was not influenced by para-chlorophenylalanine (PCPA) pre-treatment, indicating a lack of involvement of serotonergic system activation in the antidepressant-like effects of jointly given scopolamine and LY341495. Therefore, the combined administration of low doses of the antimuscarinic drug scopolamine and the group II mGlu receptor antagonist LY341495 might be a new, effective and safe strategy in the therapy of depression.

Topics: Amino Acids; Animals; Antidepressive Agents; Depressive Disorder; Excitatory Amino Acid Antagonists; Male; Maze Learning; Mice; Mice, Inbred C57BL; Motor Activity; Prefrontal Cortex; Quinoxalines; Receptors, AMPA; Receptors, Metabotropic Glutamate; Scopolamine; Serotonin; Xanthenes

The NMDA receptor antagonist, CGP 37849-induced reduction in immobility time in the forced swim test in mice was not antagonized by pre-treatment with the AMPA receptor antagonist NBQX. This is the first demonstration of the antidepressant effect of the NMDA antagonist not being dependent on the AMPA transmission.

Topics: 2-Amino-5-phosphonovalerate; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Antidepressive Agents; Depressive Disorder; Excitatory Amino Acid Antagonists; Mice; Motor Activity; N-Methylaspartate; Quinoxalines; Receptors, N-Methyl-D-Aspartate; Swimming