ly-341495 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

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

Reduced motivation is an important marker of psychiatric disorders, including depression. We describe the female encounter test, a novel method of evaluating reward-seeking behavior in mice.. The test apparatus consists of three open chambers, formed with partitions that allow the animal to move freely from one chamber to another. A test male mouse is habituated in the apparatus, and subsequently a female and male mouse are introduced into a wire-mesh box in the left and right chamber, respectively. The time the test male mouse spends in the female or male area is measured for 10 min.. All six strains of mice tested showed a significant preference for female encounters. The preference was observed in 7-30-week-old mice. The preference was blocked by castration of the resident male test mouse, and was not affected by the phase of the menstrual cycle of the female intruder. The preference was impaired in mouse models of depression, including social isolation-reared, corticosterone-treated, and lipopolysaccharide-treated mice. The impairment was alleviated by fluvoxamine in isolation-reared and lipopolysaccharide-treated mice, and it was improved by the metabotropic glutamate 2/3 receptor antagonist LY341495 in corticosterone-treated mice. Encounter with a female, but not male, mouse increased c-Fos expression in the nucleus accumbens shell of test male mice. Furthermore, both the preference and encounter-induced increases in c-Fos expression were blocked by dopamine D1 and D2 receptor antagonists.. These findings indicate that motivation in adult male mice can be easily evaluated by quantitating female encounters.

Topics: Amino Acids; Animals; Antidepressive Agents, Second-Generation; Castration; Choice Behavior; Corticosterone; Depressive Disorder; Disease Models, Animal; Equipment Design; Estrous Cycle; Excitatory Amino Acid Antagonists; Female; Fluvoxamine; Lipopolysaccharides; Male; Mice; Motivation; Nucleus Accumbens; Psychological Tests; Reward; Social Behavior; Social Isolation; Xanthenes

We previously revealed that the activation of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor and mammalian target of rapamycin signaling contributed to the antidepressant-like effects of group II metabotropic glutamate (mGlu2/3) receptor antagonists, suggesting that the signaling pathway may be similar to the molecular mechanisms underlying the antidepressant-like action of ketamine, a noncompetitive N-methyl-D-aspartate receptor antagonist that exertes rapid and sustained antidepressant effects in patients with depressive disorder. Although brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase B (TrkB) signaling reportedly participates in the antidepressant-like effects of ketamine, the involvement of BDNF/TrkB signaling in the action of mGlu2/3 receptor antagonists has not been investigated. We therefore examined whether the activation of BDNF/TrkB signaling is required for the antidepressant-like effects of LY341495, an mGlu2/3 receptor antagonist, in animal models of depression such as the tail suspension test (TST) and the novelty-suppressed feeding test (NSFT). The administration of LY341495 at 30 min prior to the test exerted antidepressant-like effects (acute effects) lasting for at least 24 h (sustained effects) when evaluated using the TST and NSFT. Pretreatment with K252a, a TrkB tyrosine kinase inhibitor, blocked the sustained, but not the acute, effects of LY341495. These results suggest that BDNF/TrkB signaling may be involved in the sustained antidepressant-like effects of LY341495, as observed for ketamine treatment.

Topics: Amino Acids; Animals; Antidepressive Agents; Behavior, Animal; Brain-Derived Neurotrophic Factor; Depressive Disorder; Disease Models, Animal; Excitatory Amino Acid Antagonists; Exploratory Behavior; Hindlimb Suspension; Male; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Receptor, trkB; Receptors, Metabotropic Glutamate; Signal Transduction; Xanthenes

Topics: Adjuvants, Pharmaceutic; Amino Acids; Animals; Antidepressive Agents, Tricyclic; Bridged Bicyclo Compounds, Heterocyclic; Depressive Disorder; Disease Models, Animal; Drug Interactions; Drug Therapy, Combination; Excitatory Amino Acid Agents; Hippocampus; Imipramine; In Vitro Techniques; Mice; Neurons; Rats; Rats, Inbred Strains; Receptor Cross-Talk; Receptors, Metabotropic Glutamate; Time Factors; Xanthenes