igmesine and Memory-Disorders

There is evidence for the existence of two classes of sigma binding sites, termed "site 1" and "site 2", that are distinct from opioid and PCP receptors. Sigma receptor ligands may be useful in the treatment of schizophrenia, since they improve not only positive but also negative symptoms with little extrapyramidal side effects in animal models. In addition, recent experiments have demonstrated that sigma receptor ligands attenuate the motor suppression and colonic motor disturbances seen under mentally stressful situations, stimulate the central cholinergic function thereby ameliorating impairment of learning and memory, and protect cerebral neurons against cerebral ischemic insult. The present review describes the neuropharmacological effects of sigma receptor ligands, especially anxiolytic (anti-stress) effects, ameliorating effects on impairment of learning and memory, and neuroprotective effects.

Topics: Animals; Antipsychotic Agents; Anxiety; Brain Ischemia; Cinnamates; Cyclopropanes; Humans; Learning Disabilities; Memory Disorders; Phenazocine; Phencyclidine; Receptors, sigma

The sigma-1 (σ₁) protein regulates calcium homeostasis and acts as an endoplasmic reticulum chaperone. It can be activated by ligands which impact memory, depression, anxiety or addiction processes. We here characterized the behavioural phenotype of knockout (KO) mice for the σ₁ protein. Two-month old male σ₁⁻/⁻ mice showed signs of anxiety in the open-field, passive avoidance or elevated plus-maze test, but other activity or memory responses were unchanged. Female σ₁⁻/⁻ mice showed deficits in spontaneous alternation or water-maze learning. Twelve-month old σ₁⁺/⁻ female mice showed deficits in alternation and σ₁⁻/⁻ mice in avoidance escape latency. Two- and 14-month old female σ₁⁻/⁻ mice showed decreased plasma 17β-estradiol levels. Treatment with 17β-estradiol (0.1, 0.2 mg/kg i.p.) reversed the spatial memory deficits in young and aged mice. Male σ₁ KO mice showed enhanced response in the forced swimming test. Igmesine, a σ₁ agonist, failed to decrease immobility in σ₁ KO mice. Fluoxetine and sertraline were more efficient in σ₁ KO mice, an effect likely related to their σ₁ antagonist activity. Imipramine, desipramine and amitriptyline were equally active. σ₁ protein invalidation therefore affected stress or anxiety response but not memory in males. Changes in steroid tonus in female animals led, however, to memory impairments that increased with age.

Topics: Age Factors; Aging; Animals; Antidepressive Agents; Anxiety; Behavior, Animal; Cinnamates; Cyclopropanes; Depression; Escape Reaction; Estradiol; Female; Genotype; Male; Maze Learning; Memory; Memory Disorders; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Motor Activity; Phenotype; Reaction Time; Receptors, sigma; Sex Factors; Sigma-1 Receptor; Time Factors

1. Stress during pregnancy results in complex neurochemical and behavioral alterations throughout the offspring lifetime. We here examined the impact of prenatal stress (PS) on memory functions in male and female offspring and report the efficacy of a selective sigma(1) (sigma(1)) receptor agonist, igmesine, in alleviating the observed deficits. 2. Dams received an unpredictable 90-min duration restraint stress from gestational day E17 to E20. Learning was examined in offspring between day P24 and P36 using spontaneous alternation in the Y-maze, delayed alternation in the T-maze, water-maze learning and passive avoidance. 3. Both male and female PS rats showed impairments of spontaneous and delayed alternation performances. Acquisition of a fixed platform position in the water-maze was unchanged in PS rats, but the probe test revealed a diminution of time spent in the training quadrant. Acquisition of a daily changing platform position demonstrated impaired working memory for male and female PS rats. Finally, passive avoidance deficits were observed. 4. Pretreatment with the selective sigma(1) agonist igmesine (1-10 mg x kg(-1) i.p.) reversed the PS-induced learning deficits in offspring rats for each test. The sigma(1) antagonist BD1063 failed to affect performances alone but blocked the igmesine effect, confirming the involvement of the sigma(1) receptor. 5. PS thus induces delayed memory deficits, affecting spatial and nonspatial, short- and long-term memories in juvenile male and female offspring rats. Activation of the sigma(1) neuromodulatory receptor allows a significant recovery of the memory functions in PS rats.

Topics: Animals; Animals, Newborn; Avoidance Learning; Behavior, Animal; Cinnamates; Cyclopropanes; Female; France; Gestational Age; Injections, Intraperitoneal; Learning Disabilities; Male; Maternal Exposure; Maze Learning; Memory Disorders; Piperazines; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Receptors, sigma; Restraint, Physical; Time Factors