Copolymer-1 enhances cognitive performance in young adult rats.

Cognitive impairment is a dysfunction observed as a sequel of various neurodegenerative diseases, as well as a concomitant element in the elderly stages of life. In clinical settings, this malfunction is identified as mild cognitive impairment. Previous studies have suggested that cognitive impairment could be the result of a reduction in the expression of brain-derived neurotrophic factor (BDNF) and/or immune dysfunction. Copolymer-1 (Cop-1) is an FDA-approved synthetic peptide capable of inducing the activation of Th2/3 cells, which are able to release BDNF, as well as to migrate and accumulate in the brain. In this study, we evaluated the effect of Cop-1 immunization on improvement of cognition in adult rats. For this purpose, we performed four experiments. We evaluated the effect of Cop-1 immunization on learning/memory using the Morris water maze for spatial memory and autoshaping for associative memory in 3- or 6-month-old rats. BDNF concentrations at the hippocampus were determined by ELISA. Cop-1 immunization induced a significant improvement of spatial memory and associative memory in 6-month-old rats. Likewise, Cop-1 improved spatial memory and associative memory when animals were immunized at 3 months and evaluated at 6 months old. Additionally, Cop-1 induced a significant increase in BDNF levels at the hippocampus. To our knowledge, the present investigation reports the first instance of Cop-1 treatment enhancing cognitive function in normal young adult rats, suggesting that Cop-1 may be a practical therapeutic strategy potentially useful for age- or disease-related cognitive impairment.

Serotonin and emotion, learning and memory.

Serotonin (5-hydroxytryptamien, 5-HT) has been linked to emotional and motivational aspects of human behavior, including anxiety, depression, impulsivity, etc. Several clinically effective drugs exert effects via 5-HT systems. Growing evidence suggests that those effects play an important role in learning and memory. Whether the role of serotonin is related to memory and/or behavioral or emotional aspects remains an important question. A key question that remains is whether 5-HT markers (e.g., receptors) directly or indirectly participate and/or contribute to the physiological and pharmacological basis of memory and its pathogenesis. The major aim of this paper is to re-examine some recent advances regarding mammalian 5-HT receptors and transporter in light of their physiological, pathophysiological and therapeutic implications for memory. We particularly address evidence involving 5-HT systems in behavioral, pharmacological, molecular, genetic and imaging results and memory. Finally, this paper aims to summarize a portion of the evidence about serotonin, memory and emotion from animal and human studies and provide an overview of potential tools, markers and cellular and molecular candidate mechanisms. It should be noted that there are several subjects that this paper only briefly touches upon, presenting only what may be the most salient findings in the context of memory, emotion and serotonin.

GABA, glutamate, dopamine and serotonin transporters expression on forgetting.

Notwithstanding several neurotransmission systems are frequently related to memory formation; forgetting process and neurotransmission systems or their transporters; the role of γ-aminobutyric acid (GAT1), glutamate (EACC1), dopamine (DAT) and serotonin (SERT) is poorly understood. Hence, in this paper western-blot analysis was used to evaluate expression of GAT1, EAAC1, DAT and SERT during forgetting in trained and untrained rats treated with the selective serotonin transporter inhibitor fluoxetine, the amnesic drug d-methamphetamine (METH) and fluoxetine plus METH. Transporters expression was determined in the hippocampus (HIP), prefrontal cortex (PFC) and striatum (STR). Results indicated that forgetting of Pavlovian/instrumental autoshaping was associated to up-regulation of GAT1 (PFC and HIP) and DAT (PFC) while SERT (HIP) was down-regulated; no-changes were observed in striatum. Methamphetamine administration did not affect forgetting at 216 h post-training but up-regulated hippocampal DAT and EACC, prefrontal cortex DAT and striatal GAT1 or EACC1. Fluoxetine alone prevented forgetting, which was associated to striatal GAT1 and hippocampal DAT up-regulation, but prefrontal cortex GAT1 down-regulation. Fluoxetine plus METH administration was also able to prevent forgetting, which was associated to hippocampal DAT, prefrontal cortex SERT and striatal GAT1, DAT or SERT up-regulation, but prefrontal cortex GAT1 down-regulation. Together these data show that forgetting provokes primarily hippocampal and prefrontal cortex transporters changes; forgetting represent a behavioral process hardly modifiable and its prevention could causes different transporters expression patterns.

Lithium, phenserine, memantine and pioglitazone reverse memory deficit and restore phospho-GSK3ß decreased in hippocampus in intracerebroventricular streptozotocin induced memory deficit model.

Intracerebroventricular (ICV) streptozotocin (STZ) treated rat has been described as a suitable model for sporadic Alzheimer's disease (AD). Central application of STZ has demonstrated behavioral and neurochemical features that resembled those found in human AD. Chronic treatments with antioxidants, acetylcholinesterase (AChE) inhibitors, or improving glucose utilization drugs have reported a beneficial effect in ICV STZ-treated rats. In the present study the post-training administration of a glycogen synthase kinase (GSK3) inhibitor, lithium; antidementia drugs: phenserine and memantine, and insulin sensitizer, pioglitazone on memory function of ICV STZ-rats was assessed. In these same animals the phosphorylated GSK3ß (p-GSK3ß) and total GSK3ß levels were determined, and importantly GSK3ß regulates the tau phosphorylation responsible for neurofibrillary tangle formation in AD. Wistar rats received ICV STZ application (3mg/kg twice) and 2 weeks later short- (STM) and long-term memories (LTM) were assessed in an autoshaping learning task. Animals were sacrificed immediately following the last autoshaping session, their brains removed and dissected. The enzymes were measured in the hippocampus and prefrontal cortex (PFC) by western blot. ICV STZ-treated rats showed a memory deficit and significantly decreased p-GSK3ß levels, while total GSK3ß did not change, in both the hippocampus and PFC. Memory impairment was reversed by lithium (100mg/kg), phenserine (1mg/kg), memantine (5mg/kg) and pioglitazone (30 mg/kg). The p-GSK3ß levels were restored by lithium, phenserine and pioglitazone in the hippocampus, and restored by lithium in the PFC. Memantine produced no changes in p-GSK3ß levels in neither the hippocampus nor PFC. Total GSK3ß levels did not change with either drug. Altogether these results show the beneficial effects of drugs with different mechanisms of actions on memory impairment induced by ICV STZ, and restored p-GSK3ß levels, a kinase key of signaling cascade of insulin receptor.

Effects of 5-HT drugs in prefrontal cortex during memory formation and the ketamine amnesia-model.

This article describes a series of experiments investigating the effects of systemic or intraprefrontal administration of serotonergic agents on ketamine induced memory deficits in rats. First, rats were trained on an operant autoshaping task. Immediately after training, rats were injected with different doses of drug or saline. Following drug administration, rats were tested after 1.5 h for short-term memory (STM) and 24 h for long-term memory (LTM) of conditioned response. An increase or decrease in number of conditioned responses was an index of retention. The major results of this work show that ketamine impaired STM and this effect was reversed, by either systemic or intraprefrontal cortex administration of the agonist 5-HT(1A/7) 8-OH-DPAT, the 5-HT receptor antagonists MDL100907 (5-HT(2A)), SB-399885 (5-HT(6)), and SB-269970 (5-HT(7)). The ketamine STM-impairment effect was not altered by the 5-HT(1A) antagonist WAY 100635 or the 5-HT(1B) antagonist SB-224289. Notably, prefrontal cortex inhibition of translation or transcription interrupted STM without affecting LTM suggesting different signaling mechanisms. The interacting effect of NMDA and serotonin agents in memory function is an interesting and important area of study; both receptors are considered to be important targets for the development of antipsychotic medication. Particularly, 5-HT(1A/7), 5-HT(2A) 5-HT(6), and 5-HT(7) receptors present in prefrontal cortex, represent important targets for development of drugs for the treatment of SMT-deficits.

Role of 5-HT1-7 receptors in short- and long-term memory for an autoshaping task: intrahippocampal manipulations.

It was previously reported that brain areas containing serotonin (5-hydroxytryptamine, 5-HT) receptors mediate memory consolidation as well as short (STM)- and long-term memory (LTM). Here the effects of systemic and intrahippocampal administration of 5-HT agonists and antagonists on an autoshaping learning task were explored, which requires hippocampal translation and transduction as well as 5-HT receptors expression. As previously reported ketamine (glutamatergic antagonist) and two well-known amnesic drugs, scopolamine (cholinergic antagonist) and dizocilpine (NMDA antagonist) impaired STM but not LTM; dizocilpine even improved the latter. Since ketamine produces hallucinations and impairs memory in humans, we address the question if well-known antipsychotic haloperidol and clozapine might affect STM deficit. Indeed, systemic administration of clozapine