Improvements in hippocampal-dependent learning and decremental attention in 5-HT(3) receptor overexpressing mice

The 5-HT3 receptor for serotonin is expressed within limbic structures and is known to modulate neurotransmitter release, suggesting that this receptor may influence learning and memory. Perturbations in serotonergic neurotransmission lead to changes in the ability to attend, learn, and remember. To examine the role of 5-HT3 receptors in learning, memory, and attention, 5-HT3 receptor overexpressing (5-HT3-OE) transgenic mice and their wild-type littermates (WT) were tested in Pavlovian contextual and cued fear conditioning, fear extinction, and latent inhibition (LI) paradigms. Prepulse inhibition (PPI) was assessed to reveal changes in sensorimotor gating. Additionally, anxious behaviors, shock sensitivity, and reactions to novel stimuli were evaluated. 5-HT3-OE mice displayed enhanced contextual conditioning, whereas cued conditioning remained the same as that of WT mice. 5-HT3-OE mice did not differ from WT in extinction rates to either the context or cue. LI was enhanced for 5-HT3-OE mice compared to WT. PPI remained unchanged. No differences in sensitivity to footshock or startle were found. However, 5-HT3-OE mice demonstrated heightened exploratory behavior in response to novel environmental stimuli and decreased anxiety as measured in the elevated plus-maze. Results indicate that overexpression of the 5-HT3 receptor in mouse forebrain results in enhanced hippocampal-dependent learning and attention. Enhanced inspective behavior in response to novelty may contribute to the observed improvements in learning, memory, and attention due to 5-HT3 receptor overexpression.     

A pharmacological analysis of an associative learning task: 5-HT(1) to 5-HT(7) receptor subtypes function on a pavlovian/instrumental autoshaped memory

Recent studies using both invertebrates and mammals have revealed that endogenous serotonin (5-hydroxytryptamine [5-HT]) modulates plasticity processes, including learning and memory. However, little is currently known about the mechanisms, loci, or time window of the actions of 5-HT. The aim of this review is to discuss some recent results on the effects of systemic administration of selective agonists and antagonists of 5-HT on associative learning in a Pavlovian/instrumental autoshaping (P/I-A) task in rats. The results indicate that pharmacological manipulation of 5-HT1-7 receptors or 5-HT reuptake sites might modulate memory consolidation, which is consistent with the emerging notion that 5-HT plays a key role in memory formation.     

Mouse genetic approaches to feeding regulation: serotonin 5-HT2C receptor mutant mice

Neural mechanisms underlying the regulation of ingestive behavior and energy balance are well conserved among mammals. Many neural pathways, each reflecting the function of many genes, interact to regulate these processes. Systematic genetic perturbations are not feasible in humans--the examination of gene functions relevant to feeding regulation must be performed in other species. Many advances in this field have been made through molecular genetic studies of mice, the most genetically tractable of mammalian species. The relevance of mouse ingestive behavior to the mechanisms underlying the regulation of feeding in humans is discussed. Approaches for evaluating the contributions of genes to the regulation of energy balance and to the actions of anorectic drugs are described in the context of studies focused on a line of mice lacking the serotonin 5-HT2C receptor subtype. These animal display reduced responsiveness to serotonergic anorexic drugs and a late-onset obesity syndrome associated with features reminiscent of common forms of human obesity. Developmental studies of energy balance uncovered a novel age-dependent physiological process that may contribute generally to the predisposition of humans and other mammals to accumulate fat stores during "middle-age." These findings are presented to illustrate considerations in the use of mouse molecular genetic technologies to investigate genetic influences on ingestive behavior and energy balance.     

Rapid visual learning in the rat: Effects at the 5-HT 1a receptor subtype

The 5-hydroxytryptamine 1a (5-HT 1a ) receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT; 0.15 mg/kg) impaired rats' rapid visual learning on a computerized maze. This treatment also increased decision time (DT) but the learning impairment was not necessarily a side-effect of slower responding because, in this task, responses made at long DT are more accurate than those at short DT. The selective 5-HT 1a receptor antagonist WAY-100635 (0.3 mg/kg) was itself without effect on accuracy, but was effective in reversing effects of 8-OH-DPAT (on both accuracy and DT). Within problems (i.e., over the 40-60 trials of a single discrimination), performance was reduced by treatment with 8-OH-DPAT at all stages of learning. We conclude that this effect is mediated through the 5-HT 1a receptor site (rather than through some other serotonergic receptor site or non-specific mechanism) as it was reversible by treatment with WAY-100635. Although it could still arise from behaviourally non-specific effects, the performance deficit finds its best account in terms of the psychological processes necessary to visual learning. Its reversal with WAY-100635 offers support to the hypothesis that 5-HT 1a receptor antagonists could improve cognitive function, under conditions of pre-existing impairment due to overactive serotonergic inhibition, as is thought to occur in Alzheimer's disease.     

Mitral cell beta1 and 5-HT2A receptor colocalization and cAMP coregulation: a new model of norepinephrine-induced learning in the olfactory bulb

In the present study we assess a new model for classical conditioning of odor preference learning in rat pups. In preference learning beta(1)-adrenoceptors activated by the locus coeruleus mediate the unconditioned stimulus, whereas olfactory nerve input mediates the conditioned stimulus, odor. Serotonin (5-HT) depletion prevents odor learning, with 5-HT(2A/2C) agonists correcting the deficit. Our new model proposes that the interaction of noradrenergic and serotonergic input with odor occurs in the mitral cells of the olfactory bulb through activation of cyclic adenosine monophosphate (cAMP). Here, using selective antibodies and immunofluorescence examined with confocal microscopy, we demonstrate that beta(1)-adrenoceptors and 5-HT(2A) receptors colocalize primarily on mitral cells. Using a cAMP assay and cAMP immunocytochemistry, we find that beta-adrenoceptor activation by isoproterenol, at learning-effective and higher doses, significantly increases bulbar cAMP, as does stroking. As predicted by our model, the cAMP increases are localized to mitral cells. 5-HT depletion of the olfactory bulb does not affect basal levels of cAMP but prevents isoproterenol-induced cAMP elevation. These results support the model. We suggest the mitral-cell cAMP cascade converges with a Ca(2+) pathway activated by odor to recruit CREB phosphorylation and memory-associated changes in the olfactory bulb. The dose-related increase in cAMP with isoproterenol implies a critical cAMP window because the highest dose of isoproterenol does not produce learning.     

5-HT1A receptors modulate the consolidation of learning in normal and cognitively impaired rats

Attempts were made to further analyze the role of 5-HT1A receptors in consolidation of learning by evaluating the role of these receptors in cognitively normal and impaired animals. The effects of post-training administration of 8-OH-DPAT and 5-HT1A receptor antagonists, WAY 100135, WAY 100635, and S-UH-301, plus the cholinergic and glutamatergic antagonists, scopolamine and dizolcipine, respectively, were determined using an autoshaping learning task. The results showed that 8-OH-DPAT increased the number of conditioned responses, whereas WAY100135, WAY100635, and S-UH-301, and the 5-HT depleter, p-chloroamphetamine (PCA), had no effect. PCA did not change the silent properties of the 5-HT1A receptor antagonists. PCA, WAY100635, and S-UH-301, but not GR127935 (a 5-HT1B/1D-receptor antagonist) or MDL100907 (a 5-HT2A receptor antagonist), reversed the effect to 8-OH-DPAT. Ketanserin (a 5-HT2A/2C receptor antagonist) and ondansetron (a 5-HT3 receptor antagonist), at a dose that increased the conditioned responses by itself, reversed the effect of 8-OH-DPAT. Moreover, 8-OH-DPAT or S-UH-301 reversed the learning deficit induced by scopolamine and dizocilpine whereas WAY100635 reversed the effect of scopolamine only. These data confirm a role for presynaptic 5-HT1A receptors during the consolidation of learning and support the hypothesis that serotonergic, cholinergic, and glutamatergic systems interact in cognitively impaired animals.     

Spatial learning in the 5-HT1B receptor knockout mouse: selective facilitation/impairment depending on the cognitive demand

Age-related memory decline is associated with a combined dysfunction of the cholinergic and serotonergic systems in the hippocampus and frontal cortex, in particular. The 5-HT1B receptor occupies strategic cellular and subcellular locations in these structures, where it plays a role in the modulation of ACh release. In an attempt to characterize the contribution of this receptor to memory functions, 5-HT1B receptor knockout (KO) mice were submitted to various behavioral paradigms carried out in the same experimental context (water maze), which were aimed at exposing mice to various levels of memory demand. 5-HT1BKO mice exhibited a facilitation in the acquisition of a hippocampal-dependent spatial reference memory task in the Morris water maze. This facilitation was selective of task difficulty, showing thus that the genetic inactivation of the 5-HT1B receptor is associated with facilitation when the complexity of the task is increased, and reveals a protective effect on age-related hippocampal-dependent memory decline. Young-adult and aged KO and wild-type (WT) mice were equally able to learn a delayed spatial matching-to-sample working memory task in a radial-arm water maze with short (0 or 5 min) delays. However, 5-HT1BKO mice, only, exhibited a selective memory impairment at intermediate and long (15, 30, and 60 min) delays. Treatment by scopolamine induced the same pattern of performance in wild type as did the mutation for short (5 min, no impairment) and long (60 min, impairment) delays. Taken together, these studies revealed a beneficial effect of the mutation on the acquisition of a spatial reference memory task, but a deleterious effect on a working memory task for long delays. This 5-HT1BKO mouse story highlights the problem of the potential existence of "global memory enhancers."     

Transient overexpression of the 5-HT1A receptor impairs water-maze but not hole-board performance

Previously, we showed that mice that overexpress the 5-HT(1A) receptor transiently from embryonic to perinatal stages show reduced anxiety and changes in brain serotonin turnover as adults. Here, we investigated the long-term effects of the temporary overexpression of the 5-HT(1A) receptor during early embryonic and perinatal development on the performance in two memory tasks. In the hole-board test mice that were homozygous for the transgene showed similar behavioral habituation but increased locomotion compared to heterozygous mice. In contrast water-maze performance of homozygous mice was impaired compared to heterozygous mice. These results suggest that a transient overexpression of 5-HT(1A) receptor during embryonic and perinatal development has detrimental effects on water-maze performance at adult stages.     

Enhanced retention in the passive-avoidance task by 5-HT(1A) receptor blockade is not associated with increased activity of the central nucleus of the amygdala

The effect of blockade of 5-HT1A receptors was investigated on (1). retention in a mildly aversive passive-avoidance task, and (2). spontaneous single-unit activity of central nucleus of the amygdala (CeA) neurons, a brain site implicated in modulation of retention. Systemic administration of the selective 5-HT1A antagonist NAN-190 immediately after training markedly-and dose-dependently-facilitated retention in the passive-avoidance task; enhanced retention was time-dependent and was not attributable to variations in wattages of shock received by animals. Systemic administration of NAN-190 had mixed effects on spontaneous single-unit activity of CeA neurons recorded extracellularly in vivo; microiontophoretic application of 5-HT, in contrast, consistently and potently suppressed CeA activity. The present findings-that 5-HT1A receptor blockade by NAN-190 (1). enhances retention in the passive-avoidance task, and (2). does not consistently increase spontaneous neuronal activity of the CeA-provide evidence that a serotonergic system tonically inhibits modulation of retention in the passive-avoidance task through activation of the 5-HT1A receptor subtype at brain sites located outside the CeA.     

Dysfunctional attitudes and the serotonin transporter promoter polymorphism (5-HTTLPR)

Dysfunctional attitudes may be one phenotype by which genes increase risk for depression. Building on research demonstrating associations between serotonin abnormalities and dysfunctional attitudes, we examined the covariation between dysfunctional attitudes and the serotonin transporter gene-linked polymorphic region (5-HTTLPR). In a sample of nondepressed young adults (N = 131), people with one or two copies of the low-expressing alleles reported stronger endorsement of dysfunctional attitudes regarding performance evaluation than people who were homozygous for the high-expressing alleles; there was no association between the 5-HTTLPR polymorphism and dysfunctional attitudes regarding approval by others. These results add to the literature linking the 5-HTTLPR polymorphism and cognitive vulnerabilities for depression.     

Depletion of brain serotonin differently affects behaviors induced by 5HT1A, 5HT1C, and 5HT2 receptor activation in rats.

5-hydroxytryptamine (5HT)-depleted rats were subjected to behavioral experiments in which the response to activation of 5HT1A, 5HT1c, and 5HT2 receptor subtypes was measured. Depletion of 5HT was produced by unilateral intracerebroventricular injection of 5,7-dihydroxytryptamine (100 micrograms/rat) or by systemic injection of p-chlorophenylalanine (150 mg/kg injected intraperitoneally 72, 48, and 24 h before the test). The dose-response curve of the 5HT1A-mediated, 8-hydroxy-2-(di-n-propylamino)tetralin (0.022-0.46 mg/kg)-induced lower lip retraction was not changed after depletion, nor was the dose-response curve of the 5HT2 receptor-mediated (+-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (0.046-1.0 mg/kg)-induced head shake response. The dose-response curve for penile erections, a 5HT1c receptor-mediated response after mCPP (0.1-1.0 mg/kg), a direct 5HT1c agonist, is shifted to the left after 5HT depletion, whereas the response to indirect activation of the 5HT1c receptor with the 5HT reuptake inhibitors citalopram (2.2-4.6 mg/kg) and paroxetine (0.22-2.2 mg/kg) was inhibited after 5HT depletion. These results suggest that 5HT1c receptors are more subject to denervation supersensitivity than 5HT1A and 5HT2 receptors. This lesion model may be useful to discriminate behaviorally between direct and indirect activation of the 5HT1c receptor.     

Impaired discrimination learning in mice lacking the NMDA receptor NR2A subunit

N-Methyl-D-aspartate receptors (NMDARs) mediate certain forms of synaptic plasticity and learning. We used a touchscreen system to assess NR2A subunit knockout mice (KO) for (1) pairwise visual discrimination and reversal learning and (2) acquisition and extinction of an instrumental response requiring no pairwise discrimination. NR2A KO mice exhibited significantly retarded discrimination learning. Performance on reversal was impaired in NR2A KO mice during the learning phase of the task; with no evidence of heightened perseverative responses. Acquisition and extinction of an instrumental behavior requiring no pairwise discrimination was normal in NR2A KO mice. The present findings demonstrate a significant and selective deficit in discrimination learning following loss of NR2A.     

Behavioral inhibition and triallelic genotyping of the serotonin transporter promoter (5-HTTLPR) polymorphism

To examine the genetic bases of the behavioral inhibition system (BIS) and the behavioral approach system (BAS), we evaluated the association between the BIS, the BAS, and a functional length polymorphism in the promoter of the serotonin transporter gene (5-HTTLPR) in an unscreened sample of undergraduates (N = 211); analyses were conducted using a two-variant (i.e., biallelic) genotyping and three-variant (i.e., triallelic) genotyping of the 5-HTTLPR polymorphism. People with one or two copies of the low-expressing alleles reported stronger endorsement of the BIS than people who were homozygous for the high-expressing alleles; this association was found for triallelic but not biallelic genotyping of the 5-HTTLPR polymorphism. There was no association between the 5-HTTLPR polymorphism and the BAS scales.     

5-HT2A: its role in frontally mediated executive function and related psychopathology

Serotonin (5-HT)2A receptors are widely distributed, with high levels in the frontal cortex, where postsynaptic activation may increase activity in pyramidal glutamatergic neurons and mediate various executive functions. More specifically, reciprocal cortical-raphe pathways may allow the ventral prefrontal cortex to inhibit stress-induced neural activity in the brainstem when stressors are perceived as controllable. However, early adversity and negative attitudes may be associated with higher frontal 5-HT2A receptor levels and greater risk for stress-induced psychopathology, and certain 5-HT2A gene variants have been associated with increased risk for impulsive behavior. Conversely, many antidepressants result in decreased levels of 5-HT2A receptor levels, and blockade of 5-HT2A receptors has proven useful in the treatment of a number of psychiatric disorders.     

Time-course of 5-HT6 receptor mRNA expression during memory consolidation and amnesia

Growing evidence indicates that antagonists of the 5-hydroxytryptamine (serotonin) receptor₆ (5-HT₆) improve memory and reverse amnesia although the mechanisms involved are poorly understood. Hence, in this paper RT-PCR was used to evaluate changes in mRNA expression of 5-HT₆ receptor in trained and untrained rats treated with the 5-HT₆ receptor antagonist SB-399885 and amnesic drugs scopolamine or dizocilpine. Changes in mRNA expression of 5-HT₆ receptor were investigated at different times in prefrontal cortex, hippocampus and striatum. Data indicated that memory in the Pavlovian/instrumental autoshaping task was a progressive process associated to reduced mRNA expression of 5-HT₆ receptor in the three structures examined. SB-399885 improved long-term memory at 48 h, while the muscarinic receptor antagonist scopolamine or the non-competitive NMDA receptor antagonist dizocilpine impaired it at 24 h. Autoshaping training and treatment with SB-399885 increased 5-HT₆ receptor mRNA expression in (maximum increase) prefrontal cortex and striatum, 24 or 48 h. The scopolamine-induced amnesia suppressed 5-HT₆ receptor mRNA expression while the dizocilpine-induced amnesia did not modify 5-HT₆ receptor mRNA expression. SB-399885 and scopolamine or dizocilpine were able to reestablish memory and 5-HT₆ receptor mRNA expression. These data confirmed previous memory evidence and of more interest is the observation that training, SB-399885 and amnesic drugs modulated 5-HT₆ receptor mRNA expression in prefrontal cortex, hippocampus and striatum. Further investigation in different memory tasks, times and amnesia models together with more complex control groups might provide further clues.     

Role of serotonin in human aggressive behaviour

This study aimed to evaluate a peripheral serotonergic marker, ³H-imipramine (³H-IMI) binding to platelet membranes, in a group of severely aggressive subjects (A), institutionalized since childhood for mental retardation, as compared with suicide attempters (S) and healthy controls (H). The maximum binding capacity of ³H-IMI to platelet membranes was statistically lower in (A) and (S) than in (H). In addition, a statistically significant difference was observed between the Bmax values of aggressive subjects and those of suicide attempters. No changes in the dissociation constant (Kd) of IMI binding were observed. These data provide further supporting evidence for the hypothesis of an abnormality of the 5HT system in aggressive behaviour and suggest that such an abnormality, as reflected by platelet markers, is more severe in suicide attempters. © 1993 Wiley-Liss, Inc.     

Role of magnitude of reinforcement in spaced-trial instrumental learning in turtles (Geoclemys reevesii)

The runway performance of turtles (Geoclemys reevesii) was studied as a function of magnitude of reinforcement under spaced training conditions (one trial per day). A large reward magnitude (24 pellets) produced faster acquisition than a small magnitude (2 pellets). After a shift from the large to the small magnitude, latencies of the shifted animals continued to be significantly lower than the latencies of the non-shifted, small-magnitude controls, and similar to those of the non-shifted, large-magnitude controls. There was no evidence of the successive negative contrast effect. Extinction latencies were also significantly lower after training with the large magnitude than after training with the small magnitude; that is, there was no evidence of the magnitude of reinforcement extinction effect. The results are discussed in relation to the comparative analysis of the so-called paradoxical effects of reward, a family of learning phenomena that has not yet been found in a variety of experiments with fish, amphibians, and reptiles trained under widely spaced conditions.     

Role of the serotonin transporter gene in temperament and character

The biosocial model postulates that personality is comprised of two broad domains: temperament, which is largely due to inherited variations in specific monoamine neurotransmitter systems; and character, which arises from socioculturally learned differences in values, goals, and self-concepts and is the strongest predictor of personality disorders. The model also proposes that serotonin modulates the temperament trait of harm avoidance. We analyzed the association of temperament and character traits with the 5-HTTLPR, an inherited variation that modulates serotonin transporter gene expression, in 634 volunteer subjects. Contrary to theory, the 5-HTTLPR was most strongly associated with the character traits of cooperativeness and self-directedness. Associations with the temperament traits of reward dependence and harm avoidance were weaker and could be attributable largely to cross-correlations with the character traits and demographic variables. Psychometric analysis indicated that the serotonin transporter influences two broad areas of personality, negative affect and social disaffiliation, that are consistent across inventories but are more concisely described by the 5-factor model of personality than by the biosocial model. These results suggest that there is no fundamental mechanistic distinction between character and temperament in regard to the serotonin transporter gene, and that a single neurotransmitter can influence multiple personality traits.     

Discrimination learning in Rora(sg) and Grid2(ho) mutant mice

Rora(sg) mutants with mild cerebellar granule cell degeneration were compared to Grid2(ho) mutants with more severe granule cell degeneration as well as Purkinle cell atrophy for left-right and dark-light discrimination learning tasks in a water-filled T-maze. The acquisition rate of both cerebellar mutants was slowed down during light-dark but not left-right discrimination learning. However, the mutants were impaired in reversal training in both tasks. In contrast, neither mutant differed from controls in passive avoidance learning. These results indicate that mice with cerebellar damage are affected in some instrumental learning tasks and have perseverative tendencies.