Active vs passive novelty-related strategies: Sex differences in exploratory behaviour and monoaminergic systems.

Sex differences are apparent in numerous behavioural characteristics. In order to compare and characterise male and female variability of exploratory behaviour, 365 male and 401 female rats were assessed in a task where a bimodal response distribution had previously been established in males. Female rats had significantly higher exploratory activity, and presented normal distribution of the behaviour, very differently from the bimodal distribution of males. No major effect of litter or oestrous cycle was detected. Several differences between male and female rats were found in monoamine metabolism measured ex vivo. Male rats had lower levels of dopamine (DA) in frontal cortex, and higher levels of 3,4-dihydroxyphenylacetic acid (DOPAC) in raphe area; higher levels of serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) in dorsal striatum but lower levels of 5-HT and 5-HIAA in locus coeruleus area, 5-HIAA levels were also lower in hippocampus as compared to females. Males had higher noradrenaline (NA) levels in hippocampus and lower normetanephrine (NMN) levels in striatum, in both brain regions male animals had lower NMN/NA ratio. No sex difference was found in accumbens. The only brain region with an interaction between sex and the expression of exploratory activity was raphe: Here 5-HT levels were lower, and DOPAC levels and DOPAC/DA and 5-HIAA/5-HT ratios higher in low exploring male but not female rats. Conclusively, female rats not only display higher levels of exploration but the population distribution of this behaviour is distinct; this may be related to differences in the monoaminergic systems between female and male animals.

Extracellular Dopamine Levels in Nucleus Accumbens after Chronic Stress in Rats with Persistently High vs. Low 50-kHz Ultrasonic Vocalization Response.

Fifty-kHz ultrasonic vocalizations (USVs) in response to an imitation of rough-and-tumble play ('tickling') have been associated with positive affective states and rewarding experience in the rat. This USV response can be used as a measure of inter-individual differences in positive affect. We have previously shown that rats with persistently low positive affectivity are more vulnerable to the effects of chronic variable stress (CVS). To examine whether these differential responses are associated with dopaminergic neurotransmission in the nucleus accumbens (NAc), juvenile male Wistar rats were categorized as of high or low positive affectivity (HC and LC, respectively), and after reaching adulthood, extracellular dopamine (DA) levels in the NAc shell were measured using in vivo microdialysis after three weeks of CVS. Baseline levels of DA were compared as well as the response to K+-induced depolarization and the effect of glial glutamate transporter EAAT2 inhibition by 4 mM l-trans-pyrrolidine-2,4-dicarboxylate (PDC). DA baseline levels were higher in control LC-rats, and stress significantly lowered the DA content in LC-rats. An interaction of stress and affectivity appeared in response to depolarization where stress increased the DA output in HC-rats whereas it decreased it in LC-rats. These results show that NAc-shell DA is differentially regulated in response to stress in animals with high and low positive affect.

Expression and impact of Lsamp neural adhesion molecule in the serotonergic neurotransmission system.

Limbic system associated membrane protein (Lsamp) is a neural adhesion protein which has been recently found to be differentially expressed between serotonergic neuron subtypes. We have previously shown elevated serotonin (5-HT) turnover rate in Lsamp-deficient mice. The purpose of the current study was to elucidate the role of Lsamp in serotonergic neurotransmission. Chronic (18 days) administration of serotonin reuptake inhibitor (SSRI) escitalopram (10 mg/kg) significantly increased general activity in wild-type mice in the open field and protected exploration in Lsamp-/- mice in the elevated-plus maze. An important psychopathology-related endophenotype, elevated 5-HT turnover in the brain of Lsamp-deficient mice, was reproduced in the saline group. Escitalopram restored the elevated 5-HT turnover of Lsamp-deficient mice to a level comparable with their wild-type littermates, suggesting that high 5-HT turnover in mutants is mediated by the increased activity of serotonin transporter (SERT protein encoded by Slc6a4 gene). The baseline level of Slc6a4 transcript was not changed in Lsamp-deficient mice, however, our immunohistochemical analysis showed partial co-expression of Lsamp with both SERT and Tph2 proteins in raphe. Overactivity of SERT in Lsamp-/- mice is further supported by significant elevation of Maoa transcript and increase of DOPAC, another Mao A product, specifically in the raphe. Again, elevation of DOPAC was reduced to the level of wild-type by chronic SSRI treatment. The activity of Lsamp gene promoters varied in 5-HT producing nuclei: both Lsamp 1a and 1b promoters were active in the dorsal raphe; most of the expression in the median raphe was from 1b promoter, whereas Lsamp 1a promoter was almost exclusively active in the caudal subgroup of raphe nuclei. We suggest that Lsamp may have an impact on the integrity of serotonergic synapses, which is possibly the neurochemical basis of the anxiety- and sociability-related phenotype in Lsamp-deficient mice.

Effect of chronic variable stress on sensitization to amphetamine in high and low sucrose-consuming rats.

BACKGROUND: Individual vulnerability to stress manifests in the interaction of innate properties and environment. There is a growing interest in the individual variability in vulnerability to stress and how it contributes to the development of psychiatric disorders. Intake of palatable substances is often measured in animal models. We have previously demonstrated that the consumption of sucrose solution is a stable trait in rats. AIMS: The present study aimed to compare the sensitivity of rats with high vs low liquid sucrose consumption to chronic variable stress and the stress effect on behavioural sensitization to amphetamine. METHODS: Male Wistar rats were subjected to a chronic stress regimen and subsequent repeated treatment with amphetamine (1 mg/kg, intraperitoneally). Fifty-kHz ultrasonic vocalizations, locomotor activity and stereotypies were measured. RESULTS: In no-stress baseline conditions, the behavioural response to acute amphetamine was similar in rats with high vs low sucrose consumption. Prior chronic stress potentiated the effect of amphetamine only in rats with high sucrose consumption. Behavioural sensitization to repeated administration of amphetamine was observed in non-stressed rats with lower sucrose preference, but not in the respective stressed group that had increased monoamine turnover in the nucleus accumbens. In contrast, in rats with high sucrose preference the amphetamine sensitization effect was prevalent in stressed rats, but not in non-stressed animals. INTERPRETATION: Chronic stress can change the psychostimulant effect but this depends on the inherent reward sensitivity of the animal. Trait-wise, sucrose intake reflects vulnerability to chronic stress and may interact with the development of addiction.

Chronic stress sensitizes amphetamine-elicited 50-kHz calls in the rat: Dependence on positive affective phenotype and effects of long-term fluoxetine pretreatment.

High level of positive affectivity acts as a protective factor against adverse effects of stress and decreases vulnerability to mood disorders and drug abuse. Fifty-kHz ultrasonic vocalizations (50-kHz USV) index the level of positive affect in the rat, whereas stable, trait-like inter-individual differences in terms of vocalization activity exist. Previously we have demonstrated that chronic stress can alter the effect of repeated amphetamine administration on 50-kHz vocalizations, and this effect is different in rats with high and low positive affectivity. In the present study it was tested whether the chronic stress effect on amphetamine-induced 50-kHz USV activity is altered by inhibition of serotonin reuptake. Male Wistar high (HC) and low (LC) 50-kHz vocalizing rats were subjected to 43-day chronic variable stress (CVS) regimen. On day 17 of the CVS, the four-week once a day fluoxetine (10 mg/kg) treatment was started. After the CVS and fluoxetine treatment, amphetamine (1 mg/kg) was daily administered for ten days and again nine days after withdrawal. Chronically stressed rats developed cross-sensitization of 50-kHz USV-s with repeated administration of amphetamine except the stressed LC rats that had not received fluoxetine. Amphetamine treatment decreased serotonin turnover in the fluoxetine-treated HC rats, but increased it in fluoxetine-treated LC rats. The effect of amphetamine on levels of amino acids in frontal cortex and hippocampus also depended on previous experience with chronic stress, repeated treatment with fluoxetine, and positive affectivity. Hence, this study provides further evidence the effects of chronic stress, psychostimulants, and a selective serotonin reuptake inhibitor are influenced by the inherent positive affectivity.