Acute and long-term effects elicited by psychoactive drugs on 50-kHz ultrasonic vocalizations in rats: development of a new experimental tool for the study of drug-mediated reward.

Ultrasonic vocalizations (USVs) have recently emerged as an indicator of the emotional state of rats, and the evaluation of the USVs in the 50-kHz range has been proposed as a tool to investigate the affective properties of drugs of abuse. To clarify the relevance of 50-kHz USVs to drug-induced reward, the acute and long-term effects elicited by different psychoactive drugs [ amphetamine, 3,4-methylenedioxymethamphetamine (MDMA, ecstasy), methylphenidate, morphine, and nicotine ] were characterized in adult male rats. Amphetamine and methylphenidate were the only drugs that stimulated the emission of 50-kHz USVs by rats after their acute administration. Moreover, amphetamine was the only drug that elicited a significant emission of 50-kHz USVs after repeated administration. However, rats in all the treatment groups emitted 50-kHz USVs when later re-exposed to the environment previously paired with repeated drug administration, likely indicative of drug-mediated environmental conditioning. Taken together, these results demonstrate the existence of major differences in the acute and long-term effects of different psychoactive drugs on the emission of 50-kHz USVs by rats. Moreover, these results provide a better understanding of the usefulness of 50-kHz USVs as a new tool for the assessment of drug-mediated reward, with implications for the preclinical study of addictive behavior

Influence of acute caffeine on 50-kHz ultrasonic vocalizations in male adult rats and relevance to caffeine-mediated psychopharmacological effects

To further characterize caffeine-mediated psychopharmacological effects, the present study investigated whether acute caffeine (3, 10, 30, 50 mg/kg i.p.) exerted any influence on the emission and features of ultrasonic vocalizations (USVs), which are thought to index changes involving emotional state, in male adult rats. The results obtained demonstrate that caffeine can trigger modifications in the maximum peak frequency and bandwidth of the 50-kHz range USVs. However, such an effect was not accompanied by a significant elevation in the number of 50-kHz USVs, relative to administration of vehicle. Under the same experimental conditions, acute amphetamine (2 mg/kg i.p.) robustly elevated the number of 50-kHz USVs emitted by rats, although it did not affect the maximum peak frequency and bandwidth of USVs. Thus, both qualitative and quantitative differences in the effects exerted by caffeine and amphetamine on 50-kHz USVs were observed. Taken together, these findings further clarify the features of caffeine-mediated psychopharmacological effects, and may help to elucidate the differences between the central effects of caffeine and those elicited by other psychostimulant

Direct and long-lasting effects elicited by repeated drug administration on 50-kHz ultrasonic vocalizations are regulated differently: Implications for the study of the affective properties of drugs of abuse

Several studies suggest that 50-kHz ultrasonic vocalizations (USVs) may indicate a positive affective state in rats, and these vocalizations are increasingly being used to investigate the properties of psychoactive drugs. Previous studies, however, have focused on dopaminergic psychostimulants and morphine, whereas little is known about how other drugs modulate 50-kHz USVs. To further elucidate the neuropharmacology of 50-kHz USVs, the present study characterized the direct and long-lasting effects of different drugs of abuse, by measuring the number of 50-kHz USVs and their 'trill' subtype emitted by adult male rats. Rats received repeated administrations of amphetamine (2 mg/kg, i.p.), 3,4-methylenedioxymethamphetamine (MDMA, 7.5 mg/kg, i.p.), morphine (7.5 mg/kg, s.c.), or nicotine (0.4 mg/kg, s.c.), on either consecutive or alternate days (five administrations in total) in a novel environment. Seven days later, rats were re-exposed to the drug-paired environment, subjected to USVs recording, and then challenged with the same drug. Finally, 7 d after the challenge, rats were repeatedly exposed to the drug-paired environment and vocalizations were measured. Amphetamine was the only drug to stimulate 50-kHz USVs and 'trill' subtype emission during administration and challenge. Conversely, all rats emitted 50-kHz USVs when re-exposed to the test cage, and this effect was most marked in morphine-treated rats, and less evident in nicotine-treated rats. This study demonstrates that the direct and long-lasting effects of drugs on 50-kHz USVs are regulated differently, providing a better understanding of the usefulness of these vocalizations in the study of psychoactive drugs

Involvement of Glutamate NMDA Receptors in the Acute, Long-Term, and Conditioned Effects of Amphetamine on Rat 50kHz Ultrasonic Vocalizations

BACKGROUND: Rats emit 50kHz ultrasonic vocalizations (USVs) in response to either natural or pharmacological pleasurable stimuli, and these USVs have emerged as a new behavioral measure for investigating the motivational properties of drugs. Earlier studies have indicated that activation of the dopaminergic system is critically involved in 50kHz USV emissions. However, evidence also exists that non-dopaminergic neurotransmitters participate in this behavioral response. METHODS:To ascertain whether glutamate transmission plays a role in 50kHz USV emissions stimulated by amphetamine, rats received five amphetamine (1-2mg/kg, i.p.) administrations on alternate days in a test cage, either alone or combined with the glutamate N-methyl-D-aspartate receptor antagonist MK-801 (0.1-0.5mg/kg, i.p.). Seven days after treatment discontinuation, rats were re-exposed to the test cage to assess drug conditioning, and afterwards received a drug challenge. USVs and locomotor activity were evaluated, along with immunofluorescence for Zif-268 in various brain regions and spontaneous alternation in a Y maze. RESULTS:Amphetamine-treated rats displayed higher 50kHz USV emissions and locomotor activity than vehicle-treated rats, and emitted conditioned vocalizations on test cage re-exposure. Rats co-administered amphetamine and MK-801 displayed lower and dose-dependent 50kHz USV emissions, but not lower locomotor activity, during repeated treatment and challenge, and scarce conditioned vocalization compared with amphetamine-treated rats. These effects were associated with lower levels of Zif-268 after amphetamine challenge and spontaneous alternation deficits. CONCLUSIONS: These results indicate that glutamate transmission participates in the acute, long-term, and conditioned effects of amphetamine on 50kHz USVs, possibly by influencing amphetamine-induced long-term neuronal changes and/or amphetamine-associated memories

Association between novel object recognition/spontaneous alternation behavior and emission of ultrasonic vocalizations in rats: Possible relevance to the study of memory

Rats emit ultrasonic vocalizations (USVs) in situations with emotional valence, and USVs have also been proposed as a marker for memories conditioned to those situations. This study investigated whether USV emissions can predict and/or be associated with the behavior of rats in tests that evaluate unconditioned memory. To this end, rats were subjected to “tickling”, a procedure of heterospecific play that has emotional valence and elicits the emission of USVs, and afterwards evaluated in the novel object recognition test (NOR) and in the single trial continuous spontaneous alternation behavior (SAB) test in a Y-maze. The number of 22-kHz USVs (aversive) and 50-kHz USVs (appetitive) emitted in response to tickling and during NOR and SAB tests were scored, and the correlations among them and with rats’ behavior evaluated. Rats emitted 50-kHz USVs, but not 22-kHz USVs, during the NOR and SAB tests, and such calling behavior was not linked with the behavioral readouts indicative of memory function in either test. However, rats that prevalently emitted 22-kHz USVs in response to tickling displayed an impaired NOR performance. These findings suggest that measuring the emission of USVs could be of interest in studies of unconditioned memory, at least with regard to 22-kHz USVs

Mouse and rat ultrasonic vocalizations in neuroscience and neuropharmacology: State of the art and future applications

Mice and rats emit ultrasonic vocalizations (USVs), which may express their arousal and emotional states, to communicate with each other. There is continued scientific effort to better understand the functions of USVs as a central element of the rodent behavioral repertoire. However, studying USVs is not only important because of their ethological relevance, but also because they are widely applied as a behavioral readout in various fields of biomedical research. In mice and rats, a large number of experimental models of brain disorders exist and studying the emission of USVs in these models can provide valuable information about the health status of the animals and the effectiveness of possible interventions, both environmental and pharmacological. This review (i) provides an updated overview of the contexts in which ultrasonic calling behaviour of mice and rats has particularly high translational value, and (ii) gives some examples of novel approaches and tools used for the analysis of USVs in mice and rats, combining qualitative and quantitative methods. The relevance of age and sex differences as well as the importance of longitudinal evaluations of calling and non-calling behaviour is also discussed. Finally, the importance of assessing the communicative impact of USVs in the receiver, that is, through playback studies, is highlighted

Activation of Antioxidant and Proteolytic Pathways in the Nigrostriatal Dopaminergic System After 3,4-Methylenedioxymethamphetamine Administration: Sex-Related Differences

3,4-Methylenedioxymethamphetamine (MDMA, “ecstasy”) is an amphetamine-related drug that may damage the dopaminergic nigrostriatal system. To investigate the mechanisms that sustain this toxic effect and ascertain their sex-dependence, we evaluated in the nigrostriatal system of MDMA-treated (4 × 20 mg/kg, 2 h apart) male and female mice the activity of superoxide dismutase (SOD), the gene expression of SOD type 1 and 2, together with SOD1/2 co-localization with tyrosine hydroxylase (TH)-positive neurons. In the same mice and brain areas, activity of glutathione peroxidase (GPx) and of β2/β5 subunits of the ubiquitin-proteasome system (UPS) were also evaluated. After MDMA, SOD1 increased in striatal TH-positive terminals, but not nigral neurons, of males and females, while SOD2 increased in striatal TH-positive terminals and nigral neurons of males only. Moreover, after MDMA, SOD1 gene expression increased in the midbrain of males and females, whereas SOD2 increased only in males. Finally, MDMA increased the SOD activity in the midbrain of females, without affecting GPx activity, decreased the β2/β5 activities in the striatum of males and the β2 activity in the midbrain of females. These results suggest that the mechanisms of MDMA-induced neurotoxic effects are sex-dependent and dopaminergic neurons of males could be more sensitive to SOD2- and UPS-mediated toxic effects

Unconventional Vortices and Phase Transitions in Rapidly Rotating Superfluid ^{3}He

This paper studies vortex-lattice phases of rapidly rotating superfluid ^3He based on the Ginzburg-Landau free-energy functional. To identify stable phases in the p-Omega plane (p: pressure; Omega: angular velocity), the functional is minimized with the Landau-level expansion method using up to 3000 Landau levels. This system can sustain various exotic vortices by either (i) shifting vortex cores among different components or (ii) filling in cores with components not used in the bulk. In addition, the phase near the upper critical angular velocity Omega_{c2} is neither the A nor B phases, but the polar state with the smallest superfluid density as already shown by Schopohl. Thus, multiple phases are anticipated to exist in the p-Omega plane. Six different phases are found in the present calculation performed over 0.0001 Omega_{c2} <= Omega <= Omega_{c2}, where Omega_{c2} is of order (1- T/T_c) times 10^{7} rad/s. It is shown that the double-core vortex experimentally found in the B phase originates from the conventional hexagonal lattice of the polar state near Omega_{c2} via (i) a phase composed of interpenetrating polar and Scharnberg-Klemm sublattices; (ii) the A-phase mixed-twist lattice with polar cores; (iii) the normal-core lattice found in the isolated-vortex calculation by Ohmi, Tsuneto, and Fujita; and (iv) the A-phase-core vortex discovered in another isolated-vortex calculation by Salomaa and Volovik. It is predicted that the double-core vortex will disappear completely in the experimental p-T phase diagram to be replaced by the A-phase-core vortex for Omega >~ 10^{3} ~ 10^{4} rad/s. C programs to minimize a single-component Ginzburg-Landau functional are available at {http://phys.sci.hokudai.ac.jp/~kita/index-e.html}.Comment: 13 pages, 9 figure

Gut Microbiota and Metabolome Alterations Associated with Parkinson's Disease.

Parkinson's disease is a neurodegenerative disorder characterized by the accumulation of intracellular aggregates of misfolded alpha-synuclein along the cerebral axis. Several studies report the association between intestinal dysbiosis and Parkinson's disease, although a cause-effect relationship remains to be established. Herein, the gut microbiota composition of 64 Italian patients with Parkinson's disease and 51 controls was determined using a next-generation sequencing approach. A real metagenomics shape based on gas chromatography-mass spectrometry was also investigated. The most significant changes within the Parkinson's disease group highlighted a reduction in bacterial taxa, which are linked to anti-inflammatory/neuroprotective effects, particularly in the Lachnospiraceae family and key members, such as Butyrivibrio, Pseudobutyrivibrio, Coprococcus, and Blautia The direct evaluation of fecal metabolites revealed changes in several classes of metabolites. Changes were seen in lipids (linoleic acid, oleic acid, succinic acid, and sebacic acid), vitamins (pantothenic acid and nicotinic acid), amino acids (isoleucine, leucine, phenylalanine, glutamic acid, and pyroglutamic acid) and other organic compounds (cadaverine, ethanolamine, and hydroxy propionic acid). Most modified metabolites strongly correlated with the abundance of members belonging to the Lachnospiraceae family, suggesting that these gut bacteria correlate with altered metabolism rates in Parkinson's disease.IMPORTANCE To our knowledge, this is one of the few studies thus far that correlates the composition of the gut microbiota with the direct analysis of fecal metabolites in patients with Parkinson's disease. Overall, our data highlight microbiota modifications correlated with numerous fecal metabolites. This suggests that Parkinson's disease is associated with gut dysregulation that involves a synergistic relationship between gut microbes and several bacterial metabolites favoring altered homeostasis. Interestingly, a reduction of short-chain fatty acid (SCFA)-producing bacteria influenced the shape of the metabolomics profile, affecting several metabolites with potential protective effects in the Parkinson group. On the other hand, the extensive impact that intestinal dysbiosis has at the level of numerous metabolic pathways could encourage the identification of specific biomarkers for the diagnosis and treatment of Parkinson's disease, also in light of the effect that specific drugs have on the composition of the intestinal microbiota

Curriculum and Teacher Education Reforms in Finland That Support the Development of Competences for the Twenty-First Century

Abstract This chapter analyzes how learning twenty-first century competences has been implemented in the Finnish educational context through the enactment of national and local level curricula and the design of a teacher education development program in a decentralized education system, in which teachers, schools, municipalities, and universities have high autonomy. The curricula and development program emphasize learning twenty-first century competences. Both were designed in collaboration with Finnish teachers and teacher educators, representatives from the Ministry of Education and Culture, the Association of Finnish Local and Regional Authorities, the Teacher’s Union, the Student’s Unions, and the Principal Association. The major actions taken to implement these changes included piloting, seminars and conferences, having different support and local level collaborations, and networking. According to recent evaluations, both endeavors – the development of national and local level curricula and a teacher education development program – have resulted in progress towards implementing twenty-first century competences in schools and for teacher education.Peer reviewe