Long-term effects of a single adult methamphetamine challenge: Minor impact on dopamine fibre density in limbic brain areas of gerbils

BACKGROUND: The aim of the study was to test long-term effects of (+)-methamphetamine (MA) on the dopamine (DA) innervation in limbo-cortical regions of adult gerbils, in order to understand better the repair and neuroplasticity in disturbed limbic networks. METHODS: Male gerbils received a single high dose of either MA (25 mg/kg i.p.) or saline on postnatal day 180. On postnatal day 340 the density of immunoreactive DA fibres and calbindin and parvalbumin cells was quantified in the right hemisphere. RESULTS: No effects were found in the prefrontal cortex, olfactory tubercle and amygdala, whereas the pharmacological impact induced a slight but significant DA hyperinnervation in the nucleus accumbens. The cell densities of calbindin (CB) and parvalbumin (PV) positive neurons were additionally tested in the nucleus accumbens, but no significant effects were found. The present results contrast with the previously published long-term effects of early postnatal MA treatment that lead to a restraint of the maturation of DA fibres in the nucleus accumbens and prefrontal cortex and a concomitant overshoot innervation in the amygdala. CONCLUSION: We conclude that the morphogenetic properties of MA change during maturation and aging of gerbils, which may be due to physiological alterations of maturing vs. mature DA neurons innervating subcortical and cortical limbic areas. Our findings, together with results from other long-term studies, suggest that immature limbic structures are more vulnerable to persistent effects of a single MA intoxication; this might be relevant for the assessment of drug experience in adults vs. adolescents, and drug prevention programs

Influence of methylphenidate on brain development – an update of recent animal experiments

Methylphenidate (MPH) is the most commonly used drug to treat attention deficit/hyperactivity disorder (ADHD) in children effectively and safely. In spite of its widespread application throughout one of the most plastic and sensitive phases of brain development, very little is known to date about its long-term effects on brain structure and function. Hence, this short review updates the influence of MPH on brain development, since recent human and animal studies suggest that MPH alters the dopaminergic system with long-term effects beyond the termination of treatment. Animal studies imply that the effects of MPH may depend on the neural responder system: Whereas structural and functional parameters are improved by MPH in animals with psychomotor impairments, they remain unaltered or get worse in healthy controls. While recent behavioural studies do not fully support such a differential effect of MPH in ADHD, the animal studies certainly prompt for further investigation of this issue. Furthermore, the abuse of MPH, when (rarely) intravenously applied, may even impair the maturation of dopaminergic fibres in subcortical brain areas. This argues for careful clinical assessment and diagnostics of ADHD symptomatology not only in conjunction with the prescription of MPH. Hence, one should be assured that MPH is only given to children with clear ADHD symptomatology leading to psychosocial impairment. The animal data suggest that under these conditions MPH is supportive for brain development and the related behaviour in children with ADHD

A novel European H5N8 influenza A virus has increased virulence in ducks but low zoonotic potential

We investigated in a unique setup of animal models and a human lung explant culture biological properties, including zoonotic potential, of a representative 2016 highly pathogenic avian influenza virus (HPAIV) H5N8, clade 2.3.4.4 group B (H5N8B), that spread rapidly in a huge and ongoing outbreak series in Europe and caused high mortality in waterfowl and domestic birds. HPAIV H5N8B showed increased virulence with rapid onset of severe disease and mortality in Pekin ducks due to pronounced neuro- and hepatotropism. Cross-species infection was evaluated in mice, ferrets, and in a human lung explant culture model. While the H5N8B isolate was highly virulent for Balb/c mice, virulence and transmissibility were grossly reduced in ferrets, which was mirrored by marginal replication in human lung cultures infected ex vivo. Our data indicate that the 2016 HPAIV H5N8B is avian-adapted with augmented virulence for waterfowl, but has low zoonotic potential. The here tested combination of animal studies with the inoculation of human explants provides a promising future workflow to evaluate zoonotic potential, mammalian replication competence and avian virulence of HPAIV.Peer Reviewe

Environmental enrichment has no effect on the development of dopaminergic and GABAergic fibers during methylphenidate treatment of early traumatized gerbils

It is widely believed, that environmental factors play a crucial role in the etiology and outcome of psychiatric diseases such as Attention-Deficit/Hyperactivity Disorder (ADHD). A former study from our laboratory has shown that both methylphenidate (MP) and handling have a positive effect on the dopaminergic fiber density in the prefrontal cortex (PFC) of early traumatized gerbils (Meriones unguiculatus). The current study was performed to investigate if enriched environment during MP application has an additional influence on the dopaminergic and GABAergic fiber densities in the PFC and amygdala in this animal model

Zum Einfluss von Methylphenidat (MPH; Ritalin®) auf die Reifung von Dopamin in limbo-präfrontalen Arealen von Meriones unguiculatus

Grund T. Zum Einfluss von Methylphenidat (MPH; Ritalin®) auf die Reifung von Dopamin in limbo-präfrontalen Arealen von Meriones unguiculatus. Bielefeld (Germany): Bielefeld University; 2005.Methylphenidat (MPH; z.B. Ritalin® und Medikinet®), ein zu den Psychostimulanzien gehörendes Amphetaminderivat, wird heute als Mittel der Wahl bei der Behandlung der Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung (ADHS) eingesetzt, obwohl die therapeutische Wirkung des Medikaments immer noch weitgehend unverstanden ist. Das Dopaminsystem gilt bei der ADHS als ursächlich betroffen. Da MPH sein Wirkungsprofil speziell über diesen Transmitter entfaltet, steht Dopamin im Zentrum der hirnphysiologischen Forschung zur ADHS. Mit der vorliegenden Arbeit wurde die Langzeitwirkung einer chronischen MPH-Gabe während der Adoleszenz auf die strukturelle Reifung des Dopaminsystems im limbo-präfrontalen System der Wüstenrennmaus (Meriones unguiculatus) untersucht. Zum Einsatz kam (1) die orale Vergabeform mit einer klinisch relevanten Dosierung (5 mg/kg/Tag), für die zwei Kontrollgruppen, eine mit Wasser behandelte und eine gänzlich unbehandelte Gruppe, zur Verfügung standen. Außerdem kam (2) die bei Menschen nur in Missbrauchsfällen angewandte, aber in präklinischen Tierstudien übliche, intraperitoneale (i.p.) Vergabe zum Einsatz. Hierfür wurden eine klinisch relevante (5 mg/kg/Tag) und eine überhöhte (50 mg/kg/Tag) Dosierung verglichen. Die Ansätze (1) und (2) wurden durch entsprechende Studien an frühkindlich traumatisierten Tieren (einmalige Methamphetamin-(MA-)Intoxikation) ergänzt, die wie die Tiere aus (1) und (2) aus restriktiver Aufzucht stammten. Die Untersuchung sämtlicher Gruppen (pro Gruppe jeweils zwischen 8 und 11 Tiere) erfolgte im jungerwachsenen Alter (P 90), in dem Gerbils die adulte Ausreifung des Dopaminfasersystems vollzogen haben. Die quantitativen Analysen der dopaminergen Faserdichte wurden im medialen präfrontalen Kortex (mPFC), im ventralen Striatum, d.h. Nucleus accumbens (NAc) und olfaktorischer Tuberkel (OT), und in dem lateralen (LA), dem basolateralen (BLA), dem lateralen zentralen (CeAl) und dem medialen zentralen Kern (CeAm) der Amygdala durchgeführt. - Die unbehandelte Kontrollgruppe stellte sich im Nachhinein als besonders wertvolles Werkzeug für eine angemessene Interpretation der MPH-Wirkung nach oraler Vergabe heraus. Denn allein die Behandlung der Tiere mit Wasser führte zu einer verstärkten Reifung der Dopaminfasern im PFC. Das ist als positiver Effekt zu werten, da Käfigtiere per se im Vergleich zu Aufzuchten aus angereicherter Umgebung unter einer suppressiv gereiften Dopamininnervation im PFC leiden, wie frühere Arbeiten gezeigt haben. - Die orale Vergabe von MPH (Ritalin®) im jugendlichen Alter führte im Vergleich zur gehandelten Kontrollgruppe zu keinen Veränderungen in den gemessenen Gebieten. Die signifikante Anhebung der Dopaminfaserdichte nach Handling wird in den MPH-behandelten Tieren aber in fast allen untersuchten Regionen und Laminae des PFC und im BLA knapp verfehlt, d.h. die MPH-Behandlung beeinträchtigt leicht den Handlingeffekt. - Die frühkindliche Traumatisierung mittels MA-Intoxikation und anschließende Behandlung mit Wasser bedingte eine suppressive Reifung der dopaminergen Faserdichte im PFC und im BLA. - Bei traumatisierten Tieren führte die MPH-Behandlung in präfrontalen Gebieten und im BLA zu einer erhöhten dopaminergen Innervationsdichte. Diese gezeigte morphogene Wirkung von MPH auf die Reifung des dopaminergen Transmittersystems ist als positiv zu werten, da sie die suppressive Reifung verhindert. - Nach i.p.-Vergabe von MPH zeigt sich ein gänzlich anderes Bild. Hier bewirkt die klinisch relevante Dosierung eine Absenkung der dopaminergen Faserdichte im NAc und im CeAm. - Die Behandlung mit der überhöhten Dosierung bedingt demgegenüber im NAc und im BLA eine erhöhte Faserdichte. - Bei traumatisierten Tieren führt die Behandlung mit der überhöhten MPH-Dosierung im CeAl zu einer exzessiven Reifung der Dopaminprojektionen. Für die orale sowie für die i.p.-Studie gilt gleichermaßen, dass MPH (z.B. Ritalin®) eine veränderte Entwicklung des mesokortikolimbischen Dopaminsystems induziert. Notwendigerweise werden die Ergebnisse beider Vergabeformen getrennt in Bezug auf bekannte akute und langfristige Veränderungen nach MPH-Gabe bewertet. Mit dem hier verfolgten breiten Ansatz ist eine morphogene Wirkung von MPH auf die Reifung des dopaminergen Systems belegt. Das Resultat dieser morphogenen Wirkung ist von den begleitenden Umständen, denen die Tiere ausgesetzt waren, abhängig

Developmental effects on dopamine projections and hippocampal cell proliferation in the rodent model of postweaning social and physical deprivation can be triggered by brief changes of environmental context

Lehmann K, Grund T, Bagorda A, et al. Developmental effects on dopamine projections and hippocampal cell proliferation in the rodent model of postweaning social and physical deprivation can be triggered by brief changes of environmental context. BEHAVIOURAL BRAIN RESEARCH. 2009;205(1):26-31.Periadolescence is a critical period during which environmental stimuli modulate developmental neural plasticity. This includes the density of mesolimbic dopamine (DA) projections and the mitotic dynamic in the hippocampal dentate gyrus, both involved in central structures for emotional and cognitive functioning. Behavioural tests suggest that even short periods of stimulation can have lasting developmental effects on cognitive and emotional measures. We therefore exposed animals kept in isolation to brief daily context changes during periadolescence (postnatal days 30-60). We assessed the effects on neural development after animals had reached adulthood at postnatal day 90 by measuring the density of dopamine fibres in the medial prefrontal cortex (PFC), nucleus accumbens (core and shelf), olfactory tubercle, and amygdala (basolateral and central), and by labelling mitoses in the dentate gyrus by BrdU. In experimental animals as compared to deprived controls, dopamine fibre densities were increased in the PFC and basolateral amygdala, decreased in the central amygdala, but not altered in the ventral striatum. Hippocampal cell proliferation was decreased. These results show that even a low level of experimental sensory stimulation during periadolescence triggers neural developmental processes, with lasting effects into adulthood. (C) 2009 Elsevier B.V. All rights reserve

Administration of oral methylphenidate during adolescence prevents suppressive development of dopamine projections into prefrontal cortex and amygdala after an early pharmacological challenge in gerbils

Grund T, Teuchert-Noodt G, Busche A, et al. Administration of oral methylphenidate during adolescence prevents suppressive development of dopamine projections into prefrontal cortex and amygdala after an early pharmacological challenge in gerbils. BRAIN RESEARCH. 2007;1176:124-132.The enduring effects of postweaning subchronic methylphenidate (MP) treatment and/or previous early preweaning methamphetamine (MA) application on dopamine (DA) fiber density were investigated in multiple cortical and subcortical areas of the gerbil brain. The study aimed to explore three questions: (1) is the development of DA fiber innervation in control animals sensitive to a clinically relevant subchronic treatment with MP? (2) Is the development of DA fiber innervation in the forebrain altered by a single early MA challenge? (3) if so, might the subsequent institution of a therapeutically relevant MP application scheme interfere with such early induced alternative developmental trajectories for DA fiber innervation? For this purpose, gerbils pretreated both with saline and MA (50 mg/kg, i. p.) on day 14 received either H2O or MP (5 mg/kg) orally on days 30 to 60. On day 90, DA fibers were immunohistochemically detected and quantified. As a result, MP on its own did not have any significant influence on the postnatal development of the DA fiber systems, whereas it prevented a previously MA triggered suppressive development of DA fiber innervation in the prefrontal cortex and amygdala complex (30% less fiber innervation in both areas). Thus, MP prevented previously initiated miswiring of DA fibers from actually being implemented in the gerbil forebrain. During earlier studies, rather complex miswiring has been documented in response to an early preweaning MA challenge. This miswiring was associated with functional deficits resembling some of the symptoms of patients with ADHD. Therefore, morphogenetic properties of MP need further attention. (C) 2007 Elsevier B.V. All rights reserved

On the Q&P Potential of a Commercial Spring Steel

Over the last years heat treatment concept of “quenching and partitioning” (Q&P) has reached popularity for its ability to precisely adjust material properties to desired values. Mostly, Q&P process are applied on tailor-made materials with high purities or prototype alloys. The research in hand presents the whole routine of how to investigate the potential of a commercial 0.54C-1.45Si-0.71Mn spring steel in terms of Q&P heat treatment from lab scale in dilatometer measurements to widely used inductive heat treatment on larger scale. In order to obtain the small process window for this material we were focusing on the interplay of the formed microstructure and the resulting mechanical properties in hardness measurements, compression tests as well as tensile tests. After full austenitizing, three different Q&P processing routes were applied. Microstructural analyses by optical microscopy, Scanning Electron Microscopy (SEM) and Electron Backscatter Diffraction (EBSD) exhibit a condition with 6.4% and 15% volume fraction of fine distributed retained austenite. Interestingly, the 15% of retained austenite developed during the partitioning heat treatment. Contradictory to our expectations, tensile and compression testing were showing that the 6.4% condition achieved improved mechanical properties compared to the 15% retained austenite condition. The remarkable conclusion is that not only volume fraction and fine distribution of retained austenite determines the potential of improving mechanical properties by Q&P in commercial alloys: also the process step when the retained austenite is developing as well as occurring parallel formation of carbides may strongly influence this potential