Embryonic exposure to valproic acid (VPA) is known to produce sociability deficits, resembling human autistic phenotypes, in several vertebrate species. Animals living in groups prefer the proximity of peers and have the ability to perceive and to respond to social signals for modifying behavior. Chicks of Galliform birds, known to display early preference behaviors, have been used extensively for adaptive learning studies. Young precocial birds seem to be useful models also for studying the effect of embryonic VPA treatment. Here, domestic chicken eggs were injected with sodium valproate (200 μl of 35 μmol/L solution) or with vehicle (distilled water) on the 14th day of incubation. After hatching, the chicks were tested for one-trial passive avoidance learning at day 1, vocalization due to isolation as a measure of stress level (day 2), approach preference to large versus small groups of age-matched conspecifics (day 5), and to those with normal versus blurred head features (day 7). In addition, we tested the preference of birds to conspecifics reared in group versus those reared in isolation (day 9), as well as the preference of chicks to familiar versus non-familiar conspecifics (day 21). Our findings confirm previous reports concerning an adverse effect of VPA on embryonic development, including a tendency for aborted or delayed hatching and, occasionally, for locomotor disorders in a small percentage of birds (eliminated from later studies). Otherwise, VPA treatment did not impair motor activity or distress level. Memory formation for the aversive stimulus and discrimination of colors were not impaired by VPA treatment either. Innate social predispositions manifested in approach preferences for the larger target group or for the birds with natural facial features remained unaffected by VPA exposure. The most prominent finding was attenuation of social exploration in VPA-exposed birds (expressed as the frequency of positional switches between two stimulus chicks after the first choice), followed by a deficit in the recognition of familiar conspecifics, unfolding at the end of the third week. Social exploration and recognition of familiar individuals are the key elements impaired at this stage. The results underline the importance of early social exploration in ASD.

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Gestational exposure to valproic acid (VPA) is known to cause behavioral deficits of sociability, matching similar alterations in human autism spectrum disorder (ASD). Available data are scarce on the neuromorphological changes in VPA-exposed animals. Here, we focused on alterations of the dopaminergic system, which is implicated in motivation and reward, with relevance to social cohesion. Whole brains from 7-day-old mice born to mothers given a single injection of VPA (400 mg/kg b.wt.) on E13.5 were immunostained against tyrosine hydroxylase (TH). They were scanned using the iDISCO method with a laser light-sheet microscope, and the reconstructed images were analyzed in 3D for quantitative morphometry. A marked reduction of mesotelencephalic (MT) axonal fascicles together with a widening of the MT tract were observed in VPA treated mice, while other major brain tracts appeared anatomically intact. We also found a reduction in the abundance of dopaminergic ventral tegmental (VTA) neurons, accompanied by diminished tissue level of DA in ventrobasal telencephalic regions (including the nucleus accumbens (NAc), olfactory tubercle, BST, substantia innominata). Such a reduction of DA was not observed in the non-limbic caudateputamen. Conversely, the abundance of TH+ cells in the substantia nigra (SN) was increased, presumably due to a compensatory mechanism or to an altered distribution of TH+ neurons occupying the SN and the VTA. The findings suggest that defasciculation of the MT tract and neuronal loss in VTA, followed by diminished dopaminergic input to the ventrobasal telencephalon at a critical time point of embryonic development (E13-E14) may hinder the patterning of certain brain centers underlying decision making and sociability.

The member of synthetic cathinone family, methylenedioxypyrovalerone (MDPV), is a frequently used psychoactive drug of abuse. The objective of our study was to determine the effect of MDPV (administered from the 8th to the 14th day of gestation) on the behavior of neonatal and adolescent mice, as well as its effect on maternal care. We measured maternal care (pup retrieval test, nest building), locomotor activity (open field test), and motor coordination (grip strength test) of dams, whereas on pups we examined locomotor activity at postnatal day 7 and day 21 (open field test) and motor coordination on day 21 (grip strength test). On fresh-frozen brain samples of the dams we examined the expression of two important peptides implicated in the regulation of maternal behavior and lactation: tuberoinfundibular peptide 39 (TIP39) mRNA in the thalamic posterior intralaminar complex, and amylin mRNA in the medial preoptic nucleus. We detected decreased birth rate and survival of offspring, and reduced maternal care in the drug-treated animals, whereas there was no difference between the motility of treated and control mothers. Locomotor activity of the pups was increased in the MDPV treated group both at 7 and 21 days of age, while motor coordination was unaffected by MDPV treatment. TIP39 and amylin were detected in their typical location but failed to show a significant difference of expression between the drug-treated and control groups. The results suggest that chronic systemic administration of the cathinone agent MDPV to pregnant mice can reduce birth rate and maternal care, and it also enhances motility (without impairment of motor coordination) of the offspring.

A dizájner drog metiléndioxi-pirovaleron hatása a fejlődő idegrendszerre kísérletes állatmodellbenGerecsei László István oh. ■ Ádám Ágota dr. Semmelweis Egyetem, Anatómiai, Szövet-és Fejlődéstani Intézet, BudapestBevezetés: A szintetikus kationok családjába tartozó "dizájner drog", a metiléndioxi-pirovaleron gyakran használt pszichoaktív szer. Célkitűzés: A szerzők arra a kérdésre kerestek választ, hogyan hat a metiléndioxi-pirovaleron a vemhesség 8. és 14. napja között adva az utódegerek központi idegrendszerének fejlődésére és a viselkedésükre. Módszer: Nőstény egereket a vemhesség ezen időszakában 1×10 mg/ttkg metiléndioxi-pirovaleron-oldattal kezeltek subcutan, a kontrollcsoport fi ziológiás sóoldatot kapott. Mérték az anyaállatok utódgondozási hajlandóságát, lokomotoros aktivitását és motoros koordinációját. Az utódokon a postnatalis 7. és 21. napon ugyanezeket a teszteket végezték el. Eredmények: Az anyaállatok utódgondozási hajlandósága csökkent. A lokomotoros aktivitási tesztben nem volt kü-lönbség a krónikusan kezelt állatok és a kontrollcsoport között. A motoros koordinációs teszt eredményei alapján a krónikusan kezelt állatok motoros koordinációja rosszabb volt. A metiléndioxi-pirovaleronnal krónikusan kezelt utódoknál a lokomotoros aktivitás csökkent. Következtetések: Az eredmények arra utalnak, hogy a metiléndioxi-pirovaleron hátrányosan befolyásolja a központi idegrendszer neuronjainak integritását. Orv. Hetil., 2015, 156(30), 1221-1225. Kulcsszavak: dizájner drog, 3,4-metiléndioxi-pirovaleron, viselkedés, terhesség, teratogenitás Effects of the designer drug methylenedioxypyrovalerone on the developing brain in experimental animal modelIntroduction: The designer drug methylenedioxypyrovalerone is a frequently used psychoactive drug of abuse. Aim: The aim of this study was to determine the effect of methylenedioxypyrovalerone, administrated from the 8th to the 14th day of the gestation, on the development of central nervous system and on the behaviour of offspring mice. Method: Pregnant mice were treated during this period either with subcutaneous injection of 1×10 mg/kg body weight methylenedioxypyrovalerone or vehicle (saline