Antonio Plumitallo

Pharmacological characterization of 50-kHz ultrasonic vocalizations in rats: Comparison of the effects of different psychoactive drugs and relevance in drug-induced reward

Significant evidence suggests that ultrasonic vocalizations (USVs) may index the emotional state in rats, and 50-kHz USVs have been proposed as a tool to investigate the rewarding properties of drugs. Apart from the evidence on some psychostimulants, little is known about the effects of other drugs with rewarding properties on emission of 50-kHz USVs. To further elucidate the neuropharmacology of 50-kHz USVs and their relevance in drug-induced reward, this study characterized the effects of different drugs possessing rewarding properties on 50-kHz USVs in adult male rats. Rats received the acute administration of 3,4-methylenedioxymethamphetamine (MDMA, 5-15 mg/kg, i.p.), methylphenidate (2.5-10 mg/kg, i.p.), morphine (1-5 mg/kg, s.c.), or nicotine (0.1-0.4 mg/kg, s.c.). The number and acoustic features of 50-kHz USVs and their subtypes were then measured. As a comparison, additional rats received the acute administration of amphetamine (2 mg/kg, i.p.), which strongly stimulates the emission of 50-kHz USVs. Methylphenidate, similar to amphetamine, increased the total number of 50-kHz USVs emitted by rats, and also modified their acoustic features. Conversely, MDMA, morphine, and nicotine did not elevate the total number of 50-kHz USVs. However, these drugs modified the acoustic features of 50-kHz USVs, as well as the number and acoustic features of specific subtypes of vocalizations. This study demonstrates that major differences exist in the effects of psychoactive drugs on 50-kHz USVs in rats. These findings provide a better understanding of psychoactive properties of drugs with rewarding properties and usefulness of 50-kHz USVs in assessment of these properties.

Differential effects of intravenous R,S-(+/-)-3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) and its S(+)- and R(-)-enantiomers on dopamine transmission and extracellular signal regulated kinase phosphorylation (pERK) in the rat nucleus accumbens shell and core

R,S(±)‐3,4‐methylenedioxymethamphetamine (R,S(±)‐MDMA, ‘Ecstasy’) is known to stimulate dopamine (DA) transmission in the nucleus accumbens (NAc). In order to investigate the post‐synaptic correlates of pre‐synaptic changes in DA transmission and their relationship with MDMA enantiomers, we studied the effects of R,S(±)‐MDMA, S(+)‐MDMA, and R(−)‐MDMA on extracellular DA and phosphorylated extracellular signal regulated kinase (pERK) in the NAc shell and core. Male Sprague–Dawley rats, implanted with a catheter in the femoral vein and vertical concentric dialysis probes in the NAc shell and core, were administered i.v. saline, R,S(±)‐MDMA, S(+)‐MDMA, or R(−)‐MDMA. Extracellular DA was monitored by in vivo microdialysis with HPLC. Intravenous R,S(±)‐MDMA (0.64, 1, and 2 mg/kg) increased dialysate DA, preferentially in the shell, in a dose‐related manner. S(+)‐MDMA exerted similar effects but at lower doses than R,S(±)‐MDMA, while R(−)‐MDMA (1 and 2 mg/kg) failed to affect dialysate DA. R,S(±)‐ and S(+)‐MDMA but not R(−)‐MDMA increased ERK phosphorylation (expressed as density/neuron and number of pERK‐positive neurons/area) in both subdivisions of the NAc. The administration of the D1 receptor antagonist, SCH 39166, prevented the increase in pERK elicited by R,S(±)‐MDMA and S(+)‐MDMA, while the D2/3 receptor antagonist, raclopride, increased pERK in the NAc core per se but failed to affect the R,S(±)‐MDMA‐elicited stimulation of pERK. The present results provide evidence that the DA stimulant effects of racemic MDMA are accounted for by the S(+)‐enantiomer and that pERK may represent a post‐synaptic correlate of the stimulant effect of R,S(±)‐MDMA on D1‐dependent DA transmission.

MPTP‐induced dopamine neuron degeneration and glia activation is potentiated in MDMA‐pretreated mice

Clinical observations report a greater propensity to develop Parkinsons disease (PD) in amphetamine users. 3,4‐Methylenedioxymethamphetamine (MDMA; “ecstasy”) is an amphetamine‐related drug that is largely consumed by adolescents and young adults, which may have neuroinflammatory and neurotoxic effects. Here, the objective was to evaluate in mice whether consumption of MDMA during adolescence might influence the neuroinflammatory and neurotoxic effects of 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP), a toxin known to induce PD in humans. The activation of astroglia and microglia by glial fibrillary acidic protein (GFAP) and complement receptor type 3 (CD11b) immunohistochemistry and the degeneration of dopaminergic neurons by tyrosine hydroxylase (TH) immunohistochemistry were evaluated. MPTP (20 mg/kg × 4) was administered to mice treated from ages 8 weeks to 17 weeks with MDMA (10 mg/kg twice daily, two times a week). In mice that were chronically treated with MDMA, administration of MPTP induced a higher microglial and astroglial response in both the striatum and the substantia nigra pars compacta (SNc) compared with vehicle‐treated or vehicle + MPTP‐treated mice. Inflammatory changes were associated with a decrease in TH immunoreactivity in the SNc of MDMA‐treated mice and with a further decrease in the striatum and the SNc of MDMA + MPTP‐treated mice compared with vehicle‐treated, MDMA‐treated, and MPTP‐treated mice. The results demonstrate that chronic administration of MDMA during late adolescence in mice exacerbates the neurodegeneration and neuroinflammation caused by MPTP, suggesting that MDMA may constitute a risk factor for dopaminergic neuron degeneration.

Microglial and astroglial activation by 3,4-methylenedioxymethamphetamine (MDMA) in mice depends on S(+) enantiomer and is associated with an increase in body temperature and motility.

Evidence is accumulating to suggest that 3,4‐methylenedioxymethamphetamine (MDMA) has neurotoxic and neuroinflammatory properties. MDMA is composed of two enantiomers with different biological activities. In this study, we evaluated the in vivo effects of S(+)‐MDMA, R(−)‐MDMA, and S(+)‐MDMA in combination with R(−)‐MDMA on microglial and astroglial activation compared with racemic MDMA, by assessment of complement type 3 receptor (CD11b) and glial fibrillary acidic protein (GFAP) immunoreactivity in the mouse striatum, nucleus accumbens, motor cortex, and substantia nigra. Motor activity and body temperature were also measured, to elucidate the physiological modifications paired with the observed glial changes. Similar to racemic MDMA (4 × 20 mg/kg), S(+)‐MDMA (4 × 10 mg/kg) increased both CD11b and GFAP in the striatum, although to a lower degree, whereas R(−)‐MDMA (4 × 10 mg/kg) did not induce any significant glial activation. Combined administration of S(+) plus R(−)‐MDMA did not induce any further activation compared with S(+)‐MDMA. In all other areas, only racemic MDMA was able to slightly activate the microglia, but not the astroglia, whereas enantiomers had no effect, either alone or in combination. Racemic MDMA and S(+)‐MDMA similarly increased motor activity and raised body temperature, whereas R(−)‐MDMA affected neither body temperature nor motor activity. Interestingly, the increase in body temperature was correlated with glial activation. The results show that no synergism, but only additivity of effects, is caused by the combined administration of S(+)‐ and R(−)‐MDMA, and underline the importance of investigating the biochemical and behavioral properties of the two MDMA enantiomers to understand their relative contribution to the neuroinflammatory and neurotoxic effects of MDMA.

Synthesis and antimicrobial activity of novel arylideneisothiosemicarbazones.

Arylidenimidazoles bearing a thioethereal function in the position 2 of the imidazole ring show good antimicrobial activity. We now report on the synthesis and the biological properties of some novel arylidenisothiosemicarbazones, structurally related to the arylideneiminoimidazoles of which they can be considered the linear precursors. Particular attention has been put on the influence of structural modifications on the biological activity.

C-13 and O-17 NMR studies on N-sulfinylanilines

Abstract N-sulfinylanilines have been studied by C-13 and O-17 NMR in chloroform and pyridine; they interact with pyridine, yielding a complex which is stable in solution. The study by O-17 NMR spectroscopy shows that for the NSO group the SO bond is a true π bond.

New cycloalkylpyrazoles as potential cyclooxygenase inhibitors.

In this study some cycloalkyl-3-(N-substituted carbamoyl)-1-phenylpyrazoles have been synthesized in order to screen their capability to inhibit human cyclooxygenase. The synthetic pathway is based on the well known property of nitrilimines to undergo 1,3-dipolar cycloaddition reactions. The structures of all the synthesized compounds have been elucidated by means of both analytical and spectroscopic methods.

17O NMR STUDIES ON DIALKOXY DISULFIDES

17O NMR spectra, at natural isotopic abundance, of dialkoxy disulfides are presented and β‐ and γ‐SCS effects shortly discussed.

Widespread reduction of dopamine cell bodies and terminals in adult rats exposed to a low dose regimen of MDMA during adolescence

&NA; Although MDMA (3,4‐methylendioxymethamphetamine, ecstasy) neurotoxicity in serotonin neurons is largely recognized in a wide variety of species including man, neurotoxicity in dopamine (DA) neurons is thought to be species‐specific. MDMA is mainly consumed by adolescents, often in conjunction with caffeine (Energy Drinks) and this association has been reported to exacerbate MDMA toxic effects. In order to model these aspects of MDMA use, vis‐à‐vis their impact on DA neurons, we investigated the effects of adolescent exposure to low doses of MDMA (5 mg/kg for 10 days), alone or in combination with caffeine (10 mg/kg) on neuronal and functional DA indices and on recognition memory in adult rats. MDMA reduced density of tyrosine hydroxylase (TH) positive neurons in the ventral tegmental area and in the substantia nigra pars compacta, and immunoreactivity of TH and DA transporter in the nucleus accumbens (NAc) shell and core, and caudate‐putamen. This same treatment caused a reduction of basal dialysate DA in the NAc core. MDMA‐pretreated rats also showed behavioral sensitization to a MDMA challenge at adulthood and potentiation of MDMA‐induced increase of dialysate DA in the NAc core, but not in the NAc shell. In addition, MDMA‐treated rats displayed a deficit in recognition memory. Caffeine co‐administration did not affect the above outcomes. Our results show that adolescent exposure of rats to low doses of MDMA induces long‐lasting and widespread reduction of DA neurons indicative of a neurotoxic effect on DA neurons and suggestive of a degeneration of the same neurons. HighlightsAdolescent exposure to MDMA causes a loss of DA neurons in rat VTA and SNc.Adolescent MDMA exposure impairs recognition memory at adulthood.Impaired recognition memory appears to be associated with reduced DA levels in NAc core.MDMA sensitization is associated with an increase in DA response in the NAc core.

Conformations of vicinal-triketones. A theoretical and 17O NMR approach

The conformations of a representative group of vicinal triketones have been studied by 17O NMR spectroscopy and, for some of them, DFT calculations have been performed in order to rationalize the results and gain an insight into their geometry; 17O NMR chemical shifts have also been computed by the GIAO method. A dependence of chemical shifts on intercarbonyl dihedral angles, like that observed for α-dicarbonyl systems, has been observed. A constraint to changing conformation, which overrides steric destabilization, has also been observed.