Differential effects of modafinil, methamphetamine, and MDMA on agonistic behavior in male mice.

The aim of the present study was to compare the behavioral effects of modafinil, an atypical psychostimulatory acting and cognitive-function improving drug, with the effects of the psychostimulants methamphetamine (MET) and MDMA (3,4-methylenedioxymethamphetamine, or "ecstasy") in a model of mouse agonistic behavior. This model enables the observation of ethologically well-defined sociable, timid, aggressive, and locomotor behavioral acts and postures. Singly-housed male mice (isolates) were separated into 4 groups. The observations were performed in 4 sessions, 1 week apart. In each interaction, singly-housed mice were paired with non-aggressive group-housed partners for 4 min in a neutral environment. The isolates received, in a Latin square design, either a) a vehicle or modafinil at doses 2.0, 10.0, or 50.0 mg/kg; or b) a vehicle or MET at doses 1.0, 5.0, or 10.0 mg/kg; or c) a vehicle or MDMA at doses 2.5, 10.0, or 30.0 mg/kg. The isolates were categorized as timid or aggressive according to their behavior in the control interaction (vehicle pre-treatment). Elements of locomotor, sociable, aggressive, and timid behavior were evaluated (one-way ANOVA). In the aggressive mice, no change in the sum of aggressive behavior was measured following modafinil administration, while both methamphetamine and MDMA produced dose-dependent inhibition of aggression (p<0.01). The substantial difference in the tested drug effects on agonistic behavior was an increased occurrence of sociable acts (p<0.01) accompanied by a simultaneous increase of timid acts (p<0.01) recorded after MDMA, but not after modafinil or methamphetamine administration. In the timid mice, at least some doses of modafinil decreased timidity (p<0.01) and increased aggression (p<0.01) with no effect on sociability. Administration of MDMA increased timid activities (p<0.01). Both MDMA and MET decreased sociability (p<0.01).

Could piracetam potentiate behavioural effects of psychostimulants?

Press and internet reports mention abuse of nootropic drug piracetam (PIR) in combination with psychostimulants methamphetamine (MET) or 4-methylenedioxymethamphetamine (MDMA). These combinations are believed to produce more profound desirable effects, while decreasing hangover. However, there is a lack of valid experimental studies on such drug-drug interactions in the scientific literature available. Our hypothesis proposes that a functional interaction exists between PIR and amphetamine psychostimulants (MET and MDMA) which can potentiate psychostimulant behavioural effects. Our hypothesis is supported by the results of our pilot experiment testing acute effects of drugs given to mice intraperitoneally (Vehicle, n=12; MET 2.5mg/kg, n=10; MDMA 2.5mg/kg, n=11; PIR 300 mg/kg, n=12; PIR+MET, n=12; PIR+MDMA, n=11) in the Open Field Test (Actitrack, Panlab, Spain). PIR given alone caused no significant changes in mouse locomotor/exploratory behaviour, whereas the same dose combined with either MET or MDMA significantly enhanced their stimulatory effects. Different possible neurobiological mechanism underlying drug-drug interaction of PIR with MET or MDMA are discussed, as modulation of dopaminergic, glutamatergic or cholinergic brain systems. However, the interaction with membrane phospholipids seems as the most plausible mechanism explaining PIR action on activities of neurotransmitter systems. Despite that our behavioural experiment cannot serve for explanation of the pharmacological mechanisms of these functional interactions, it shows that PIR effects can increase behavioural stimulation of amphetamine drugs. Thus, the reported combining of PIR with MET or MDMA by human abusers is not perhaps a coincidental phenomenon and may be based on existing PIR potential to intensify acute psychostimulant effects of these drugs of abuse.

The effects of methamphetamine self-administration on behavioural sensitization in the olfactory bulbectomy rat model of depression.

Depression is frequently comorbid with a drug addiction and may seriously complicate its treatment. Currently, there is no routinely used animal model to investigate this comorbidity. In this study the effect of repeated administration of methamphetamine on i.v. drug self-administration in an olfactory bulbectomy model of depression in rats was investigated in order to propose and validate a rat model of comorbid depression and addiction. Male Wistar rats were either olfactory-bulbectomized (OBX) or sham-operated. They subsequently underwent a methamphetamine sensitization regime, which consisted of daily i.p. injections of methamphetamine for a 14-d period; controls received Sal injections at the same frequency. The i.v. self-administration of methamphetamine (0.08 mg/kg in one infusion) paradigm on a fixed ratio schedule of reinforcement was performed using operant chambers. A significant decrease of the drug intake was recorded in sham-operated animals pretreated with methamphetamine when compared to the unpretreated group. This was not apparent in the OBX groups. Both groups of OBX animals exhibited a higher intake of methamphetamine compared to the corresponding sham-operated groups, thus confirming the hypothesis of higher drug intake in depressive conditions in this rodent model. The procedure of behavioural sensitization to methamphetamine decreased the number of self-administered drug doses per session in the sham-operated rats. It is hypothesized that this phenomenon resulted from increasing efficacy of the drug after behavioural sensitization caused by repeated methamphetamine intermittent administration.

Comparison of diazinon toxicity to embryos of Xenopus laevis and Danio rerio; degradation of diazinon in water.

The aim of this study was to determine the toxic effect of diazinon (organophosphate insecticide) to embryos of Xenopus laevis and Danio rerio. The 96-h LC50 values showed higher toxicity of diazinon for X. leavis in standard solution (9.84 mg/L) compared to the pond water (12.64 mg/L). Teratogenic index for diazinon was 1.3 and 1.6, respectively. The 96-h LC50 diazinon values demonstrated similar sensitivity of embryos D. rerio (8.21-9.34 mg/L) and X. laevis in standard test solutions. Our results reflect that direct application of diazinon into the water can be associated with significant risks to aquatic organisms.

Impact of repeated methamphetamine pretreatment on intravenous self-administration of the drug in males and estrogenized or non- estrogenized ovariectomized female rats.

OBJECTIVE: The female animals were already recorded to respond differently to methamphetamine (MET) abuse than males. This gender dissimilarity may be caused by the influence of estral cycles and different susceptibility to behavioural sensitization. METHODS: Influences of gender and pre-exposure to MET were studied in the rat model of MET intravenous self-administration (IVSA). The fixed ratio (FR) paradigm was employed in male rats (M) and estrogenized (F-ESTR) and non-estrogenized ovariectomized female rats (F-OVX) either pre-exposed or not-exposed to MET pretreatment. RESULTS: In rats that were not pre-exposed to MET, F-ESTR self-administered more MET infusions than each of the other groups, but F-OVX self-administered less than each of the other groups; the same trend was apparent in the MET pretreated groups. MET pre-exposure decreased subsequent MET IVSA in all groups except F-OVX. CONCLUSION: Thus, pre-exposure to MET and the loss of inherent estrogen in females notably decreased the intake of MET by rats, suggesting that abuse liability was reduced. Estrogen's effects on MET self-administration here correspond with accumulating evidence of stronger behavioural responses of females to drugs of abuse.

Toxicity of complex cyanobacterial samples and their fractions in Xenopus laevis embryos and the role of microcystins.

This work evaluated the effects of various cyanobacterial fractions in Frog Embryo Teratogenesis Assay Xenopus (FETAX) with African clawed frog embryos. Fractions were prepared from five biomasses with different dominant genera (Microcystis, Aphanizomenon, Anabaena, Planktothrix) and different microcystin content. Effects of following fractions were investigated: (I) homogenate of complex cyanobacterial biomass, (II) cell debris (pellet) after centrifugation of complex biomass, (III) supernatant after centrifugation of complex biomass (= crude aqueous extract), (IV) permeate after passing of crude extract through C-18 column (fraction devoid of microcystins), and (V) eluate from C-18 column (containing microcystins, if present). Besides classical parameters evaluated in 96 h FETAX (mortality, growth inhibition, malformations), we have also assessed the effects on biochemical markers of oxidative stress and detoxification (glutathione pool, GSH; activity of glutathione peroxidase, GPx; glutathione reductase, GR; activity of glutathione-S-transferase, GST). Complex biomass (I) and aqueous extract (III) were generally the most toxic fractions in terms of mortality and growth inhibition, whereas eluates containing microcystins (V) were generally less toxic. On the other hand, the same fraction (eluates) induced significant malformations in low concentrations but the effects were not related to the content of microcystins. Biomarkers were affected in variable manner but no significant effect or clear relation to microcystin content was observed. Our data support the hypothesis that microcystins are not the only or major toxic compounds in the complex cyanobacterial samples (at least for some species) and that more attention should be paid to other components of complex cyanobacterial biomass including non-specific parameters such as oxygen content or toxic ammonia released during bacterial decay of organic material.