Ketamine treatment upon memory retrieval reduces fear memory in marmoset monkeys

Emotionally arousing experiences are retained very well as seen in posttraumatic stress disorder (PTSD). Various lines of evidence indicate that reactivation of these memories renders them labile which offers a potential time-window for intervention. We tested in non-human primates whether ketamine, administered during fear memory reactivation, affected passive (inhibitory) avoidance learning. For the consolidation of contextual emotional memory, the unescapable foot-shock paradigm in a passive avoidance task with two compartments (dark vs illuminated) was used. After entering the dark compartment, marmoset monkeys received four random foot-shocks (1 mA, 4 s) within 15-min. This stressful exposure increased the saliva cortisol and heart rate and impaired REM-sleep (p  <0.05). One week later the monkeys were re-exposed to the stressful situation for the reconsolidation of the fearful experience. During the re-exposure the monkeys were treated with ketamine (0.5 mg/kg) or saline. In week 3, the monkeys were placed in the experimental setting to test their memory for the fearful experience. In contrast to the vehicle-treated monkeys, who avoided the dark compartment, the ketamine-treated monkeys entered the dark compartment that was previously associated with the fearful experience (p < 0.05). Post-mortem analysis of the hippocampus showed that ketamine-treated animals exhibited less doublecortin positive neurons and BrdU-labeled cells in the dentate gyrus. This study reveals that a single low dose of ketamine, administered upon fear retrieval in monkeys, reduce contextual fear memory and attenuate neurogenesis in the hippocampus. These are important findings for considering ketamine as a potential candidate to target traumatic memories in PTSD

Відкриття української книгарні “Смолоскип”

The present medication in Parkinson’s disease (PD) is unable to stop or slow down the progression of the disease. Therefore pharmacological intervention at crucial steps in the neuronal cell death processes would be a better strategy. Cannabinoids are potent neuroprotective compounds in models of oxidative stress and excitotoxicity and offer potential protection in models of PD. Therefore the present study determines the neuroprotective effects of 9- tetrahydrocannabinol ( 9-THC) in the marmoset 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model on behavior and pathology. Twelve marmoset monkeys were treated with a total cumulative dose of 6 mg/kg MPTP in 9 days. Seven of these animals received simultaneously a daily oral dose of 9-THC (4 mg/kg) and five animals received simultaneously vehicle for 27 days. The parkinsonian symptoms were observed daily and locomotor activity and hand-eye coordination were tested once a week during the experimental period. Postmortem, dopamine levels in the striatum were analyzed and tyrosine hydroxylase immunohistochemistry was applied to determine viable dopaminergic neurons in the substantia nigra. 9-THC has no protective effects on any parameter. These negative results might be related to the severity of the cell death induction by MPTP in relation to the low dose of 9-THC used in this Parkinson model

Efficacy of prophylaxis and treatment against soman intoxication

The efficacy against lethality and post-intoxication incapacitation after 2x LD50 soman of different subacute pretreatment scenarios of 12 days was tested with or without post-intoxication therapy in guinea pigs. These pretreatment regimes were 1) the currently used pretreatment with pyridostigmine (PYR, 0.04 mg/kg/hr), 2) the combination of physostigmine (PHY, 0.025 mg/kg/hr) with the muscarinic receptor antagonist scopolamine (SCO, 0.018 mg/kg/hr), and 3) the combination of PHY with the anti-Parkinson drug procyclidine (PC, 3 mg/kg, sc). The post-intoxication therapy consisted of HI-6 (21.4 mg/kg, im), atropine sulphate (AS, 0.085 mg/kg, im), and diazepam (DZP, 0.21 mg/kg, im). Different behavioral and observational read-out systems were used to elucidate objectively the severity of soman induced incapacitation. There were no big differences in the symptomatology between the animals pretreated with PHY+SCO or with PYR. On the other hand, animals pretreated with PHY+PC did not show worse symptoms as was found in the other groups. In some cases the post-intoxication therapy was even not necessary. Although the symptomatology between the animals treated with PHY+SCO and PYR were comparable the effects on incapacitation and survival were not comparable: all animals pretreated with PYR and the post- intoxication therapy did not perform in the behavioral test systems and died within 24 hours. This was the same result as what was found in unpretreated animals which were treated only with the post-intoxication therapy. The mortality in animals pretreated with PHY+SCO was 25%. The addition of a post intoxication therapy in PHY+SCO pretreated animals did not improve the efficacy. On the other hand, animals pretreated with PHY+PC all survived even without post-intoxication therapy. The performance in the behavioral test systems was similar for animals retreated with PHY+SCO or PHY+PC. Animals without any treatment, besides soman, all died within one hour. Prophylaxis with the combination of PHY and SCO seems to be a good alternative for the current PYR pretreatment, in particular since this pretreatment showed no side effects in previous studies with guinea pigs and marmoset monkeys and protects efficiently against 2x LD50 soman. The addition of PC to PHY, instead of SCO, augments the efficacy of the pretreatment against soman poisoning. In that case an additional post-intoxication therapy is not necessary. The combination of PHY + PC seems to be very promising and should be further investigated

Non-enzymatic pretreatment of nerve agent (soman) poisoning: A brief state-of-the-art review

The rapid onset of toxic signs following nerve agent intoxication and the apprehension that current therapy (atropine, oxime, diazepam) may not prevent brain damage, requires supportive pretreatment. Since the current pretreatment drug pyridostigmine fails in protecting brain-AChE, more effective pretreatment is necessary.A main focus of present-day pretreatment research is on bioscavengers, another is on centrally active reversible AChE-inhibitors combined with drugs showing anti-cholinergic, anti-glutamatergic, neuroprotective and non-sedating GABA-ergic activity. Strategies aimed at improving efficacy of pharmacological pretreatment will briefly be discussed. Galantamine, given as a pretreatment or stand-alone therapy, emerged as one of the best medical countermeasures against nerve agent poisoning in guinea pigs. Other preclinical studies demonstrated effective pretreatment consisting of physostigmine combined with procyclidine, scopolamine or bupropion (all single injections), against nerve agent poisoning in guinea pigs. A long sign-free pretreatment with physostigmine (Alzet pump), combined with single injection of procyclidine just before soman poisoning, enhanced the efficacy of a post-poisoning therapy consisting of 3 autoinjector equivalents of HI-6, atropine and diazepam, considerably. © 2011 Elsevier Ireland Ltd

Two new test methods to quantify motor deficits in a marmoset model for Parkinson's disease

The validity of the common marmoset (Callithrix jacchus) as a model for human disease depends on the development of parameters with clinical relevance. We tested the effect of treatment with MPTP in two newly developed non-invasive motor behavioral paradigms in the context of Parkinson's disease. The "Tower" was designed to quantify the marmoset's natural jumping behavior as a measure for akinesia, the "Hourglass" to test the marmoset's natural righting reflex as measure for rigidity, analogous to axial motor behavior in humans. MPTP treatment affected marmoset behavior in both testing paradigms. The marmoset's righting reflex in the Hourglass remained significantly impaired during the full 3-week period after the MPTP intoxication. In the Tower, the marmosets were not able to jump the largest distances one week after MPTP and showed a persistent reduction in activity during the 3-week period after the MPTP intoxication. Because not all aspects of motor behavior are similarly affected by MPTP, a complete behavioral sketch of parkinsonian marmosets should preferably include a range of motor behavior functions to create an overview of the full range of motor impairments. Both the Hourglass and Tower test provide important behavioral parameters in a clinically relevant multiple testing approach in motor disorder models

Brain Machine Interfaces : technology status, applications and the way to the future

Brain Machine Interfaces (BMIs) enable direct communication between the brain or nervous system and a machine without involving the sensory-motor system. BMIs are an embryonic technology and remarkable accomplishments have recently been reported. BMIs have a high potential and possibly an enormous impact on society, and may evoke a revolution in the way we interact with computers. If we look at the Human Factors and Ergonomics communitys position in the BMI field, we do not have a meaningful track record yet. However, the thesis of this paper is that we as a community are in a good position to (1) facilitate a broadening of the focus of BMIs from therapeutic applications to general use and (2) to realise a spin-in of BMI technology to domains such as Human Computer Interaction, supporting people with special needs, and training and simulation

Therapeutic effects of Delta9-THC and modafinil in a marmoset Parkinson model

Current therapies for Parkinson's disease (PD) like l-dopa and dopamine (DA) agonists have declined efficacy after long term use. Therefore, research towards supplementary or alternative medication is needed. The implementation in PD can be expedited by application of compounds already used in the clinic. In this study the therapeutic effects of the psychoactive compounds Δ9-tetrahydrocannabinol (Δ9-THC) and modafinil were tested in the 1-methyl-1,2,3,6-tetrahydropyridine (MPTP)–marmoset model for PD. The anti-parkinson effects of Δ9-THC (4 mg/kg) and modafinil (100 mg/kg) in parkinsonian marmosets were assessed with two behavioral rating scales covering parkinsonian symptoms and involuntary movements and two test systems assessing the locomotor activity and hand–eye coordination. Δ9-THC improved activity and hand–eye coordination, but induced compound-related side-effects. Modafinil improved activity and observed parkinsonian symptoms but not hand–eye coordination. It can be concluded that both compounds have therapeutic values and could supplement existing therapies for PD