Distinct cognitive and discriminative stimulus effects of ketamine enantiomers in rats

Although (S)-ketamine was approved for use in treatment-resistant depression in 2019, new preclinical findings suggest that (R)-ketamine might produce better efficacy and tolerability relative to (S)-ketamine. Here we evaluated the effects of (R)-, (S)-, and (R,S)-ketamine on executive functions as measured in the attentional set shifting task (ASST) and on their discriminative stimulus effects in rats. Earlier data demonstrated that cognitive flexibility is compromised by (R,S)-ketamine, but the effects of enantiomers in rats are unknown. Separate cohorts of rats were tested in ASST and trained to discriminate either (R,S)-ketamine, (S)-ketamine, or (R)-ketamine (all at 10 mg/kg) from saline; in order to maintain the discrimination, a higher (R)-ketamine dose (17.5 mg/kg) was subsequently instituted. In ASST, all three forms increased the trials to criterion measure at reversal learning and extra-dimensional set-shifting phases. However, in contrast to (R)- and (S)-ketamine, (R,S)-ketamine prolonged the mean time to complete a single trial during early stages, suggesting increased reaction time, and/or unspecific side-effects related to motor or motivational impairments. In the drug discriminations, all rats acquired their respective discriminations between drug and saline. In (R,S)-ketamine-trained rats, (R)-ketamine and (S)-ketamine only partially substituted for the training dose of (R,S)-ketamine. Further, (R)-ketamine did not fully substitute in rats trained to (S)-ketamine. The data suggest more serious cognitive deficits produced by (R,S)-ketamine than its enantiomers. Furthermore, (R,S)-ketamine and its isomers share overlapping but not isomorphic discriminative stimulus effects predicting distinct subjective responses to (R)- vs. (S)-ketamine in humans

Memantine reduces consumption of highly palatable food in a rat model of binge eating

Excessive consumption of highly palatable food has been linked to the development of eating disorders and obesity, and can be modeled in non-food-deprived rats by offering them a limited (2-h daily) access to an optional dietary fat. Since the glutamatergic system has recently emerged as a viable target for binge-eating medication development, we compared the effects of subchronic treatment with glutamatergic receptor antagonists to the effects of a reference appetite-suppressing agent sibutramine on highly palatable food (lard) and normal chow intake. In three separate experiments, the consumption of a standard laboratory chow and lard were measured during 12 days of medication treatment and for 6 days afterwards. Generalized estimating equations analysis demonstrated that sibutramine (7.5 mg/kg, PO) significantly decreased lard consumption, with a concurrent increase in chow consumption. Sibutramine effects disappeared after treatment discontinuation. The NMDA receptor antagonist memantine (5 mg/kg, IP) significantly decreased lard consumption and increased chow consumption, comparable to effects of sibutramine; however, memantine’s effects persisted after treatment discontinuation. The effects of the mGluR5 antagonist MTEP (7.5 mg/kg, IP) on food consumption were in the same direction as seen with memantine, but the observed differences were not significant. In an additional control experiment, sibutramine and memantine reduced unlimited (24 h) chow intake during the treatment phase. Present results provide evidence that glutamatergic neurotransmission might be involved in the regulation of excessive consumption of highly palatable foods, and suggest that NMDA receptor may be an attractive target for developing obesity and disordered eating pharmacotherapies

Computational planning of the synthesis of complex natural products

Training algorithms to computationally plan multistep organic syntheses has been a challenge for more than 50 years(1-7). However, the field has progressed greatly since the development of early programs such as LHASA(1,7), for which reaction choices at each step were made by human operators. Multiple software platforms(6,8-14) are now capable of completely autonomous planning. But these programs 'think' only one step at a time and have so far been limited to relatively simple targets, the syntheses of which could arguably be designed by human chemists within minutes, without the help of a computer. Furthermore, no algorithm has yet been able to design plausible routes to complex natural products, for which much more far-sighted, multistep planning is necessary(15,16) and closely related literature precedents cannot be relied on. Here we demonstrate that such computational synthesis planning is possible, provided that the program's knowledge of organic chemistry and data-based artificial intelligence routines are augmented with causal relationships(17,18), allowing it to 'strategize' over multiple synthetic steps. Using a Turing-like test administered to synthesis experts, we show that the routes designed by such a program are largely indistinguishable from those designed by humans. We also successfully validated three computer-designed syntheses of natural products in the laboratory. Taken together, these results indicate that expert-level automated synthetic planning is feasible, pending continued improvements to the reaction knowledge base and further code optimization. A synthetic route-planning algorithm, augmented with causal relationships that allow it to strategize over multiple steps, can design complex natural-product syntheses that are indistinguishable from those designed by human experts

A complex interaction between glycine/NMDA receptors and serotonergic/noradrenergic antidepressants in the forced swim test in mice

Both clinical and preclinical studies demonstrate the antidepressant activity of the functional NMDA receptor antagonists. In this study, we assessed the effects of two glycine/NMDA receptor ligands, namely L-701,324 (antagonist) and d-cycloserine (a partial agonist) on the action of antidepressant drugs with different pharmacological profiles in the forced swim test in mice. Swim sessions were conducted by placing mice individually in glass cylinders filled with warmed water for 6 min. The duration of behavioral immobility during the last 4 min of the test was evaluated. The locomotor activity of mice was measured with photoresistor actimeters. L-701,324 and d-cycloserine given with reboxetine (administered in subeffective doses) did not change the behavior of animals in the forced swim test. A potentiating effect was seen when both tested glycine site ligands were given concomitantly with imipramine or fluoxetine in this test. The lesion of noradrenaline nerve terminals produced by DSP-4 neither altered the baseline activity nor influenced the antidepressant-like action of L-701,324 or d-cycloserine. The depletion of serotonin by p-CPA did not alter baseline activity in the forced swim test. However, it completely antagonized the antidepressant-like action produced by L-701,324 and d-cycloserine. Moreover, the antidepressant-like effects of imipramine, fluoxetine and reboxetine were abolished by d-serine, a full agonist of glycine/NMDA receptors. The present study demonstrates that glycine/NMDA receptor functional antagonists enhance the antidepressant-like action of serotonin, but not noradrenaline-based antidepressants and such their activity seems to depend on serotonin rather than noradrenaline pathway

PRZEGLĄD PIŚMIENNICTWA

Artur Ławniczak, Finansowanie partii politycznych, Wydawnictwo Sejmowe, Warszawa 2001, ss. 187

PRZEGLĄD PIŚMIENNICTWA

Artur Ławniczak, Finansowanie partii politycznych, Wydawnictwo Sejmowe, Warszawa 2001, ss. 187

Glutamate-based antidepressants: 20 years on

El pdf del artículo es el manuscrito de autor.Depression is a chronic recurring illness that affects more than 120 million people worldwide. Drugs increasing the synaptic availability of serotonin and norepinephrine (biogenic amine-based agents) have been used to treat depression for more than 50 years. However, significant symptom improvement requires ≥2–4 weeks of treatment and a first course of therapy provides symptom relief to only 60–65% of patients. Roche and Evotec recently announced plans to develop N-methyl-D-aspartate (NMDA) receptor antagonists targeting the NR2B subtype for treatment-resistant depression. This announcement closely follows a report that another NR2B antagonist, traxoprodil (CP 101 606), has antidepressant effects in patients unresponsive to a serotonin selective reuptake inhibitor, as well as reports of rapid and sustained antidepressant effects following a single injection of the NMDA antagonist ketamine. Here we describe evidence that glutamate-based therapies might represent an effective alternative to biogenic-amine-based agents for depression and provide perspectives on the development of these agents.R.T. is supported by the Ministerio Ciencia e Innovación of Spain, grant SAF2008-03514 and by the Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED).Peer reviewe