The neuropharmacological profile of N-methyl-N-propargyl-2-aminotetralin: a potent monoamine oxidase inhibitor

Summary N-methyl-N-propargyl-2-aminotetralin (N-0425), a semi rigid analogue of deprenyl was found to be a potent inhibitor of monoamine oxidase type-A and-B. The MAO inhibitory potency was determined in in-vitro, ex-vivo and in-vivo experiments for racemic N-0425 and for both enantiomers, and compared with deprenyl. Racemic N-0425 and (–)N-0425 were found to inactivate both MAO-A and-B to about the same extent in rat brain homogenates, whereas (+)N-0425 was 10 times more potent in inhibiting MAO-B than MAO-A under in-vitro conditions. The latter compound was almost 3 times less active than (–)deprenyl with respect to inactivation of MAO-B. In ex-vivo experiments it was shown that (±)- and (+)N-0425 inhibited rat striatal MAO-B activity almost completely 2 h after a dose of 0.01 mmol/kg ip, whereas both compounds produced a much less rapid inactivation of type-A MAO, which was about 65% after 23 h. No potentiation of the tyramine induced increase in systolic blood pressure was found in normotensive rats following doses up to 0.01 mmol/kg ip of racemic N-0425, but a potentiation was observed after a higher dose of 0.04 mmol/kg. Levels of dopamine and noradrenaline were both increased in rat frontal cortex after the administration of N-0425, which can be interpreted as a reflection of MAO inactivation. Since we were able to select a dose of (±)N-0425 which potently inhibits MAO, without producing a concomittant potentiation of the tyramine effect on blood pressure in normotensive rats, it is reasonable to suggest that this compound, like deprenyl, could be useful in the treatment of Parkinson's disease.Abbreviations used MAO monoamine oxidase - l-DOPA 3,4-dihydroxyphenylalamine - DA dopamine - DOPAC 3,4-dihydroxyphenylacetic acid - HVA homovanillic acid - 3-MT 3-methoxytyramine - NA noradrenaline - NM normetanephrine - 5-HT 5-hydroxytryptamine - 5-HIAA 5-hydroxyindoleacetic acid - PEA -phenylethylamine - N-0425 N-methyl-N-propargyl-2-aminotetralin Some of these results have been presented in a preliminary form at the 5th International Catecholamine Symposium, Göteborg, Sweden, June 12–16, 1983. This work was partly supported by a grant from Nelson Research, Irvine, California, USA     

Strategic down‐regulation of attentional resources as a mechanism of proactive response inhibition

Efficiently avoiding inappropriate actions in a changing environment is central to cognitive control. One mechanism contributing to this ability is the deliberate slowing down of responses in contexts where full response cancellation might occasionally be required, referred to as proactive response inhibition. The present electroencephalographic (EEG) study investigated the role of attentional processes in proactive response inhibition in humans. To this end, we compared data from a standard stop‐signal task, in which stop signals required response cancellation (‘stop‐relevant’), to data where possible stop signals were task‐irrelevant (‘stop‐irrelevant’). Behavioral data clearly indicated the presence of proactive slowing in the standard stop‐signal task. A novel single‐trial analysis was used to directly model the relationship between response time and the EEG data of the go‐trials in both contexts within a multilevel linear models framework. We found a relationship between response time and amplitude of the attention‐related N1 component in stop‐relevant blocks, a characteristic that was fully absent in stop‐irrelevant blocks. Specifically, N1 amplitudes were lower the slower the response time, suggesting that attentional resources were being strategically down‐regulated to control response speed. Drift diffusion modeling of the behavioral data indicated that multiple parameters differed across the two contexts, likely suggesting the contribution from independent brain mechanisms to proactive slowing. Hence, the attentional mechanism of proactive response control we report here might coexist with known mechanisms that are more directly tied to motoric response inhibition. As such, our study opens up new research avenues also concerning clinical conditions that feature deficits in proactive response inhibition.     

Selective attention and audiovisual integration: is attending to both modalities a prerequisite for early integration?

Interactions between multisensory integration and attention were studied using a combined audiovisual streaming design and a rapid serial visual presentation paradigm. Event-related potentials (ERPs) following audiovisual objects (AV) were compared with the sum of the ERPs following auditory (A) and visual objects (V). Integration processes were expressed as the difference between these AV and (A + V) responses and were studied while attention was directed to one or both modalities or directed elsewhere. Results show that multisensory integration effects depend on the multisensory objects being fully attended--that is, when both the visual and auditory senses were attended. In this condition, a superadditive audiovisual integration effect was observed on the P50 component. When unattended, this effect was reversed; the P50 components of multisensory ERPs were smaller than the unisensory sum. Additionally, we found an enhanced late frontal negativity when subjects attended the visual component of a multisensory object. This effect, bearing a strong resemblance to the auditory processing negativity, appeared to reflect late attention-related processing that had spread to encompass the auditory component of the multisensory object. In conclusion, our results shed new light on how the brain processes multisensory auditory and visual information, including how attention modulates multisensory integration processes.     

Physiologically-based pharmacokinetic modeling for absorption,transport, metabolism and excretion

The seminal paper on the liver physiologically-based pharmacokinetic (PBPK) model by Rowland et al. (J Pharmacokinet Biopharm 1:123–136, 1973) that described the influence of blood flow, intrinsic clearance, and binding on hepatic clearance had inspired further development of PBPK modeling of the liver, kidney and intestine as well as whole body. Shortly thereafter, a series of papers from Pang and Rowland compared the well-stirred and parallel-tube liver models and sparked further development on clearance concepts in the liver, including those described by the dispersion model. From 2005 onwards, several seminal papers by Rodgers and Rowland, in their recognition of the binding of molecules to tissue acidic and neutral phospholipids, improved the methodology in providing estimates of the tissue-to-plasma coefficient and rendering easy calculation of these hard-to-get constants. The improvement has strongly consolidated the basic premise on PBPK modeling and simulations and these basics have allowed scientists to focus on other important variables: membrane barriers, and transporter and enzyme and their heterogeneities that further impact drug disposition. In particular, the PBPK models have delved into sequential metabolism and futile cycling to illustrate how transporters and enzymes could affect the metabolism of drugs and metabolites. PBPK models that are especially pertinent to metabolite kinetics are being utilized in drug studies and risk assessment. These types of PBPK modeling reveal differences in kinetics between the formed vs. preformed metabolite, showing special considerations for membrane barriers, and the influence of competing pathways and competing organs.     

Good times for multisensory integration: Effects of the precision of temporal synchrony as revealed by gamma-band oscillations

The synchronous occurrence of the unisensory components of a multisensory stimulus contributes to their successful merging into a coherent perceptual representation. Oscillatory gamma-band responses (GBRs, 30-80 Hz) have been linked to feature integration mechanisms and to multisensory processing, suggesting they may also be sensitive to the temporal alignment of multisensory stimulus components. Here we examined the effects on early oscillatory GBR brain activity of varying the precision of the temporal synchrony of the unisensory components of an audio-visual stimulus. Audio-visual stimuli were presented with stimulus onset asynchronies ranging from -125 to +125 ms. Randomized streams of auditory (A), visual (V), and audio-visual (AV) stimuli were presented centrally while subjects attended to either the auditory or visual modality to detect occasional targets. GBRs to auditory and visual components of multisensory AV stimuli were extracted for five subranges of asynchrony (e.g., A preceded by V by 100+/-25 ms, by 50+/-25 ms, etc.) and compared with GBRs to unisensory control stimuli. Robust multisensory interactions were observed in the early GBRs when the auditory and visual stimuli were presented with the closest synchrony. These effects were found over medial-frontal brain areas after 30-80 ms and over occipital brain areas after 60-120 ms. A second integration effect, possibly reflecting the perceptual separation of the two sensory inputs, was found over occipital areas when auditory inputs preceded visual by 100+/-25 ms. No significant interactions were observed for the other subranges of asynchrony. These results show that the precision of temporal synchrony can have an impact on early cross-modal interactions in human cortex.