Stimulus transfer

Based on the modest ability of the (+)-isomers of MDMA and MBDB to inhibit the reuptake of norepinephrine (NE) into hypothalamic synaptosomes (Steele et al. 1987). it seemed possible that noradrenergic pathways might be involved in the eue. In ano er series of drug discrimination experiments designed to test this hypothesis, the specific NE uptake inhibitor (-)-tomoxctine was tested for stimulus transfer in doses up to 10 mg/kg in MDMA-trained rats. At 5 mg/kg, 67 percent of the animals responded on, the drug lever. However, pretreatment with tomoxetine in six rats trained to discriminate MDMA from saline had no effect on the discrimination of a subsequent dose of MDMA. 

Explosive Stimulus Transfer. Under a program to develop a technique to compute probability of detonation transfer between a donor and an acceptor, experiments were performed to measure the effects of seven variables. These included two donor parameters fragment slack energy and five acceptor parameters confinement, closure thickness, explosive material, explosive particle size and closure material... 

The effect on detonation transfer of the parameters shown in Fig Ex22 were reviewed for the donor and acceptor expls RDX, HNS-1 (2,4,6,2/,4/,6/-Hexanitrostilbene of 3 microns particle size) HNS-11 (Same as HNS-1, except of 200-300 microns particle size), DATB (1,3-Diamino-2,4,6-trinitrobenzene), and TATB (1,3,5-Triamino-2,4,6-trinitrobenzene) with a wide cross-section of sensitivities. Eash of these parameters has been individually qualified and explained on both the theoretical level and the impact on practical hardware design. The experimental study is described in Ref 2 Refs 1) M.L.Schimmel, "Quantitative Understanding of Explosive Stimulus Transfer... 

QUEST), McDonnell Douglas Corp Summary Report-Tasks 1 thru 6, MDC AID21, St.Louis, Missouri (June 1971) 2)L.J.Bement, Quantitative Understanding of Explosive Stimulus Transfer , Mail. Stop 498, NASA Langley Re search Center, Hampton, Virginia, 23365 3)G.Cohn, Edit, Expls Pyrots 5(5), 1972... 

ADP-stimulated Na+ influx. Although the nature of the ADP interaction with platelet receptors to induce calcium redistribution is unknown, it is clear that ADP does not penetrate the membrane (35J. It is possible that the ADP-platelet interaction involves the flux of other ions as part of the stimulus-transfer... 

Whether the uptake of Na+ associated with ADP-induced shape change and aggregation is the primary stimulus-transfer pathway of activation has not been established. Platelets maintain a membrane potential (negative inside) (41), and... 

Strychnine enhances stimulus transfer in the spinal marrow resulting in characteristic spasms. It has a characteristic stimulating effect on the respiratory and vascular motor centres, as well as on the cerebral cortex. 

Assuming that the amount (concentration) of receptors occupied is the limiting factor, then the drug A reaches its maximal effect E m when occupying all the receptors when it occupies 50% of the receptors, 50% of the maximal drug effect is obtained. Linear stimulus transfer exists in this case, the concentration [/ yf] being directly proportional to the effect Ex -... 

The case discussed above does not exhaust all the possibilities of non-competitive antagonist action. Instead of blocking some important site closely related to the macromolecule carrying the receptor R, the antagonist could block some steps of the reaction chain called stimulus transfer well behind the agonist-receptor interaction. Schematically the situation may be given as follows ... 

Some Complicating Factors 6.2.8.1. Non-linear Stimulus Transfer... 

The considerations and calculations mentioned above all assume a linear relationship between [RA and Ea, and thus a linear stimulus transfer . This assumption has been shown to be acceptable in the majority of cases. 

It has been mentioned, however, that—concerning the receptor—there are many more things we do not know than ones we really do. For the complicated reaction chain called stimulus transfer the same is true, and an apodictic declaration of the existence of linear relationships in unknown processes might, therefore, sometimes be erroneous. 

Fig. 12. Non-linear stimulus transfer (leceptm- reserve). DRC of the agonist A interacting with irreversible antagonist fi acting in a constant concentration for different time intervals tg,. In the course of one time unit the antagonist eliminates 90% of reactive receptors at tg, = 0, 100% are reactive, at = 1, only 10% Rf, at tg, = 2, only 1% remains. The true KJ = 4-05 is lower than the original pZJj — initial parallel shift of the curves and their depression...

Receptor reserve and non-linear stimulus transfer have been described only in a limited number of cases. It is not possiUe to assume that this phenomenrm is a regular and very common one. In other words, in the majority of cases the concentration of occupied receptors can be assumed to be the limiting reaction step. However, if after a certain fraction of the total receptors have been activated a further limit is met, the occupation of further receptors is gradually less and less effective the stimulus transfer thus being non-linear. 

Whatever the actual reason for non-linear stimulus transfer may be in any of the cases studied, the character of pure competitive antagonist actions as well as the p/f 2 and Kb values remain unchanged. 

It may be concluded that even in the complicated case of non-linear stimulus transfer the estimation of Ka and of the efficacy is possible using irreversible antagonists... 

Comparing with equation (3) it is seen that the intrinsic activity a represents the velocity constant characterizing the reaction chain called stimulus triggering 4- stimulus transfer . 

These equations show that, in all the cases mentioned, the effect is proportional to [RA therefore, the effect increases at the start of the reaction from zero to the equilibrium level proportionally to the increase in and shows no fade. The reaction behaves occupation-like with linear stimulus transfer. 

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