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The Modeling of Central Nervous Pharmacological Effects with Special Regard to Doses and Environmental Illumination
THE MODELING OF CENTRAL NERVOUS PHARMACOLOGICAL EFFECTS WITH SPECIAL REGARD TO DOSES AND + ENVIRONMENTAL ILLUMINATIO~
Tamara Hecht, K. Treptow, K. Hecht and M Peschel German Academy of Science at Berlin Institute of Cortico-Visceral Pathology and Therapy, Berlin-South
In conditioning experiments on albino rats, we succeeded in demonstrating that the effect of a number of neuropsychological drugs depends on the brightness of the environment.
Practical and theoretical considerations induced us to try and find generalizing relationships (between the three variables listed hereafter) which are valid for a mean effect or a theoretically conceivable "mean-value organism". For this purpose, we developed a demonstration model with the aid of which expected values of the 3rd variable can be calculated, if the two other variables are shown or selected at random.
Figure I shows how one hour after doses of caffeine, ethyl-crotyl-barbiturate, benactyzine and chlorpromazine and two hours after a dose of reserpine, the effects of these drugs on a stabilized conditioned escape reflex are influenced by light: The different doses and the existing light intensities (0.35; 15; 1,000 lux) can be ta ken from the Figure. The applied doses of all drugs are within the range of the characteristic effects and do not allow any subliminal or toxic influence. The reaction times obtained with the usual working illumination of 15 lux represent in all cases the relative values. Comparing these relative values with the variations in reaction times produced by the different drugs,we checked the variation for their statistical significance. The arrows (t)indicate the statistically significant stimulant variation from the relative value; the black arrows (~) represent the depressive effect on the conditioned activity. The dot indicates that no statistically verified variation from the control values was observed.
included the following variable
~odeling
values: 1. the mean reaction time of the conditioned escape reflex, which, with certain reservations, represents a rough measure of the central nervous functional status actually existing; 2. the dose of the pharmacological agent; 3.
the intensity of light.
To describe the correlation between the doses of centrally acting drugs and different light intensities in conditioning experiments, we used a linear equation of the form R
As can be seen from the survey, identical doses of the above drugs produced with different light intensities different effects, which sometimes differed extremely from the characteristic effects or were even oppo sit e to it, as for example with caffeine doses of 10.0 and 20.0 mg/kg weight with an illumination of 1,000 lux. An examinati on of the effects shown in the table offers a separation of the applied drugs into situation-unstable drugs (caffeine, ethyl-crotyl-barbiturate, benactyzine) and situation-stable drugs (chlorpromazine and res e rpine).
=
b
l
(D)
+ b 2
(L)
+
a
and a logarithmic equation of the form R = bl
(In D)
+ bZ
(In L)
+
a
In these equations, we used R for the mean reaction time, 0 for the dose and L for the intensity of light. Calculation of the regression factors bl and b 2 and factor a was carried out in the usual way by the minimizing method for the square variations of the measured values from those to be taken from the equation. We obtained the mean reaction time from the measured values of the 15 responses produced by each animal of a group of 10 animals. The formation of mean values
429
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mean reaction times with increasing environmental brightness can be interpreted as an overstrain inhibition. The additive increase in excitation , as a result of an increase in the dose of caffeine, and the influence of the stronger afferentation of light on the central nervous system obviously overstrain the animals' adaptability, which still exist _ists in a darker situation. This conception seems to be reasonable, since the exciting effect of the drug manifests itself by a marked decrease in the mean reaction time -- as compared to the nor_ mal original value -- even in an almost dark situation of 0.35 lux . As a resul~ the model plan describes a correlation which, with doses and environmental illumination increasing, indicates a tendency of additive inhibition.
from normal and delayed reaction times supports, due to its continuous variability, the linear dependence of the model conception. The significance of correspondence of the mean measured values with the mean model value5 amounts to at least 98.5 per cent for numerical modeling and at least 99 . 6 p er cent for logarithmic modeling, which gives proof of the linear or logarithmic correlation between the size of dose and the intensity of light with regard to their influence on the conditioned reaction time . Logarithmic mode ling shows a favorable correspondence every time the intensities of light are chosen quasi-geometrically, with the doses being vari e d quasi-geometrically. Figure 2 demonstrates the modeling of the above relationships with regard to drugs which are sit uatim-unstable in their effe ct.
Numerical modeling comes within 99 . 9 per cent of the mean measured values, logarithmic mode ling comes within 99.6 per cent. These tendencies occurring with both an increase in the dose and the intensity of light can be statistically verified by the -test, s-method and variance analysis. The discrepancy of this reaction is underlined by an almost absolute inhomogeneity of the individual reaction time variations, which by far exceeds that relative to ethyl-crotylbarbiturate and benactyzine.
1. Ethyl-crotyl-barbiturate is a typical example of a correlative dependence between the size of dose and the intensity of light . Numerical modeling reveals a correspondence of 99.2 per cent with the mean measured values; logarithmic modeling - a correspondence of 99 . 9 per cent .. It is statistically verified that an increase in the dose results in a stronger sedative effect, while an increase in the intensity of light reduces this effect, as is shown in the statistics ..
Figure 3 demonstrates the modeling of situation-stable drugs.
This statement can be made despite the fact that inhomo !J!neity exists as is shown by the -test and the variance analysis, the latter demonstrating the animals' reaction times inter - individual= ly .
1. Inessential tendencies of the mean reaction times in different directions indicate the influence of light on the effect of reserpine. The increasing characteristic effects in the graph are a result of larger doses applied and can be significantly verified. Numerical and logarithmic mode ling reveals a correspondence with the measured values which is > 99 . 9 per cent .
2. With benactyzine, the correlative dependence is i n the main caused by the influence of light. Numerical modeling reveals a correspondence of 98.5 per cent with the mean reaction times, logarithmic modeli ng -- a correspondence of 99.9 per cent . While an increase in the dose results in a somewhat stronger sedative e f f e c t, a hi g her de g r e e 0 f i l l urn i n at i on of the environment leads to a marked decrease in the same. Both symptoms are statistically significant according to the -test, s-method and variance analysis. Benactyzine, too, does not produce homogeneous res JDnses in all animals, as was noted in relation to ethyl-crotylbarbi turate.
The animals frequently responded with different reaction times . 2. Chlorpromazine (aninazine), too, produces a situation-stable effect, since a · change in the mean reaction times is a mere result of changes in the dosage. This again was statistically verified by the -test, s-method and variance analysis. Correspondence with the numerical and l~arithmic model planes shows a probability which is > 99 . 9 per cent. The animals responded homogeneously - with a few exceptions only.
3 . With caffeine, the collective responses, in its dependence on the dose, reveals two different tendencies. With 5 mg/kg weight being applied, an increasing intensity of light results in an increase in excitation. Doses of 10.0 and 20.0 mg/kg weight seem to have the opposite effect, since a prolongation of the
Situation-labile drugs may be classified according to the regression coefficients of changes in optical afferentation, which represent the degree to which their effect can be influenced by afferentation;
431
Benact~zine seems to be most affected by different quantities of light.
Kaly-none's effect seems to be a little less dependent upon different light intensities. The effect of caffeine seems to be less dependent upon the Intensity of light than is the case with the two above drugs. The general relationships which were called for at the beginning in connection with a mean effect or a theoretically conceivable "mean-value organism" can be derived from the model plane, which is collectively vali d. Expected values of a third variable, with two known variables or varia bles selected at random, can be obtained by calculating isometric lines in the model plane. The latter gi ve the geome tri c locus of light intensities and dos a ge quotas of the same value which may lead to a certain central nervous response. Hence, the following quantities can be determined with the aid of the above straight lines: 1.
the mean reaction time which - with certain reservations - can be a rough measure of the actual status of reaction;
2.
the mean dose necessary to replace a certain effect of light, if the organi sn' s a ctual status of reaction is known;
3.
the mean intensity of light which possibly r epl aces a certain dose effect in a known status of reaction.
Since the use 0 f different light intensities is - as we learned - but one way to influence the effects of drugs by changing the functional status of the central nervous systen, our demonstration model cannot claim to be complex in a larger sense , unless other technically recordable quantities, which the exogeneous environment influencing the "milieu interieur" is composed of, are incorporated into it. To improve the model, we will present another paper which deals with the application of existing experimental data about the correlation between the effect of drug doses and different intensities of acoustic afferentation to our model. It can, however, be developed into a research model, if it is extrapolated in anyone direction and the obtained data are experimentally checked for their validity - always taking into account
432
subliminal doses, toxically acting components, etc., or if, on the basis of a comparison of the mean-value model with the individual model and on the basis of the animals' typological characteristics the way of response of an individual, whose typological characteristics are know, can be predicted.
Tamara Hecht, K. Treptow, K. Hecht and M Peschel German Academy of Science at Berlin Institute of Cortico-Visceral Pathology and Therapy, Berlin-South
In conditioning experiments on albino rats, we succeeded in demonstrating that the effect of a number of neuropsychological drugs depends on the brightness of the environment.
Practical and theoretical considerations induced us to try and find generalizing relationships (between the three variables listed hereafter) which are valid for a mean effect or a theoretically conceivable "mean-value organism". For this purpose, we developed a demonstration model with the aid of which expected values of the 3rd variable can be calculated, if the two other variables are shown or selected at random.
Figure I shows how one hour after doses of caffeine, ethyl-crotyl-barbiturate, benactyzine and chlorpromazine and two hours after a dose of reserpine, the effects of these drugs on a stabilized conditioned escape reflex are influenced by light: The different doses and the existing light intensities (0.35; 15; 1,000 lux) can be ta ken from the Figure. The applied doses of all drugs are within the range of the characteristic effects and do not allow any subliminal or toxic influence. The reaction times obtained with the usual working illumination of 15 lux represent in all cases the relative values. Comparing these relative values with the variations in reaction times produced by the different drugs,we checked the variation for their statistical significance. The arrows (t)indicate the statistically significant stimulant variation from the relative value; the black arrows (~) represent the depressive effect on the conditioned activity. The dot indicates that no statistically verified variation from the control values was observed.
included the following variable
~odeling
values: 1. the mean reaction time of the conditioned escape reflex, which, with certain reservations, represents a rough measure of the central nervous functional status actually existing; 2. the dose of the pharmacological agent; 3.
the intensity of light.
To describe the correlation between the doses of centrally acting drugs and different light intensities in conditioning experiments, we used a linear equation of the form R
As can be seen from the survey, identical doses of the above drugs produced with different light intensities different effects, which sometimes differed extremely from the characteristic effects or were even oppo sit e to it, as for example with caffeine doses of 10.0 and 20.0 mg/kg weight with an illumination of 1,000 lux. An examinati on of the effects shown in the table offers a separation of the applied drugs into situation-unstable drugs (caffeine, ethyl-crotyl-barbiturate, benactyzine) and situation-stable drugs (chlorpromazine and res e rpine).
=
b
l
(D)
+ b 2
(L)
+
a
and a logarithmic equation of the form R = bl
(In D)
+ bZ
(In L)
+
a
In these equations, we used R for the mean reaction time, 0 for the dose and L for the intensity of light. Calculation of the regression factors bl and b 2 and factor a was carried out in the usual way by the minimizing method for the square variations of the measured values from those to be taken from the equation. We obtained the mean reaction time from the measured values of the 15 responses produced by each animal of a group of 10 animals. The formation of mean values
429
i.a.; . croI,L.~ R. CU2s>(,.OJ-QI561,,"Ll·O.rul
R.5O',. .. R. 0.1701 Iu. OJ
.002"1'_ L) .1.26'1
o
"..... "
1l1ulllnaUoll 11; 1:1 OIg/kS 0_ .2 - 0.5 lx '.
...
•• Cl ( •• ~ )
.j:>
V' 0
5 ••
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10.0
C&!h1.ne
20.0
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5 ••
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)0.0
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1~.o
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15.0
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• .-
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Figure
Figure 2
-
Figure 3
\0<10
mean reaction times with increasing environmental brightness can be interpreted as an overstrain inhibition. The additive increase in excitation , as a result of an increase in the dose of caffeine, and the influence of the stronger afferentation of light on the central nervous system obviously overstrain the animals' adaptability, which still exist _ists in a darker situation. This conception seems to be reasonable, since the exciting effect of the drug manifests itself by a marked decrease in the mean reaction time -- as compared to the nor_ mal original value -- even in an almost dark situation of 0.35 lux . As a resul~ the model plan describes a correlation which, with doses and environmental illumination increasing, indicates a tendency of additive inhibition.
from normal and delayed reaction times supports, due to its continuous variability, the linear dependence of the model conception. The significance of correspondence of the mean measured values with the mean model value5 amounts to at least 98.5 per cent for numerical modeling and at least 99 . 6 p er cent for logarithmic modeling, which gives proof of the linear or logarithmic correlation between the size of dose and the intensity of light with regard to their influence on the conditioned reaction time . Logarithmic mode ling shows a favorable correspondence every time the intensities of light are chosen quasi-geometrically, with the doses being vari e d quasi-geometrically. Figure 2 demonstrates the modeling of the above relationships with regard to drugs which are sit uatim-unstable in their effe ct.
Numerical modeling comes within 99 . 9 per cent of the mean measured values, logarithmic mode ling comes within 99.6 per cent. These tendencies occurring with both an increase in the dose and the intensity of light can be statistically verified by the -test, s-method and variance analysis. The discrepancy of this reaction is underlined by an almost absolute inhomogeneity of the individual reaction time variations, which by far exceeds that relative to ethyl-crotylbarbiturate and benactyzine.
1. Ethyl-crotyl-barbiturate is a typical example of a correlative dependence between the size of dose and the intensity of light . Numerical modeling reveals a correspondence of 99.2 per cent with the mean measured values; logarithmic modeling - a correspondence of 99 . 9 per cent .. It is statistically verified that an increase in the dose results in a stronger sedative effect, while an increase in the intensity of light reduces this effect, as is shown in the statistics ..
Figure 3 demonstrates the modeling of situation-stable drugs.
This statement can be made despite the fact that inhomo !J!neity exists as is shown by the -test and the variance analysis, the latter demonstrating the animals' reaction times inter - individual= ly .
1. Inessential tendencies of the mean reaction times in different directions indicate the influence of light on the effect of reserpine. The increasing characteristic effects in the graph are a result of larger doses applied and can be significantly verified. Numerical and logarithmic mode ling reveals a correspondence with the measured values which is > 99 . 9 per cent .
2. With benactyzine, the correlative dependence is i n the main caused by the influence of light. Numerical modeling reveals a correspondence of 98.5 per cent with the mean reaction times, logarithmic modeli ng -- a correspondence of 99.9 per cent . While an increase in the dose results in a somewhat stronger sedative e f f e c t, a hi g her de g r e e 0 f i l l urn i n at i on of the environment leads to a marked decrease in the same. Both symptoms are statistically significant according to the -test, s-method and variance analysis. Benactyzine, too, does not produce homogeneous res JDnses in all animals, as was noted in relation to ethyl-crotylbarbi turate.
The animals frequently responded with different reaction times . 2. Chlorpromazine (aninazine), too, produces a situation-stable effect, since a · change in the mean reaction times is a mere result of changes in the dosage. This again was statistically verified by the -test, s-method and variance analysis. Correspondence with the numerical and l~arithmic model planes shows a probability which is > 99 . 9 per cent. The animals responded homogeneously - with a few exceptions only.
3 . With caffeine, the collective responses, in its dependence on the dose, reveals two different tendencies. With 5 mg/kg weight being applied, an increasing intensity of light results in an increase in excitation. Doses of 10.0 and 20.0 mg/kg weight seem to have the opposite effect, since a prolongation of the
Situation-labile drugs may be classified according to the regression coefficients of changes in optical afferentation, which represent the degree to which their effect can be influenced by afferentation;
431
Benact~zine seems to be most affected by different quantities of light.
Kaly-none's effect seems to be a little less dependent upon different light intensities. The effect of caffeine seems to be less dependent upon the Intensity of light than is the case with the two above drugs. The general relationships which were called for at the beginning in connection with a mean effect or a theoretically conceivable "mean-value organism" can be derived from the model plane, which is collectively vali d. Expected values of a third variable, with two known variables or varia bles selected at random, can be obtained by calculating isometric lines in the model plane. The latter gi ve the geome tri c locus of light intensities and dos a ge quotas of the same value which may lead to a certain central nervous response. Hence, the following quantities can be determined with the aid of the above straight lines: 1.
the mean reaction time which - with certain reservations - can be a rough measure of the actual status of reaction;
2.
the mean dose necessary to replace a certain effect of light, if the organi sn' s a ctual status of reaction is known;
3.
the mean intensity of light which possibly r epl aces a certain dose effect in a known status of reaction.
Since the use 0 f different light intensities is - as we learned - but one way to influence the effects of drugs by changing the functional status of the central nervous systen, our demonstration model cannot claim to be complex in a larger sense , unless other technically recordable quantities, which the exogeneous environment influencing the "milieu interieur" is composed of, are incorporated into it. To improve the model, we will present another paper which deals with the application of existing experimental data about the correlation between the effect of drug doses and different intensities of acoustic afferentation to our model. It can, however, be developed into a research model, if it is extrapolated in anyone direction and the obtained data are experimentally checked for their validity - always taking into account
432
subliminal doses, toxically acting components, etc., or if, on the basis of a comparison of the mean-value model with the individual model and on the basis of the animals' typological characteristics the way of response of an individual, whose typological characteristics are know, can be predicted.