Thomas A. Ban
Neuropsychopharmacology in Historical Perspective.

Education in the field in the Post-Psychopharmacology Era

Collated 23

Joseph Knoll: From the Theory of Active Reflexes to a Neurochemical Concept of Innate and Acquired Drive



1. The Theory of Active Reflexes. An Analysis of Some Fundamental Mechanism of Higher Nervous Activity. Budapest/New York: Publishing House of the Hungarian Academy of Sciences/Hafner Publishing Company; 1969.

2. The Brain and Its Self. A Neurochemical Concept of the Innate and Acquired Drives. Berlin: Springer; 2005.


Joseph Knoll: The Theory of Active Reflexes. An Analysis of Some Fundamental Mechanism of Higher Nervous Activity. Budapest/New York: Publishing House of the Hungarian Academy of Sciences/Hafner Publishing Company; 1969 (131 pages) 

INFORMATION ON CONTENTS: This monograph was a trial to analyze drive-motivated goal-directed psychic activity, perceived as a specialactive reflex.” It is divided into seven chapters.

Chapter I. The basic principles of the theory of the active reflexes. A special stimulus (A) induces and maintains an “excitatory focus” (“active focus”) (A), which is regulating and programming general activity, a chain of “orientatory-searching reflexes,” elicited and maintained by the given environment. This chain persists until the goal (B) is reached, which results in the disappearance of the “active focus” as well as of all its consequences.

Chapter II. Experimental proof of food-seeking activity being an unconditioned active reflex.

Chapter III. Experimental analysis of an avoidance reaction being an unconditioned “active reflex.”

Chapter IV. Experimental analysis of “cylinder-seeking” activity being a conditioned active reflex. The technique for how to fix a special acquired urge, the “glass-cylinder-seeking drive,” in the brain of rats is presented in this chapter. Based on an unconditioned avoidance reflex (escape from a hot plate) and using the sound of a shrill bell to play the role of  conditioned stimulus, rats were trained to search for a 30-cm-high glass cylinder and jump to the rim of it. The cylinder was open at the bottom and top with diameters of 16 cm and 12 cm, respectively, and with a side opening through which a rat (up to 350-400 g body weight) could manage to get inside the cylinder. In the training procedure, the rat was ushered through the side opening of the glass-cylinder to a metal plate heated to 60°C and the jumping reflex was elicited for a couple of weeks, three times daily on 10-50 occasions at 10s intervals with bell and heat stimulation. An extinguishable conditioned reflex (ECR) is transiently developing and after a short training period, a chain of inextinguishable conditioned reflexes (ICRs) developed and the rat displayed indefatigably the jumping reflex without heat stimulation, even as much as 100 times in succession. This was a transient stage, which led to the manifestation of the glass-cylinder-seeking drive. The rats that performed best in this study acquired the glass-cylinder-seeking drive in a stable manner thereafter maintaining this unnatural urge for a lifetime. The rats showed the same high-grade adaptability and readiness in overcoming different obstacles during goal-attainment as the ones influenced by innate drives, such as hunger or sexual desire. In the most efficiently trained, best performing rats, the acquired drive was so powerful that it prevailed over life-important innate drives. When such a rat has been deprived of food for 48 hours and then food was offered within the usual setup that contained the glass cylinder, the rat looked for the glass-cylinder and left the food untouched. Similarly, when a receptive female was offered to a fully sexually active glass-cylinder-seeking male rat in the usual setup, the male looked for the glass cylinder and neglected the receptive female. The mouse, a rodent closely related to the rat, trained under the same experimental conditions as the rat, was unable to acquire the glass-cylinder-seeking drive.

Chapter V. Temporary connections in the light of the active reflex. The main novel finding in this Chapter was the demonstration of the difference between EEG records of untrained rats and rats trained using the sound of a bell as a conditioned stimulus, to build an extinguishable or an inextinguishable conditioned reflex (ECR or ICR, respectively). The effect of 20 min continuous bell ringing on the EEG arousal reaction was examined. In the untrained rat, when the bell ringing started – a new stimulus! – desynchronization, i.e., excitation of the non-specific activation system, set in. This state lasted for a short period; after habituation to the stimulus, synchronized cortical activity was restored. In the rats with ECR, habituation after EEG arousal set in at practically the same rate as in the untrained controls. However, in the rats with ICR, the bell had a lasting capacity to cause excitation in the non-specific activation system.

Chapter VI. Inhibitory processes in the light of the active reflexes. In our studies with glass-cylinder-seeking rats, we saw that once the animals manifested the acquired drive they searched for the glass cylinder repeatedly and for long periods of time without any signs of trouble. As time passed, however, tedious repetitions of glass cylinder search efforts in an unchanged environment led to a peculiar behavioral modification. The phenomenon, strikingly reminiscent to boredom, appeared in rats that were compelled, after the acquisition of the glass-cylinder-seeking drive, to search for the glass cylinder at least 20 times a day in an unchanged environment for a longer period of time. As a consequence of this form of training, the characteristic change in behavior was already observable in some of the well-performing rats within 3-4 weeks, though with the others, months passed until the phenomenon appeared. As soon as we changed the environment where the animal lingered a long time, the rat started immediately working with the highest intensity. We never observed the phenomenon reminiscent of “boredom” in connection with innate drives, where the inexhaustible mesencephalic neurons keep the cortical neurons active. It, therefore, seems that tedious repetitions of glass cylinder searches with 30s intervals in an unchanged environment sooner or later lead to the decline of  the specific stimulation-induced enhanced excitability in the sensitive group of cortical neurons (active focus) responsible for regulating and programming general activity of the glass-cylinder-seeking behavior until the goal is reached.  

Chapter VII. Influence of drugs on the activation process of the central nervous system. We found conspicuous differences in sensitivity to drugs between the extinguishable and inextinguishable conditioned reflexes. The ECR was readily inhibited by sedative-hypnotics and neuroleptic agents; the ICR displayed selective sensitivity to neuroleptics.  On the other hand, we found that 2 mg/kg amphetamine enhances significantly the ability of the rat to build a conditioned reflex.

AUTHOR’S STATEMENT:  In the late 1950s, the careful analysis of the nature and physiological significance of the acquired drives called my attention to the catecholaminergic brain engine which plays the key role in the activation of the cortex. In case I needed to stimulate the catecholaminergic neurons, I used necessarily the best disposable experimental tools: the long-acting b-phenylethylamine (PEA)-derivatives, amphetamine and methamphetamine. My problem with the amphetamines was that as soon as the dose surpassed the 1-2 mg/kg level, the drug-induced continuous, irresistible release of catecholamines from their intraneuronal stores in the brainstem neurons reached an intensity resulting in aimless hypermotility, which blocked purposeful behavior.  In the early 1960s, monoamine oxidase (MAO) inhibitors represented a new type of central stimulation, so I decided to start the structure-activity-relationship study with methamphetamine containing a propargyl-group attached to the nitrogen. This group was known to form a covalent binding with the flavin in MAO and block the enzyme irreversibly. Out of a series of newly synthesized patentable methamphetamine derivatives, E-250 (later named deprenyl) was selected as the most suitable. (-)-Deprenyl (Selegiline) is now a drug used worldwide to treat Parkinson’s disease (PD), Alzheimer’s disease (AD) and major depressive disorder (MDD).


February 27, 2014

Joseph Knoll: The Brain and Its Self. A Neurochemical Concept of the Innate and Acquired Drives. Berlin: Springer; 2005 (176 pages).

INFORMATION ON CONTENTS: The Introduction and Chapter 1 recapitulate the main conclusion of the 16-year research period summarized in a monograph (Knoll: The Theory of Active Reflexes, 1969). The first monograph was based on the discovery that the manipulability of the behavior of highly developed mammals depends on the ability of their cortex to fix acquired drives, unusual urges that in contrast to the innate drives are unnecessary to the survival of the individual or the species. The present book is a summary of the results and conclusions of the following 36-year research period. Chapter 2 is a brief summary of the conception that whatever humans achieved derives from the unrestricted capacity of their brain to acquire drives.  Chapter 3, an analysis of the operation of the enhancer regulation, is a summary of the results of a neurochemical approach to the innate and acquired drives in five parts: 3.1. defines the enhancer regulation; describes b-phenylethylamine (PEA) and tryptamine as endogenous enhancers of the catecholaminergic and serotonergic neurons; shows the role of (-)-deprenyl in the discovery of the enhancer regulation in the catecholaminergic neurons; analyses (-)-deprenyl as the PEA-derived enhancer substance and R-(-)-1-(benzofuran-2yl)-2-propylaminopentane [(-)-BPAP] as the tryptamine-derived enhancer substance; 3.2. describes (-)-BPAP as the specific experimental tool to detect the specific and non-specific form of enhancer regulation; 3.3. is a consideration about enhancer receptors; 3.4. is an assumption about the physiological significance of cortical enhancer regulation; thoughts about its role in the modification of behavior through exercise, training or practice; and brief summary of an experiment supporting the concept that learning is a cortical enhancer regulation dependent function; and 3.5. is a summary of therapeutic aspects of the synthetic enhancer substances. Chapter 4, in two parts, approaches old problems from a new angle: 4.1. is a new interpretation of the substantial individual differences in behavioral performances and 4.2. is a new interpretation of forgetting, remembering and boredom. Chapter 5, also in two parts, analyses theoretical aspects of the enhancer regulation approach: 5.1. describes the simultaneous coexistence of determinants of order and chaos in the human brain and its role in the origin of science and art and 5.2. emphasizes the timeliness of the conception of the enlightenment: sapere aude (dare to go independently).

AUTHOR’S STATEMENT: The purposeful manipulation of the human brain (domestication) is the sine qua non for the establishment and maintenance of a community. The billions who remained during the history of mankind untouched by their wartime killings of the masses of their innocent peers and were ready to die in the name of “God,” “fatherland” and so on illustrate the consequences of the practically unlimited capacity of the human brain to fix acquired drives. Even in the dark history of mankind, the Holocaust – the extermination of millions within a few years with unprecedented success, due to a systematically planned and executed evil mass manipulation of a whole nation – was a unique event. This horrifying recent example testifies to the fact that the potential to misuse the physiological endowments of the human cortex is practically unlimited. Since the human being, a building block in the creation of the most gigantic product on earth: human society, was born with a brain capable to create a non-existing world, Homo sapiens created necessarily a myths-directed society, which is still in the trial-and-error phase of its development and seeks  to arrive at the final state a rationally organized human society. Only a global change of education based fully on the exact knowledge of the brain mechanisms that enable the manipulation of individuals can lead, at some point in the future, to the desired rationally directed society.


January 23, 2014

            March 19, 2020