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

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

Chapter I. The basic principals 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 how to fix a special acquired urge, the “glass-cylinder-seeking drive”, into 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 on 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 arrives to an intensity resulting in aimless hypermotility, which blocks 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).

Joseph Knoll

February 27 2014