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Sunday, 17.11.2019

Thomas A. Ban: A brief historical exchange between Larry Stein and Joseph Knoll 


        Joseph Knoll (1925 – 2018), a Hungarian pioneer of neuropsychopharmacology,  published his text, The Theory of Active  Reflexes, An analysis  of Fundamental Mechanisms of Higher Nervous Activity, in 1969; his monograph on The Brain and Its Self, A Neurochemical Concept of Innate and Acquired Drives, in 2005; and his treatise on How Selegiline [(-Deprenyl} Slows Brain Aging, in 2013. His reviews on these three books were posted to INHN in “Books” on February 7, 2014; January 23, 2014; and November 26, 2915, respectively.

        Stein (1932-2019), an American pioneer of neuropsychopharmacology, and Knoll were working in somewhat similar areas of research. With Knoll’s 90th birthday approaching Stein was invited to comment on Knoll’s work and his comment was posted on September 18, 2014. Knoll replied to Stein’s comment without delay and his reply was posted on November 6, 2014   

        To provide self-contained information the following includes:

1.      Joseph  Knoll’s review of his The Theory of Active Reflexes

2.      Joseph Knoll’s review of his The Bran and Its Self

3.      Joseph Knoll’s review How Selegiline Slows Brian Aging

4.      Larry Stein’s comments on Joseph Knoll’s work

5.      Joseph Knoll’s reply to Larry Stein’s comments


1.     Joseph Knoll: The Theory of Active Reflexes. An Analysis of Some Fundamental Mechanism of Higher Nervous Activity

Budapest: Publishing House of the Hungarian Academy of Sciences; 1969

and New York:  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 special “active 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 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).


February 27 2014


2.     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 recapitulates 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. 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. 3.5. is a summary of therapeutic aspects of the synthetic enhancer substances. Chapter 4 approaches old problems from a new angle. 4.1. is a new interpretation of the substantial individual differences in behavioral performances. 4.2. is a new interpretation of forgetting, remembering, and boredom. Chapter 5 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. 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


3.     Joseph Knoll: How Selegiline Slows Brain Aging

Bentham e Books; 2012 (142 pages)


INFORMATION ON CONTENTS: (-)-Deprenyl/Selegiline (D), a phenylethylamine, is a levomethamphetamine derivative with a propargyl group  attached to the nitrogen atom. The substance is registered in 63 countries and marketed world-wide under more than 100 trade-names to treat Parkinson’s disease (PD), Alzheimer’s disease (AD) and major depressive disorder (MDD). D was developed in the early1960s, in the midst of the golden era when within less than 20 years the development of new families of pharmacological agents led to the science of  neuropsychopharmacology which changed the principles of behavioral studies in a revolutionary manner and radically altered human attitudes toward derangements in psychic function. This book looks back to the theoretical foundation of the development of D (Introduction). Chapter 1 briefly summarizes the “First Research Period (1960-1978)” when the drug achieved its place in research and therapy as the first selective inhibitor of B-type monoamine oxidase (MAO). Chapter 2 describes the discovery of the catecholaminergic activity enhancer (CAE) effect of D, and the development of R-(-)-1-(benzofuran-2-yl)-2-propylaminopentane (BPAP), the presently known most potent and selective enhancer substance which exerts this effect in femto-picomolar concentrations. Chapter 3 demonstrates that from weaning until sexual maturity an increased enhancer regulation operates in the catecholaminergic and serotonergic neurons. This mechanism is responsible for the exuberant physical strength and mental vigor in the uphill period of life in mammals. Sex hormones bring back the enhanced enhancer regulation to the pre-weaning level. This mechanism terminates developmental longevity and constitutes the foundation of the transition from adolescence to adulthood. Chapter 4 analyzes the antioxidant and neuroprotective effect of D and their relation to the enhancer effect. Chapter 5 analyzes the aging-related decline of dopaminergic activity and the reason why low dose of D slows brain aging and prolongs life. After analyzing the benefits of D in PD (Chapter 6), AD (Chapter 7) and MDD (Chapter 8), the unique quality of the enhancer substances compatible with lifelong preventive medication to slow brain aging is discussed (Chapter 9). Finally an Appendix summarizes the milestones in D research extracting the most significant papers of the several thousands published on D.


AUTHOR’S STATEMENT: The age-related decay in the supply of the brain with β-phenethylamine (PEA), due to the progressive increase of MAO-B activity in the aging brain, and dopamine, due to the better than average decline of the dopaminergic neuronal activity during the post-developmental phase of life, are biochemical lesions of aging. The speed of deterioration of behavioral performances with the passing of time and longevity depends significantly on the pace of these lesions. D increases the supply of PEA and dopamine in the brain and thereby counteracts the aging process. Our first longevity study has proven that male rats maintained on lifelong D preserved their learning ability longer, lost their ability to ejaculate later, and lived longer than their placebo-treated peers. Due to their CAE effect, D and BPAP, maintain the activity of the catecholaminergic neuronal system on a higher activity level. None of the types of drugs used today to increase catecholaminergic and/or serotonergic neuronal activity in the brain share with D or BPAP the enhancer effect. PEA-derived D and tryptamine-derived BPAP are synthetic analogues of physiological enhancer substances and act accordingly. The enhancer substances do not change the environmental milieu of the enhancer-sensitive neurons when administered in the specific enhancer dose-range. They are just changing the catecholaminergic neuron born with a lower excitability, to a better performing one. In our second longevity study we selected out of a population of 1,600 male rats the 94 sexually lowest performing (LP) males and the 99 highest performing (HP) rats. We treated 44 LP rats with saline and 50 HP rats with D. The saline-treated LP rats lived 134.58 (2.29) weeks, their D-treated peers lived 152.54 (1.36) weeks, as long as the selected saline-treated HP rats (151.24) (1.36 weeks). Thus maintenance on D transformed the low performing rats to high performing ones. Experimental and clinical studies with D strongly support the proposal that preventive administration of a synthetic enhancer substance during post-developmental life could significantly slow the unavoidable decay of behavioral performances with the passing of time, prolong life, and prevent or delay the onset of aging-related neurodegenerative diseases, such as PD and AD. Since D is at present the only worldwide registered CAE substance, in humans, implementation of a properly designed clinical trial on healthy volunteers to measure its anti-aging effect by maintaining subjects on the substance from sexual maturity may be warranted.


September 5, 2013


4.     Larry Stein’s comment on Joseph Knoll’s work

At the approach of Professor Joseph Knoll’s 90th birthday next year -- and honored to be asked to add a few words to the detailed commentaries of Dr. Miklya and others who worked with him -- I wish to underscore the contributions of this brilliant and courageous Jewish-Hungarian scientist to neuropsychopharmacology.

Why the emphasis on “Jewish-Hungarian scientist”?  I am recalling the five extraordinary Jewish-Hungarian scientists -- von Kármán, Szilard, Wigner, von Neumann, and Teller -- whose remarkable insights changed twentieth-century physics and made vital contributions to the defense of the free world in World War II (see I. Hargittai, “Martians of Science,” Oxford University Press, 2006). In neuroscience, too, Hungarian researchers have made historic contributions. Following University of California Irvine neurobiologist Ivan Soltesz (Trends Neurosci. Oct 2011; 34(10): 501–503), I could mention “Károly Schaffer (of ‘Schaffer collaterals’), Mihály Lenhossék (who introduced the term ‘astrocyte’), and János Szentágothai (whose numerous contributions include the recognition of the basis of lateral inhibition in the cerebellar cortex) and others” (p. 501). Might there be a special Hungarian gene pool which favors the scientific enterprise, one wonders, marked perhaps by a surplus of alleles for creativity and imagination?

Why ”courageous”? First, there is Knoll’s personal life story. As Dr. Miklya briefly indicates, he is an indomitable survivor of Auschwitz and Dachau. Secondly, I salute his intellectual valor.  It must have required unusual courage for Knoll -- in communist Hungary in the 1960s -- to depart from the traditions of Pavlovian reflexology and focus instead on the American behaviorist approaches of Thorndike and Skinner.  At an early point, Knoll thus recognized that goal-directed (operant) behavior provides a more fruitful target than the conditioned reflex for the scientific investigation of neurological and psychiatric illnesses and for therapeutic drug discovery.  In describing his neurobehavioral hypotheses, Knoll prefers the conceptual term "drive" to "reinforcement" (the term favored by Olds and myself, and later Crow, Koob, Wise and others, in our related work on brain self-stimulation and drug self-administration reward), but there is a common emphasis on brain catecholamines as decisive neurochemical facilitators of goal-directed actions. Interestingly, Knoll and I apparently conceived our catecholamine-facilitation hypotheses from the same pharmacological fact:  i.e., serendipitous observation of markedly augmented goal-directed behavior in rats following moderate doses of amphetamine or methamphetamine. (Curiously, because his drug doses and current levels always were too high, Olds initially reported only suppression of self-stimulation with amphetamine).

Finally, Professor Knoll and I share a rare speculative interest in a potential role for the largely-neglected “trace” amine, β-phenethylamine (PEA).  In typically daring fashion, Knoll hypothesizes that PEA serves as a critical “mesencephalic enhancer substance” for the regulation of many functions, including mood, learning and memory, sexual behavior, and even longevity (The Brain and Its Self, Springer, 2005, pp. 27-90). And indeed, consistent with his hypothesis, Knoll finds significant life-extending effects in rats chronically treated with selegiline [(-)-deprenyl], a drug he himself invented, which selectively inhibits the oxidative metabolism of PEA and dopamine. My own involvement with PEA is more empirical.  In 1964, I found that PEA, largely without effect by itself on brain self-stimulation or other operant behaviors, exerted a strong stimulant action indistinguishable from that of amphetamine when rats were pretreated with iproniazid or other inhibitors of monoamine oxidase (L. Stein, Fed. Proc.23, No. 4, 836-850). This key observation, together with complementary experiments utilizing the amine-depleter reserpine, established that amphetamine’s central actions are not exerted directly on brain catecholamine or serotonin receptors, as then was generally believed, but rather are mediated indirectly via the release “of a phenethylamine derivative (such as a catecholamine)” (Knoll’s How Selegiline Slows Brain Aging).


September 18, 2014


5.     Joseph Knoll’s reply to Larry Stein’s Comment on his work


I am thankful for your comments so rich in ideas. Let me just pick out the PEA problem which still deserves special attention. Thousands of papers have described and analyzed this trace amine in the mammalian brain classified as a releaser of catecholamines. Owing to the synthesis of amphetamine and methamphetamine, the long-acting PEA-derivatives in the 1930s, these compounds played a key role as special stimulants of the catecholaminergic brain engine. However, light was thrown only in the mid 1990s on the fact that PEA is primarily an endogenous catecholaminergic activity enhancer (CAE) substance and in very high concentrations only a releaser of catecholamines. Amphetamine and methamphetamine are PEA-derived CAE substances which, like their parent compound, are releasers of catecholamines. The CAE effect of PEA and the amphetamines remained undetected for decades because the catecholamine releasing effect concealed their detectability. Only the synthesis of (-)-deprenyl, the first PEA-derivative devoid of the catecholamine releasing property, made the CAE effect clearly visible. (-)-Deprenyl, still known as the first selective inhibitor of B-type MAO, blocks this enzyme in the brain of rats in a subcutaneous dose of 0.25 mg/kg and exerts its specific CAE effect in a subcutaneous dose of 0.001 mg/kg. (-)-Deprenyl paved the way for the development of (-)-BPAP, the most selective and most potent synthetic enhancer substance known, which stimulates enhancer-sensitive neurons in femto/picomolar concentrations and is the ideal pharmacological tool to detect hitherto unknown enhancer regulations in the mammalian brain. It is my ardent wish to provoke discussion of enhancer regulation, considering all angles of the question, and to move scientists to examine closely the soundness of the available data. I count upon your aid in this undertaking and I thank you for your appreciation of my work.


November 6, 2014

            October 31, 2019