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Saturday, 25.03.2017

Comment by Larry Stein

(on all three books by Joseph Knoll)

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)” (p.850).

Larry Stein

September 18, 2014