فيل سكولنيك

In 1981, Skolnick and colleague Steven M. Paul characterized the mechanism of action of benzodiazepines, showing that they act by modifying the efficacy of the brain's primary inhibitory neurotransmitter, GABA.^[7] The following year, Skolnick and Paul, among other collaborators, showed that mammalian brain tissue contains endogenous ligands of the benzodiazepine receptor, some of the first evidence of so-called endozepines.^[4][8]

In 1985, not long after becoming section chief of NIDDK's neurobiology lab,^[1] Skolnick and colleagues published work helping to characterize the mechanism of action of barbiturates,^[9] which function as positive allosteric modulators at the GABA_A receptor—a mechanism of action they share with benzodiazepines. Later, inspired by similarities between the electroencephalographic signatures associated with hepatic coma and benzodiazepine-induced coma, Skolnick hypothesized that impaired metabolism of endogenous benzodiazepine receptor ligands may play a role in producing the symptoms of hepatic encephalopathy. This hypothesis was borne out by experimental research, where it was shown that benzodiazepine receptor antagonists can temporarily alleviate some of the cognitive symptoms of fulminant hepatic failure.^[10][11]

By the late 1980s, it was known that certain types of stress induce a behavioral profile in animals that bears a strong resemblance to the symptoms of clinical depression, and that symptoms in this experimental model respond to antidepressants such as SSRIs. This depression-like effect arises, in part, through prolonged stimulation of the NMDA subtype of the glutamate receptor.^[3] This led Skolnick and colleagues to discover in 1990 that inhibition of activity at the NMDA receptor (NMDAr) can prevent the development of this depression-like behavior, suggesting NMDA receptor antagonists—such as ketamine—as novel antidepressant therapies.^[3]

في عام 1996، وضع سكولنيك وأحد طلابه في مرحلة ما بعد الدكتوراه، أنتوني باسيل، فرضية مفادها أن النشاط غير المباشر للمضادات الحيوية من فئة الأمينوغليكوزيدات ، والتي لديها أيضًا القدرة على الارتباط بمستقبلات NMDA، قد يكون مسؤولاً عن الآثار الجانبية السامة للأذن غير المرغوب فيها لهذه الأدوية. وقد أثبت سكولنيك وباسيل هذه الفرضية من خلال مواجهة الآثار السامة للأذن للأمينوغليكوزيدات باستخدام مضاد لمستقبلات NMDA. ^{[ 1 ]}