Positive Modulation of AMPA Receptors as a Broad-Spectrum Strategy for Treating Neuropsychiatric Disorders

Abstract

The invention of centrally active, positive modulators of AMPA-type glutamate receptors (“ampakines”) was prompted by the expectation that enhancing monosynaptic, fast excitatory post synaptic currents (EPSCs) would increase throughput in cortical networks and lower the threshold for induction of long-term potentiation (LTP), two events that could potentially enhance memory and cognition. Preclinical work has largely confirmed these various predictions and a small set of reports describe positive effects in humans. Later work raised the possibility that ampakines might have somewhat broader applications, a list that now extends from respiratory distress through autism, ADHD, depression, and schizophrenia. We here describe two general hypotheses to explain why ampakines might have therapeutic value with regard to disparate psychiatric illnesses. The first of these begins with the late nineteenth century idea that the cortex, in addition to its more traditionally understood functions, serves to regulate disturbances in lower brain systems. A version of this argument emerged in the 1950s as part of the intense research that followed on the discovery of links between the reticular formation in generating EEG and behavioral arousal. Various groups obtained evidence of a reticular–frontal cortical “loop” that served to modulate behavioral/physiological excitability. More recently, Carlsson and Carlsson expanded the loop concept to include brainstem biogenic amines; their model makes the explicit prediction that enhancing descending glutamatergic projections can be used to offset abnormal activity in the ascending dopaminergic system. Collectively, these theoretical positions point to the conclusion that positive modulation of cortical AMPA receptors should acutely reduce symptomology in disorders involving norepinephrine, dopamine, and serotonin. In accord with this assumption, ampakines depress high levels of arousal, counteract the effects of stimulants, and correct behavioral abnormalities in animal models of schizophrenia, ADHD, and depression. Work on humans is limited although recent evidence points to clinically meaningful improvements in ADHD. The second hypothesis grows out of two literatures, one defining the machinery that reorganizes the spine cytoskeleton so as to encode memory and the other suggesting that defects in these same cellular processes contribute to a surprisingly large number of disorders involving memory and cognition. With regard to the present chapter, these observations are united by the discovery that a potent regulator of cytoskeleton reorganization (Brain-Derived Neurotrophic Factor: BDNF) is up-regulated by ampakines. The possibility thus arises that daily treatments with the drugs could be used to drive structural changes otherwise blocked by any of several genetic or behavioral conditions. Tests of this argument have so far been limited to animal models but the results are encouraging. Daily treatments with a short half-life ampakine that increases cortical BDNF concentrations restored synaptic plasticity in middle-aged rats and in mice carrying the Huntington’s disease mutation. In the latter case, normalization of structural and physiological plasticity was accompanied by marked improvements in learning. Collectively, the results subsumed under the two hypotheses have to be viewed as remarkable: a class of drugs that has a single biophysical target produces positive changes of unprecedented breadth. But ampakines are still a recent invention arising from ideas in basic neuroscience. Whether the observed effects in animals actually relate to the two hypotheses remains to be formally tested and, above all else, there stands the absence of data from extensive clinical trials.