nAChR agonist-induced cognition enhancement: integration of cognitive and neuronal mechanisms.
The identification and characterization of drugs for the treatment of cognitive disorders has been hampered by the absence of comprehensive hypotheses. Such hypotheses consist of (a) a precisely defined cognitive operation that fundamentally underlies a range of cognitive abilities and capacities and, if impaired, contributes to the manifestation of diverse cognitive symptoms; (b) defined neuronal mechanisms proposed to mediate the cognitive operation of interest; (c) evidence indicating that the putative cognition enhancer facilitates these neuronal mechanisms; (d) and evidence indicating that the cognition enhancer facilitates cognitive performance by modulating these underlying neuronal mechanisms. The evidence on the neuronal and attentional effects of nAChR agonists, specifically agonists selective for alpha4beta2* nAChRs, has begun to support such a hypothesis. nAChR agonists facilitate the detection of signals by augmenting the transient increases in prefrontal cholinergic activity that are necessary for a signal to gain control over behavior in attentional contexts. The prefrontal microcircuitry mediating these effects include alpha4beta2* nAChRs situated on the terminals of thalamic inputs and the glutamatergic stimulation of cholinergic terminals via ionotropic glutamate receptors. Collectively, this evidence forms the basis for hypothesis-guided development and characterization of cognition enhancers.
Sarter
Martin
M
Department of Psychology and Neuroscience Program, University of Michigan, Ann Arbor, MI 48109-1043, USA. msarter@umich.edu
Parikh
Vinay
V
Howe
William M
WM
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001288:Attention / Q000187:drug effects; D003071:Cognition / Q000187:drug effects* / Q000502:physiology; D003072:Cognition Disorders / Q000188:drug therapy / Q000503:physiopathology / Q000523:psychology; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D009415:Nerve Net / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018722:Nicotinic Agonists / Q000494:pharmacology* / Q000627:therapeutic use; D017397:Prefrontal Cortex / Q000187:drug effects / Q000502:physiology; D017470:Receptors, Glutamate / Q000502:physiology; D011978:Receptors, Nicotinic / Q000502:physiology*; D013788:Thalamus / Q000502:physiology
D018722:Nicotinic Agonists; D017470:Receptors, Glutamate; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; D018698:Glutamic Acid; D000109:Acetylcholine