Stimulation of nAChRs has been widely suggested as a new approach to treat the cognitive symptoms of a range of disorders. Our current model postulates two separate modes of cholinergic neurotransmission. First, a tonic component (changes over minutes; measured by microdialysis) of cholinergic activity modulates the gain of thalamic input processing, via stimulation of α4β2* nAChRs expressed by thalamic afferents. Second, cue-evoked glutamate release from thalamic afferents generates transient (seconds) increases in acetylcholine (ACh) release (measured by amperometry and enzyme-coated microelectrodes). Glutamatergic and cholinergic transients interact to enhance the probability and efficacy of cue detection. The tonic component of cholinergic activity is hypothesized to modulate the general readiness for cortical input processing (or “arousal”), by modulating the “neuronal salience” of the cue. The present experiments were designed to specify the regulation and role of the tonic component of cholinergic neurotransmission. To this end, we studied the behavioral/cognitive and cholinergic effects of the selective α7 nAChR agonist ABT-107, known to evoke lasting increases in tonic cholinergic activity in naïve animals, and the selective α4β2* nAChR agonist ABT-089, known to augment cholinergic transients in animals detecting cues. In animals conditioned to a simple arousing stimulus (darkness+palatable food), administration of ABT-107, but not ABT-089 increased basal and augmented stimulus-evoked increases in ACh release and increased exploratory activity. ABT-107 did not affect sustained attention performance, (SAT)-associated increases in ACh release and mildly impaired performance. ABT-089 enhanced SAT performance in non-tethered animals while lowering performance-associated increases in ACh release. These results suggest that the “arousal”-enhancing effects of increases in tonic cholinergic activity are restricted to situations devoid of behavioral/cognitive constraints. Tonic cholinergic activity supports both spontaneous and cognitive performance; however, tonic cholinergic activity is tightly regulated in cognitive contexts. In cognitive contexts, tonic activity levels are protected against pharmacological manipulation, as indicated by the absence of effects of ABT-107 in SAT performing animals and by reducing cholinergic tone in the presence of an α4β2* nAChR agonist. Finally, the two component of cholinergic activity do not necessarily co-vary, and that drug effects on cholinergic activity in naïve animals do not predict effects on cognitive performance-mediating cholinergic neurotransmission.
Multiple modes of cholinergic neurotransmission - Multiple functions
Paolone GConceptualization
;
2010-01-01
Abstract
Stimulation of nAChRs has been widely suggested as a new approach to treat the cognitive symptoms of a range of disorders. Our current model postulates two separate modes of cholinergic neurotransmission. First, a tonic component (changes over minutes; measured by microdialysis) of cholinergic activity modulates the gain of thalamic input processing, via stimulation of α4β2* nAChRs expressed by thalamic afferents. Second, cue-evoked glutamate release from thalamic afferents generates transient (seconds) increases in acetylcholine (ACh) release (measured by amperometry and enzyme-coated microelectrodes). Glutamatergic and cholinergic transients interact to enhance the probability and efficacy of cue detection. The tonic component of cholinergic activity is hypothesized to modulate the general readiness for cortical input processing (or “arousal”), by modulating the “neuronal salience” of the cue. The present experiments were designed to specify the regulation and role of the tonic component of cholinergic neurotransmission. To this end, we studied the behavioral/cognitive and cholinergic effects of the selective α7 nAChR agonist ABT-107, known to evoke lasting increases in tonic cholinergic activity in naïve animals, and the selective α4β2* nAChR agonist ABT-089, known to augment cholinergic transients in animals detecting cues. In animals conditioned to a simple arousing stimulus (darkness+palatable food), administration of ABT-107, but not ABT-089 increased basal and augmented stimulus-evoked increases in ACh release and increased exploratory activity. ABT-107 did not affect sustained attention performance, (SAT)-associated increases in ACh release and mildly impaired performance. ABT-089 enhanced SAT performance in non-tethered animals while lowering performance-associated increases in ACh release. These results suggest that the “arousal”-enhancing effects of increases in tonic cholinergic activity are restricted to situations devoid of behavioral/cognitive constraints. Tonic cholinergic activity supports both spontaneous and cognitive performance; however, tonic cholinergic activity is tightly regulated in cognitive contexts. In cognitive contexts, tonic activity levels are protected against pharmacological manipulation, as indicated by the absence of effects of ABT-107 in SAT performing animals and by reducing cholinergic tone in the presence of an α4β2* nAChR agonist. Finally, the two component of cholinergic activity do not necessarily co-vary, and that drug effects on cholinergic activity in naïve animals do not predict effects on cognitive performance-mediating cholinergic neurotransmission.
I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
