Modulators in concert for cognition: Modulator interactions in the prefrontal cortex

Abstract

Research on the regulation and function of ascending noradrenergic, dopaminergic, serotonergic, and cholinergic systems has focused on the organization and function of individual systems. In contrast, evidence describing co-activation and interactions between multiple neuromodulatory systems has remained scarce. However, commonalities in the anatomical organization of these systems and overlapping evidence concerning the post-synaptic effects of neuromodulators strongly suggest that these systems are recruited in concert; they influence each other and simultaneously modulate their target circuits. Therefore, evidence on the regulatory and functional interactions between these systems is considered essential for revealing the role of neuromodulators. This postulate extends to contemporary neurobiological hypotheses of major neuropsychiatric disorders. These hypotheses have focused largely on aberrations in the integrity or regulation of individual ascending modulatory systems, with little regard for the likely possibility that dysregulation in multiple ascending neuromodulatory systems and their interactions contribute essentially to the symptoms of these disorders. This review will paradigmatically focus on neuromodulator interactions in the PFC and be further constrained by an additional focus on their role in cognitive functions. Recent evidence indicates that individual neuromodulators, in addition to their general state-setting or gating functions, encode specific cognitive operations, further substantiating the importance of research concerning the parallel recruitment of neuromodulator systems and interactions between these systems.

Sensorimotor Gating is Associated with CHRNA3 Polymorphisms in Schizophrenia and Healthy Volunteers

“…Given that schizophrenia patients display PPI deficits, that PPI and symptom severity are modulated by CHRNA3 polymorphisms, and that the nAChR system is an important neuromodulator, a future promising target of schizophrenia research might be the development of new medications for treating schizophrenia or at least cognitive deficits in schizophrenia, which affect the a3 subunits of the nAChR in the central nervous system. It is possible that abnormally reactive cholinergic responsivity is sufficient to cause an altered dopaminergic transmission (Briand et al, 2007), hence stabilizing the cholinergic system should also regulate the dopaminergic system that is well-known to be affected in schizophrenia (Howes and Kapur, 2009). A measure of sensory gating is the suppression of the auditory-evoked potential P50 response to repeated stimuli (for a review, see Turetsky et al, 2007).…”

Stress, genotype and norepinephrine in the prediction of mouse behavior using reinforcement learning

“…Notably, DBA/2 mice, whose reward discount factors were lower than those of C57BL/6 mice, are known to have reduced expression of D2 receptors in nucleus accumbens 35 . As neuromodulatory systems are known to interact with each other 36 , the effect of norepinephrine increase on future reward discounting may not be direct, but may instead be mediated through interactions with other neuromodulators, such as serotonin and dopamine.…”

Reboxetine Enhances the Olanzapine-Induced Antipsychotic-Like Effect, Cortical Dopamine Outflow and NMDA Receptor-Mediated Transmission

“…Moreover, glutamate, the excitatory transmitter in cortical pyramidal cells, is involved in higher mental functions, such as cognition, memory and learning, and a glutamatergic synaptic hypofunction in schizophrenia seems indicated (see Coyle et al, 2003), a notion recently supported by the demonstration of a reduced prefrontal expression of the N-methyl-D-aspartate (NMDA) receptor subunits NR1, NR2A and NR2C in schizophrenic patients (Beneyto and Meador-Woodruff, 2008). In addition, several other transmitter systems are in all probability involved in the control of cognitive functions (see Briand et al, 2007), as well as in the pathophysiology of schizophrenia, such as the catecholaminergic systems, because elevation of central noradrenergic and secondarily dopaminergic activity, for example, by administration of a 2 -adenoreceptor antagonists, has been shown to improve working memory, as well as attention, learning and memory in rodents (Lapiz and Morilak, 2006;Sara and Devauges, 1989).…”