Dopamine’s Actions in Primate Prefrontal Cortex: Challenges for Treating Cognitive Disorders

Arnsten, Amy F.T.; Wang, Min; Paspalas, Constantinos D.

doi:10.1124/pr.115.010512

Cited by 139 publications

(137 citation statements)

References 160 publications

(175 reference statements)

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“…Given that disruption of the excitation/inhibition balance in the PFC has been associated with many aforementioned psychiatric disorders such as schizophrenia (Krause et al, 2013; Lisman, 2012; Winterer and Weinberger, 2004; Yizhar et al, 2011) and ADHD (Moll et al, 2003; Pouget et al, 2009; Won et al, 2011), the individual actions as well as cooperative effects of both transmitters on synaptic transmission, intracellular signaling, and neuronal integration within immature and mature PFC circuitry are thus critical for the execution of prefrontal functions. How NE and DA, individually or synergistically, activate their respective receptors and the effects this on prefrontal functioning at the cellular, physiological, and behavioral level has been well-studied and reviewed in the past (Arnsten, 2011; Arnsten and Pliszka, 2011; Arnsten et al, 2015a; Arnsten et al, 2012b; Berridge and Waterhouse, 2003; Berridge and Arnsten, 2013; Brennan and Arnsten, 2008; Clark and Noudoost, 2014; Puig et al, 2014; Ramos and Arnsten, 2007; Seamans and Yang, 2004; Spencer et al, 2015; Tritsch and Sabatini, 2012). Nevertheless, recent compelling evidence demonstrates that the functional interaction between NE and DA exerts powerful biological effects by activating converging synaptic pathways in PFC circuitry; however this interaction has yet to be well characterized.…”

Section: The Roles Ne and Da Play In Regulating Prefrontal Synaptimentioning

confidence: 99%

Norepinephrine versus dopamine and their interaction in modulating synaptic function in the prefrontal cortex

2016

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Among the neuromodulators that regulate prefrontal cortical circuit function, the catecholamine transmitters norepinephrine (NE) and dopamine (DA) stand out as powerful players in working memory and attention. Perturbation of either NE or DA signaling is implicated in the pathogenesis of several neuropsychiatric disorders, including attention deficit hyperactivity disorder (ADHD), post-traumatic stress disorder (PTSD), schizophrenia, and drug addiction. Although the precise mechanisms employed by NE and DA to cooperatively control prefrontal functions are not fully understood, emerging research indicates that both transmitters regulate electrical and biochemical aspects of neuronal function by modulating convergent ionic and synaptic signaling in the prefrontal cortex (PFC). This review summarizes previous studies that investigated the effects of both NE and DA on excitatory and inhibitory transmissions in the prefrontal cortical circuitry. Specifically, we focus on the functional interaction between NE and DA in prefrontal cortical local circuitry, synaptic integration, signaling pathways, and receptor properties. Although it is clear that both NE and DA innervate the PFC extensively and modulate synaptic function by activating distinctly different receptor subtypes and signaling pathways, it remains unclear how these two systems coordinate their actions to optimize PFC function for appropriate behavior. Throughout this review, we provide perspectives and highlight several critical topics for future studies.

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Section: The Roles Ne and Da Play In Regulating Prefrontal Synaptimentioning

confidence: 99%

Norepinephrine versus dopamine and their interaction in modulating synaptic function in the prefrontal cortex

2016

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“…133,134 Similarly, either too little or too much DA D1R stimulation erodes delay cell firing. 135,136 High levels of both NE and DA are released in the PFC during stress, rapidly taking PFC “off-line” to switch control of behavior to more primitive circuits that mediate habitual responses 33 (Figure 1B). Thus, the stress-induced impairments in PFC neuronal firing and working memory performance can be mimicked by stimulating α 1-AR or D1R in PFC and can be prevented by blocking these receptors.…”

Section: Dynamic Network Connectivity Of Dlpfc Layer Iii: Unique Neurmentioning

confidence: 99%

Unique Molecular Regulation of Higher-Order Prefrontal Cortical Circuits: Insights into the Neurobiology of Schizophrenia

Datta

Arnsten

2018

ACS Chem. Neurosci.

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Schizophrenia is associated with core deficits in cognitive abilities and impaired functioning of the newly evolved prefrontal association cortex (PFC). In particular, neuropathological studies of schizophrenia have found selective atrophy of the pyramidal cell microcircuits in deep layer III of the dorsolateral PFC (dlPFC) and compensatory weakening of related GABAergic interneurons. Studies in monkeys have shown that recurrent excitation in these layer III microcircuits generates the precisely patterned, persistent firing needed for working memory and abstract thought. Importantly, excitatory synapses on layer III spines are uniquely regulated at the molecular level in ways that may render them particularly vulnerable to genetic and/or environmental insults. Glutamate actions are remarkably dependent on cholinergic stimulation, and there are inherent mechanisms to rapidly weaken connectivity, e.g. during stress. In particular, feedforward cyclic adenosine monophosphate (cAMP)-calcium signaling rapidly weakens network connectivity and neuronal firing by opening nearby potassium channels. Many mechanisms that regulate this process are altered in schizophrenia and/or associated with genetic insults. Current data suggest that there are “dual hits” to layer III dlPFC circuits: initial insults to connectivity during the perinatal period due to genetic errors and/or inflammatory insults that predispose the cortex to atrophy, followed by a second wave of cortical loss during adolescence, e.g. driven by stress, at the descent into illness. The unique molecular regulation of layer III circuits may provide a nexus where inflammation disinhibits the neuronal response to stress. Understanding these mechanisms may help to illuminate dlPFC susceptibility in schizophrenia and provide insights for novel therapeutic targets.

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“…It can be assessed with a number of tasks including the Stop-Signal Task (SST) and the Go/No-Go task (Eagle, Bari, & Robbins, 2008). Working memory refers to the ability to keep in mind an event that had just been experienced or to retrieve information from long-term memory storage and manipulate this information or use this information to regulate behavior (Arnsten, Wang, & Paspalas, 2015). There are many measures of working memory including auditory or visuo-spatial span tasks, which require information to be kept in mind while it is actively updated or manipulated.…”

Section: Diagnosis and Models Of Addictionmentioning

confidence: 99%

Cognitive Function as a Transdiagnostic Treatment Target in Stimulant Use Disorders

Sofuoglu

DeVito

Waters

et al. 2016

Journal of Dual Diagnosis

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Stimulant use disorder is an important public health problem, with an estimated 2.1 million current users in the United States alone. No pharmacological treatments are approved by the U.S. Food and Drug Administration (FDA) for stimulant use disorder and behavioral treatments have variable efficacy and limited availability. Most individuals with stimulant use disorder have other comorbidities, most with overlapping symptoms and cognitive impairments. The goal of this article is to present a rationale for cognition as a treatment target in stimulant use disorder, and to outline potential treatment approaches. Rates of lifetime comorbid psychiatric disorders among people with stimulant use disorders are estimated at 65% - 73%, with the most common being mood disorders (13% - 64%) and anxiety disorders (21% - 50%), as well as non-substance induced psychotic disorders (under 10%). There are several models of addictive behavior, but the dual process model particularly highlights the relevance of cognitive impairments and biases to the development and maintenance of addiction. This model explains addictive behavior as a balance between automatic processes and executive control, which in turn are related to individual (genetics, comorbid disorders, psychosocial factors) and other (craving, triggers, drug use) factors. Certain cognitive impairments, such as attentional bias and approach bias, are most relevant to automatic processes, while sustained attention, response inhibition, and working memory are primarily related to executive control. These cognitive impairments and biases are also common in disorders frequently comorbid with stimulant use disorder, and predict poor treatment retention and clinical outcomes. As such, they may serve as feasible trans-diagnostic treatment targets. There are promising pharmacological, cognitive, and behavioral approaches that aim to enhance cognitive function. Pharmacotherapies target cognitive impairments associated with executive control and include cholinesterase inhibitors (e.g., galantamine, rivastigmine) and monoamine transporter inhibitors (e.g., modafinil, methylphenidate). Cognitive behavioral therapy and cognitive rehabilitation also enhance executive control, while cognitive bias modification targets impairments associated with automatic processes. Cognitive enhancements to improve treatment outcomes is a novel and promising strategy, but its clinical value for the treatment of stimulant use disorder, with or without other psychiatric comorbidities, remains to be determined in future studies.

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Dopamine’s Actions in Primate Prefrontal Cortex: Challenges for Treating Cognitive Disorders

Cited by 139 publications

References 160 publications

Norepinephrine versus dopamine and their interaction in modulating synaptic function in the prefrontal cortex

Norepinephrine versus dopamine and their interaction in modulating synaptic function in the prefrontal cortex

Unique Molecular Regulation of Higher-Order Prefrontal Cortical Circuits: Insights into the Neurobiology of Schizophrenia

Cognitive Function as a Transdiagnostic Treatment Target in Stimulant Use Disorders

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