Biphasic effects of 5-HT1A agonism on impulsive responding are dissociable from effects on anxiety in the variable consecutive number task

Groft, Miranda L; Normann, Marigny C; Nicklas, Paige R.; Jagielo-Miller, Julia E.; McLaughlin, Peter

doi:10.1007/s00210-019-01684-5

Cited by 8 publications

(3 citation statements)

References 43 publications

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“…It is suggested here that determining the conditions under which these modulators exhibit u-shaped or Janus-faced properties, including at a molecular or receptor level, is an open question for future experimental investigation. There are already some studies suggesting u-shaped or Janus-faced relationships for all five neuromodulators described here [ 26 , 31 , 32 , 71 , 72 , 73 , 74 , 75 , 76 ].…”

Section: U-shaped or Janus-faced Dose-response Curvesmentioning

confidence: 88%

Norepinephrine May Oppose Other Neuromodulators to Impact Alzheimer’s Disease

Fitzgerald

2021

IJMS

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While much of biomedical research since the middle of the twentieth century has focused on molecular pathways inside the cell, there is increasing evidence that extracellular signaling pathways are also critically important in health and disease. The neuromodulators norepinephrine (NE), serotonin (5-hydroxytryptamine, 5HT), dopamine (DA), acetylcholine (ACH), and melatonin (MT) are extracellular signaling molecules that are distributed throughout the brain and modulate many disease processes. The effects of these five neuromodulators on Alzheimer’s disease (AD) are briefly examined in this paper, and it is hypothesized that each of the five molecules has a u-shaped (or Janus-faced) dose-response curve, wherein too little or too much signaling is pathological in AD and possibly other diseases. In particular it is suggested that NE is largely functionally opposed to 5HT, ACH, MT, and possibly DA in AD. In this scenario, physiological “balance” between the noradrenergic tone and that of the other three or four modulators is most healthy. If NE is largely functionally opposed to other prominent neuromodulators in AD, this may suggest novel combinations of pharmacological agents to counteract this disease. It is also suggested that the majority of cases of AD and possibly other diseases involve an excess of noradrenergic tone and a collective deficit of the other four modulators.

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Section: U-shaped or Janus-faced Dose-response Curvesmentioning

confidence: 88%

Norepinephrine May Oppose Other Neuromodulators to Impact Alzheimer’s Disease

Fitzgerald

2021

IJMS

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“… Blue and orange shading represent directionality (decreased or increased, respectively) of receptor activation effects on reward-related behaviors and impulsive action. 1 Balleine et al (1996) , 2 Fletcher et al (1993) , 3 Fletcher et al (1995) , 4 Groft et al (2019) , 5 Miyazaki et al (2012) , 6 Korte et al (2017) , 7 Harrison et al (1999b) , 8 Desrochers et al (2021) , 9 Acosta et al (2005) , 10 Fletcher et al (2002) , 11 Pattij et al (2003) , 12 Frick et al (2015) , 13 Fletcher et al (2017) , 14 Koskinen et al (2000a) , 15 Silveira et al (2020) , 16 Talpos et al (2006) , 17 Fletcher et al (2007) , 18 Doly et al (2009) , 19 Goldman et al (2010) , 20 Fletcher and Higgins (1997) , 21 Roger-Sánchez et al (2013) , 22 Kelley and Hodge (2003) , 23 Rodd-Henricks et al (2003) , 24 Rompré et al (1995) , 25 Higgins et al (1992) , 26 Reavill et al (1998) , 27 Mitchell et al (2007) , 28 Brodsky et al (2016) , 29 Ferguson et al (2008) , 30 Valentini et al (2013) , 31 da Silva et al (2018) , and 32 de Bruin et al (2013) . …”

Section: Introductionmentioning

confidence: 99%

A Role for Serotonin in Modulating Opposing Drive and Brake Circuits of Impulsivity

Desrochers

Spring

Nautiyal

2022

Front. Behav. Neurosci.

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Impulsivity generally refers to a deficit in inhibition, with a focus on understanding the neural circuits which constitute the “brake” on actions and gratification. It is likely that increased impulsivity can arise not only from reduced inhibition, but also from a heightened or exaggerated excitatory “drive.” For example, an action which has more vigor, or is fueled by either increased incentive salience or a stronger action-outcome association, may be harder to inhibit. From this perspective, this review focuses on impulse control as a competition over behavioral output between an initially learned response-reward outcome association, and a subsequently acquired opposing inhibitory association. Our goal is to present a synthesis of research from humans and animal models that supports this dual-systems approach to understanding the behavioral and neural substrates that contribute to impulsivity, with a focus on the neuromodulatory role of serotonin. We review evidence for the role of serotonin signaling in mediating the balance of the “drive” and “brake” circuits. Additionally, we consider parallels of these competing instrumental systems in impulsivity within classical conditioning processes (e.g., extinction) in order to point us to potential behavioral and neural mechanisms that may modulate the competing instrumental associations. Finally, we consider how the balance of these competing associations might contribute to, or be extracted from, our experimental assessments of impulsivity. A careful understanding of the underlying behavioral and circuit level contributions to impulsivity is important for understanding the pathogenesis of increased impulsivity present in a number of psychiatric disorders. Pathological levels of impulsivity in such disorders are likely subserved by deficits in the balance of motivational and inhibitory processes.

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“…This may be a surprising finding since a number of the monoaminergic theories of MDD suggest that elevated monoamines should produce mania or hypomania (Schildkbaut, 1965 ; Coppen, 1967 ; Janowsky et al, 1972 ), and by inference transmission reducing drugs may have mood-stabilizing properties but not necessarily be antidepressants. However, a growing body of evidence suggests that endogenous serotonin, NE, and dopamine have u-shaped or Janus-faced dose-response properties for a range of behaviors, wherein too much or too little signaling may be pathological (Baldi and Bucherelli, 2005 ; Arnsten, 2007 ; Vijayraghavan et al, 2007 ; Giustino et al, 2016 ; Giustino and Maren, 2018 ; Groft et al, 2019 ). In this scenario, perhaps a non-optimal (i.e., decreased or elevated) synaptic concentration of each monoamine may result in MDD, at least in some individuals with the disorder.…”

Section: Introductionmentioning

confidence: 99%

Are Noradrenergic Transmission Reducing Drugs Antidepressants?

Fitzgerald

2021

Front. Behav. Neurosci.

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Major depressive disorder (MDD) remains a significant public health problem worldwide, and revised treatment strategies are therefore urgently needed, including the creation of novel antidepressant compounds or using existing molecular entities in new ways. Etiologic theories of MDD from decades ago have suggested that synaptic deficiencies of monoaminergic neurotransmitters play a causative role in this neuropsychiatric disorder, and that boosting monoamines with drugs such as SSRIs, SNRIs, TCAs, and MAOIs has antidepressant effects and in some individuals can even induce hypomania or mania. While other factors, such as various intracellular molecular pathways and hippocampal neurogenesis, undoubtedly also play a role in MDD, monoaminergic boosting drugs nonetheless have clearly demonstrated antidepressant properties. There is also, however, a body of studies in the preclinical literature suggesting that monoaminergic transmission reducing drugs, including noradrenergic ones, also have antidepressant-like behavioral properties in rodents. Given that there is increasing evidence that the monoamines have u-shaped or Janus-faced dose-response properties, in which a mid-range value is “optimal” in a variety of behavioral and physiological processes, it is plausible that either too much or too little synaptic norepinephrine in key circuits may exacerbate MDD in some individuals. Here we briefly review rodent depression-related behavioral data, focusing on the forced swim test, from three major classes of noradrenergic transmission reducing drugs (alpha2 agonists, beta blockers, alpha1 antagonists), and find much support for the hypothesis that they have antidepressant-like properties. Whether these drugs are antidepressants in human subjects remains to be determined.

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Biphasic effects of 5-HT1A agonism on impulsive responding are dissociable from effects on anxiety in the variable consecutive number task

Cited by 8 publications

References 43 publications

Norepinephrine May Oppose Other Neuromodulators to Impact Alzheimer’s Disease

Norepinephrine May Oppose Other Neuromodulators to Impact Alzheimer’s Disease

A Role for Serotonin in Modulating Opposing Drive and Brake Circuits of Impulsivity

Are Noradrenergic Transmission Reducing Drugs Antidepressants?

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