Actions of α-2 noradrenergic agonists on spatial working memory and blood pressure in rhesus monkeys appear to be mediated by the same receptor subtype

Franowicz, Jenna S; Arnsten, Amy F.T.

doi:10.1007/s00213-002-1110-6

Cited by 25 publications

(12 citation statements)

References 39 publications

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“…Indeed, the same knockdown of DISC1 in rat PFC used in the present study has now been shown to lower the threshold for stress-induced working memory deficits (19), consistent with the altered PFC physiology observed in the current study. Moreover, our results showing that reducing cAMP with guanfacine rescues pyramidal cell function in DISC1 compromised neurons are consistent with numerous reports showing that guanfacine improves working memory in rats (60, 62) monkeys (41, 60, 63–66) and humans (67–70) through inhibition of cAMP signaling in the PFC (41, 60). Taken together, these findings provide a plausible mechanism for working memory deficits observed in mice and humans in which DISC1 is impaired (2, 71).…”

Section: Discussionsupporting

confidence: 92%

Disrupted in Schizophrenia 1 Modulates Medial Prefrontal Cortex Pyramidal Neuron Activity Through cAMP Regulation of Transient Receptor Potential C and Small-Conductance K+ Channels

El-Hassar¹,

Simen²,

Duque³

et al. 2014

Biological Psychiatry

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Background Disrupted in Schizophrenia 1 (DISC1) is a protein implicated in schizophrenia, bipolar disorder, major depressive disorder, and autism. To date, most of research examining DISC1 function has focused on its role in neurodevelopment, despite its presence throughout life. DISC1 also regulate cAMP signaling by increasing PDE4 catabolism of cAMP when cAMP concentrations are high. In this study, we tested the hypothesis that DISC1, through its regulation of cAMP, modulates I-SK and I-TRPC channel-mediated ionic currents that we have shown previously to regulate the activity of mature prefrontal cortical pyramidal neurons. Methods We used patch-clamp recordings in prefrontal cortical slices from adult rats in which DISC1 function was reduced in vivo by shRNA viral knockdown or in vitro by dialysis of DISC1 antibodies. Results We found that DISC1 disruption resulted in an increase of: mGluR-induced intracellular Ca2+ waves, SK-mediated hyperpolarization and a decrease of TRPC-mediated sustained depolarization. Consistent with a role for DISC1 in regulation of cAMP signaling, forskolin-induced cAMP production also increased intracellular Ca2+ waves, I-SK and decreased I-TRPC. Lastly, inhibiting cAMP generation with guanfacine, an α2A-noradrenergic agonist, normalized the function of SK and TRPC channels. Conclusions Based on our findings, we propose that diminished DISC1 function, such as occurs in some mental disorders, can lead to the disruption of normal patterns of PFC activity through the loss of cAMP regulation of mGluR-mediated intracellular Ca2+ waves, SK and TRPC channel activity.

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Section: Discussionsupporting

confidence: 92%

Disrupted in Schizophrenia 1 Modulates Medial Prefrontal Cortex Pyramidal Neuron Activity Through cAMP Regulation of Transient Receptor Potential C and Small-Conductance K+ Channels

El-Hassar¹,

Simen²,

Duque³

et al. 2014

Biological Psychiatry

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“…This almost unique versatility of clonidine in the clinical arena is somewhat surprising in view of its known sedative properties; and its antihypertensive action would be considered an off-target side effect for many of the compound's noncardiovascular indications. Even more surprising is that despite initial sedation associated with clonidine administration, the drug has been reported to produce cognition enhancement in animal models, most particularly nonhuman primates (see Terry et al 1993;Franowicz and Arnsten 2002). The less-sedating α 2 -adrenergic agonist guanfacine also shares this clonidine-like action in monkeys (Arnsten et al 1988;Avery et al 2000).…”

Section: Introductionmentioning

confidence: 93%

Protracted cognitive effects produced by clonidine in Macaca nemestrina performing a delayed matching task

et al. 2008

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“…Second, clonidine has consistently shown greater side effects compared with both guanfacine and lofexidine in terms of orthostatic hypotension, sexual dysfunction and withdrawal syndrome following cessation, (Gish, Miller, Honey, & Johnson, 2010; Sorkin & Heel, 1986). In addition, guanfacine has been shown to enhance selective executive and inhibitory control processes underlying impulsivity and other behavioral factors associated with outcome in substance abuse (Brady, Gray, & Tolliver, 2011; Sofuoglu, DeVito, Waters, & Carroll, 2013) in non-human primates (Franowicz & Arnsten, 2002), healthy volunteers (Jakala, Riekkinen, Sirvio, Koivisto, Kejonen, et al, 1999; Jakala, Riekkinen, Sirvio, Koivisto, & Riekkinen, 1999) and other clinical populations (Swartz, McDonald, Patel, & Torgersen, 2008). Conversely, although few studies assessing the cognitive profile of lofexidine have been conducted, one study documented decreased cognitive efficiency after lofexidine administration compared with placebo, in fourteen opioid dependent individuals stabilized on methadone (Schroeder et al, 2007).…”

Section: Guanfacine As a Medication For Substance Abuse Compared Withmentioning

confidence: 99%

The Role of Guanfacine as a Therapeutic Agent to Address Stress-Related Pathophysiology in Cocaine-Dependent Individuals

Fox

Sinha

2014

Advances in Pharmacology

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The pathophysiology of cocaine addiction is linked to changes within neural systems and brain regions that are critical mediators of stress system sensitivity as well as behavioral processes associated with the regulation of adaptive goal-directed behavior. This is characterized by the up-regulation of core adrenergic and corticotrophin releasing factor (CRF) mechanisms which sub-serve negative affect and anxiety and impinge upon intracellular pathways in the prefrontal cortex underlying cognitive regulation of stress and negative emotional state. Not only are these mechanisms essential to the severity of cocaine withdrawal symptoms, and hence the trajectory of clinical outcome, but they may also be particularly pertinent to the demography of cocaine dependence. The ability of guanfacine to target overlapping stress, reward and anxiety pathophysiology suggests that it may be a useful agent for attenuating the stress and cue-induced craving state in women especially, but also in men. This is supported by recent research findings from our own laboratory. Additionally, the ability of guanfacine to improve regulatory mechanisms that are key to exerting cognitive and emotional control over drug seeking behavior also suggest that guanfacine may be an effective medication for reducing craving and relapse vulnerability in many drugs of abuse. As cocaine dependent individuals are typically polydrug abusers, and women may be at a greater disadvantage for compulsive drug use than men, it is plausible that medications which target catecholaminergic fronto-striatal inhibitory circuits and simultaneously reduce stress system arousal may provide added benefits for attenuating cocaine dependence.

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Actions of α-2 noradrenergic agonists on spatial working memory and blood pressure in rhesus monkeys appear to be mediated by the same receptor subtype

Abstract: The identical pattern of dose-dependent reversal of cognitive improvement and hypotension indicates that, in non-human primates, the same receptor subtype mediates both effects. Previous evidence suggests that the most likely candidate is the alpha-2A receptor subtype.

Cited by 25 publications

References 39 publications

Disrupted in Schizophrenia 1 Modulates Medial Prefrontal Cortex Pyramidal Neuron Activity Through cAMP Regulation of Transient Receptor Potential C and Small-Conductance K+ Channels

Disrupted in Schizophrenia 1 Modulates Medial Prefrontal Cortex Pyramidal Neuron Activity Through cAMP Regulation of Transient Receptor Potential C and Small-Conductance K+ Channels

Protracted cognitive effects produced by clonidine in Macaca nemestrina performing a delayed matching task

The Role of Guanfacine as a Therapeutic Agent to Address Stress-Related Pathophysiology in Cocaine-Dependent Individuals

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