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Guanfacine for the treatment of cognitive disorders: a century of discoveries at Yale.

Arnsten AF, Jin LE - Yale J Biol Med (2012)

Bottom Line: It regulates behavior, thought, and emotion using working memory.A century of discoveries at Yale Medical School has revealed the neurobiology of PFC cognitive functions, as well as the molecular needs of these circuits.Recent research has found that the noradrenergic α2A agonist guanfacine can improve PFC function by strengthening PFC network connections via inhibition of cAMP-potassium channel signaling in postsynaptic spines.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurobiology, Yale School of Medicine, New Haven, CT 06510, USA. amy.arnsten@yale.edu

ABSTRACT
The prefrontal cortex (PFC) is among the most evolved brain regions, contributing to our highest order cognitive abilities. It regulates behavior, thought, and emotion using working memory. Many cognitive disorders involve impairments of the PFC. A century of discoveries at Yale Medical School has revealed the neurobiology of PFC cognitive functions, as well as the molecular needs of these circuits. This work has led to the identification of therapeutic targets to treat cognitive disorders. Recent research has found that the noradrenergic α2A agonist guanfacine can improve PFC function by strengthening PFC network connections via inhibition of cAMP-potassium channel signaling in postsynaptic spines. Guanfacine is now being used to treat a variety of PFC cognitive disorders, including Tourette's Syndrome and Attention Deficit Hyperactivity Disorder (ADHD). This article reviews the history of Yale discoveries on the neurobiology of PFC working memory function and the identification of guanfacine for treating cognitive disorders.

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Related in: MedlinePlus

The α2A adrenoceptor agonist guanfacine improves PFC neuronal firingand cognitive function through actions at α2A receptors on spines inlayer III dlPFC neurons. A. Top: Systemic administration ofguanfacine to aged monkeys improves working memory performance and isparticularly effective in protecting performance from the deleteriouseffects of distracters presented during the delay period. Artisticallyrendered based on Arnsten and Contant, 1992 [52]. Bottom: Infusion ofguanfacine directly into the rat PFC improved performance of a workingmemory task (similar effects were seen with guanfacine infusions into monkeydlPFC by the Li lab in China [103]). Guanfacine’s enhancing effects were blocked byco-infusion of the cAMP analog, Sp-cAMPS, demonstrating actions through cAMPsignaling pathways. Artistically rendered based on Ramos et al., 2006[60].B. Iontophoresis of guanfacine directly onto dlPFC neuronsin monkeys performing a working memory task significantly increaseddelay-related firing. Firing was suppressed when Sp-cAMPS was co-appliedwith the guanfacine. Similar enhancing effects were observed with the HCNchannel blocker ZD7288, which reversed the suppressive effects of the α2blocker, yohimbine (not shown). Artistically rendered based on Wang et al.,2007 [62].C. Double-label immunogold electron microscopy by Dr.Constantinos Paspalas demonstrating α2A-receptors co-localized with HCNchannels in the spines of layer III dlPFC network synapses.
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Figure 5: The α2A adrenoceptor agonist guanfacine improves PFC neuronal firingand cognitive function through actions at α2A receptors on spines inlayer III dlPFC neurons. A. Top: Systemic administration ofguanfacine to aged monkeys improves working memory performance and isparticularly effective in protecting performance from the deleteriouseffects of distracters presented during the delay period. Artisticallyrendered based on Arnsten and Contant, 1992 [52]. Bottom: Infusion ofguanfacine directly into the rat PFC improved performance of a workingmemory task (similar effects were seen with guanfacine infusions into monkeydlPFC by the Li lab in China [103]). Guanfacine’s enhancing effects were blocked byco-infusion of the cAMP analog, Sp-cAMPS, demonstrating actions through cAMPsignaling pathways. Artistically rendered based on Ramos et al., 2006[60].B. Iontophoresis of guanfacine directly onto dlPFC neuronsin monkeys performing a working memory task significantly increaseddelay-related firing. Firing was suppressed when Sp-cAMPS was co-appliedwith the guanfacine. Similar enhancing effects were observed with the HCNchannel blocker ZD7288, which reversed the suppressive effects of the α2blocker, yohimbine (not shown). Artistically rendered based on Wang et al.,2007 [62].C. Double-label immunogold electron microscopy by Dr.Constantinos Paspalas demonstrating α2A-receptors co-localized with HCNchannels in the spines of layer III dlPFC network synapses.

Mentions: Arnsten and Goldman-Rakic set out to study the cognitive-enhancing effects of DAagonists in aged monkeys with naturally occurring DA depletion, but the compoundthat produced the most dramatic improvement in their cognitive performance was not aDA drug, but clonidine. Following clonidine administration, the aged monkeys werealmost asleep and yet performed near perfectly [39]. However, these beneficial cognitive effects werenot due to the expected presynaptic effects of clonidine on LC neurons, but ratherarose from actions at post-synaptic receptors in the dlPFC [39]. Indeed, destruction of thepresynaptic sites only made clonidine’s effects more potent [39,48]. Further research revealed that the α2A-adrenoceptor subtype wasessential for these actions [49] and that the α2A-preferring agonist guanfacine can improveworking memory [50,51], attention regulation (Figure 5A, top) [52,53], andbehavioral inhibition [54]independent of its sedative actions. Guanfacine is more selective for the α2Areceptor subtype than is clonidine, which also binds with high affinity to α2B, α2C,and imidazoline receptors [55,56]. Guanfacine is weaker thanclonidine in producing hypotension and sedation [50] and has weaker presynaptic actions in the brain,i.e., it is 10 times less effective in reducing LC firing and decreasing NE release[57]. However, guanfacineis more potent than clonidine in enhancing PFC working memory function in agedmonkeys, suggesting greater efficacy at post-synaptic sites in PFC [50]. Most recently, guanfacine has beenshown to improve impulse control in monkeys performing a delayed discounting task,i.e., increasing the ability to resist an immediate, small reward and instead waitfor a larger reward [58]. ThePFC is the site of beneficial drug actions, as guanfacine improves cognitiveperformance when infused directly into the rat or monkey PFC (Figure 5A, bottom) [59-61]. Indeed,guanfacine’s enhancing effects can even be observed at the cellular level, whereapplication of drug directly onto dlPFC neurons increases the delay-related neuronalfiring needed for working memory [62] (Figure 5B). Conversely,blocking α2A receptors in the monkey dlPFC markedly impairs working memory[63] and behavioralinhibition [64,65] and greatly reduces persistent neuronal firing[62,66], demonstrating that endogenous NE stimulation ofα2A receptors is essential for PFC regulation of behavior, thought, and emotion.


Guanfacine for the treatment of cognitive disorders: a century of discoveries at Yale.

Arnsten AF, Jin LE - Yale J Biol Med (2012)

The α2A adrenoceptor agonist guanfacine improves PFC neuronal firingand cognitive function through actions at α2A receptors on spines inlayer III dlPFC neurons. A. Top: Systemic administration ofguanfacine to aged monkeys improves working memory performance and isparticularly effective in protecting performance from the deleteriouseffects of distracters presented during the delay period. Artisticallyrendered based on Arnsten and Contant, 1992 [52]. Bottom: Infusion ofguanfacine directly into the rat PFC improved performance of a workingmemory task (similar effects were seen with guanfacine infusions into monkeydlPFC by the Li lab in China [103]). Guanfacine’s enhancing effects were blocked byco-infusion of the cAMP analog, Sp-cAMPS, demonstrating actions through cAMPsignaling pathways. Artistically rendered based on Ramos et al., 2006[60].B. Iontophoresis of guanfacine directly onto dlPFC neuronsin monkeys performing a working memory task significantly increaseddelay-related firing. Firing was suppressed when Sp-cAMPS was co-appliedwith the guanfacine. Similar enhancing effects were observed with the HCNchannel blocker ZD7288, which reversed the suppressive effects of the α2blocker, yohimbine (not shown). Artistically rendered based on Wang et al.,2007 [62].C. Double-label immunogold electron microscopy by Dr.Constantinos Paspalas demonstrating α2A-receptors co-localized with HCNchannels in the spines of layer III dlPFC network synapses.
© Copyright Policy - open access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3313539&req=5

Figure 5: The α2A adrenoceptor agonist guanfacine improves PFC neuronal firingand cognitive function through actions at α2A receptors on spines inlayer III dlPFC neurons. A. Top: Systemic administration ofguanfacine to aged monkeys improves working memory performance and isparticularly effective in protecting performance from the deleteriouseffects of distracters presented during the delay period. Artisticallyrendered based on Arnsten and Contant, 1992 [52]. Bottom: Infusion ofguanfacine directly into the rat PFC improved performance of a workingmemory task (similar effects were seen with guanfacine infusions into monkeydlPFC by the Li lab in China [103]). Guanfacine’s enhancing effects were blocked byco-infusion of the cAMP analog, Sp-cAMPS, demonstrating actions through cAMPsignaling pathways. Artistically rendered based on Ramos et al., 2006[60].B. Iontophoresis of guanfacine directly onto dlPFC neuronsin monkeys performing a working memory task significantly increaseddelay-related firing. Firing was suppressed when Sp-cAMPS was co-appliedwith the guanfacine. Similar enhancing effects were observed with the HCNchannel blocker ZD7288, which reversed the suppressive effects of the α2blocker, yohimbine (not shown). Artistically rendered based on Wang et al.,2007 [62].C. Double-label immunogold electron microscopy by Dr.Constantinos Paspalas demonstrating α2A-receptors co-localized with HCNchannels in the spines of layer III dlPFC network synapses.
Mentions: Arnsten and Goldman-Rakic set out to study the cognitive-enhancing effects of DAagonists in aged monkeys with naturally occurring DA depletion, but the compoundthat produced the most dramatic improvement in their cognitive performance was not aDA drug, but clonidine. Following clonidine administration, the aged monkeys werealmost asleep and yet performed near perfectly [39]. However, these beneficial cognitive effects werenot due to the expected presynaptic effects of clonidine on LC neurons, but ratherarose from actions at post-synaptic receptors in the dlPFC [39]. Indeed, destruction of thepresynaptic sites only made clonidine’s effects more potent [39,48]. Further research revealed that the α2A-adrenoceptor subtype wasessential for these actions [49] and that the α2A-preferring agonist guanfacine can improveworking memory [50,51], attention regulation (Figure 5A, top) [52,53], andbehavioral inhibition [54]independent of its sedative actions. Guanfacine is more selective for the α2Areceptor subtype than is clonidine, which also binds with high affinity to α2B, α2C,and imidazoline receptors [55,56]. Guanfacine is weaker thanclonidine in producing hypotension and sedation [50] and has weaker presynaptic actions in the brain,i.e., it is 10 times less effective in reducing LC firing and decreasing NE release[57]. However, guanfacineis more potent than clonidine in enhancing PFC working memory function in agedmonkeys, suggesting greater efficacy at post-synaptic sites in PFC [50]. Most recently, guanfacine has beenshown to improve impulse control in monkeys performing a delayed discounting task,i.e., increasing the ability to resist an immediate, small reward and instead waitfor a larger reward [58]. ThePFC is the site of beneficial drug actions, as guanfacine improves cognitiveperformance when infused directly into the rat or monkey PFC (Figure 5A, bottom) [59-61]. Indeed,guanfacine’s enhancing effects can even be observed at the cellular level, whereapplication of drug directly onto dlPFC neurons increases the delay-related neuronalfiring needed for working memory [62] (Figure 5B). Conversely,blocking α2A receptors in the monkey dlPFC markedly impairs working memory[63] and behavioralinhibition [64,65] and greatly reduces persistent neuronal firing[62,66], demonstrating that endogenous NE stimulation ofα2A receptors is essential for PFC regulation of behavior, thought, and emotion.

Bottom Line: It regulates behavior, thought, and emotion using working memory.A century of discoveries at Yale Medical School has revealed the neurobiology of PFC cognitive functions, as well as the molecular needs of these circuits.Recent research has found that the noradrenergic α2A agonist guanfacine can improve PFC function by strengthening PFC network connections via inhibition of cAMP-potassium channel signaling in postsynaptic spines.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurobiology, Yale School of Medicine, New Haven, CT 06510, USA. amy.arnsten@yale.edu

ABSTRACT
The prefrontal cortex (PFC) is among the most evolved brain regions, contributing to our highest order cognitive abilities. It regulates behavior, thought, and emotion using working memory. Many cognitive disorders involve impairments of the PFC. A century of discoveries at Yale Medical School has revealed the neurobiology of PFC cognitive functions, as well as the molecular needs of these circuits. This work has led to the identification of therapeutic targets to treat cognitive disorders. Recent research has found that the noradrenergic α2A agonist guanfacine can improve PFC function by strengthening PFC network connections via inhibition of cAMP-potassium channel signaling in postsynaptic spines. Guanfacine is now being used to treat a variety of PFC cognitive disorders, including Tourette's Syndrome and Attention Deficit Hyperactivity Disorder (ADHD). This article reviews the history of Yale discoveries on the neurobiology of PFC working memory function and the identification of guanfacine for treating cognitive disorders.

Show MeSH
Related in: MedlinePlus