The Experts below are selected from a list of 210 Experts worldwide ranked by ideXlab platform
Bridgette L Jones - One of the best experts on this subject based on the ideXlab platform.
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clinical and pharmacologic considerations for Guanfacine use in very young children
Journal of Child and Adolescent Psychopharmacology, 2016Co-Authors: Benjamin T Black, Sarah E Soden, Gregory L Kearns, Bridgette L JonesAbstract:Abstract Objective: Guanfacine, in the immediate release form, remains a commonly used medication for the treatment of clinically significant hyperactivity, impulsivity, or disruptive behaviors. This article reviews the available literature regarding Guanfacine use in very young children (<6 years of age), and explores some of the factors that may uniquely impact the clinical pharmacology of Guanfacine in very young children and that deserve consideration when it is used in this patient population. Methods: The authors performed electronic literature searches in PubMed through October 2015 using the terms attention-deficit/hyperactivity disorder, Guanfacine, and alpha agonists. We also performed an informal review of the literature and used selected articles from relevant reference lists. The result was a broad, qualitative review of the literature, with a focus on specific factors regarding Guanfacine use in very young children. Results: Despite the fact that Guanfacine is commonly used in very young chi...
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Clinical and Pharmacologic Considerations for Guanfacine Use in Very Young Children
Journal of child and adolescent psychopharmacology, 2016Co-Authors: Benjamin T Black, Sarah E Soden, Gregory L Kearns, Bridgette L JonesAbstract:Abstract Objective: Guanfacine, in the immediate release form, remains a commonly used medication for the treatment of clinically significant hyperactivity, impulsivity, or disruptive behaviors. This article reviews the available literature regarding Guanfacine use in very young children (
Danny G. Winder - One of the best experts on this subject based on the ideXlab platform.
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α_2A-adrenergic heteroreceptors are required for stress-induced reinstatement of cocaine conditioned place preference
Neuropsychopharmacology, 2020Co-Authors: Rafael E. Perez, Aakash Basu, Bretton P. Nabit, Nicholas A. Harris, Oakleigh M. Folkes, Sachin Patel, Ralf Gilsbach, Lutz Hein, Danny G. WinderAbstract:The α_2a-adrenergic receptor (α_2a-AR) agonist Guanfacine has been investigated as a potential treatment for substance use disorders. While decreasing stress-induced reinstatement of cocaine seeking in animal models and stress-induced craving in human studies, Guanfacine has not been reported to decrease relapse rates. Although Guanfacine engages α_2a-AR autoreceptors, it also activates excitatory G_i-coupled heteroreceptors in the bed nucleus of the stria terminalis (BNST), a key brain region in driving stress-induced relapse. Thus, BNST α_2a-AR heteroreceptor signaling might decrease the beneficial efficacy of Guanfacine. We aimed to determine the role of α_2a-AR heteroreceptors and BNST G_i-GPCR signaling in stress-induced reinstatement of cocaine conditioned place preference (CPP) and the effects of low dose Guanfacine on BNST activity and stress-induced reinstatement. We used a genetic deletion strategy and the cocaine CPP procedure to first define the contributions of α_2a-AR heteroreceptors to stress-induced reinstatement. Next, we mimicked BNST G_i-coupled α_2a-AR heteroreceptor signaling using a G_i-coupled designer receptor exclusively activated by designer drug (G_i-DREADD) approach. Finally, we evaluated the effects of low-dose Guanfacine on BNST cFOS immunoreactivity and stress-induced reinstatement. We show that α_2a-AR heteroreceptor deletion disrupts stress-induced reinstatement and that BNST G_i-DREADD activation is sufficient to induce reinstatement. Importantly, we found that low-dose Guanfacine does not increase BNST activity, but prevents stress-induced reinstatement. Our findings demonstrate a role for α_2a-AR heteroreceptors and BNST G_i-GPCR signaling in stress-induced reinstatement of cocaine CPP and provide insight into the impact of dose on the efficacy of Guanfacine as a treatment for stress-induced relapse of cocaine use.
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α2A-adrenergic heteroreceptors are required for stress-induced reinstatement of cocaine conditioned place preference.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 2020Co-Authors: Rafael E. Perez, Aakash Basu, Bretton P. Nabit, Nicholas A. Harris, Oakleigh M. Folkes, Sachin Patel, Ralf Gilsbach, Lutz Hein, Danny G. WinderAbstract:The α2a-adrenergic receptor (α2a-AR) agonist Guanfacine has been investigated as a potential treatment for substance use disorders. While decreasing stress-induced reinstatement of cocaine seeking in animal models and stress-induced craving in human studies, Guanfacine has not been reported to decrease relapse rates. Although Guanfacine engages α2a-AR autoreceptors, it also activates excitatory Gi-coupled heteroreceptors in the bed nucleus of the stria terminalis (BNST), a key brain region in driving stress-induced relapse. Thus, BNST α2a-AR heteroreceptor signaling might decrease the beneficial efficacy of Guanfacine. We aimed to determine the role of α2a-AR heteroreceptors and BNST Gi-GPCR signaling in stress-induced reinstatement of cocaine conditioned place preference (CPP) and the effects of low dose Guanfacine on BNST activity and stress-induced reinstatement. We used a genetic deletion strategy and the cocaine CPP procedure to first define the contributions of α2a-AR heteroreceptors to stress-induced reinstatement. Next, we mimicked BNST Gi-coupled α2a-AR heteroreceptor signaling using a Gi-coupled designer receptor exclusively activated by designer drug (Gi-DREADD) approach. Finally, we evaluated the effects of low-dose Guanfacine on BNST cFOS immunoreactivity and stress-induced reinstatement. We show that α2a-AR heteroreceptor deletion disrupts stress-induced reinstatement and that BNST Gi-DREADD activation is sufficient to induce reinstatement. Importantly, we found that low-dose Guanfacine does not increase BNST activity, but prevents stress-induced reinstatement. Our findings demonstrate a role for α2a-AR heteroreceptors and BNST Gi-GPCR signaling in stress-induced reinstatement of cocaine CPP and provide insight into the impact of dose on the efficacy of Guanfacine as a treatment for stress-induced relapse of cocaine use.
Pia Steensland - One of the best experts on this subject based on the ideXlab platform.
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evaluation of Guanfacine as a potential medication for alcohol use disorder in long term drinking rats behavioral and electrophysiological findings
Neuropsychopharmacology, 2015Co-Authors: Ida Fredriksson, Malin Wirf, Kent Jardemark, Nitya Jayaramlindstrom, Erik Nylander, Erica Nystrom, Pia SteenslandAbstract:One of the main treatment challenges in alcohol use disorder (AUD) is the high rate of craving in combination with decreased cognitive functioning including impaired decision making and impulse control that often lead to relapse. Recent studies show that Guanfacine, an α-2-adrenoceptor agonist and FDA-approved ADHD medication, attenuates stress-induced relapse of several drugs of abuse including alcohol. Here we evaluated Guanfacine's effects on voluntary alcohol intake, the alcohol deprivation effect (ADE), alcohol seeking behavior, and cue/priming-induced reinstatement in Wistar rats that had voluntarily consumed alcohol for at least 2 months before treatment. In addition, Guanfacine's ability to regulate glutamatergic neurotransmission was evaluated through electrophysiological recordings in medial prefrontal cortex (mPFC) slices prepared from long-term drinking rats (and alcohol-naive controls) that had received three daily Guanfacine (0.6 mg/kg/day) or vehicle injections in vivo. Guanfacine decreased alcohol intake in high, but not low, alcohol-consuming rats and the effects were generally more long lasting than that of the AUD medication naltrexone. Repeated Guanfacine treatment induced a long-lasting decrease in alcohol intake, persistent up to five drinking sessions after the last injection. In addition, Guanfacine attenuated the ADE as well as alcohol seeking and cue/priming-induced reinstatement of alcohol seeking. Finally, subchronic Guanfacine treatment normalized an alcohol-induced dysregulated glutamatergic neurotransmission in the mPFC. These results support previous studies showing that Guanfacine has the ability to improve prefrontal connectivity through modulation of the glutamatergic system. Together with the fact that Guanfacine appears to be clinically safe, these results merit evaluation of Guanfacine's clinical efficacy in AUD individuals.
Susan L. Andersen - One of the best experts on this subject based on the ideXlab platform.
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Juvenile exposure to methylphenidate and Guanfacine in rats: effects on early delay discounting and later cocaine-taking behavior
Psychopharmacology, 2019Co-Authors: Nadja Freund, Chloe J. Jordan, Kevin J. Norman, Jodi L Lukkes, Susan L. AndersenAbstract:RationaleBoth methylphenidate (MPH), a catecholamine reuptake blocker, and Guanfacine, an alpha2A agonist, are used to treat attention-deficit hyperactivity disorder (ADHD). Childhood impulsivity, including delay discounting, is associated with increased substance use during adolescence. These effects can be mitigated by juvenile exposure to MPH, but less is known about the long-term effects of developmental exposure to Guanfacine in males and females.ObjectiveThis study aims to determine sex differences and dose-dependent effects of juvenile exposure to MPH or Guanfacine on delay-discounting and later cocaine self-administration.MethodsThe dose-dependent effects of vehicle, MPH (0.5, 1, and 2 mg/kg p.o.) or Guanfacine (0.003, 0.03, and 0.3 mg/kg, i.p.) on discounting were determined in male and female Sprague-Dawley rats beginning at postnatal day (P)20. At P90, the amount, motivation, and sensitivity to cocaine following early drug exposure were determined with self-administration.ResultsGuanfacine, but not MPH, significantly reduced weight by 22.9 ± 4.6% in females. MPH dose dependently decreased delay discounting in both juvenile males and females, while Guanfacine was only effective in males. Discounting was associated with cocaine self-administration in vehicle males ( R ^2 = −0.4, P
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juvenile exposure to methylphenidate and Guanfacine in rats effects on early delay discounting and later cocaine taking behavior
Psychopharmacology, 2019Co-Authors: Nadja Freund, Chloe J. Jordan, Kevin J. Norman, Jodi L Lukkes, Susan L. AndersenAbstract:RATIONALE Both methylphenidate (MPH), a catecholamine reuptake blocker, and Guanfacine, an alpha2A agonist, are used to treat attention-deficit hyperactivity disorder (ADHD). Childhood impulsivity, including delay discounting, is associated with increased substance use during adolescence. These effects can be mitigated by juvenile exposure to MPH, but less is known about the long-term effects of developmental exposure to Guanfacine in males and females. OBJECTIVE This study aims to determine sex differences and dose-dependent effects of juvenile exposure to MPH or Guanfacine on delay-discounting and later cocaine self-administration. METHODS The dose-dependent effects of vehicle, MPH (0.5, 1, and 2 mg/kg p.o.) or Guanfacine (0.003, 0.03, and 0.3 mg/kg, i.p.) on discounting were determined in male and female Sprague-Dawley rats beginning at postnatal day (P)20. At P90, the amount, motivation, and sensitivity to cocaine following early drug exposure were determined with self-administration. RESULTS Guanfacine, but not MPH, significantly reduced weight by 22.9 ± 4.6% in females. MPH dose dependently decreased delay discounting in both juvenile males and females, while Guanfacine was only effective in males. Discounting was associated with cocaine self-administration in vehicle males (R2 = -0.4, P < 0.05) and self-administration was reduced by Guanfacine treatment (0.3 mg/kg). Guanfacine significantly decreased cocaine sensitivity in both sexes. CONCLUSIONS These data suggest that MPH is effective in reducing delay discounting in both sexes. Due to both weight loss and ineffectiveness on discounting in females, Guanfacine should be used only in males to reduce delay discounting and later cocaine use.
Sherry A Mckee - One of the best experts on this subject based on the ideXlab platform.
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pharmacokinetics and pharmacodynamics of immediate release versus extended release Guanfacine in adult daily smokers
Journal of Clinical Psychopharmacology, 2019Co-Authors: Terril L Verplaetse, Walter Roberts, Kelly E Moore, Mackenzie R Peltier, Lindsay Oberleitner, Sherry A MckeeAbstract:BACKGROUND Guanfacine is Food and Drug Administration approved for hypertension and attention-deficit hyperactivity disorder and has been used off-label for migraine prophylaxis, heroin withdrawal, and more recently smoking cessation. Previous studies have shown positive effects of 3 mg/d of immediate-release (IR) Guanfacine on smoking outcomes, but the dose equivalency of the IR and extended-release (ER) formulations is unknown. PROCEDURES A within-subject design was used to compare the pharmacokinetics and pharmacodynamics of 3 mg/d of IR, 4 mg/d of ER, and 6 mg/d of ER Guanfacine in adult daily smokers (n = 5). Plasma medication levels, vital signs, cigarettes per day, tobacco craving, and adverse events were assessed. Medication was titrated to stable dosing after each laboratory day (3 mg/d IR, then 4 mg/d ER, then 6 mg/d ER). RESULTS Plasma medication levels did not differ between the 3 mg/d of IR and 4 mg/d of ER doses after 24 hours from last dose and were highest at the 6 mg/d of ER dose (3 mg/d IR: M = 3.40 ng/mL, SE = 0.34 vs 4 mg/d ER: M = 3.46 ng/mL, SE = 0.67 vs 6 mg/d ER: M = 5.92 ng/mL, SE = 1.02). All doses of Guanfacine decreased heart rate and blood pressure from baseline. Absolute values of cigarettes per day (6 mg/d ER) and tobacco craving (4 and 6 mg/d ER) were lowest with the ER formulations. Treatment-emergent adverse events were subject rated as minimal to mild, except dry mouth. CONCLUSIONS We demonstrated similar pharmacokinetic profiles between 3 mg/d of IR Guanfacine and 4 mg/d of ER Guanfacine, as hypothesized. All doses of Guanfacine were well tolerated.
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the effect of treatment with Guanfacine an alpha2 adrenergic agonist on dopaminergic tone in tobacco smokers an 11c flb457 pet study
Neuropsychopharmacology, 2018Co-Authors: Christine M Sandiego, David Matuskey, Meaghan Lavery, Erin Mcgovern, Yiyun Huang, Nabeel Nabulsi, Jim Ropchan, Marina R Picciotto, Evan D Morris, Sherry A MckeeAbstract:Guanfacine, a noradrenergic alpha2a agonist, reduced tobacco smoking in a 4-week trial and in animal models has been shown to reduce cortical dopamine release, which is critically involved in the reinforcing effect of tobacco smoking. We measured amphetamine-induced extrastriatal dopamine release before and after treatment with Guanfacine with [11C]FLB457, a dopamine D2/D3 receptor radiotracer, and positron emission tomography (PET). Sixteen tobacco smokers had one set of [11C]FLB457 PET scans on the same day, one before and one at 2.5–3 h after amphetamine (0.4–0.5 mg/kg, PO). A subset (n=12) then underwent Guanfacine treatment (3 mg/day for 3 weeks) and the set of scans were repeated. [11C]FLB457-binding potential (BPND) was measured pre- and post amphetamine in extrastriatal brain regions. The fractional change in BPND after vs before amphetamine (Δ BPND) is an indirect measure of DA release and was compared between the untreated and Guanfacine-treated conditions. Guanfacine treatment attenuated amphetamine-induced DA release; however, the change was due to a global 8% decrease in baseline BPND from the untreated to the Guanfacine-treated condition. Chronic Guanfacine treatment reduced [11C]FLB457 BPND in tobacco smokers, suggesting an increase in dopaminergic tone. Guanfacine-induced normalization of dopamine signaling may be an important mesocortical mechanism contributing to its ability to aid in tobacco smoking cessation.
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A case series on the heightened autonomic response due to Guanfacine and amphetamine interaction.
Journal of clinical psychopharmacology, 2015Co-Authors: Edward C. Gaiser, David Matuskey, Sherry A Mckee, Evgenia Perkins, Cynthia D’amico, Osama Abdelghany, Kelly P. CosgroveAbstract:Guanfacine is used clinically as either monotherapy or adjunct therapy (along with psychostimulants) for the treatment of attention deficit hyperactivity disorder (ADHD) due to its hypothesized action of increasing network connections in the prefrontal cortex (1). Guanfacine is a selective α2A-adrenoreceptor (α2A-receptor) agonist that activates central nervous system (CNS) norepinephrine receptors in the locus coeruleus. This action results in reduced peripheral sympathetic tone of both systolic (SBP) and diastolic blood pressure (DBP), which was its original indication as an antihypertensive (2). Additionally, Guanfacine has been investigated for the treatment of substance abuse disorders (SUD) due to its ability to decrease both stress and cue induced craving (3). Dextroamphetamine (AMP) is a monoamine agonist that blocks neurotransmitter reuptake at the presynaptic transporter and is also taken up by the vesicular monoamine transporter 2, resulting in catecholamine release and CNS stimulation (4). AMP is a well-established therapy for ADHD; however, it also has a propensity to be abused due to its similarity to drugs of abuse such as cocaine and methamphetamine (5) and its cognitive enhancing properties. As part of a larger study, nine otherwise healthy nicotine dependent volunteers were recruited to take part in a positron emission tomography (PET) protocol examining the effects of oral Guanfacine on dopamine release. All subjects were required to stop smoking by midnight the night before all scans, which was verified by carbon monoxide levels less than 10 ppm. Subjects were imaged at baseline (under no pharmacological intervention) and after an oral AMP challenge to assess pre-Guanfacine treatment dopamine release the following day. As part of the PET scanning procedure, vital sign measurements were taken twice at baseline and then every 15 minutes after being administered AMP for the duration of the 180-minute scans, which were averaged to reduce potential variability for the purpose of this case series. After pre-treatment scans were complete, subjects took part in a Guanfacine escalation paradigm to 3mg daily over fifteen days then remained on a steady state of 3mg Guanfacine for eight additional days. To confirm medication compliance, a riboflavin marker detectable in urine by ultraviolet light was added to each dose. After the three weeks of Guanfacine monotherapy, subjects took part in a post-Guanfacine treatment baseline scan accompanied by a fourth and final scan using the same AMP challenge to examine the effects of chronic Guanfacine treatment on dopamine release. All nine subjects completed the pre-AMP challenge baseline scans without incident and remained normotensive throughout scanning sessions evidenced by an average SBP of 129 mmHg, an average DBP of 75 mmHg, and an average heart rate (HR) of 73 bpm. The first two subjects in the study received 0.5mg/kg (mean of 40mg per dose) of AMP for their pre-Guanfacine treatment dopamine release scans without incident and experienced expected autonomic nervous system (ANS) changes as SBP increased by 14% (mean of 151 mmHg), DBP increased by 12% (mean of 76 mmHg), and HR increased by 10% (mean of 80 bpm) over the session as compared to pre-AMP baseline. After the three weeks of Guanfacine montherapy, the same two subjects were scanned before a second AMP challenge and, as expected, decreases in ANS measures were observed as compared to their pre-Guanfacine baseline scans. Specifically, there was a 13% decrease in SBP (mean of 114 mmHg), a 1% increase in DBP (mean of 69 mmHg), and a 19% decrease in HR (mean of 59 bpm), respectively. Surprisingly however, after receiving 0.5mg/kg of AMP after three weeks of Guanfacine monotherapy, those two subjects became acutely stage II hypertensive as reflected by a 50% increase in SBP (mean of 170 mmHg), a 42% increase in DBP (mean of 97 mmHg), and a 1% decrease in HR (mean of 59 bpm). Subjects were asymptomatic with the exception of a mild to moderate headache that subsided without intervention in one of the subjects (See Figure 1). Figure 1 Relative change between Guanfacine and Guanfacine + dextroamphetamine (AMP) (along with S.E.M) in systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR). AMP was given as two different single doses. Doses of AMP were then adjusted to 0.4mg/kg in order to safely complete the study on the seven additional subjects (mean of 31mg per dose) and, again, an expected autonomic response was observed during their pre-Guanfacine treatment dopamine release scan as AMP increased SBP by 16% (mean of 148 mmHg) and DBP by 9% (mean of 83 mmHg), and decreased HR by 5% (mean of 69 bpm) as compared to their pre-AMP baseline scans. After the three weeks of Guanfacine monotherapy, the seven subjects were scanned before their second AMP challenge and deceases in SBP of .1% (mean of 127 mmHg), DBP of 9% (mean of 71 mmHg), and HR of 8% (mean of 65 bpm) were observed as compared to their pre-AMP baseline. Those same subjects experienced asymptomatic acute stage I hypertension (rather than stage II hypertension previously observed with 0.5mg/kg in the prior two subjects) after receiving 0.4mg/kg of AMP. Although autonomic changes were still observed, they were of more benign nature evidenced by a 24% increase in SBP (mean of 156 mmHg), a 23% increase in DBP (mean of 87 mmHg), and a 1% increase in HR (mean of 65 bpm) as compared the post-Guanfacine baseline scan (See Figure 1).
