A placebo-controlled study of guanfacine in the treatment of children with tic disorders and attention deficit hyperactivity disorder.

OBJECTIVE: This study evaluated the efficacy and safety of guanfacine in treating children with tic disorders and attention deficit hyperactivity disorder (ADHD). METHOD: Subjects from a specialty tic disorders clinic were randomly assigned to receive 8 weeks of treatment with guanfacine or placebo under double-blind conditions. Follow-up visits occurred every 2 weeks for safety monitoring and dose adjustment. RESULTS: Thirty-four medication-free subjects (31 boys and three girls with a mean age of 10.4 years) with ADHD, combined type, and a tic disorder participated. After 8 weeks of treatment, guanfacine was associated with a mean improvement of 37% in the total score on the teacher-rated ADHD Rating Scale, compared to 8% improvement for placebo. Nine of 17 subjects who received guanfacine were blindly rated on the Clinical Global Improvement scale as either much improved or very much improved, compared with none of 17 subjects who received placebo. The mean score on the parent-rated hyperactivity index improved by 27% in the guanfacine group and 21% in the placebo group, not a significant difference. On the Continuous Performance Test, commission errors decreased by 22% and omission errors by 17% in the guanfacine group, compared with increases of 29% in commission errors and of 31% in omission errors in the placebo group. Tic severity decreased by 31% in the guanfacine group, compared to 0% in the placebo group. One guanfacine subject with sedation withdrew at week 4. Guanfacine was associated with insignificant decreases in blood pressure and pulse. CONCLUSIONS: Guanfacine appears to be a safe and effective treatment for children with tic disorders and ADHD.     

Growth hormone response to guanfacine in boys with attention deficit hyperactivity disorder: a preliminary study

OBJECTIVE: This preliminary study evaluated a method for assessing central noradrenergic function in children via the growth hormone response to a single dose of the alpha-2 adrenergic receptor agonist guanfacine and examined whether this measure distinguishes between attention deficit hyperactivity disorder (ADHD) boys with and without reading disabilities (RD). METHODS: Plasma growth hormone was assessed before and after the oral administration of guanfacine and placebo in boys with ADHD who were divided into subgroups based on the presence (n = 3) or absence (n = 5) of RD. RESULTS: Guanfacine and placebo conditions did not differ at baseline, but peak growth hormone was significantly higher following guanfacine. The increase in growth hormone following guanfacine was significantly greater in boys without RD as compared to those with RD, with no overlap between the groups. CONCLUSIONS: Consistent with findings using peripheral measures of noradrenergic function, these preliminary data suggest that ADHD boys with and without RD may differ in central noradrenergic function.     

Neuropsychiatric effects of guanfacine in children with mild tourette syndrome: a pilot study

The objective of this study was to evaluate the neuropsychiatric effects of the alpha-2a adrenergic agonist guanfacine in children with Tourette syndrome (TS). Twenty-four children with TS participated in a 4-week, double-blind, placebo-controlled study of guanfacine. Tic severity, neuropsychologic functioning, and parent ratings of behavior were evaluated pre- and post-treatment. The sample had mild tic severity and subtle neuropsychologic dysfunction pretreatment. Post-treatment, patients receiving guanfacine were rated by parents as significantly improved (compared to placebo) on one measure of executive function (parent-rated metacognition). Improvement on tic severity, performance-based neuropsychologic measures, and all other parent ratings were not significantly better than placebo. At a moderate dose and short-term treatment duration, guanfacine did not provide significant neuropsychiatric benefits in this group of children with mild TS.     

The alpha-2 adrenergic agonist guanfacine improves memory in aged monkeys without sedative or hypotensive side effects: evidence for alpha-2 receptor subtypes

The present study attempted to identify an alpha-2 agonist that could improve working memory in aged nonhuman primates without the marked hypotensive and sedative side effects produced by clonidine. Toward this end, the hypotensive, sedative, and memory-altering properties of the alpha-2 adrenergic agonists, B-HT920 and guanfacine, were compared with clonidine's effects in 9 aged rhesus monkeys. Memory capacity was assessed by a variable delay, spatial delayed response paradigm that requires the animal to remember information over short temporal intervals and to update this information on every trial. B-HT920 was found to produce a dose-response profile qualitatively similar to, but weaker than, clonidine: low doses impaired memory and began to lower blood pressure and produce sedation, while high doses improved memory. In contrast, guanfacine produced a dose-response profile opposite to that seen with clonidine: low doses improved memory without inducing hypotension or sedation, while the memory-impairing, hypotensive, and sedating properties of the drug were observed at higher doses. The potency of the 3 agonists to lower blood pressure was clonidine = B-HT920 greater than guanfacine; sedation was affected in the order clonidine greater than B-HT920 greater than guanfacine; for memory impairment, as measured by performance on the delayed response task, the rank order potency was clonidine greater than B-HT920 greater than guanfacine, while for memory improvement it was guanfacine greater than clonidine greater than B-HT920. These differences in rank order potency are consistent with the recent proposal of alpha-2 receptor subtypes, a rauwolscine-sensitive site (Rs) that binds clonidine greater than B-HT920 greater than guanfacine and a rauwolscine-insensitive site (Ri) that binds guanfacine greater than clonidine greater than B-HT920 (Boyajian and Leslie, 1987). The data suggest that the hypotensive, sedating, and memory-impairing effects of alpha-2 agonists may be due to actions at one subtype of receptor (Rs), while the memory-enhancing effects of these drugs may result from actions at another alpha-2 receptor subtype, the Ri site. The ability of low doses of guanfacine to improve memory without inducing hypotension or sedation indicates that this agonist may be an excellent candidate for treating memory disorders in man.     

No improvement of posttraumatic stress disorder symptoms with guanfacine treatment

OBJECTIVE: The authors report an 8-week, double-blind, randomized controlled trial of guanfacine versus placebo for posttraumatic stress disorder (PTSD). METHOD: Veterans with chronic PTSD who were medication-free or receiving stable pharmacotherapy were randomly assigned to guanfacine (N=29) versus placebo (N=34). RESULTS: Guanfacine had no effect on PTSD symptoms, subjective sleep quality, or general mood disturbances. Guanfacine was associated with a number of side effects. CONCLUSIONS: These results do not support the use of alpha 2 agonists in veterans with chronic PTSD.     

Once-daily treatment of ADHD with guanfacine: patient implications

The standard of care for treating ADHD is to use a psychostimulant as the first line agent. Recent medical literature reports that approximately 70%-90% of patients with ADHD received some benefit from a stimulant medication. Even though psychostimulants have a high rate of efficacy, an estimated 30%-50% of children and adults may discontinue psychostimulants secondary to adverse effects or inadequate response. Guanfacine has been used for a number of years as an off label alternative to psychostimulants. This article reviews the current literature on the effectiveness of guanfacine in treating ADHD. It also introduces the preliminary data for guanfacine extended release and its effectiveness in decreasing the symptoms of ADHD.     

Preliminary results of guanfacine treatment of acute opiate withdrawal

Ten patients experiencing sudden opiate withdrawal received low doses of guanfacine. Improvement was noticeable within the first 4 days and was most evident in moderate to severe cases. The major effect was on autonomic symptoms. Tolerance to guanfacine was excellent.     

Treatment of heroin withdrawal with guanfacine: an open clinical investigation

The alpha 2-adrenoceptor stimulant, guanfacine, was used to treat, under open conditions, heroin addicts who volunteered to withdraw from heroin usage. Thirty-four addicts (29 males, 5 females) aged 17 to 31 years were treated for 5 to 15 days with varying doses of guanfacine (0.03 up to 1.75 mg daily). Efficacy was determined by the "Opiate Withdrawal Checklist" (OWCL), administered several times during the day, and by the Clinical Global Impression (CGI) scale. All symptom categories of the OWCL, except "sleep disturbances" were equally ameliorated by the treatment. According to the CGI, 88% of the cases were judged as having had a very good or good improvement. Tolerability to the medication was judged as good or very good in 94% of the cases.     

The effects of guanfacine on context processing abnormalities in schizotypal personality disorder.

BACKGROUND: The signature of impaired cognition in people with schizotypal personality disorder (SPD) may be centrally related to working memory impairments. Guanfacine, an alpha2A agonist that acts post-synaptically in the prefrontal cortex (PFC), has shown potential for reducing working memory limitations in other populations. This study examined the potential of guanfacine for improving context processing, a feature of working memory, in SPD. METHODS: 29 individuals with SPD entered into a 4-week, randomized parallel-design, double-blind, placebo-controlled trial of guanfacine treatment, followed by a 4-week open-label extension. A modified version of the AX-Continuous Performance Test (AX-CPT) was administered. On this task, evidence of intact context processing includes few BX errors (false cue, correct probe) and higher levels of AY errors (correct cue, false probe). RESULTS: At the end of double-blind treatment, participants treated with guanfacine demonstrated a significant reduction in BX errors and a small but significant increase in AY errors, a pattern that was not seen in the participants treated with placebo. CONCLUSIONS: SPD participants improved in their context processing toward a normal response bias, making fewer BX and more AY errors, after being treated with guanfacine.     

Noradrenergic modulation of space exploration in visual neglect

Visual neglect after stroke is often associated with a failure to explore contralesional space. Here, we show that guanfacine, a noradrenergic agonist that modulates dorsolateral prefrontal cortex, improves leftward space exploration in selected right-hemisphere patients with neglect. The positive effects of guanfacine were associated with extended ability to maintain attention on task. The results suggest that neuropharmacological targeting of intact frontal areas might be one way to enhance cognitive function after damage to posterior brain regions in selected individuals.     

Effects of the alpha-2 adrenoceptor agonist guanfacine on attention and working memory in aged non-human primates

Alpha-2 adrenergic receptors are potential targets for ameliorating cognitive deficits associated with aging as well as certain pathologies such as attention deficit disorder, schizophrenia and Parkinson's disease. Although the alpha-2 agonist guanfacine has been reported to improve working memory in aged primates, it has been difficult to assess the extent to which these improvements may be related to drug effects on attention and/or memory processes involved in task performance. The present study investigated effects of guanfacine on specific attention and memory tasks in aged monkeys. Four Rhesus monkeys (18-21 years old) performed a sustained attention (continuous performance) task and spatial working memory task (self-ordered spatial search) that has minimal demands on attention. Effects of a low (0.0015 mg/kg) and high (0.5 mg/kg) dose of gunafacine were examined. Low-dose guanfacine improved performance on the attention task [i.e. decreased omission errors by 50.8 ± 4.3% (P = 0.001) without an effect on commission errors] but failed to improve performance on the spatial working memory task. The high dose of guanfacine had no effects on either task. Guanfacine may have a preferential effect on some aspects of attention in normal aged monkeys and in doing so may also improve performance on other tasks, including some working memory tasks that have relatively high attention demands.     

Divergent effects of putative anxiolytics on stress-induced fos expression in the mesoprefrontal system of the rat

Previously, we reported that R(+)HA-966, a weak partial agonist for the glycine/NMDA receptor, and guanfacine, a noradrenergic alpha2 agonist, have anxiolytic-like actions on the biochemical activation of the mesoprefrontal dopamine neurons and fear-induced behaviors. Here, we examined these two putative anxiolytic agents, both with primary actions independent of GABAergic systems, for their ability to alter stress-induced Fos-like immunoreactivity in the mesoprefrontal cortex and in tyrosine hydroxylase-stained, presumed dopaminergic, neurons in the ventral tegmental area. The benzodiazepine agonist, lorazepam, and partial agonist, bretazenil, were also tested in this footshock paradigm [10 x 0.5 sec, 0.8 mA paired with a 5-sec tone]. In saline-treated rats, footshock resulted in an increase in Fos-li in the prelimbic and infralimbic cortices and tyrosine hydroxylase-labeled cells in the ventral tegmental area. Treatment with lorazepam or bretazenil prevented the stress-induced activation in Fos-li nuclei in all regions of the medial prefrontal cortex and in dopaminergic neurons in the ventral tegmental area. In contrast, the actions of the novel anxiolytic-like agents on stress-induced Fos-li were different than those observed with benzodiazepine agonists. Both putative anxiolytics, R(+)HA-966 and guanfacine, did not reduce, but significantly enhanced the stress-induced Fos-li in the prelimbic region of the medial prefrontal cortex. Additionally, treatment with R(+)HA-966 completely blocked, while guanfacine attenuated, the stress-induced increase in the number of Fos-li, TH-li cells in the ventral tegmental area. These results indicate that the putative anxiolytics, R(+)HA-966 and guanfacine, have actions on the stress-sensitive mesoprefrontal system which appear distinct from those of traditional anxiolytics.     

Evidence that behavioural and electrocortical sleep induced by guanfacine is due to stimulation of α2-adrenoceptors

The effects of guanfacine and other drugs acting at α₁- and α₂-adrenoceptors on behaviour, electrocrotical activity and ECoG spectrum power were studied in chicks and rats. Guanfacine, given systematically in chicks, produced behavioural and electrocoritcal slow-wave sleep lasting 100–200 min, depending on the dose; these effects were prevented by yohimbine, a selective antagonist, at α₂-adrenoceptors and potentiated by prazosin, a selective antagonist, at α₁-adrenoceptors. Similar behavioural and electrocortical effects were obtained after systemic or intraventricular infusion of guanfacine in rats. In addition, a significant increase in total and in lower frequency band (0–4; 4–8 Hz) voltage power was observed. Behavioural and ECoG effects of guanfacine were prevented by phentolamine or yohimbine, whereas prazosin and propranolol were ineffective. Yohimbine itself, given systemically in chicks, produced behavioural stimulation, vocalization, increase in locomotor activity and ECoG desynchronization, with a significant fall in total and 0–3, 3–6, 6–9 and 9–12 Hz voltage power lasting approx. 3 h. Desipramine, an inhibitor of noradrenaline reuptake, produced in chicks behavioural and ECoG arousal, vocalization, pecking, escape responses and aggressive behaviour.In conclusion, the present experiments show that guanfacine sedative effects seem to be mediated predominantly via an activation of presynaptic α₂-adrenoceptors and suggest that arousal is due to stimulation of post-synaptic α₁-adrenoceptors.     

Electroencephalographic and psychometric assessment of the CNS effects of single doses of guanfacine hydrochloride (Estulic) and clonidine (Catapres)

A double-blind, placebo-controlled study was carried out in 10 young healthy volunteers to investigate the effects of single doses of 1 and 2 mg guanfacine hydrochloride (Estulic) and 0.15 and 0.3 mg clonidine (Catapres) on the electroencephalogram (EEG), subjective mental and emotional state, blood pressure and heart rate. These doses are considered to be equipotent with regard to their antihypertensive effects, as shown in long-term therapeutic trials. Each subject received all five treatments in random sequence at intervals of 1 week. The EEG tracings were evaluated quantitatively by spectral analysis. Procedures were carried out before and at 1, 2, 4, 6 and 8 h after drug administration. After clonidine the EEG showed increased slow-wave activity and decreased alpha activity, these effects being dose-dependent. They were of the sedative type and did not clearly indicate specific psychotropic properties. The subjective mental and emotional state questionnaire indicated a decrease of alertness, extroversion, concentration and mood (in that order), changes which paralleled the EEG changes. The changes observed after guanfacine were qualitatively similar to those after clonidine, but were of considerably lower intensity. Our data suggest that guanfacine has less central nervous system-depressant activity than clonidine.     

Methylphenidate,Guanfacine, and Combined Treatment Effects on Electroencephalography Correlates of Spatial Working Memory in Attention-Deficit/Hyperactivity Disorder

ObjectiveThe combination of d-methylphenidate and guanfacine (an α-2A adrenergic agonist) may be an effective alternative to either agent as monotherapy in children with attention-deficit/hyperactivity disorder (ADHD). This study investigated the neural mechanisms underlying medication effects using cortical source analysis of electroencephalography (EEG) data.MethodA total of 172 children with ADHD (aged 7-14; 118 boys) completed an 8-week randomized, double-blind, comparative study with 3 treatment arms: d-methylphenidate, guanfacine, or their combination. EEG modulations of brain oscillations at baseline and end point were measured during a spatial working memory task from cortical sources localized within the anterior cingulate (midfrontal) and primary visual cortex (midoccipital), based on previously reported ADHD and control differences. Linear mixed models examined treatment effects on EEG and performance measures.ResultsCombined treatment decreased midoccipital EEG power across most frequency bands and task phases. Several midoccipital EEG measures also showed significantly greater changes with combined treatment than with monotherapies. D-methylphenidate significantly increased midoccipital theta during retrieval, while guanfacine produced only trend-level reductions in midoccipital alpha during maintenance and retrieval. Task accuracy improved with combined treatment, was unchanged with d-methylphenidate, and worsened with guanfacine. Treatment-related changes in midoccipital power correlated with improvement in ADHD severity.ConclusionThese findings show that combined treatment ameliorates midoccipital neural activity associated with treatment-related behavioral improvements and previously implicated in visuo-attentional deficits in ADHD. Both monotherapies had limited effects on EEG measures, with guanfacine further showing detrimental effects on performance. The identified midoccipital EEG profile may aid future treatment monitoring for children with ADHD.Clinical trial registration informationSingle Versus Combination Medication Treatment for Children With Attention Deficit Hyperactivity Disorder (Project1); https://clinicaltrials.gov/; NCT00429273.Diversity & Inclusion StatementWe worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure sex and gender balance in the recruitment of human participants. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. While citing references scientifically relevant for this work, we also actively worked to promote sex and gender balance in our reference list. We actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our author group. We actively worked to promote sex and gender balance in our author group.     

Anxiolytics, adrenergic agents, and naltrexone

OBJECTIVE: To review extant data on the efficacy and safety of anxiolytic medications (benzodiazepines, buspirone, and other serotonin 1A agonists), adrenergic agents (beta-blockers and alpha 2-adrenergic agonists clonidine and guanfacine), and the opiate antagonist naltrexone that have been used to treat various psychopathologies in children and adolescents. To identify critical gaps in our current knowledge about these agents and needs for further research. METHOD: All available controlled trials of these medications in children and adolescents published in English through 1997 were reviewed. In addition, selected uncontrolled studies are included. RESULTS: The major finding, that there are virtually no controlled data that support the efficacy of most of these drugs for the treatment of psychiatric disorders in children and adolescents, is both surprising and unfortunate. For some drugs, e.g., buspirone and guanfacine, this is because no controlled studies have been carried out in children and/or adolescents. For other drugs, e.g., clonidine and naltrexone, most of the placebo-controlled studies have failed to demonstrate efficacy. CONCLUSIONS: The strongest recommendations for controlled studies of safety and efficacy in children and adolescents can be given for the following drugs: benzodiazepines for acute anxiety; buspirone (and newer serotonin 1A agonists as they become available) for anxiety and depression; beta-blockers for aggressive dyscontrol; guanfacine for attention-deficit/hyperactivity disorder; and naltrexone for hyperactivity, inattention, and aggression in autistic disorder.     

Noradrenergic alpha-2 agonists have anxiolytic-like actions on stress-related behavior and mesoprefrontal dopamine biochemistry

Clonidine (CLON), an alpha-2 agonist, has anxiolytic-like actions on the response of mesoprefrontal dopamine (DA) neurons to aversive stimuli in addition to some fear-related behavioral responses. We hypothesized that the anxiolytic-like actions of clonidine could be mimicked by stimulation of alpha-2 receptors on the mesoprefrontal dopamine neurons. Here, we test this hypothesis using clonidine or guanfacine (GFC), another alpha-2 agonist, in a model of aversive conditioning that selectively activates the mesoprefrontal dopamine neurons. One day prior to testing with drugs, rats were conditioned to fear a soft tone by pairing it with a footshock. During testing, the animals were subjected to the tones alone after drugs were administered systemically, or by local infusion into the regions containing the cell bodies and terminals of the mesoprefrontal dopamine neurons, namely, the ventral tegmental area (VTA) and the prelimbic (PL) cortex. Systemic administration of guanfacine blocked the increase in immobility in response to the conditioned tone and prevented the stress-associated increase in dopamine turnover in the prelimbic cortex. Systemic clonidine also prevented the stress-associated increase in dopamine turnover but caused sedation preventing behavioral measures. Guanfacine was then used in all local injection studies. The local application of guanfacine into either the prelimbic cortex or the ventral tegmental area did not prevent the conditioned fear-induced increase in dopamine turnover or the increase in immobility in response to the conditioned tones. We conclude that the anxiolytic-like actions of alpha-2 agonists are not due to binding to alpha-2 receptors on the stress-sensitive mesoprefrontal dopamine neurons.     

Effects of α-adrenoceptor agonists in chronic morphine administered DSP4-treated rats: Evidence for functional cross-sensitization

Five experiments were performed to study the effects of the α-adrenoceptor agonists, clonidine and guanfacine, upon spontaneous motor activity in chronically morphine administered DSP4-treated and control rats. DSP4 (2 × 50 mg/kg, with a 10-day interval between injections) and vehicle (distilled water) were injected i.p., on each occasion 30 min after zimeldine (20 mg/kg). Morphine dosages were raised incrementally from 5 mg/kg (Days 1–3), through 10 mg/kg (Days 4–17) and 20 mg/kg (Days 8–14), to 30 mg/kg (Days 15–20). Motor activity testing occurred on Day 21, Day 22 as well as in Experiments II-V, (from 1^st morphine injection). DSP4 pretreatment and chronic morphine injections each reduced motor activity during the first 30 min of testing; combined DSP4 and morphine treatment potentiated the hypoactivity. Habituation quotients indicated deficits in habituation to the novel test environment by the Vehicle-morphine (Quotient² only) and DSP4-morphine groups. Acute clonidine treatment (0.04 mg/kg, s.c.) reduced motor activity during the first 30 min of testing but attenuated or blocked the morphine-induced hypoactivity in DSP4-treated and control rats. During the 60–90 min test period, clonidine, but not guanfacine (0.08 mg/kg), potentiated morphine-induced hyperactivity in control rats; acute clonidine enhanced this effect, whereas acute guanfacine reduced it, in the DSP4-treated rats. The enhanced hyperactivity of morphine-clonidine suggest a cross-sensitivity effect. Naloxone (0.1 mg/kg, s.c), injected after the 1^st 30-min of testing, potentiated markedly the clonidine-induced elevations of motor activity in morphine-administered control rats; in the DSP4-treated rats, these effects were dramatically potentiated, underlining the cross-sensitivity effect. Acute guanfacine treatment reduced motor activity during the first 30 min of testing but did not attenuate reliably morphine-induced hypoactivity in control or DSP4 rats. Naloxone did not potentiate the guanfacine-induced hyperactivity of morphine-administered control rats but induced a marked enhancement in the DSP4-treated rats, a specific case of cross-sensitivity. The major findings pertain to a cross-sensitization effect of morphine upon clonidine-induced motor activity in both DSP4-treated and control rats, and to a lesser extent between morphine and guanfacine in NA-denervated rats only. The results may offer interactive implications for noradrenergic-opiate system functioning that may be of influence under neuropathological conditions.     

Spontaneous EEG paroxysms in the rat: effects of psychotropic and alpha-adrenergic agents

Approximately 20% of Charles River rats which were chronically implanted with brain electrodes for EEG recordings exhibited within half a year of the implantation spontaneous, paroxysmally occurring, steep EEG potentials of high amplitude (spikes and waves) whilst falling asleep. These EEG paroxysms were dose dependently antagonized by the 'petit mal' drugs dipropylacetate, ethosuximide and trimethadione as well as by the anticonvulsant drugs diazepam and nitrazepam. The neuroleptics chlorpromazine, haloperidol and thioridazine prolonged the EEG paroxysms. The alpha 1-adrenoceptor antagonist prazosin and the alpha 2-adrenoceptor agonists guanfacine and clonidine prolonged, whereas the alpha 2-adrenoceptor antagonist yohimbine shortened, the EEG paroxysms. The effect of guanfacine was antagonized by yohimbine. The convulsant drugs bicuculline, 3-mercaptopropionic acid and pentetrazol had only a slight influence on the EEG paroxysms. The results are discussed with respect to the anti- and proconvulsant and convulsant activity of psychotropic drugs and their underlying mechanisms of action, particularly with regard to their interaction with central alpha-adrenergic mechanisms.     

Local infusion of an alpha-1 adrenergic agonist into the prefrontal cortex impairs spatial working memory performance in monkeys.

BACKGROUND: Stimulation of alpha-2 adrenoceptors in the monkey or rat prefrontal cortex (PFC) has been known to improve spatial working memory (SWM) and stimulation of alpha-1 adrenoceptors in the rat PFC has been reported to impair SWM. The present study attempted to replicate in monkey the rat experiments on alpha-1 adrenoceptor stimulation. METHODS: The alpha-1 adrenergic agonist phenylephrine or the alpha-2 adrenergic agonist guanfacine was infused into the dorsolateral prefrontal cortex (dlPFC) of monkeys performing the delayed-response (DR) task, a task of SWM, to see how the drugs affect SWM performance. RESULTS: Phenylephrine infusion in dlPFC significantly impaired DR performance, whereas guanfacine improved performance. The effects of both drugs were delay-dependent. Infusions outside dlPFC were ineffective. CONCLUSIONS: Stimulation of prefrontal cortical alpha-1 adrenoceptors impairs SWM function in monkeys, consistent with the parallel study in rats, whereas stimulation of alpha-2 adrenoceptors improves SWM, indicating that alpha-1 and alpha-2 adrenoceptors may have opposing roles in the PFC.