Many of us have experienced the fight-or-flight response to stressful situations such as exams, important business meetings or public speeches. Many stage performers are plagued by “stage fright”, aka performance anxiety, manifesting itself as rapid heartbeat, sweating, butterflies in the stomach, urge to urinate, shaky hands and legs, nausea and dry mouth. This is the main action of the sympathetic nervous system (SNS) whose neurons release norepinephrine (noradrenaline) in response to fear, which further triggers the release of epinephrine (adrenaline) from the adrenal medulla, which in turn triggers changes in different parts of the body such as increased heart rate, vasoconstriction, sweating, bladder contraction, etc. The purpose of this sympathetic response is to prime our body for fighting or fleeing, which helped our ancestors to survive. However, in modern times, this response often reduces our social functioning: the fight response leads to angry confrontations, and the flight response leads to social withdrawal, both of which are typical in autism. Norepinephrine-induced hyperarousal also interferes with learning. “Norepinephrine may play a role in some… cognitive impairments associated with ASD” [R].
Mechanism of NE action
Norepinephrine (NE) is the primary neurotransmitter of the sympathetic nervous system. It is formed from the amino acid L-tyrosine, which is first converted to L-dopa through tyrosine hydroxylase and then to dopamine by dopa-decarboxylase and then to NE through β-hydroxylation inside storage vesicles of adrenergic neurons. NE is released by these neurons in response to fear. It then activates postsynaptic β-adrenergic receptors, which are coupled to the stimulatory G proteins, Gs. Upon their activation, Gs-proteins stimulate adenylyl cyclase to form cAMP from ATP. Increased cAMP activates a cAMP-dependent protein kinase (PKA) that phosphorylates L-type calcium channels, which causes increased calcium entry into the cell (excitation). Depending on the cell location in the body, the described sympathetic activation leads to different attributes of the fight-or-flight response: vasoconstriction, increased heart rate, reduced pain sensitivity, etc. Elevated NE is typical in hypertension and bipolar disorder. It can also lead to excessive neuronal activity and seizures [R].
NE interacts with adrenoreceptors. There are two main groups of adrenoreceptors, α and β, with 9 subtypes in total:
- α are divided to α1 (α1A, α1B and α1D) and α2 (α2A, α2B and α2C)
- β are divided to β1, β2 and β3.
Activation of α1 receptors by NE activates phospholipase C activity through Gq protein, which in turn triggers a cascade of reactions leading to the influx of calcium into the cell. This causes vasoconstriction in many blood vessels, including those of the brain. β-adrenoceptors are coupled to Gs-proteins, which activate adenylyl cyclase to form cAMP from ATP. Increased cAMP activates a cAMP-dependent protein kinase (PKA) that phosphorylates L-type calcium channels, which causes increased calcium entry into the cells. This increases the heart rate. Activation of postsynaptic α2 receptors by NE decreases adenylyl cyclase activity through the inhibitory G protein, Gi, which is the opposite action to β-adrenergic receptors. Activation of presynaptic α2 adrenergic receptors reduces the release of NE from the presynaptic neuron. Because β- and α2-adrenoreceptors have the opposite effect on the NE activity, their combined net effect depends on their relative ratio in a specific tissue.
The stimulating effect of NE on its target organs such as blood vessels and heart is counteracted by the acetylcholine-mediated effects of the parasympathetic nervous system. These organs are innervated by both sympathetic adrenergic and parasympathetic cholinergic nerves. On one hand, acetylcholine (ACh) triggers NE release from the sympathetic adrenergic nerves, which acts on α and β adrenoreceptors and causes vasoconstriction and increased heart rate. On the other hand, ACh released from the parasympathetic cholinergic nerves stimulates muscarinic receptors on the same organs, reducing vasoconstriction and heart rate.
NE and aggression
Limbic regions of the brain, such as the frontal neocortex and hypothalamus, are known to contain significant levels of adrenergic receptors and to modulate behavior. High levels of NE have been associated with aggression [R, R, R, R]. A genetic deficiency in the MAOA enzyme (the ‘warrior gene’) increases NE and has been linked to the inheritable ‘hot temper’. Substances that enhance central NE function, such as tricyclic antidepressants, MAOA inhibitors, presynaptic α2 antagonists, and β agonists have been shown to increase fighting in rodents [R, R, R]. Total β-adrenoreceptor concentration in the cerebellum cortex of aggressive Alzheimer’s disease (AD) patients has been found to be 25% higher than that of age-matched nonaggressive AD patients and healthy controls [R], suggesting a possible link between aggression and β-adrenoreceptors. Among these receptors, blocking β2 but not β1 receptors reduced aggression in mice, triggered by tricyclic antidepressant Desipramine [R].
Along with social dysfunction and restricted behaviors, autism is often accompanied by impulsivity, anxiety, and aggression that resemble states of sympathetic autonomic arousal, suggesting a possible involvement of NE. Autistic children demonstrate rapid heart rate and elevated sweating compared with children without ASD [R, R] – markers that are associated with aggression [R]. NE induces the secretion of adrenocorticotropic hormone (ACTH) from the pituitary gland, which in turn induces cortisol secretion from the adrenal glands, thus leading to anxiety.
Hypoglycemia triggers the release of another fight-or-flight hormone, epinephrine (adrenalin), from the adrenal glands, which signals the liver and kidneys to produce more glucose [R]. It is also associated with adverse behaviors such as aggression, social withdrawal and depression [R, R, R]. These behaviors have been shown to be dependent on β2-receptor-mediated pathway [R]. Blocking β2 receptors blocks sympathetic manifestations of hypoglycemia.
NE and cognition
NE increases alertness as part of the fight-or-flight response. However, it may produce hyperarousal that interferes with learning. It has been associated with some autism-related cognitive impairments [R]. Overactivity of NE has also been associated with positive symptoms of schizophrenia [R]. NE is also implicated in the pathogenesis of some AD cases, as suggested by an elevated endogenous NE in the Alzheimer’s brains [R] and the ability of the α1 antagonist Prazosin to reduce the generation of amyloid β (Aβ) in N2a cells and promote an anti-inflammatory response and better memory [R].
In the prefrontal cortex (PFC), activation of either α1 or β receptors leads to opening of nearby potassium (K+) channels to rapidly weaken connections and reduce PFC neuronal firing. Activation of α2 receptors inhibits adenylyl cyclase and closes these potassium channels, thus strengthening the functional connectivity of PFC networks [R, R]. Because α1 and β adrenoceptors have lower affinity to NE than α2 receptors [R], cognition is an inverse U function of NE levels: it peaks at certain NE levels and then drops. Low NE levels (as in non-stress situations) favorably activate α2-receptors, thus improving the PFC function [R]. Under conditions of high NE release such as stress, NE activates favorably lower-affinity α1 and β adrenoceptors, thus suppressing PFC firing and impairing cognition [R, R]. Under these conditions, emotional responses of amygdala are amplified by NE and DA-mediated activation of β, α1 and D1 receptors [R] and weakly attenuated by α2 receptor activation [R, R]. High levels of NE and DA can switch the behavioral control from PFC to amygdala resulting in ADHD comorbid symptoms of impulsivity and aggression [R].
Blockade of α2 adrenoceptors markedly impairs PFC function and mimics most of the ADHD symptoms, including impulsivity and hyperactivity [R]. It also prevents methylphenidate (which increases NE and DA) from improving working memory [R]. Conversely, stimulation of α2 adrenoceptors improves working memory, strengthens PFC regulation of behavior, and reduces distractibility [R]. However, there is contradicting data that stimulation of α2A receptors inhibits excitatory synaptic transmission in the mPFC through a post-synaptic mechanism [R]. This inhibition of mPFC cannot lead to “strengthening PFC function”. The view on α1 adrenoceptors is also controversial. Activation of α1 receptors in medial PFC has been shown to impair working memory performance of rats but improve their performance in sustained attention and a set-shifting task [R, R], which measures the ability to inhibit responding to the initial rule and adapt responding according to the second rule. Conversely, blockade of α1 receptors improves working memory but completely prevents the beneficial effects of methylphenidate on sustained attention [R]. There are also contradicting reports that α1 agonism improves working memory performance [R].
- Propranolol is a nonselective beta (both β1 and β2) blocker. Originally approved as a high-blood-pressure medication, it has been successfully used off-label to treat “stage fright” in stage performers and violent behaviors in psychiatric and autistic patients [R, R, R, R]. Small studies showed that Propranolol also improves verbal fluency, conversational reciprocity and working memory in autistic patients [R, R, R]. These effects may be due to reduced hyperarousal. As patients become less anxious and defensive, more social and adaptive behaviors appear. There is an ongoing clinical trial of Propranolol on social interaction, language tasks, anxiety, and adaptive behaviors in autistic children and young adults [R]. In studies on rats, Propranolol reduced Yohimbine-induced perseverative behavior whereas Guanfacine and Prazosin had no effect [R]. Some rare side effects include abnormally low heart rate (bradycardia), fatigue, reduced exercise capacity, depression, and sexual dysfunction. The last side effect is due to the Propranolol’s ability to significantly reduce free and total testosterone [R], which is why this drug is often used off label to treat hypersexuality [R].
Summary of clinical trials [R]: From the eight single-dose clinical trials, Propranolol led to significant improvements in cognitive performance – verbal problem solving, social skills, mouth fixation, and conversation reciprocity; and changes in neural correlates – improvement in semantic networks and functional connectivity. The remaining eight case series and single case reports showed improvements in EBAD, anxiety, aggressive, self-injurious and hypersexual behaviors. Additionally, Propranolol significantly improved similar behavioral domains (aggression and self-injury) for those with acquired brain injury.
Case report 1 [R]: A 20-year-old man diagnosed as having moderate intellectual disability and generalized epilepsy … with severe aggression, both verbal and physical, occurring with little or no provocation over the past 3 years. These episodes would last up to several hours and often led to food refusal… After the onset of his aggression, it was difficult to engage him in any activities, including basic self-care… He was seizure-free for the past 4 years on Carbamazepine 1,000 mg/d and Diazepam 10 mg/d, and he had never exhibited postictal aggression in the past. He had already received trials of Olanzapine (up to 15 mg/d for 6 weeks) and Chlorpromazine (up to 400 mg/d for 3 months) without significant improvement… He was given a trial of Propranolol, starting at 20 mg/d and increased by 20 mg every week. At 40 mg/d, there was a significant reduction in his aggression, and his food intake was better. On further increasing the dose to 60 mg/d, his mother reported that he was essentially “normal,” with no significant episodes of aggression. Over the next year, Olanzapine and Chlorpromazine were tapered and stopped, and he remained stable. He has been well on Carbamazepine 1,000 mg/d, Propranolol 60 mg/d, and Diazepam 10 mg/d for the past 3 months with no recurrence of either seizures or aggression, and it is now possible to engage him in household tasks and speech therapy.
Case report 2 [R]: A 25-year old man with ASD was admitted to the hospital due to “getting angry at home” for over a month… Discussions between the patient and his mother became increasingly heated, and the patient began to exhibit behavior that ranged from verbal insults to destruction of doors and windows in their shared home. His previously fluent speech began to include stuttering and echolalia, which were mild prior to his exacerbation. His past medications included Clomipramine, Risperidone, and Pemoline (a dopaminergic stimulant), but he had been stable off of medication prior to this exacerbation. When initially evaluated, the patient … displayed impulsive and inappropriate behaviors that included shouting jokes into the telephone handset, pacing the hallways, knocking on other patients’ doors, and initiating loud conversations with inappropriate laughter. When playing board games, he would exhibit aggressive outbursts and sweep the game pieces off the board when he lost. Throughout his hospital stay, he stuttered during single sentences and experienced episodes of noticeable echolalia. A basic metabolic panel, lipid panel, and electrocardiogram obtained on admission were normal. Monotherapy with the beta blocker Propranolol 20 mg twice daily was started for behavioral and verbal control and its known benefit in the treatment of neuroleptic-induced akathisia, which was a possible contributor to the patient’s agitation from prior antipsychotic use. Two days later, he impulsivity subsided, and he participated in group activities on the unit without disruption. Four days into treatment, he developed friendships on the unit, held quiet conversations, and engaged in board games without anger. He tolerated emotional conversations…, and the frequency of stuttering and echolalia decreased. He denied any side effects… With the behavioral improvement on Propranolol and stable vital signs, the patient was safely discharged without additional medications.
Case report 3 [R]: A 13-year-old boy with a history of autism was presented to the outpatient psychiatric clinic for hypersexual behaviors that started at the onset of puberty. The behaviors affected his functioning both at school and home. A trial of low-dose Propranolol, 0.3 mg/kg/d (10 mg twice a day), targeting hypersexual behavior led to remarkable clinical improvement. The behaviors remained stable on this dose of Propranolol for 1 year.
- Guanfacine, a selective α2A receptor agonist, and Clonidine, a nonselective α1/α2 receptor agonist, have been used off-label to treat oppositional and aggressive behaviors mainly in children with ADHD [R, R, R, R]. Both drugs suppress the NE release from sympathetic nerve endings in different organs including prefrontal cortex, which helps to eliminate irrelevant attention and behavioral reaction to stressors and improve task-specific focus [R], which is why they have been approved and used as nonstimulant ADHD drugs [R]. Both drugs improve spatial memory performance in humans, but only Guanfacine improve planning and working memory performance whereas Clonidine disrupts it [R]. Clonidine also disrupts performance in an attentional task with distractors [R] but significantly ameliorates PPI deficits in schizophrenia [R]. Both drugs have a pronounced sedative effect (Clonidine is even used off-label as a sleep-aid medication). Clonidine impaired alertness while reducing left PFC activity during temporal orienting and right superior parietal cortex activity during spatial orienting whereas Guanfacine showed no such effect [R]. On the contrary, Guanfacine has been shown to increase cerebral blood flow in the dorsolateral PFC of monkeys performing a spatial working memory task [R] and of cocaine addicts during drug cue conditions [R]. At high doses, Clonidine can actually cause aggression due to its blockade of adenosine receptors [R] and has been used to model aggression in mice [R]. Both drugs counteract the hyperdopaminergic state induced by NMDA antagonists [R]. Guanfacine and Clonidne must not be combined with Propranolol because all three reduce blood pressure.
- Prazosin is the only clinically available α1 adrenoceptor antagonist that readily crosses from the blood into the brain. Originally developed to treat hypertension, it is widely used to treat PTSD-related nightmares and insomnia [R, R]. When compared to Propranolol and Hydrochlorothiazide, Prazosin had the most advantageous profile of blood pressure control, cognitive and psychomotor effects, changes in lipid levels, and magnitude of side effects in hypertensive patients [R]. In a randomized study of patients with Alzheimer’s disease, Prazosin administration was associated with substantial reduction in agitation and aggression without hypotension or other significant adverse effects [R]. Prazosin has been shown to improve PFC function and weaken amygdala function in animal studies [R]. In combination with a 5-HT6 antagonist, Prazosin alleviated stereotypy and hyperactivity while enhancing memory in an object recognition task, and reversed sensory-gating deficits induced by the NMDA blocker Dizocilpine [R]. On the other hand, Prazosin reversed the cognitive enhancing effects of Modafinil in healthy volunteers [R] and impaired spatial avoidance learning in rats when combined with Propranolol [R].
- Anticonvulsant Carbamazepine, which is also used to treat bipolar disorder, decreases NE release in people suffering from mania [R]. It has been shown to reduce aggression in mice evoked by high dose of Clonidine [R].
- Calcium channel blockers such as Verapamil, Nifedipine and Diltiazem, inhibit NE release from the sympathetic nerve endings [R, R, R]. Activating L-type calcium channels has been shown to trigger self-injurious biting in mice, which was inhibited by pretreating the mice with dihydropyridine L-type calcium channel antagonists such as Nifedipine, Nimodipine, or Nitrendipine [R]. Verapamil diminished aggressive behavior in male Siamese fighting fish [R]. There have been no published reports on use of calcium channel blockers to control aggression in humans. The number of articles on the use of calcium channel blockers in the treatment of anxiety disorders is low. Three reports (two open, one double-blind) described some success in the treatment of panic disorder with Verapamil, Diltiazem, or Nimodipine and one open-label study described unsuccessful treatment of anxiety and phobia with Nifedipine in patients with various anxiety disorders [R]. Chronic use of calcium channel blockers for hypertension has been shown to reduce risk of AD [R].
- Among supplements, lithium decreases NE availability and increases tryptophan uptake. Tryptophan reduces tyrosine absorption and also increases serotonin. It should not be combined with SSRI’s. Taurine and L-theanine reduce NE release [R, R, R, R]. Magnesium inhibits NE release by blocking N-type calcium channels [R]. St John’s wort inhibits dopamine β-hydroxylase (DBH) [R, R, R], which converts dopamine into NE. Blocking DBH reduces NE but also increases dopamine, which can worsen or cause mania [R]. St. John’s wort should not be combined with SSRI’s because of its MAO inhibition. Avoid things that increase NE such as B6, folate, caffeine, tyrosine, phenylalanine, L-dopa, acetyl-L-carnitine, phosphatidylserine, Atomoxetine (Strattera), Bupropion (Wellbutrin), Amphetamine, Modafinil, tricyclic antidepressants, Yohimbine, Ginkgo Biloba [R], Curcumin, Ginseng, etc.
Norepinephrine is the key neurotransmitter responsible for acute anxiety and anger related to the fight-or-flight response. Poor feedback control of NE action is the cause of “bad temper”. Activation of beta (and more specifically β2) adrenergic receptors by NE is responsible for aggression. It can be successfully treated by the non-selective beta-blocker Propranolol, which is a blood pressure medication often used off-label by stage performers for performance anxiety. Guanfacine can also reduce impulsivity by activating α2A receptors and increasing the PFC function and its behavioral control. Adding lithium orotate (5-10mg), magnesium, taurine (500mg before bed) and tryptophan (500mg before bed) can further reduce anxiety and aggression and improve sleep.