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Overview of Neurotransmission: Relationship to the Action of Antiepileptic Drugs
Published in Carl L. Faingold, Gerhard H. Fromm, Drugs for Control of Epilepsy:, 2019
Unlike the nicotinic cholinergic receptor and the GABAA receptor, which are intimately associated with an ion channel and produce ultra-rapid effects, the catecholamine receptors mediate their effects through second messenger systems and guanine nucleotide regulatory proteins or G-proteins.4,10 Both beta-1 and beta-2 adrenoceptors are linked to adenylate cyclase in the membrane by a Gs (stimulatory G) protein which is activated by a combination between the receptor protein and an adrenergic agonist. The alpha subunit of the Gs protein with GTP bound to it can then interact with adenylate cyclase and activate it, leading to the conversion of ATP to cyclic AMP. The latter can in turn activate various protein kinases which are involved in the phosphorylation of various proteins that regulate membrane ion transport to alter membrane potentials (Figure 4). The alpha-2 adrenergic receptor also mediates its effect on membrane potential through a G-protein and adenylate cyclase activity, but unlike the beta receptors, the alpha-2 receptor is linked to a Gi protein which causes an inhibition of adenylate cyclase and a reduction in the amount of cyclic AMP (and presumably a reduction in protein phosphorylation) in the neuron.
Anxiolytics: Predicting Response/Maximizing Efficacy
Published in Mark S. Gold, R. Bruce Lydiard, John S. Carman, Advances in Psychopharmacology: Predicting and Improving Treatment Response, 2018
Stimulation of the afferent receptors depresses neuronal firing or removes active neurotransmitters. Opiates stimulate the endorphin receptor.Benzodiazepines stimulate the benzodiazepine receptor.Clonidine stimulates the alpha-2 adrenergic receptor.Blockade of the afferent receptors enhances neuronal firing and adds active neurotransmitter.Naloxone blocks the endorphin receptor.157
Chronic Fatigue Syndrome: Limbic Encephalopathy in a Dysregulated Neuroimmune Network
Published in Jay A. Goldstein, Chronic Fatigue Syndromes, 2020
Temperature regulation occurs, in part, in the anterior hypothalamus, where the “thermostat” is. This group of cells senses the temperature of the blood flowing through this region and adjusts the heat conservation and dissipation mechanisms accordingly. The most effective way the body has to eliminate heat is by perspiration, which involves the sympathetic and parasympathetic nervous system and cutaneous vasodilatation. Body temperature can be regulated by altering the hypothalamic “set point.” Fever is probably caused by cytokines such as IL-1 which has a dense receptor population in the anterior hypothalamus. CFS patients are well known to have disorders of temperature regulation. Perhaps one-third have intermittent mild fevers. More commonly, subnormal temperatures are encountered, although patients may feel warm. Night sweats occur primarily in NREM sleep and may be related to the alpha-EEG abnormality and dysregulation of nocturnal IL-1 secretion. The perspiration that CFS patients report is not due to gonadal steroid insufficiency with elevated gonadotropic hormones, since estrogen replacement therapy is usually ineffective, and other signs of a menopausal syndrome are not present. Elevated levels of cytokines in the CFS patient may be responsible for raising the hypothalamic set point in some patients, but a more likely cause is a hypothalamic dysfunction in the autonomic integration required for the maintenance of body temperature. Supporting this hypothesis is the observation that alterations in temperature can increase CFS symptomatology. The most obvious example is in Raynaud’s syndrome. A subpopulation of patients with fibromyalgia have increased density of platelet alpha-2 adrenergic receptors, which may predispose them to cold-induced and emotionally induced vasospasm.86 Platelet adrenergic receptor status may mirror that of the brain adrenergic receptors. Thus it is likely that either alpha-2 adrenergic receptor density is altered in limbic structures, and/or that the regulation of expression of peripheral adrenergic receptors is deranged. Efferent pathways from the anterior hypothalamus to other limbic structures and to the periphery may be responsible for CFS relapse during hot or cold weather. The increased density of alpha-2 adrenergic receptors may be responsible for some of the pain in FM as well, since autonomic dysregulation of blood flow to muscles has been postulated as being contributory to FM, and sometimes regional sympathetic blockade relieves pain in FM. Clonidine often relieves CFS night sweats, probably by its action as a presynaptic alpha-2 agonist. Heat often exacerbates CFS symptoms, as it does to those of multiple sclerosis. Heat and humidity have been suggested as the precipitants of summer seasonal affective disorder.
Sublingual dexmedetomidine: repurposing an anesthetic as an anti-agitation agent
Published in Expert Review of Neurotherapeutics, 2023
Justin Faden, Meghan Musselman, Leslie Citrome
The alpha-2-adrenergic receptor is an autoreceptor that regulates the release of norepinephrine. Excess norepinephrine is a contributor to hyperarousal states such as agitation and panic. There are three subtypes of the alpha-2 adrenergic receptor, alpha-2A, alpha-2B, and alpha-2C, with alpha-2A being predominant in the locus coeruleus, a region of the brain associated with the arousal system [43,44]. Several alpha-2 adrenergic receptor agonists are currently available including clonidine, dexmedetomidine, guanfacine, and lofexidine. Of these options, dexmedetomidine has the highest affinity and highest intrinsic action on the alpha-2A receptor, thereby perhaps better positioned to ameliorate hyperarousal states[27]. Additionally, although dexmedetomidine is more sedating than clonidine due to greater selectivity for alpha 2 receptors than alpha 1 receptors (A2:A1 ratio 1620:1 vs 220:1), an important attribute of dexmedetomidine-based sedation is that patients remain easily arousable [45,46].
Aripiprazole for the treatment of Tourette syndrome
Published in Expert Review of Neurotherapeutics, 2021
Joanna H. Cox, Andrea E. Cavanna
Other medications used in the treatment of TS include alpha-2 adrenergic receptor agonists, namely clonidine and guanfacine. The widespread noradrenergic modulation properties of alpha-2 adrenergic receptor agonists are reflected by the indications of clonidine in the management of hypertension, drug and alcohol withdrawal, ADHD, and menopausal flushing symptoms [49]. Alpha-2 agonists are commonly used in young patients with TS, especially when co-morbid ADHD is present [46]. Adverse effects tend to be dose-dependent and include dizziness, postural hypotension, and sedation. The antiepileptic medication topiramate has also been shown to be potentially useful in the treatment of TS [42,43], however further studies with larger sample sizes are required to confirm preliminary findings about its anti-tic properties [50]. In general, over the last few years the treatment of TS and other tic disorders has been relatively slow to evolve and no new classes of compounds have entered clinical practice or late development stage. This highlights the unmet needs of currently available therapies, including the identification of an agent that combines satisfactory efficacy in tic control with acceptable tolerability.
Opioid overdoses involving xylazine in emergency department patients: a multicenter study
Published in Clinical Toxicology, 2023
Jennifer S. Love, Michael Levine, Kim Aldy, Jeffrey Brent, Alex J. Krotulski, Barry K. Logan, Carmen Vargas-Torres, Sara E. Walton, Alexandra Amaducci, Diane Calello, Robert Hendrickson, Adrienne Hughes, Anita Kurt, Bryan Judge, Anthony Pizon, Evan Schwarz, Joshua Shulman, Timothy Wiegand, Paul Wax, Alex F. Manini
Xylazine, a potent central alpha-2 adrenergic agonist used in veterinary medicine with ketamine or opioids, is used for large-animal anesthesia or pain management [10]. Xylazine is structurally related to clonidine (Figure 1), resulting in central nervous system (CNS) depressant effects (sedation) and cardiovascular side effects (bradycardia, hypotention, and cardiac arrest) [10]. By bolstering alpha-2 adrenergic receptor activity, xylazine decreases norepinephrine presynaptic release, subsequently decreasing an adrenergic physiologic response [10]. Animal studies using a mouse model have also demonstrated xylazine activity at mu-opioid receptors [11].