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HistoryMost dissociative anesthetics are members of the phenyl cyclohexamine group of chemicals. Agentsfrom this group werefirst utilized in clinical practice in the 1950s. Early experience with representatives fromthis group, such as phencyclidine and cyclohexamine hydrochloride, revealed an unacceptably highincidence of insufficient anesthesia, convulsions, and psychotic signs (Pender1971). Theseagents never ever got in regular scientific practice, however phencyclidine (phenylcyclohexylpiperidine, commonly described as PCP or" angel dust") has actually stayed a drug of abuse in lots of societies. Inclinical screening in the 1960s, ketamine (2-( 2-chlorophenyl) -2-( methylamino)- cyclohexanone) wasshown not to trigger convulsions, but was still connected with anesthetic development phenomena, such as hallucinations and agitation, albeit of shorter duration. It ended up being commercially readily available in1970. There are 2 optical isomers of ketamine: S(+) ketamine and ketamine. The S(+) isomer is roughly three to four times as powerful as the R isomer, most likely since of itshigher affinity to the phencyclidine binding sites on NMDA receptors (see subsequent text). The S(+) enantiomer may have more psychotomimetic properties (although it is unclear whether thissimply shows its increased strength). On The Other Hand, R() ketamine may preferentially bind to opioidreceptors (see subsequent text). Although a clinical preparation of the S(+) isomer is readily available insome nations, the most common preparation in clinical usage is a racemic mixture of the two isomers.The just other agents with dissociative functions still frequently used in clinical practice arenitrous oxide, initially used medically in the 1840s as an inhalational anesthetic, and dextromethorphan, a representative used as an antitussive in cough syrups given that 1958. Muscimol (a powerful GABAAagonistderived from the amanita muscaria mushroom) and salvinorin A (ak-opioid receptor agonist derivedfrom the plant salvia divinorum) are also stated to be dissociative drugs and have been utilized in mysticand religious routines (seeRitual Uses of Psychoactive Drugs"). * Email:

nlEncyclopedia of PsychopharmacologyDOI 10.1007/ 978-3-642-27772-6_341-2 #Springer- Verlag Berlin Heidelberg 2014Page 1 of 6
Over the last few years these have actually been a resurgence of interest in the usage of ketamine as an adjuvant agentduring general anesthesia (to help reduce acute postoperative pain and to help avoid developmentof chronic pain) (Bell et al. 2006). Current literature suggests a possible function for ketamine asa treatment for chronic discomfort (Blonk et al. 2010) and depression (Mathews and Zarate2013). Ketamine has actually also been used as a design supporting the glutamatergic hypothesis for the pathogen-esis of schizophrenia (Corlett et al. 2013). Mechanisms of ActionThe main direct molecular mechanism of action of more info ketamine (in common with other dissociativeagents such as laughing gas, phencyclidine, and dextromethorphan) occurs by means of a noncompetitiveantagonist result at theN-methyl-D-aspartate (NDMA) receptor. It may also act through an agonist effectonk-opioid receptors (seeOpioids") (Sharp1997). Positron emission tomography (FAMILY PET) imaging studies suggest that the mechanism of action does not include binding at theg-aminobutyric acid GABAA receptor (Salmi et al. 2005). Indirect, downstream results are variable and somewhat controversial. The subjective effects ofketamine seem mediated by increased release of glutamate (Deakin et al. 2008) and also byincreased dopamine release mediated by a glutamate-dopamine interaction in the posterior cingulatecortex (Aalto et al. 2005). In spite of its specificity in receptor-ligand interactions noted earlier, ketamine might trigger indirect repressive effects on GABA-ergic interneurons, resulting ina disinhibiting impact, with a resulting increased release of serotonin, norepinephrine, and dopamineat downstream sites.The websites at which dissociative representatives (such as sub-anesthetic doses of ketamine) produce theirneurocognitive and psychotomimetic impacts are partially comprehended. Practical MRI (fMRI) (see" Magnetic Resonance Imaging (Practical) Studies") in healthy subjects who were provided lowdoses of ketamine has actually revealed that ketamine triggers a network of brain areas, including theprefrontal cortex, striatum, and anterior cingulate cortex. Other studies suggest deactivation of theposterior cingulate region. Remarkably, these results scale with the psychogenic results of the agentand are concordant with practical imaging problems observed in patients with schizophrenia( Fletcher et al. 2006). Similar fMRI studies in treatment-resistant major depression indicate thatlow-dose ketamine infusions modified anterior cingulate cortex activity and connectivity with theamygdala in responders (Salvadore et al. 2010). In spite of these data, it remains unclear whether thesefMRIfindings directly determine the sites of ketamine action or whether they characterize thedownstream effects of the drug. In particular, direct displacement studies with PET, using11C-labeledN-methyl-ketamine as a ligand, do disappoint clearly concordant patterns with fMRIdata. Further, the function of direct vascular results of the drug stays unsure, given that there are cleardiscordances in the local uniqueness and magnitude of modifications in cerebral bloodflow, oxygenmetabolism, and glucose uptake, as studied by ANIMAL in healthy people (Langsjo et al. 2004). Recentwork suggests that the action of ketamine on the NMDA receptor results in anti-depressant effectsmediated via downstream results on the mammalian target of rapamycin leading to increasedsynaptogenesis

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