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HistoryMost dissociative anesthetics are members of the phenyl cyclohexamine group of chemicals. Agentsfrom this group werefirst used in medical practice in the 1950s. Early experience with agents fromthis group, such as phencyclidine and cyclohexamine hydrochloride, showed an unacceptably highincidence of inadequate anesthesia, convulsions, and psychotic symptoms (Pender1971). Theseagents never went into routine medical practice, but phencyclidine (phenylcyclohexylpiperidine, typically referred to as PCP or" angel dust") has 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 introduction phenomena, such as hallucinations and agitation, albeit of much shorter duration. It became commercially available in1970. There are 2 optical isomers of ketamine: S(+) ketamine and ketamine. The S(+) isomer is around 3 to 4 times as potent as the R isomer, probably because of itshigher affinity to the phencyclidine binding sites on NMDA receptors (see subsequent text). The S(+) enantiomer may have more psychotomimetic homes (although it is not clear whether thissimply reflects its increased effectiveness). Alternatively, R() ketamine might preferentially bind to opioidreceptors (see subsequent text). Although a clinical preparation of the S(+) isomer is available insome countries, the most typical preparation in scientific use is a racemic mixture of the 2 isomers.The just other representatives with dissociative functions still commonly utilized in medical practice arenitrous oxide, first utilized medically in the 1840s as an inhalational anesthetic, and dextromethorphan, an agent utilized as an antitussive in cough syrups given that 1958. Muscimol (a potent GABAAagonistderived from the amanita muscaria mushroom) and salvinorin A (ak-opioid receptor agonist derivedfrom the plant salvia divinorum) are likewise stated to be dissociative drugs and have been utilized in mysticand religious routines (seeRitual Uses of Psychedelic Drugs"). * Email:





nlEncyclopedia of PsychopharmacologyDOI 10.1007/ 978-3-642-27772-6_341-2 #Springer- Verlag Berlin Heidelberg 2014Page 1 of 6
Recently these have been a resurgence of interest in making use of ketamine as an adjuvant agentduring general anesthesia (to help in reducing acute postoperative pain and to assist prevent developmentof persistent pain) (Bell et al. 2006). Current literature suggests a possible function for ketamine asa treatment for chronic pain (Blonk et al. 2010) and anxiety (Mathews and Zarate2013). Ketamine has likewise been used as a model supporting the glutamatergic hypothesis for the pathogen-esis of schizophrenia (Corlett et al. 2013). Systems of ActionThe primary direct molecular system of action of ketamine (in typical with other dissociativeagents such as nitrous oxide, phencyclidine, and dextromethorphan) takes place via a noncompetitiveantagonist impact at theN-methyl-D-aspartate (NDMA) receptor. It might also act through an agonist effectonk-opioid receptors (seeOpioids") (Sharp1997). Positron emission tomography (PET) imaging studies recommend that the system of action does not involve binding at theg-aminobutyric acid GABAA receptor (Salmi et al. 2005). Indirect, downstream impacts vary and somewhat controversial. The subjective results ofketamine appear to be mediated by increased release of glutamate (Deakin et al. 2008) and likewise byincreased dopamine release moderated by a glutamate-dopamine interaction in the posterior cingulatecortex (Aalto et al. 2005). Despite its specificity in receptor-ligand interactions noted previously, ketamine may trigger indirect inhibitory impacts on GABA-ergic interneurons, resulting ina disinhibiting result, with a resulting increased release of serotonin, norepinephrine, and dopamineat downstream sites.The websites at which dissociative agents (such as sub-anesthetic doses of ketamine) produce theirneurocognitive and psychotomimetic impacts are partially comprehended. Functional MRI (fMRI) (see" Magnetic Resonance Imaging (Functional) Studies") in healthy subjects who were provided lowdoses of ketamine has actually revealed that ketamine triggers a network of brain regions, consisting of theprefrontal cortex, striatum, and anterior cingulate cortex. Other studies recommend deactivation of theposterior cingulate area. Surprisingly, these effects scale with the psychogenic effects of the agentand are concordant with functional imaging irregularities observed in clients with schizophrenia( Fletcher et al. 2006). Comparable fMRI research studies in treatment-resistant significant anxiety show thatlow-dose ketamine infusions transformed anterior cingulate cortex activity and connection with theamygdala in responders (Salvadore et al. 2010). Despite these data, it remains uncertain whether thesefMRIfindings straight identify the websites of ketamine action or whether they identify thedownstream effects of the drug. In specific, direct displacement research studies with FAMILY PET, using11C-labeledN-methyl-ketamine as a ligand, do disappoint plainly concordant patterns with fMRIdata. Even more, the function of direct vascular impacts of the drug remains unpredictable, because there are cleardiscordances in the regional specificity and magnitude of changes in cerebral bloodflow, oxygenmetabolism, and glucose uptake, as studied by PET in healthy human beings (Langsjo et al. 2004). Recentwork recommends that the action of ketamine on the NMDA get more info receptor leads to anti-depressant effectsmediated through downstream impacts on the mammalian target of rapamycin resulting in increasedsynaptogenesis

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