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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 representatives 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 remained a drug of abuse in many societies. Inclinical testing in the 1960s, ketamine (2-( 2-chlorophenyl) -2-( methylamino)- cyclohexanone) wasshown not to cause convulsions, but was still associated with anesthetic emergence phenomena, such as hallucinations and agitation, albeit of shorter period. It ended up being commercially readily available in1970. There are 2 optical isomers of ketamine: S(+) ketamine and ketamine. The S(+) isomer is around 3 to four times as potent as the R isomer, most likely due to the fact that of itshigher affinity to the phencyclidine binding websites on NMDA receptors (see subsequent text). The S(+) enantiomer might have more psychotomimetic residential or commercial properties (although it is not clear whether thissimply reflects its increased potency). Alternatively, R() ketamine might preferentially bind to opioidreceptors (see subsequent text). Although a medical preparation of the S(+) isomer is offered insome countries, the most typical preparation in medical use is a racemic mixture of the 2 isomers.The only other agents with dissociative functions still typically used in scientific practice arenitrous oxide, initially used clinically in the 1840s as an inhalational anesthetic, and dextromethorphan, a representative used as an antitussive in cough syrups since 1958. Muscimol (a powerful GABAAagonistderived from the amanita muscaria mushroom) and salvinorin A (ak-opioid receptor agonist derivedfrom the plant salvia divinorum) are also said to be dissociative drugs and have actually been used in mysticand spiritual rituals (seeRitual Utilizes of Psychedelic 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 revival of interest in using ketamine as an adjuvant agentduring basic anesthesia (to help in reducing severe postoperative pain and to assist avoid developmentof chronic pain) (Bell et al. 2006). Current literature recommends a possible function for ketamine asa treatment for chronic discomfort (Blonk et al. 2010) and depression (Mathews and Zarate2013). Ketamine has likewise 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 ketamine (in typical with other dissociativeagents such as laughing gas, phencyclidine, and dextromethorphan) takes place through a noncompetitiveantagonist effect at theN-methyl-D-aspartate (NDMA) receptor. It may likewise act via an agonist effectonk-opioid receptors (seeOpioids") (Sharp1997). Positron emission tomography (FAMILY PET) imaging studies suggest 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). In spite of its uniqueness in receptor-ligand interactions kept in mind earlier, ketamine may trigger indirect repressive Additional info 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 effects are partly comprehended. Practical MRI (fMRI) (see" Magnetic Resonance Imaging (Functional) Studies") in healthy subjects who were provided lowdoses of ketamine has actually revealed that ketamine activates a network of brain regions, including 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 indicate thatlow-dose ketamine infusions altered 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 define thedownstream impacts of the drug. In particular, direct displacement studies with ANIMAL, using11C-labeledN-methyl-ketamine as a ligand, do not show clearly concordant patterns with fMRIdata. Further, the role of direct vascular effects of the drug remains uncertain, because there are cleardiscordances in the regional specificity and magnitude of modifications in cerebral bloodflow, oxygenmetabolism, and glucose uptake, as studied by FAMILY PET in healthy human beings (Langsjo et al. 2004). Recentwork recommends that the action of ketamine on the NMDA receptor leads to anti-depressant effectsmediated through downstream impacts on the mammalian target of rapamycin resulting in increasedsynaptogenesis

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