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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 insufficient anesthesia, convulsions, and psychotic symptoms (Pender1971). Theseagents never ever got in regular clinical practice, but phencyclidine (phenylcyclohexylpiperidine, typically described as PCP or" angel dust") has stayed a drug of abuse in numerous societies. Inclinical testing in the 1960s, ketamine (2-( 2-chlorophenyl) -2-( methylamino)- cyclohexanone) wasshown not to cause convulsions, however was still related to anesthetic development phenomena, such as hallucinations and agitation, albeit of shorter duration. It became commercially offered in1970. There are two optical isomers of ketamine: S(+) ketamine and ketamine. The S(+) isomer is roughly three to 4 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 might have more psychotomimetic properties (although it is unclear whether thissimply reflects its increased effectiveness). On The Other Hand, R() ketamine may preferentially bind to opioidreceptors (see subsequent text). Although a medical preparation of the S(+) isomer is readily available insome nations, the most typical preparation in clinical usage is a racemic mixture of the two isomers.The just other representatives with dissociative features still typically utilized in medical practice arenitrous oxide, first utilized scientifically in the 1840s as an inhalational anesthetic, and dextromethorphan, an agent used as an antitussive in cough syrups considering that 1958. Muscimol (a potent 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 been utilized in mysticand religious routines (seeRitual Utilizes of Psychoactive Drugs"). * Email:





nlEncyclopedia of PsychopharmacologyDOI 10.1007/ 978-3-642-27772-6_341-2 #Springer- Verlag Berlin Heidelberg 2014Page 1 of 6
In current years these have been a resurgence of interest in using ketamine as an adjuvant agentduring basic click here anesthesia (to help in reducing intense postoperative pain and to assist prevent developmentof persistent discomfort) (Bell et al. 2006). Recent literature suggests a possible role for ketamine asa treatment for persistent discomfort (Blonk et al. 2010) and depression (Mathews and Zarate2013). Ketamine has actually also been utilized as a model supporting the glutamatergic hypothesis for the pathogen-esis of schizophrenia (Corlett et al. 2013). Systems of ActionThe main direct molecular mechanism of action of ketamine (in typical with other dissociativeagents such as nitrous oxide, phencyclidine, and dextromethorphan) happens via a noncompetitiveantagonist impact at theN-methyl-D-aspartate (NDMA) receptor. It might also act via an agonist effectonk-opioid receptors (seeOpioids") (Sharp1997). Positron emission tomography (PET) imaging research studies suggest that the mechanism of action does not include binding at theg-aminobutyric acid GABAA receptor (Salmi et al. 2005). Indirect, downstream effects vary and rather controversial. The subjective impacts ofketamine appear to be mediated by increased release of glutamate (Deakin et al. 2008) and also byincreased dopamine release moderated by a glutamate-dopamine interaction in the posterior cingulatecortex (Aalto et al. 2005). Regardless of its uniqueness in receptor-ligand interactions kept in mind earlier, ketamine may trigger indirect repressive results 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 representatives (such as sub-anesthetic doses of ketamine) produce theirneurocognitive and psychotomimetic impacts are partially comprehended. Functional MRI (fMRI) (see" Magnetic Resonance Imaging (Practical) Research Studies") in healthy topics who were given lowdoses of ketamine has shown that ketamine triggers a network of brain areas, consisting of theprefrontal cortex, striatum, and anterior cingulate cortex. Other research studies suggest deactivation of theposterior cingulate region. Remarkably, these impacts scale with the psychogenic impacts of the agentand are concordant with practical imaging abnormalities observed in patients with schizophrenia( Fletcher et al. 2006). Similar fMRI studies in treatment-resistant major anxiety indicate thatlow-dose ketamine infusions modified anterior cingulate cortex activity and connectivity with theamygdala in responders (Salvadore et al. 2010). Regardless of these information, it remains uncertain whether thesefMRIfindings directly identify the sites of ketamine action or whether they define thedownstream effects of the drug. In specific, direct displacement studies with ANIMAL, using11C-labeledN-methyl-ketamine as a ligand, do disappoint plainly concordant patterns with fMRIdata. Further, the role 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 humans (Langsjo et al. 2004). Recentwork suggests that the action of ketamine on the NMDA receptor leads to anti-depressant effectsmediated by means of downstream results on the mammalian target of rapamycin leading to increasedsynaptogenesis

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