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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 agents fromthis group, such as phencyclidine and cyclohexamine hydrochloride, showed an unacceptably highincidence of inadequate anesthesia, convulsions, and psychotic signs (Pender1971). Theseagents never went into regular clinical 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, however was still related to anesthetic introduction phenomena, such as hallucinations and agitation, albeit of shorter period. It ended up being commercially offered in1970. There are two optical isomers of ketamine: S(+) ketamine and ketamine. The S(+) isomer is around 3 to four times as powerful as the R isomer, most likely due to the fact that of itshigher affinity to the phencyclidine binding sites on NMDA receptors (see subsequent text). The S(+) enantiomer might have more psychotomimetic residential or commercial properties (although it is unclear whether thissimply shows its increased strength). Alternatively, R() ketamine may preferentially bind to opioidreceptors (see subsequent text). Although a clinical preparation of the S(+) isomer is readily available insome countries, the most common preparation in medical usage is a racemic mix of the 2 isomers.The just other agents with dissociative features still frequently used in medical practice arenitrous oxide, initially used clinically in the 1840s as an inhalational anesthetic, and dextromethorphan, an agent utilized as an antitussive in cough syrups since 1958. Muscimol (a potent GABAAagonistderived from the amanita muscaria mushroom) and salvinorin A (ak-opioid receptor agonist derivedfrom the plant salvia divinorum) are likewise said 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
Recently these have actually been a revival of interest in using ketamine as an adjuvant agentduring basic anesthesia (to assist minimize severe postoperative discomfort and to assist prevent developmentof chronic discomfort) (Bell et al. 2006). Current literature recommends a possible function 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. read more 2013). Systems of ActionThe main direct molecular mechanism of action of ketamine (in typical with other dissociativeagents such as nitrous oxide, phencyclidine, and dextromethorphan) takes place via 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 (PET) imaging research studies recommend that the system of action does not include binding at theg-aminobutyric acid GABAA receptor (Salmi et al. 2005). Indirect, downstream results vary and somewhat questionable. The subjective results ofketamine seem 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 noted previously, ketamine may cause indirect inhibitory results on GABA-ergic interneurons, resulting ina disinhibiting impact, with a resulting increased release of serotonin, norepinephrine, and dopamineat downstream sites.The sites at which dissociative agents (such as sub-anesthetic doses of ketamine) produce theirneurocognitive and psychotomimetic effects are partly understood. Functional MRI (fMRI) (see" Magnetic Resonance Imaging (Functional) Research Studies") in healthy topics who were provided lowdoses of ketamine has actually shown that ketamine triggers a network of brain regions, consisting of theprefrontal cortex, striatum, and anterior cingulate cortex. Other research studies suggest deactivation of theposterior cingulate region. Surprisingly, these effects scale with the psychogenic effects of the agentand are concordant with functional imaging irregularities observed in patients with schizophrenia( Fletcher et al. 2006). Similar fMRI studies in treatment-resistant major depression suggest thatlow-dose ketamine infusions transformed anterior cingulate cortex activity and connection with theamygdala in responders (Salvadore et al. 2010). In spite of these data, it remains uncertain whether thesefMRIfindings straight recognize the websites of ketamine action or whether they identify thedownstream results of the drug. In specific, direct displacement research 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 regional uniqueness 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 impacts on the mammalian target of rapamycin leading to increasedsynaptogenesis

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