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HistoryMost dissociative anesthetics are members of the phenyl cyclohexamine group of chemicals. Agentsfrom this group werefirst used in scientific 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 entered 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 associated with anesthetic emergence phenomena, such as hallucinations and agitation, albeit of shorter duration. It became commercially available in1970. There are two optical isomers of ketamine: S(+) ketamine and ketamine. The S(+) isomer is approximately three to four 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 properties (although it is not clear whether thissimply reflects its increased potency). Conversely, R() ketamine may preferentially bind to opioidreceptors (see subsequent text). Although a clinical preparation of the S(+) isomer is available insome countries, the most common preparation in clinical use is a racemic mixture of the two isomers.The only other agents with dissociative features still commonly used in clinical practice arenitrous oxide, first used clinically in the 1840s as an inhalational anesthetic, and dextromethorphan, an agent used as an antitussive in cough syrups because 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 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 discomfort) (Bell et al. 2006). Recent literature recommends a possible role for ketamine asa treatment for persistent pain (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 click here of ketamine (in typical with other dissociativeagents such as nitrous oxide, phencyclidine, and dextromethorphan) happens via a noncompetitiveantagonist result at theN-methyl-D-aspartate (NDMA) receptor. It might also act through an agonist effectonk-opioid receptors (seeOpioids") (Sharp1997). Positron emission tomography (FAMILY PET) imaging studies recommend 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 rather questionable. The subjective effects ofketamine seem moderated 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). Regardless of its specificity in receptor-ligand interactions noted earlier, ketamine might trigger indirect inhibitory results on GABA-ergic interneurons, resulting ina disinhibiting effect, with a resulting increased release of serotonin, norepinephrine, and dopamineat downstream sites.The websites at which dissociative agents (such as sub-anesthetic dosages 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 triggers a network of brain areas, including theprefrontal cortex, striatum, and anterior cingulate cortex. Other research studies suggest deactivation of theposterior cingulate region. Surprisingly, these results scale with the psychogenic effects of the agentand are concordant with functional imaging irregularities observed in patients 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). In spite of these information, it stays 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 FAMILY PET, using11C-labeledN-methyl-ketamine as a ligand, do not reveal plainly concordant patterns with fMRIdata. Even more, the function of direct vascular impacts of the drug stays unpredictable, considering that there are cleardiscordances in the local specificity and magnitude of changes in cerebral bloodflow, oxygenmetabolism, and glucose uptake, as studied by PET in healthy people (Langsjo et al. 2004). Recentwork suggests that the action of ketamine on the NMDA receptor results in anti-depressant effectsmediated by means of downstream results on the mammalian target of rapamycin leading to increasedsynaptogenesis

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