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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 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 regular scientific practice, but phencyclidine (phenylcyclohexylpiperidine, frequently referred to as PCP or" angel dust") has actually remained a drug of abuse in many societies. Inclinical testing in the 1960s, ketamine (2-( 2-chlorophenyl) -2-( methylamino)- cyclohexanone) wasshown not to trigger 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 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 might have more psychotomimetic homes (although it is unclear whether thissimply shows its increased strength). On The Other Hand, R() ketamine may preferentially bind to opioidreceptors (see subsequent text). Although a clinical preparation of the S(+) isomer is available insome nations, the most common preparation in clinical usage is a racemic mix of the two isomers.The only other representatives with dissociative features still commonly utilized in medical practice arenitrous oxide, first utilized clinically in the 1840s as an inhalational anesthetic, and dextromethorphan, an agent utilized 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 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
In current years these have been a renewal of interest in using ketamine as an adjuvant agentduring basic anesthesia (to help in reducing severe postoperative pain and to help avoid developmentof chronic discomfort) (Bell et al. 2006). Recent literature recommends a possible role for ketamine asa treatment for chronic discomfort (Blonk et al. 2010) and depression (Mathews and Zarate2013). Ketamine has actually also 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 common with other dissociativeagents such as laughing gas, phencyclidine, and dextromethorphan) occurs 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 (ANIMAL) 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 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). In spite of its uniqueness in receptor-ligand interactions noted earlier, ketamine may trigger indirect repressive 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 dosages of ketamine) produce theirneurocognitive and psychotomimetic effects are partly understood. Practical MRI (fMRI) (see" Magnetic Resonance Imaging (Practical) Research Studies") in healthy topics who were given lowdoses of ketamine has shown that ketamine activates a network of brain regions, including theprefrontal cortex, striatum, and anterior cingulate cortex. Other research studies recommend deactivation of theposterior cingulate area. Surprisingly, these effects scale with the psychogenic effects of here the agentand are concordant with functional imaging abnormalities observed in patients with schizophrenia( Fletcher et al. 2006). Similar fMRI studies in treatment-resistant major depression suggest thatlow-dose ketamine infusions modified anterior cingulate cortex activity and connection with theamygdala in responders (Salvadore et al. 2010). In spite of these information, it remains unclear whether thesefMRIfindings directly determine the sites of ketamine action or whether they characterize thedownstream effects of the drug. In particular, direct displacement studies with PET, using11C-labeledN-methyl-ketamine as a ligand, do not reveal plainly concordant patterns with fMRIdata. Even more, the function of direct vascular results of the drug stays unpredictable, considering that 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 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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