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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 representatives fromthis group, such as phencyclidine and cyclohexamine hydrochloride, revealed an unacceptably highincidence of insufficient anesthesia, convulsions, and psychotic symptoms (Pender1971). Theseagents never ever got in regular clinical practice, however phencyclidine (phenylcyclohexylpiperidine, frequently described as PCP or" angel dust") has actually remained a drug of abuse in lots of societies. Inclinical testing in the 1960s, ketamine (2-( 2-chlorophenyl) -2-( methylamino)- cyclohexanone) wasshown not to cause convulsions, but was still connected with anesthetic introduction phenomena, such as hallucinations and agitation, albeit of much shorter period. It ended up being commercially readily available in1970. There are two optical isomers of ketamine: S(+) ketamine and ketamine. The S(+) isomer is around three to four times as potent as the R isomer, probably because of itshigher affinity to the phencyclidine binding websites on NMDA receptors (see subsequent text). The S(+) enantiomer might have more psychotomimetic homes (although it is unclear whether thissimply reflects 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 medical use is a racemic mix of the two isomers.The only other representatives 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 because 1958. Muscimol (a potent GABAAagonistderived from the amanita muscaria mushroom) and salvinorin A (ak-opioid receptor agonist derivedfrom the plant salvia divinorum) are likewise stated to be dissociative drugs and have been used in mysticand spiritual 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
In the last few years these have been a resurgence of interest in using ketamine as an adjuvant agentduring basic anesthesia (to help in reducing severe postoperative pain and to assist prevent developmentof persistent discomfort) (Bell et al. 2006). Recent literature recommends a possible role for ketamine asa treatment for persistent pain (Blonk et al. 2010) and anxiety (Mathews and Zarate2013). Ketamine has likewise been utilized as a design 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) takes place through a noncompetitiveantagonist result 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 system of Additional resources action does not include binding at theg-aminobutyric acid GABAA receptor (Salmi et al. 2005). Indirect, downstream impacts vary and rather controversial. 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). Despite its specificity in receptor-ligand interactions kept in mind previously, ketamine may cause indirect repressive results on GABA-ergic interneurons, resulting ina disinhibiting effect, with a resulting increased release of serotonin, norepinephrine, and dopamineat downstream sites.The sites at which dissociative representatives (such as sub-anesthetic doses of ketamine) produce theirneurocognitive and psychotomimetic effects are partially comprehended. Functional MRI (fMRI) (see" Magnetic Resonance Imaging (Functional) Studies") in healthy topics who were offered lowdoses of ketamine has revealed that ketamine triggers a network of brain areas, including theprefrontal cortex, striatum, and anterior cingulate cortex. Other studies suggest deactivation of theposterior cingulate region. Remarkably, these results scale with the psychogenic results 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 depression suggest thatlow-dose ketamine infusions modified anterior cingulate cortex activity and connection with theamygdala in responders (Salvadore et al. 2010). Regardless of these information, it stays uncertain whether thesefMRIfindings straight determine the websites of ketamine action or whether they define thedownstream impacts of the drug. In specific, direct displacement research studies with ANIMAL, using11C-labeledN-methyl-ketamine as a ligand, do not reveal clearly concordant patterns with fMRIdata. Even more, the function of direct vascular results of the drug remains uncertain, since 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 humans (Langsjo et al. 2004). Recentwork suggests that the action of ketamine on the NMDA receptor results in anti-depressant effectsmediated through downstream results on the mammalian target of rapamycin leading to increasedsynaptogenesis

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