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HistoryMost dissociative anesthetics are members of the phenyl cyclohexamine group of chemicals. Agentsfrom this group werefirst utilized 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 signs (Pender1971). Theseagents never ever got in regular scientific practice, however phencyclidine (phenylcyclohexylpiperidine, frequently described as PCP or" angel dust") has actually stayed a drug of abuse in lots of societies. Inclinical screening in the 1960s, ketamine (2-( 2-chlorophenyl) -2-( methylamino)- cyclohexanone) wasshown not to trigger convulsions, but was still connected with anesthetic emergence phenomena, such as hallucinations and agitation, albeit of much shorter duration. It ended up being commercially offered in1970. There are two optical isomers of ketamine: S(+) ketamine and ketamine. The S(+) isomer is roughly 3 to four times as powerful as the R isomer, probably since 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). On The Other Hand, R() ketamine may preferentially bind to opioidreceptors (see subsequent text). Although a clinical preparation of the S(+) isomer is readily available insome nations, the most common preparation in clinical usage is a racemic mixture of the two isomers.The just other agents with dissociative features still frequently used in clinical practice arenitrous oxide, initially used clinically in the 1840s as an inhalational anesthetic, and dextromethorphan, a representative utilized 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 said to be dissociative drugs and have actually been used in mysticand religious rituals (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 been a renewal of interest in the use of ketamine as an adjuvant agentduring general anesthesia (to assist lower acute postoperative pain and to assist prevent developmentof persistent pain) (Bell et al. 2006). Current literature suggests a possible function for ketamine asa treatment for chronic discomfort (Blonk et al. 2010) and anxiety (Mathews and Zarate2013). Ketamine has actually also 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 common with other dissociativeagents such as nitrous oxide, phencyclidine, and dextromethorphan) happens through a noncompetitiveantagonist impact at theN-methyl-D-aspartate (NDMA) receptor. It may likewise act through an agonist effectonk-opioid receptors (seeOpioids") (Sharp1997). Positron emission tomography (FAMILY PET) imaging research studies suggest that the mechanism of action does not involve binding at theg-aminobutyric acid GABAA receptor (Salmi et al. 2005). Indirect, downstream effects are variable and rather controversial. The subjective impacts ofketamine seem mediated by increased release of glutamate (Deakin et al. 2008) and likewise byincreased dopamine release moderated by a glutamate-dopamine interaction in the posterior cingulatecortex (Aalto et al. 2005). In spite of its uniqueness in receptor-ligand interactions kept in mind previously, ketamine may trigger indirect inhibitory effects 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 agents (such as sub-anesthetic dosages of ketamine) produce theirneurocognitive and psychotomimetic results are partly comprehended. Functional MRI (fMRI) (see" Magnetic Resonance Imaging (Practical) Research Studies") in healthy topics who were given lowdoses of ketamine has actually shown that ketamine activates a network of brain areas, consisting of theprefrontal cortex, striatum, and anterior read more 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 connectivity with theamygdala in responders (Salvadore et al. 2010). Regardless of these information, it remains unclear whether thesefMRIfindings directly identify the websites of ketamine action or whether they characterize thedownstream results of the drug. In specific, direct displacement studies with FAMILY PET, using11C-labeledN-methyl-ketamine as a ligand, do disappoint plainly concordant patterns with fMRIdata. Further, the function of direct vascular effects of the drug remains unsure, since there are cleardiscordances in the regional specificity and magnitude of changes in cerebral bloodflow, oxygenmetabolism, and glucose uptake, as studied by PET in healthy human beings (Langsjo et al. 2004). Recentwork suggests that the action of ketamine on the NMDA receptor leads to anti-depressant effectsmediated through downstream impacts on the mammalian target of rapamycin leading to increasedsynaptogenesis

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