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HistoryMost dissociative anesthetics are members of the phenyl cyclohexamine group of chemicals. Agentsfrom this group werefirst utilized in scientific practice in the 1950s. Early experience with agents fromthis group, such as phencyclidine and cyclohexamine hydrochloride, revealed an unacceptably highincidence of inadequate anesthesia, convulsions, and psychotic signs (Pender1971). Theseagents never ever went into routine clinical practice, however phencyclidine (phenylcyclohexylpiperidine, typically referred to as PCP or" angel dust") has actually stayed 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 ended up being commercially readily 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 websites on NMDA receptors (see subsequent text). The S(+) enantiomer might have more psychotomimetic homes (although it is unclear whether thissimply reflects its increased potency). On The Other Hand, R() ketamine may preferentially bind to opioidreceptors (see subsequent text). Although a scientific preparation of the S(+) isomer is readily available insome nations, the most common preparation in scientific usage is a racemic mixture of the two isomers.The just other agents with dissociative features still frequently utilized in clinical practice arenitrous oxide, initially 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 likewise 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
Over the last few years these have been a renewal of interest in using ketamine as an adjuvant agentduring general anesthesia (to help in reducing intense 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 depression (Mathews and Zarate2013). Ketamine has actually also been used as a design supporting the glutamatergic hypothesis for the pathogen-esis of schizophrenia Additional hints (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 by means of a noncompetitiveantagonist effect 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 involve binding at theg-aminobutyric acid GABAA receptor (Salmi et al. 2005). Indirect, downstream effects vary and somewhat questionable. The subjective effects ofketamine appear to be 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 previously, ketamine might cause indirect inhibitory impacts on GABA-ergic interneurons, resulting ina disinhibiting result, 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 results are partially understood. Functional MRI (fMRI) (see" Magnetic Resonance Imaging (Functional) Studies") in healthy topics who were offered lowdoses of ketamine has actually shown that ketamine activates a network of brain areas, including theprefrontal cortex, striatum, and anterior cingulate cortex. Other research studies suggest deactivation of theposterior cingulate region. Interestingly, these effects scale with the psychogenic impacts of the agentand are concordant with practical imaging problems observed in clients with schizophrenia( Fletcher et al. 2006). Comparable fMRI research studies in treatment-resistant significant anxiety show thatlow-dose ketamine infusions altered anterior cingulate cortex activity and connectivity with theamygdala in responders (Salvadore et al. 2010). Despite these data, it remains unclear whether thesefMRIfindings directly identify 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 local specificity 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 resulting in increasedsynaptogenesis

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