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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, revealed an unacceptably highincidence of inadequate anesthesia, convulsions, and psychotic signs (Pender1971). Theseagents never went into regular scientific practice, however phencyclidine (phenylcyclohexylpiperidine, commonly referred to as PCP or" angel dust") has remained a drug of abuse in many societies. Inclinical screening in the 1960s, ketamine (2-( 2-chlorophenyl) -2-( methylamino)- cyclohexanone) wasshown not to trigger convulsions, however was still related to anesthetic emergence phenomena, such as hallucinations and agitation, albeit of much shorter period. It ended up being commercially offered in1970. There are two optical isomers of ketamine: S(+) ketamine and ketamine. The S(+) isomer is approximately three to 4 times as powerful as the R isomer, most likely 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 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 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 used as an antitussive in cough syrups since 1958. Muscimol (a powerful GABAAagonistderived from the amanita muscaria mushroom) and salvinorin A (ak-opioid receptor agonist derivedfrom the plant salvia divinorum) are also stated to be dissociative drugs and have been utilized in mysticand religious rituals (seeRitual Utilizes 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 current years these have been a renewal of interest in using ketamine as an adjuvant agentduring general anesthesia (to assist reduce intense postoperative pain and to assist prevent developmentof persistent pain) (Bell et al. 2006). Current literature suggests 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 model supporting the glutamatergic hypothesis for the pathogen-esis of schizophrenia (Corlett et al. 2013). Systems of ActionThe primary direct molecular system of action of ketamine (in typical with other dissociativeagents such as nitrous oxide, phencyclidine, and dextromethorphan) takes place via a noncompetitiveantagonist result at theN-methyl-D-aspartate (NDMA) receptor. It may also act by means of an agonist effectonk-opioid receptors (seeOpioids") (Sharp1997). Positron emission tomography (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 impacts vary and somewhat 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). Regardless Additional reading of its specificity in receptor-ligand interactions noted previously, ketamine might 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 websites at which dissociative agents (such as sub-anesthetic dosages of ketamine) produce theirneurocognitive and psychotomimetic results are partially understood. Functional MRI (fMRI) (see" Magnetic Resonance Imaging (Functional) Research Studies") in healthy topics who were provided lowdoses of ketamine has actually revealed that ketamine activates a network of brain areas, including theprefrontal cortex, striatum, and anterior cingulate cortex. Other research studies recommend deactivation of theposterior cingulate area. Interestingly, these effects scale with the psychogenic effects of the agentand are concordant with functional imaging abnormalities observed in patients with schizophrenia( Fletcher et al. 2006). Comparable fMRI studies in treatment-resistant major anxiety indicate thatlow-dose ketamine infusions modified anterior cingulate cortex activity and connection with theamygdala in responders (Salvadore et al. 2010). Regardless of these data, it remains uncertain whether thesefMRIfindings directly determine the websites of ketamine action or whether they define thedownstream results of the drug. In particular, direct displacement studies with ANIMAL, using11C-labeledN-methyl-ketamine as a ligand, do not reveal clearly concordant patterns with fMRIdata. Further, the role of direct vascular impacts of the drug stays unsure, because there are cleardiscordances in the regional specificity and magnitude of changes in cerebral bloodflow, oxygenmetabolism, and glucose uptake, as studied by ANIMAL in healthy human beings (Langsjo et al. 2004). Recentwork suggests that the action of ketamine on the NMDA receptor results in anti-depressant effectsmediated via downstream impacts on the mammalian target of rapamycin resulting in increasedsynaptogenesis

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